Anthracycline-Induced Cardiomyopathy

Complex MONDO:0022653 Pathograph 34 Show in embeddings browser Cardiomyopathy

Anthracycline-induced cardiomyopathy is cardiac muscle dysfunction associated with exposure to agents such as doxorubicin, daunorubicin, epirubicin and idarubicin. Risk is related to cumulative exposure and modified by baseline cardiovascular disease, age, other cancer treatments and genetic susceptibility. Experimentally implicated pathways include TOP2B-associated DNA injury, altered mitochondrial biology and compartmental iron loading. Clinical expression ranges from asymptomatic ventricular dysfunction to heart failure, sometimes years after treatment. Recovery is possible; neither universal irreversibility nor one obligatory molecular pathway is established.

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11
Pathophys.
10
Phenotypes
34
Pathograph
4
Genes
9
Medical Actions
1
Trials
7
Models
22
References
1
Deep Research
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Pathophysiology

11
Anthracycline-TOP2B-DNA Complex Formation
Anthracyclines interfere with TOP2B-associated DNA cleavage and religation in cardiomyocytes. The drug-enzyme-DNA complex is distinguished from the ensuing DNA lesion and cell death. TOP2B contributes to cardiac injury in experimental systems; its expression does not imply that all cardiac toxicity follows one obligatory pathway.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Downstream
DNA Double-Strand Break Accumulation Interference with the TOP2B-DNA cleavage complex prevents normal resolution of enzyme-associated breaks.
Impaired Mitochondrial Biogenesis TOP2B-dependent transcriptome changes connect the initiating drug interaction to impaired mitochondrial biogenesis; individual transcriptional intermediates are not resolved in this entry.
Mitochondrial Structural Injury TOP2B knockdown attenuates the mitochondrial lesion, supporting a contribution through unresolved downstream mediators. Shared endpoints do not establish a strict sequence through every mapped mitochondrial process.
Sarcomere Disruption TOP2B depletion attenuates sarcomere injury in culture; the downstream mediators remain unresolved.
Increased Reactive Oxygen Species TOP2B-dependent transcriptome changes are associated with ROS formation in the mouse experiment. The source does not establish impaired biogenesis as the mediator of ROS, so these outcomes are parallel downstream branches.
Show evidence (1 reference)
PMID:39479333 SUPPORT REVIEW SYNTHESIS Other
"Anthracyclines target the Top2b-cleaved DNA complex, causing accumulation of double-strand DNA breaks and subsequent apoptosis."
The mechanistic synthesis identifies the TOP2B-associated DNA complex and its downstream damage.
DNA Double-Strand Break Accumulation
Persistent TOP2B-associated DNA lesions accumulate after doxorubicin exposure. Cardiomyocyte-specific Top2b deletion protects against these breaks in mice. TUNEL in the separate human cardiomyocyte culture study measures terminal fragmentation and is not used as a direct assay of the initiating double-strand break.
Animal models
Cardiomyocyte-specific Top2b deletion Mouse perturbs Genetic deletion reduces the doxorubicin-associated DNA lesion.
Downstream
Cardiomyocyte Death Persistent DNA injury can engage downstream death responses; the mapped evidence does not isolate one necessary p53 or caspase sequence.
Show evidence (1 reference)
PMID:23104132 SUPPORT PRIMARY RESULT Model Organism
"cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks"
The genetic mouse experiment implicates TOP2B in the initial DNA injury.
Impaired Mitochondrial Biogenesis
Doxorubicin-induced, TOP2B-dependent transcriptional changes impair mitochondrial biogenesis in the genetic mouse study. This process is separate from iron accumulation and ultrastructural injury; the later human siRNA culture study did not measure biogenesis or respiratory flux.
mitochondrion GO:0005739 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitochondrion (GO:0005739). GO:0005739 is a cellular component from the Gene Ontology.
Show evidence (1 reference)
PMID:23104132 SUPPORT PRIMARY RESULT Model Organism
"transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation."
The primary abstract reports transcription-associated impairment; detailed dosing and transcriptional mediators are not available in its cache.
Reduced ABCB8 Expression
Doxorubicin reduces the abundance of the mitochondrial iron-export regulator ABCB8 in neonatal rat cardiomyocytes and mouse hearts. The data implicate regulation at the mRNA level; direct binding of doxorubicin to the ABCB8 promoter or a measured transport-blocking interaction is not established.
Downstream
Mitochondrial Iron Accumulation Lower ABCB8 abundance can reduce iron export and favor mitochondrial retention. Knockdown and overexpression support this route without proving the complete export machinery.
Show evidence (2 references)
PMID:24382354 SUPPORT PRIMARY RESULT In Vitro
"DOX significantly reduced the mRNA and protein levels of ABCB8"
The culture and mouse expression data establish reduced abundance.
PMID:24382354 SUPPORT PRIMARY RESULT In Vitro
"These results suggest that DOX regulates ABCB8 at the mRNA level and that this regulation is independent of cytotoxic effects of the drug."
The experiment localizes the regulatory effect to mRNA-level expression rather than proving direct promoter binding.
Mitochondrial Iron Accumulation
Doxorubicin exposure increases mitochondrial iron in cardiomyocyte cultures and mouse hearts. ABCB8 manipulation supports a contribution of impaired export. Human transplant explants show the same compartmental association, but the small end-stage series cannot establish temporal causation or a clinical iron-removal treatment effect.
mitochondrion GO:0005739 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitochondrion (GO:0005739). GO:0005739 is a cellular component from the Gene Ontology.
Experimental models
Neonatal rat cardiomyocyte iron-transport perturbation OTHER Manipulation of an iron-export regulator changes compartmental iron accumulation.
Animal models
Cardiac ABCB8 overexpression Mouse perturbs Transgenic expression reduces mitochondrial iron before and after exposure.
Downstream
Increased Reactive Oxygen Species An expanded mitochondrial iron pool can promote iron-dependent redox reactions. ABCB8 manipulation lowers both iron and oxidant readouts; these experiments do not resolve every reaction or exclude parallel sources.
Cardiomyocyte Death ABCB8-dependent iron handling modifies culture injury, with oxidative and other mitochondrial intermediates unresolved.
Show evidence (2 references)
PMID:24382354 SUPPORT PRIMARY RESULT In Vitro
"Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS"
The culture and transgenic experiments test iron export as a modifiable process.
PMID:24382354 SUPPORT PRIMARY RESULT Human Clinical
"hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function."
The explant comparison is human tissue association, not an intervention trial.
Increased Reactive Oxygen Species
Anthracycline redox cycling and mitochondrial iron can increase reactive oxygen species. The iron and TOP2B-associated transcriptional branches can converge on oxidative stress. Probe-based culture readouts do not identify every radical species or show that oxidative injury is the sole human mechanism.
reactive oxygen species biosynthetic process GO:1903409 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves reactive oxygen species biosynthetic process (GO:1903409). GO:1903409 is a biological process from the Gene Ontology.
Downstream
Mitochondrial Structural Injury Oxidative injury can damage mitochondrial structure; this synthesis does not make the simultaneous probe and TEM endpoints a mediator-specific epistasis test.
Show evidence (2 references)
PMID:28185035 SUPPORT REVIEW SYNTHESIS Other
"ROS levels may also be increased by free cellular iron and potentiating ferrous-ferric cycling of molecular iron"
The review provides the chemical rationale for the iron-associated oxidant branch.
PMID:40158615 SUPPORT PRIMARY RESULT In Vitro
"Representative images (Fig. 7A) show a marked increase in mitochondrial ROS in Dox-treated hiPSC-CMs, which was reduced with Dex and TOP2B-KD interventions."
The human culture study measures a mitochondrial oxidant-probe signal.
Mitochondrial Structural Injury
Doxorubicin-exposed human iPSC-derived cardiomyocytes develop swollen or fragmented mitochondria and disrupted cristae. TOP2B knockdown attenuates these changes. Ultrastructure is not treated as a direct measurement of ATP production, respiratory flux or complete functional restoration.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
mitochondrion GO:0005739 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitochondrion (GO:0005739). GO:0005739 is a cellular component from the Gene Ontology.
Experimental models
Commercial human iPSC-derived cardiomyocyte TOP2B knockdown OTHER TOP2B knockdown attenuates the ultrastructural lesion.
Show evidence (1 reference)
PMID:40158615 SUPPORT PRIMARY RESULT In Vitro
"TEM images (Fig. 7D) indicated fragmented and swollen mitochondria with disrupted cristae in Dox treated hiPSC-CMs, along with irregular sarcomere alignment."
TEM resolves the mitochondrial lesion separately from the concurrent contractile-structure lesion.
Sarcomere Disruption
Irregular sarcomere alignment is a distinct ultrastructural lesion in doxorubicin-exposed human cardiomyocyte cultures. TOP2B knockdown partly preserves it. The study does not establish that mitochondrial structural injury necessarily occurs first or directly causes this lesion.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
sarcomere organization GO:0045214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves sarcomere organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology.
Experimental models
Commercial human iPSC-derived cardiomyocyte TOP2B knockdown OTHER Knockdown preserves sarcomere alignment in the same culture experiment.
Downstream
Reduced Ventricular Contractile Function Damage to the contractile apparatus may impair ventricular performance, but extrapolation from culture ultrastructure to patient ejection fraction is indirect.
Show evidence (1 reference)
PMID:40158615 SUPPORT PRIMARY RESULT In Vitro
"TEM images (Fig. 7D) indicated fragmented and swollen mitochondria with disrupted cristae in Dox treated hiPSC-CMs, along with irregular sarcomere alignment."
TEM resolves the mitochondrial lesion separately from the concurrent contractile-structure lesion.
Cardiomyocyte Death
Loss of cardiomyocytes contributes to anthracycline injury. DNA damage and mitochondrial stress are experimentally implicated routes. TUNEL and viability assays support injury and death but do not establish a universal exclusive death program, or identify ferroptosis from iron accumulation alone.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Downstream
Ventricular Remodeling Cumulative myocyte injury can drive maladaptive chamber remodeling through incompletely resolved tissue responses; recovery remains possible.
Show evidence (2 references)
PMID:40158615 SUPPORT PRIMARY RESULT In Vitro
"TOP2B-KD resulted in a marked decrease in the number of TUNEL-positive cells"
TOP2B perturbation reduces terminal DNA-fragmentation-positive cells.
PMID:24382354 SUPPORT PRIMARY RESULT In Vitro
"cell death, as assessed by MTS assay and TUNEL staining, was significantly higher after DOX treatment in response to ABCB8 silencing than in cells transfected with control siRNA"
The ABCB8 experiment supports an additional iron-associated injury route.
Ventricular Remodeling
Structural changes after myocardial injury can include chamber dilation and wall thinning. These changes vary with age, treatment and follow-up; pediatric survivors may develop a restrictive pattern. Remodeling is not assumed inevitable or irreversible.
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Reduced Ventricular Contractile Function Maladaptive chamber geometry and tissue remodeling can reduce contractile performance; dysfunction can also precede marked dilation.
Dilated cardiomyopathy Ventricular dilation with hypokinetic function defines the dilated phenotype in affected patients.
Show evidence (1 reference)
PMID:39479333 SUPPORT REVIEW SYNTHESIS Human Clinical
"Late onset cardiotoxicity, which becomes clinically evident more than 1 year after exposure, typically presents as hypokinetic and/or dilated cardiomyopathy with overt HF symptoms."
The review describes a late structural and functional presentation.
Reduced Ventricular Contractile Function
Anthracycline-associated left ventricular systolic dysfunction may be asymptomatic or present as heart failure. It can improve with treatment, remain impaired or emerge late. Loss of myocardium, contractile-structure injury and remodeling can contribute without a single demonstrated universal sequence.
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Isolated titin-truncation mouse cardiomyocyte mechanics OTHER Ex-vivo sarcomere mechanics provide a cellular correlate of the in-vivo functional phenotype.
Animal models
Heterozygous A-band titin-truncation mouse Mouse partially recapitulates The model reproduces sustained ventricular dysfunction after a defined drug stress.
Downstream
Reduced left ventricular ejection fraction Reduced ventricular pump performance underlies this measurable or clinical expression; asymptomatic dysfunction need not progress to overt heart failure.
Congestive heart failure Reduced ventricular pump performance underlies this measurable or clinical expression; asymptomatic dysfunction need not progress to overt heart failure.
Dyspnea Symptomatic cardiac dysfunction can produce this manifestation through hemodynamic or congestion-related intermediates. The clinical source does not measure each intermediate, and the finding is not specific for anthracycline injury.
Orthopnea Symptomatic cardiac dysfunction can produce this manifestation through hemodynamic or congestion-related intermediates. The clinical source does not measure each intermediate, and the finding is not specific for anthracycline injury.
Fatigue Symptomatic cardiac dysfunction can produce this manifestation through hemodynamic or congestion-related intermediates. The clinical source does not measure each intermediate, and the finding is not specific for anthracycline injury.
Hepatomegaly Symptomatic cardiac dysfunction can produce this manifestation through hemodynamic or congestion-related intermediates. The clinical source does not measure each intermediate, and the finding is not specific for anthracycline injury.
Pulmonary edema Symptomatic cardiac dysfunction can produce this manifestation through hemodynamic or congestion-related intermediates. The clinical source does not measure each intermediate, and the finding is not specific for anthracycline injury.
Exercise intolerance Symptomatic cardiac dysfunction can produce this manifestation through hemodynamic or congestion-related intermediates. The clinical source does not measure each intermediate, and the finding is not specific for anthracycline injury.
Edema Cardiac congestion and fluid retention can produce edema, with the intervening hemodynamics unresolved by the source case definition.
Show evidence (1 reference)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Anthracycline-induced CTRCD is a dose-dependent and cumulative process of variable onset that may present with symptomatic or asymptomatic CTRCD."
The guideline defines variable timing and clinical expression.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Anthracycline-Induced Cardiomyopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Cardiovascular 3
Reduced left ventricular ejection fraction HP:0012664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced left ventricular ejection fraction (HP:0012664). HP:0012664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"New LVEF reduction by ≥10 percentage points to an LVEF of 40–49%"
The guideline provides one moderate asymptomatic dysfunction criterion, rather than a universal threshold for all cardiac injury.
Dilated cardiomyopathy HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39479333 SUPPORT REVIEW SYNTHESIS Human Clinical
"Late onset cardiotoxicity, which becomes clinically evident more than 1 year after exposure, typically presents as hypokinetic and/or dilated cardiomyopathy with overt HF symptoms."
The review describes the late dilated phenotype.
Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28185035 SUPPORT REVIEW SYNTHESIS Human Clinical
"congestive heart failure (CHF), characterised by pulmonary oedema, fluid overload, and effort intolerance"
The review describes the clinical congestive syndrome.
Digestive 1
Hepatomegaly HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26237429 SUPPORT BACKGROUND Human Clinical
"symptoms (dyspnea, orthopnea and/or fatigue) and/or signs (edema, hepatomegaly and/or rales)"
These manifestations form part of the source clinical case definition; the passage does not supply individual-feature prevalence.
Metabolism 2
Pulmonary edema HP:0100598 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary edema (HP:0100598). HP:0100598 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28185035 SUPPORT REVIEW SYNTHESIS Human Clinical
"congestive heart failure (CHF), characterised by pulmonary oedema, fluid overload, and effort intolerance"
The review describes the clinical congestive syndrome.
Edema HP:0000969 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Edema (HP:0000969). HP:0000969 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26237429 SUPPORT BACKGROUND Human Clinical
"symptoms (dyspnea, orthopnea and/or fatigue) and/or signs (edema, hepatomegaly and/or rales)"
The source names edema without an anatomical qualifier.
Respiratory 2
Dyspnea HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspnea (HP:0002094). HP:0002094 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26237429 SUPPORT BACKGROUND Human Clinical
"symptoms (dyspnea, orthopnea and/or fatigue) and/or signs (edema, hepatomegaly and/or rales)"
These manifestations form part of the source clinical case definition; the passage does not supply individual-feature prevalence.
Orthopnea HP:0012764 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Orthopnea (HP:0012764). HP:0012764 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26237429 SUPPORT BACKGROUND Human Clinical
"symptoms (dyspnea, orthopnea and/or fatigue) and/or signs (edema, hepatomegaly and/or rales)"
These manifestations form part of the source clinical case definition; the passage does not supply individual-feature prevalence.
Constitutional 2
Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26237429 SUPPORT BACKGROUND Human Clinical
"symptoms (dyspnea, orthopnea and/or fatigue) and/or signs (edema, hepatomegaly and/or rales)"
These manifestations form part of the source clinical case definition; the passage does not supply individual-feature prevalence.
Exercise intolerance HP:0003546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28185035 SUPPORT REVIEW SYNTHESIS Human Clinical
"congestive heart failure (CHF), characterised by pulmonary oedema, fluid overload, and effort intolerance"
The review describes the clinical congestive syndrome.
🧬

Genetic Associations

4
RARG
Gene: RARG hgnc:9866 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RARG (hgnc:9866). hgnc:9866 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (2 references)
PMID:26237429 SUPPORT PRIMARY RESULT Human Clinical
"We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT"
The childhood case-control study establishes a susceptibility association.
PMID:26237429 SUPPORT PRIMARY RESULT In Vitro
"The significant 17% decrease in RARG activity conferred by the rs2229774 variant"
A transfected reporter assay measures partial functional alteration, not human clinical receptor activity.
TTN
Gene: TTN hgnc:12403 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TTN (hgnc:12403). hgnc:12403 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (3 references)
PMID:30987448 SUPPORT PRIMARY RESULT Human Clinical
"TTNtvs were identified in 16 of 213 CCM cases (7.5%)"
The numerator and denominator belong to selected mixed-treatment cases.
PMID:30987448 SUPPORT PRIMARY RESULT Human Clinical
"Recovery occurred in both groups, although the final mean LVEF was more depressed in patients with TTNtvs"
The full body qualifies the abstract wording about impaired recovery.
PMID:30987448 SUPPORT PRIMARY RESULT Human Clinical
"A more ideal comparison group would have been patients treated with chemotherapy who did not develop cardiomyopathy."
The authors acknowledge the comparator limitation.
CBR3
Gene: CBR3 hgnc:1549 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CBR3 (hgnc:1549). hgnc:1549 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (3 references)
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3383117/?pdf=render SUPPORT PRIMARY RESULT Human Clinical
"One hundred seventy patient cases with cardiomyopathy and 317 matched controls participated in this study."
Defines the selected childhood-cancer survivor case-control sample.
PMID:22124095 SUPPORT PRIMARY RESULT Human Clinical
"Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to..."
The abstract supplies the within-exposure CBR3 comparison; the full body and Table 4 were also reviewed.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3383117/?pdf=render SUPPORT PRIMARY RESULT Human Clinical
"Prevalent case-control studies, by the nature of their design, exclude fatal end points from the patient case set."
Survival selection can alter observed genotype-risk associations; this study does not measure lifetime penetrance.
CELF4
Gene: CELF4 hgnc:14015 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CELF4 (hgnc:14015). hgnc:14015 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (3 references)
PMID:26811534 SUPPORT PRIMARY RESULT Human Clinical
"No SNP was marginally associated with cardiomyopathy. However, SNP rs1786814 on the CELF4 gene passed the significance cutoff for gene-environment interaction (Pge = 1.14 × 10(-5))."
The discovery result concerns gene-by-exposure interaction rather than a marginal genome-wide disease association.
PMID:26811534 SUPPORT PRIMARY RESULT Human Clinical
"Compared with cases who had GA/AA genotype, the odds of cases who had the GG genotype being in the greater-than–300-mg/m2 versus the 300-mg/m2 –or-less anthracycline group were 5.09 times higher"
The replication comparison is explicitly restricted to cases and dose category.
PMID:26811534 SUPPORT PRIMARY RESULT Human Clinical
"The embryonic splicing variant of TNNT2 was found in 24 of the 33 heart samples and was more likely to coexist with the adult TNNT2 splicing variant in hearts homozygous for the high-risk rs1786814 genotype (GG: 19 (90.5%) of 21 samples; GA/AA: 5 (41.7%) of 12 samples; P = .005, Fisher’s exact..."
Healthy-heart tissue associates genotype with isoform coexpression; it does not directly test a drug-injury mechanism.
💊

Medical Actions

9
Dexrazoxane cardioprotection
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: dexrazoxane CHEBI:50223 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dexrazoxane, annotated with (+)-dexrazoxane (CHEBI:50223). CHEBI:50223 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Dexrazoxane is considered before anthracycline administration for selected patients at high or very high cardiac-toxicity risk or requiring substantial cumulative exposure. ESC adult prevention guidance is broader than product-label eligibility and should not be read as a universal indication. The pediatric IGHG guideline makes a moderate recommendation when anticipated cumulative doxorubicin-equivalent exposure is at least 250 mg/m²; it makes no recommendation below that threshold because evidence is insufficient. Historical secondary-neoplasm concerns remain part of benefit-risk discussion, not proof that the drug causes such cancers. TOP2B-associated DNA damage and mitochondrial iron handling are proposed cardioprotective mechanisms, distinct from clinical proof of prevention. A later survivor follow-up analyzed 195 people from legacy trials, mostly originally randomized, with modest systolic-function differences after about 18 years. The prespecified structural measure did not differ significantly, and only 41% of potentially eligible survivors enrolled; this is incomplete protection, not proven elimination of lifetime heart-failure risk.
Mechanism Target:
INHIBITS DNA Double-Strand Break Accumulation — Dexrazoxane can reduce TOP2B-associated DNA damage; this mechanistic rationale is separate from patient selection and clinical efficacy.
Show evidence (1 reference)
PMID:39479333 SUPPORT REVIEW SYNTHESIS Other
"prevent DNA double-strand breaks induced by anthracyclines through topoisomerase IIβ"
The review summarizes the TOP2B-associated protective mechanism.
Show evidence (6 references)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"Dexrazoxane should be considered in adult patients with cancer at high and very high CV toxicity risk when anthracycline chemotherapy is indicated."
ESC recommends consideration for the specified adult risk group, rather than universal administration.
PMID:36174614 SUPPORT REVIEW SYNTHESIS Other
"the benefits of dexrazoxane probably outweigh the risk of subsequent neoplasms when the cumulative doxorubicin or equivalent dose is at least 250 mg/m2 (moderate recommendation)."
The pediatric guideline weighs benefit and uncertain harm at the stated anticipated cumulative exposure.
PMID:36174614 SUPPORT REVIEW SYNTHESIS Other
"No recommendation could be formulated for cumulative doxorubicin or equivalent doses of lower than 250 mg/m2"
Insufficient evidence below the threshold is not a contraindication.
+ 3 more references
Liposomal anthracycline substitution
Action: Liposomal anthracycline substitutionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Liposomal anthracycline substitution, annotated with Chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632
Agent: doxorubicin CHEBI:28748 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses doxorubicin (CHEBI:28748). CHEBI:28748 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Delivery: Liposome
When oncologically appropriate, liposomal anthracyclines can reduce cardiotoxicity through altered distribution and are an ESC consideration for high or very high risk adults. Available formulations and indications differ by cancer. This is not proof of absent cardiac risk or equivalent efficacy in every malignancy.
Show evidence (1 reference)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"Liposomal anthracyclines should be considered in adult patients with cancer at high and very high CV toxicity risk when anthracycline chemotherapy is indicated."
The guideline supports a risk- and regimen-dependent preventive choice.
Heart-failure pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ACE Inhibitor NCIT:C247 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses ACE Inhibitor (NCIT:C247). NCIT:C247 is a therapeutic agent from the NCI Thesaurus. Angiotensin II Receptor Antagonist NCIT:C66930 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Angiotensin II Receptor Antagonist (NCIT:C66930). NCIT:C66930 is a therapeutic agent from the NCI Thesaurus. Angiotensin Receptor-Neprilysin Inhibitor NCIT:C190796 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Angiotensin Receptor-Neprilysin Inhibitor (NCIT:C190796). NCIT:C190796 is a therapeutic agent from the NCI Thesaurus. Beta-Adrenergic Antagonist NCIT:C29576 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Beta-Adrenergic Antagonist (NCIT:C29576). NCIT:C29576 is a therapeutic agent from the NCI Thesaurus. SGLT2 Inhibitor NCIT:C98083 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses SGLT2 Inhibitor (NCIT:C98083). NCIT:C98083 is a therapeutic agent from the NCI Thesaurus. Aldosterone Receptor Antagonist NCIT:C101255 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Aldosterone Receptor Antagonist (NCIT:C101255). NCIT:C101255 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Treat symptomatic dysfunction or asymptomatic moderate/severe anthracycline-related dysfunction with guideline-based heart-failure therapy. ESC lists an ACE inhibitor/ARB or ARNI, beta-blocker, SGLT2 inhibitor and mineralocorticoid receptor antagonist as appropriate and tolerated, with titration and monitoring. This imports heart-failure management evidence rather than proving each drug reverses anthracycline DNA or mitochondrial injury.
Mechanism Target:
INHIBITS Reduced Ventricular Contractile Function — This intervention addresses the indicated clinical process; the guidance does not establish reversal of each upstream molecular lesion.
Show evidence (1 reference)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"Guideline-based HF therapy is recommended in patients who de- velop symptomatic CTRCD or asymptomatic moderate or severe CTRCD during anthracycline chemotherapy. The use of an ACE-I/ ARB or angiotensin receptor –neprilysin inhibitor, a beta-blocker, a sodium–glucose co-transporter 2 inhibitor,..."
The guideline names ACE inhibitor/ARB or ARNI, beta-blocker, SGLT2 inhibitor and mineralocorticoid-receptor antagonist therapy for symptomatic or moderate/severe asymptomatic dysfunction, subject to contraindications and tolerance.
Show evidence (1 reference)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"Guideline-based HF therapy is recommended in patients who de- velop symptomatic CTRCD or asymptomatic moderate or severe CTRCD during anthracycline chemotherapy. The use of an ACE-I/ ARB or angiotensin receptor –neprilysin inhibitor, a beta-blocker, a sodium–glucose co-transporter 2 inhibitor,..."
The guideline names ACE inhibitor/ARB or ARNI, beta-blocker, SGLT2 inhibitor and mineralocorticoid-receptor antagonist therapy for symptomatic or moderate/severe asymptomatic dysfunction, subject to contraindications and tolerance.
Anthracycline interruption and individualized rechallenge
Discontinue anthracyclines for severe symptomatic dysfunction; temporarily interrupt for moderate symptomatic or moderate/severe asymptomatic dysfunction. Mild symptomatic cases require multidisciplinary benefit-risk discussion. Mild asymptomatic dysfunction with preserved LVEF generally permits continued treatment with close monitoring and selected cardioprotection. Restarting after recovery requires an oncology-cardiology decision; dose minimization, liposomal formulation and dexrazoxane may be considered, with monitoring every 1–2 cycles. These measures do not guarantee safe rechallenge.
Show evidence (2 references)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"Discontinuation of anthracycline chemotherapy is recommended in patients with cancer who develop severe symptomatic CTRCD."
This recommendation concerns clinical HF severity, not EF alone.
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"Temporary interruption of anthracycline chemotherapy and initiation of HF therapy is recommended in patients who develop asymptomatic moderate or severe CTRCD."
The anthracycline rule differs from the HER2-targeted therapy continuation rule.
Selected ACE inhibitor or ARB and beta-blocker cardioprotection
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ACE Inhibitor NCIT:C247 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses ACE Inhibitor (NCIT:C247). NCIT:C247 is a therapeutic agent from the NCI Thesaurus. Angiotensin II Receptor Antagonist NCIT:C66930 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Angiotensin II Receptor Antagonist (NCIT:C66930). NCIT:C66930 is a therapeutic agent from the NCI Thesaurus. Beta-Adrenergic Antagonist NCIT:C29576 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Beta-Adrenergic Antagonist (NCIT:C29576). NCIT:C29576 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Preventive neurohormonal therapy may be considered in adults at high or very high risk. For mild asymptomatic dysfunction during anthracyclines, ACE inhibitor/ARB and/or beta-blocker consideration is stronger for a significant GLS fall or troponin rise than for isolated natriuretic-peptide elevation. Avoid hypotension. Prevention trials predominantly measure LVEF and have not established a universal mortality or overt-HF benefit.
Mechanism Target:
INHIBITS Reduced Ventricular Contractile Function — This intervention addresses the indicated clinical process; the guidance does not establish reversal of each upstream molecular lesion.
Show evidence (2 references)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"Asymptomatic patients who have LVEF ≥ 50% and who have developed a troponin elevation .ULN should be considered for ACE-I/ARB and/ or beta-blockers."
The recommendation applies to this preserved-EF subgroup; the PDF represents the greater-than sign as a dot.
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"preventing LVEF reduction, but no statistical differences in the in- cidence of overt HF or other clinical outcomes were demonstrated"
The guideline distinguishes surrogate preservation from proven clinical-event benefit.
Show evidence (2 references)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"Asymptomatic patients who have LVEF ≥ 50% and who have developed a troponin elevation .ULN should be considered for ACE-I/ARB and/ or beta-blockers."
The recommendation applies to this preserved-EF subgroup; the PDF represents the greater-than sign as a dot.
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"preventing LVEF reduction, but no statistical differences in the in- cidence of overt HF or other clinical outcomes were demonstrated"
The guideline distinguishes surrogate preservation from proven clinical-event benefit.
Spironolactone prevention evidence
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: spironolactone CHEBI:9241 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses spironolactone (CHEBI:9241). CHEBI:9241 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A small randomized study of 83 women with breast cancer tested concurrent spironolactone and reported preservation of LVEF and diastolic measures. A later network meta-analysis ranked its LVEF effect highly, but small indirect comparisons and risk of bias limit ranking-based claims. This is limited primary-prevention evidence, distinct from mineralocorticoid receptor antagonists as established guideline HF therapy; no clinical superiority or direct antifibrotic effect in these patients is inferred.
Mechanism Target:
INHIBITS Reduced Ventricular Contractile Function — This intervention addresses the indicated clinical process; the guidance does not establish reversal of each upstream molecular lesion.
Show evidence (3 references)
PMID:25410653 SUPPORT PRIMARY RESULT Human Clinical
"Eighty-three female patients who were diagnosed with breast cancer were included in the study. The study population was randomized into spironolactone and control groups."
The primary trial defines its small breast-cancer population.
PMID:25410653 SUPPORT PRIMARY RESULT Human Clinical
"the interaction of LVEF decrease between groups was significantly lower in the spironolactone group than in the control group (P < 0.001)."
The endpoint is a ventricular-function comparison, not mortality.
PMID:40970189 SUPPORT REVIEW SYNTHESIS Human Clinical
"Spironolactone demonstrated the most significant improvement in (LVEF [MD = 12.10, 95% CI (7.50, 16.70)]"
The network estimate concerns LVEF; its ranking is not proof of the optimal patient treatment.
Show evidence (3 references)
PMID:25410653 SUPPORT PRIMARY RESULT Human Clinical
"Eighty-three female patients who were diagnosed with breast cancer were included in the study. The study population was randomized into spironolactone and control groups."
The primary trial defines its small breast-cancer population.
PMID:25410653 SUPPORT PRIMARY RESULT Human Clinical
"the interaction of LVEF decrease between groups was significantly lower in the spironolactone group than in the control group (P < 0.001)."
The endpoint is a ventricular-function comparison, not mortality.
PMID:40970189 SUPPORT REVIEW SYNTHESIS Human Clinical
"Spironolactone demonstrated the most significant improvement in (LVEF [MD = 12.10, 95% CI (7.50, 16.70)]"
The network estimate concerns LVEF; its ranking is not proof of the optimal patient treatment.
Cardiovascular risk-factor management
Assess and manage hypertension, diabetes, dyslipidemia, smoking and other modifiable risks before, during and after therapy. Coordinate oncology, cardiology and primary care; background risk and combined treatments modify vulnerability.
Show evidence (1 reference)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"Management of CVRF according to the 2021 ESC Guidelines on CVD prevention in clinical practice is recommended before,"
The guideline recommends ongoing risk-factor care, without assigning a molecular target.
Exercise and cardiovascular rehabilitation
Individualize aerobic activity and rehabilitation to cardiac status, cancer treatment and functional capacity. This supports cardiovascular health and recovery; it does not establish reversal of the molecular injury or replace HF therapy.
Show evidence (1 reference)
PMID:39479333 SUPPORT REVIEW SYNTHESIS Other
"Participating in exercise programs is known to have significant cardiac health benefits and is particularly important for cancer patients at risk of cardiotoxicity."
The cardio-oncology review supports tailored exercise-based care.
Atorvastatin prevention in selected lymphoma patients
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: atorvastatin CHEBI:39548 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses atorvastatin (CHEBI:39548). CHEBI:39548 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
STOP-CA randomized 300 adults receiving anthracycline-based lymphoma treatment to atorvastatin 40 mg daily or placebo for 12 months. Atorvastatin reduced the prespecified LVEF-decline endpoint (13/150 versus 33/150), while incident heart failure over 24 months did not differ significantly. This supports a preventive option for selected patients with lymphoma; it does not establish benefit across all cancers, treatment of established cardiomyopathy, or mortality benefit.
Mechanism Target:
INHIBITS Reduced Ventricular Contractile Function — Preventive treatment reduced the trial-defined LVEF-decline endpoint in the lymphoma study population; an upstream molecular mediator was not tested.
Show evidence (1 reference)
PMID:37552303 SUPPORT PRIMARY RESULT Human Clinical
"The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002)."
The primary endpoint was a fall of at least 10 LVEF percentage points to below 55% at 12 months, not clinical heart failure.
Show evidence (2 references)
PMID:37552303 SUPPORT PRIMARY RESULT Human Clinical
"The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002)."
The primary endpoint was a fall of at least 10 LVEF percentage points to below 55% at 12 months, not clinical heart failure.
PMID:37552303 SUPPORT PRIMARY RESULT Human Clinical
"There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26)."
The trial did not establish prevention of clinical heart failure; nonsignificance does not demonstrate equivalence.
🌍

Environmental Factors

1
Cumulative anthracycline chemotherapy exposure
exposure to anthracycline chemotherapy ECTO:0000509 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to anthracycline chemotherapy, annotated with exposure to drug (ECTO:0000509). ECTO:0000509 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Hazard type: CHEMICAL
Route: PARENTERAL
Duration: INTERMITTENT
Bound to the substance-level ECTO:0000509 (exposure to drug). ECTO was checked for an anthracycline- or doxorubicin-specific exposure class and none is bindable here; note that dismech validates ECTO against sqlite:obo:ecto, so a term resolving in OLS is not sufficient.
Therapeutic anthracycline exposure initiates cardiotoxic injury. Cumulative dose is important, but schedule, drug, coexposures and patient factors also matter; no single cumulative threshold guarantees safety.
Show evidence (1 reference)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Anthracycline-induced CTRCD is a dose-dependent and cumulative process of variable onset that may present with symptomatic or asymptomatic CTRCD."
The guideline links anthracycline exposure to dose-related cardiac dysfunction.
Mechanism Target:
TRIGGERS Anthracycline-TOP2B-DNA Complex Formation — Drug exposure permits formation and stabilization of the TOP2B-associated DNA complex.
Show evidence (1 reference)
PMID:39479333 SUPPORT REVIEW SYNTHESIS Other
"Anthracyclines target the Top2b-cleaved DNA complex, causing accumulation of double-strand DNA breaks and subsequent apoptosis."
The mechanistic synthesis identifies the TOP2B-associated DNA complex and its downstream damage.
TRIGGERS Reduced ABCB8 Expression — Doxorubicin reduces ABCB8 expression through incompletely resolved regulatory steps.
Show evidence (2 references)
PMID:24382354 SUPPORT PRIMARY RESULT In Vitro
"DOX significantly reduced the mRNA and protein levels of ABCB8"
The culture and mouse expression data establish reduced abundance.
PMID:24382354 SUPPORT PRIMARY RESULT In Vitro
"These results suggest that DOX regulates ABCB8 at the mRNA level and that this regulation is independent of cytotoxic effects of the drug."
The experiment localizes the regulatory effect to mRNA-level expression rather than proving direct promoter binding.
🔬

Biochemical Markers

2
Cardiac troponin (INCREASED)
Show evidence (2 references)
PMID:39479333 SUPPORT REVIEW SYNTHESIS Other
"Troponins, which are cardiac-specific circulating proteins, become indicative of myocardial injury when their levels exceed the 99th percentile in the general population."
The clinical review describes this circulating biomarker and its interpretation.
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"an increase in biomarker level should be interpreted in the patient clinical context (cancer treatment timing and comorbidities)."
The guideline requires contextual interpretation rather than a standalone etiologic test.
Natriuretic peptides (INCREASED)
Pathograph Readouts
Readout Of Reduced Ventricular Contractile Function Positive Monitoring
Higher values can accompany myocardial stress from dysfunction; this association is nonspecific and confounded.
Show evidence (1 reference)
PMID:39479333 SUPPORT REVIEW SYNTHESIS Other
"NPs, including B-type natriuretic peptide and N-terminal pro–B-type natriuretic peptide (NT-proBNP), are cardiac hormones critical for diagnosis and managing HF."
The clinical review describes this circulating biomarker and its interpretation.
Show evidence (2 references)
PMID:39479333 SUPPORT REVIEW SYNTHESIS Other
"NPs, including B-type natriuretic peptide and N-terminal pro–B-type natriuretic peptide (NT-proBNP), are cardiac hormones critical for diagnosis and managing HF."
The clinical review describes this circulating biomarker and its interpretation.
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"an increase in biomarker level should be interpreted in the patient clinical context (cancer treatment timing and comorbidities)."
The guideline requires contextual interpretation rather than a standalone etiologic test.
🔬

Diagnosis

5
Integrated clinical and cardiac assessment
Evaluate new cardiac symptoms and signs in the context of anthracycline dose, timing, other cancer treatments and baseline cardiovascular disease. Integrate imaging and biomarkers and consider alternative cardiac or systemic explanations. Cancer therapy-related cardiac dysfunction includes subclinical injury and is broader than established symptomatic cardiomyopathy.
Show evidence (1 reference)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"dysfunction includes new CV symptoms, new abnormalities in cardiac function on CV imaging"
The diagnosis integrates the clinical, imaging and biomarker picture.
Echocardiography and global longitudinal strain
Compare LVEF and GLS with baseline, using the same modality and strain vendor when possible. ESC asymptomatic severe dysfunction is a new LVEF below 40%; moderate dysfunction is a decline of at least 10 percentage points to 40–49%, or a smaller decline to that range with a new relative GLS fall over 15% or biomarker rise. Mild dysfunction requires LVEF at least 50% plus a new relative GLS fall over 15% and/or a biomarker rise. Symptomatic severity is graded clinically and is not interchangeable with these EF strata.
Show evidence (3 references)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"Current definitions of CTRCD are based on a reduction of LVEF and/or relative changes in global longitudinal strain (GLS)"
The guideline uses functional change rather than a single universal EF threshold.
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"New LVEF reduction by ≥10 percentage points to an LVEF of 40–49%"
This is one of the moderate asymptomatic criteria.
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"to use the same vendor to analyse GLS during cancer treatment to accurately compare values over time."
Consistent acquisition and analysis reduce measurement variability.
Cardiac magnetic resonance when echocardiography is limited
CMR can clarify ventricular function when echocardiographic images are inadequate or borderline and can characterize tissue when a specific alternative diagnosis is suspected. Tissue iron or fibrosis measurements do not by themselves establish anthracycline causation.
Show evidence (1 reference)
PMID:39479333 SUPPORT REVIEW SYNTHESIS Other
"CMR is mainly used for evaluating LVEF when echocardiography is limited by a poor acoustic window or provides borderline values"
The review identifies an adjunctive clinical indication.
Assessment of inherited cardiomyopathy susceptibility
Family history and the cardiac phenotype may prompt a cardiomyopathy genetics assessment. RARG and TTN findings do not establish a universal predictive panel: ESC 2022 does not recommend routine genetic testing solely to assess cardiac-toxicity risk before cancer therapy. The DCM GeneReviews overview recognizes an emerging genetic contribution to chemotherapy-associated DCM but explicitly excludes acquired DCM from its later evaluation and counseling recommendations.
Show evidence (2 references)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"Routine use of genetic testing for the assessment of CTR-CVT risk prior to initiation of cancer therapy is not currently recommended."
The guideline limits routine pre-treatment susceptibility testing.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/ SUPPORT REVIEW SYNTHESIS Other
"the clinical relevance of this information is currently undefined"
The DCM overview explicitly limits translation of chemotherapy-associated genetic findings.
Risk-adapted cardiac surveillance
Obtain baseline echocardiography before anthracyclines and reassess according to risk, cumulative exposure and new findings. ESC recommends an echocardiogram within 12 months after completion in all adults; high/very-high-risk patients require more frequent imaging and biomarkers. Continue risk-adapted survivorship follow-up because a normal early assessment does not eliminate late risk.
Show evidence (3 references)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"In all adults receiving anthracycline chemotherapy, an echocardiogram is recommended within 12 months after completing treatment."
The guideline gives a general adult post-treatment assessment.
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"In high- and very high-risk patients, echocardiography is recommended every two cycles and within 3 months after completing treatment."
More frequent imaging is reserved for the specified risk group.
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Other
"Lifelong sur- veillance for high-risk survivors is recommended."
The survivorship section supports continued surveillance in high-risk survivors.
📈

Progression

2
Variable onset and clinical expression
Injury can become apparent during treatment, within the first year, or years later. The dose, age, coexisting cardiovascular disease and additional therapies modify risk. A closely monitored 2625-person cohort detected 226 cases (9%), 98% of them within the first year; this cohort observation does not exclude late disease or establish a general population incidence.
Show evidence (2 references)
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Anthracycline-induced CTRCD is a dose-dependent and cumulative process of variable onset that may present with symptomatic or asymptomatic CTRCD."
The guideline recognizes variable timing and symptom status.
PMID:25948538 SUPPORT PRIMARY RESULT Human Clinical
"The overall incidence of cardiotoxicity was 9% (n=226)."
The estimate comes from the particular serial-monitoring cohort.
Recovery or persistent dysfunction
Anthracycline cardiomyopathy is not uniformly irreversible. In the serial-monitoring cohort, prompt heart-failure treatment was followed by full recovery in 11% and partial recovery in 71% of affected patients. These observational results lack a randomized untreated comparator and do not guarantee recovery. Childhood survivors can later develop a restrictive physiological pattern despite periods of compensated systolic function.
Show evidence (2 references)
PMID:25948538 SUPPORT PRIMARY RESULT Human Clinical
"Twenty-five (11%) patients had full recovery, and 160 (71%) patients had partial recovery."
The cohort distinguishes return to baseline from partial improvement.
PMID:28185035 SUPPORT REVIEW SYNTHESIS Human Clinical
"early dilated cardiomyopathy followed by a period of compensated systolic function and later restrictive physiology"
The review describes a pediatric restrictive trajectory.
🔬

Clinical Trials

1
NCT02943590 PHASE_II COMPLETED
STOP-CA was a randomized, placebo-controlled trial of atorvastatin during anthracycline-based lymphoma treatment. The primary publication reports 300 randomized adults and a lower 12-month LVEF-decline endpoint with atorvastatin, without a significant difference in clinical heart failure over 24 months.
Show evidence (4 references)
clinicaltrials:NCT02943590 SUPPORT BACKGROUND Other
"This research study will test whether atorvastatin, a drug commonly prescribed for reducing cholesterol levels, can protect the heart during chemotherapy with doxorubicin."
The registry identifies the prevention question.
url:https://clinicaltrials.gov/api/v2/studies/NCT02943590 SUPPORT BACKGROUND Other
"STOP-CA (Statins TO Prevent the Cardiotoxicity From Anthracyclines)"},"statusModule":{"statusVerifiedDate":"2025-05","overallStatus":"COMPLETED""
The official API supplies the current registry status.
PMID:37552303 SUPPORT PRIMARY RESULT Human Clinical
"The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002)."
The primary endpoint was a fall of at least 10 LVEF percentage points to below 55% at 12 months, not clinical heart failure.
+ 1 more reference
🧫

Experimental Models

4
Commercial human iPSC-derived cardiomyocyte TOP2B knockdown OTHER
Commercial CDI cardiomyocytes receive pooled TOP2B siRNAs or dexrazoxane pretreatment before 48-hour doxorubicin exposure. Knockdown improves several viability, electrical, oxidant-probe and ultrastructural readouts. It does not uniformly outperform dexrazoxane across assays or completely normalize calcium transients.
Pathograph links
Mitochondrial Structural Injury perturbs observes: cellular TOP2B knockdown attenuates the ultrastructural lesion.
Limitations: No direct ATP, oxygen-consumption or biogenesis assay is reported. Donor diversity is unspecified; pooled siRNAs lack a re-expression rescue. Pretreatment addresses acute prevention, not established cardiomyopathy.
Readouts
TEM structural preservation
TOP2B knockdown attenuates the structural abnormality relative to doxorubicin exposure alone; this is partial morphological preservation.
Direction: RESTORED
Show evidence (1 reference)
PMID:40158615 SUPPORT PRIMARY RESULT In Vitro
"TOP2B knockdown preserves mitochondrial morphology and sarcomere structure"
TEM shows attenuation of two structural lesions after siRNA pretreatment.
Show evidence (1 reference)
PMID:40158615 SUPPORT PRIMARY RESULT In Vitro
"TOP2B knockdown preserves mitochondrial morphology and sarcomere structure"
TEM shows attenuation of two structural lesions after siRNA pretreatment.
Sarcomere Disruption perturbs observes: cellular Knockdown preserves sarcomere alignment in the same culture experiment.
Limitations: Shared time-point preservation does not establish a mitochondrial-to-sarcomere causal sequence or whole-heart contractile recovery.
Readouts
TEM structural preservation
TOP2B knockdown attenuates the structural abnormality relative to doxorubicin exposure alone; this is partial morphological preservation.
Direction: RESTORED
Show evidence (1 reference)
PMID:40158615 SUPPORT PRIMARY RESULT In Vitro
"TOP2B knockdown preserves mitochondrial morphology and sarcomere structure"
TEM shows attenuation of two structural lesions after siRNA pretreatment.
Show evidence (1 reference)
PMID:40158615 SUPPORT PRIMARY RESULT In Vitro
"TOP2B knockdown preserves mitochondrial morphology and sarcomere structure"
TEM shows attenuation of two structural lesions after siRNA pretreatment.
MTT benefit exceeds the tested dexrazoxane condition whereas LDH reduction is comparable. cTnT is a transcript readout, not blood troponin. No cancer-cell killing, in-vivo delivery or long-term safety outcome establishes clinical superiority or preservation of antitumor efficacy.
Show evidence (3 references)
PMID:40158615 SUPPORT PRIMARY RESULT In Vitro
"The hiPSC-CMs procured from CDI (Cat. #R1007, FUJIFILM Cellular Dynamics Inc.) were cultured according to the manufacturer’s protocol."
The system is a commercial culture, not an identified multi-patient cohort.
PMID:40158615 SUPPORT PRIMARY RESULT In Vitro
"TOP2B knockdown preserves mitochondrial morphology and sarcomere structure"
TEM shows attenuation of two structural lesions after siRNA pretreatment.
PMID:40158615 SUPPORT PRIMARY RESULT In Vitro
"Treatment with Dox, Dox + Dex, and Dox + TOP2B-KD resulted in a significant decrease in transient amplitude"
The calcium-amplitude defect persists in treated groups.
Neonatal rat cardiomyocyte iron-transport perturbation OTHER
Doxorubicin preferentially accumulates in mitochondria in this culture system. Neonatal rat cardiomyocytes are exposed to doxorubicin with ABCB8 knockdown or overexpression. Compartmental iron, cellular oxidant probes, viability and TUNEL are assessed. Separate TOP2B and ABCB8 manipulations support parallel contributions to injury.
Pathograph links
Mitochondrial Iron Accumulation perturbs observes: cellular Manipulation of an iron-export regulator changes compartmental iron accumulation.
Limitations: Neonatal rat cultures and short high-concentration exposure differ from adult human myocardium. These assays do not identify ferroptosis specifically or establish clinical benefit of nonspecific chelation.
Readouts
Mitochondrial iron after ABCB8 knockdown
Mitochondrial iron is higher with ABCB8 siRNA plus doxorubicin than with control siRNA plus drug.
Direction: INCREASED
Show evidence (1 reference)
PMID:24382354 SUPPORT PRIMARY RESULT In Vitro
"In the presence of DOX, ABCB8 siRNA resulted in a fur- ther increase in mitochondrial iron levels"
ABCB8 depletion increases the mitochondrial iron measurement under doxorubicin exposure.
Show evidence (1 reference)
PMID:24382354 SUPPORT PRIMARY RESULT In Vitro
"In the presence of DOX, ABCB8 siRNA resulted in a fur- ther increase in mitochondrial iron levels"
ABCB8 depletion increases the mitochondrial iron measurement under doxorubicin exposure.
Drug sequestration and iron loading are measured together, but the study does not selectively perturb sequestration to establish it as the mediator of iron accumulation.
Show evidence (3 references)
PMID:24382354 SUPPORT PRIMARY RESULT In Vitro
"While ABCB8 siRNA did not affect baseline cellular ROS levels, it resulted in a significantly higher ROS after DOX treatment"
The culture perturbation changes the oxidant response after drug exposure.
PMID:24382354 SUPPORT PRIMARY RESULT In Vitro
"cell death, as assessed by MTS assay and TUNEL staining, was significantly higher after DOX treatment in response to ABCB8 silencing than in cells transfected with control siRNA"
Iron-export perturbation changes cell-injury readouts.
PMID:24382354 SUPPORT PRIMARY RESULT In Vitro
"In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels."
The observed co-occurrence is retained as experimental context without imposing a causal sequestration-to-iron arrow.
RARG Ser427Leu reporter and rat H9c2 transfection systems OTHER
Wild-type and Ser427Leu human RARG are compared in a HEK293T retinoic-acid-response reporter and in rat H9c2 cells measuring Top2b repression. The variant shows partial functional alteration.
HEK293T cells retain endogenous retinoic-acid receptors, which complicates the size of the allele effect. H9c2 is a rat cell line, not a patient heart. The experiment does not quantify patient-specific TOP2B-DNA complexes or prove clinical utility of genotype-guided cardioprotection.
Show evidence (1 reference)
PMID:26237429 SUPPORT PRIMARY RESULT In Vitro
"The significant 17% decrease in RARG activity conferred by the rs2229774 variant"
The reporter detects a partial allele-associated functional difference.
Isolated titin-truncation mouse cardiomyocyte mechanics OTHER
Cardiomyocytes isolated twelve weeks after doxorubicin exposure show depressed contractility in the heterozygous titin-truncation group compared with exposed wild-type and untreated controls.
Pathograph links
Reduced Ventricular Contractile Function partially recapitulates observes: cellular Ex-vivo sarcomere mechanics provide a cellular correlate of the in-vivo functional phenotype.
Limitations: At least 52 measured cells per group are not 52 independent animals. The assay does not directly establish patient ventricular recovery or a universal TTN-mediated structural pathway.
Readouts
Isolated cardiomyocyte contractility
Measured cellular contractility is lower in drug-exposed titin-truncation cells than the specified control groups.
Direction: DECREASED
Show evidence (1 reference)
PMID:30987448 SUPPORT PRIMARY RESULT In Vitro
"Cardiomyocytes from doxorubicin-treated Ttntv/+ mice had significantly depressed contractility"
Ex-vivo cellular mechanics corroborate persistent functional impairment.
Show evidence (1 reference)
PMID:30987448 SUPPORT PRIMARY RESULT In Vitro
"Cardiomyocytes from doxorubicin-treated Ttntv/+ mice had significantly depressed contractility"
Ex-vivo cellular mechanics corroborate persistent functional impairment.
Show evidence (1 reference)
PMID:30987448 SUPPORT PRIMARY RESULT In Vitro
"Cardiomyocytes from doxorubicin-treated Ttntv/+ mice had significantly depressed contractility"
Ex-vivo cellular mechanics corroborate persistent functional impairment.
🐁

Animal Models

3
Cardiomyocyte-specific Top2b deletion
Cardiomyocyte-specific deletion protects mice against doxorubicin-associated DNA breaks, mitochondrial transcriptional changes and progressive heart failure.
Species
Mouse
Genotype
Cardiomyocyte-restricted Top2b knockout
Publication
PMID:23104132
Pathograph links
DNA Double-Strand Break Accumulation perturbs observes: organism Genetic deletion reduces the doxorubicin-associated DNA lesion.
Limitations: The canonical cache remains abstract-only despite retrieval attempts; strain, exact dosing and deletion efficiency are not imported. Genetic deletion is not a demonstrated clinically deliverable selective inhibitor.
Readouts
Doxorubicin-associated DNA breaks
Cardiomyocyte-specific Top2b deletion reduces the drug-associated DNA lesion.
Direction: DECREASED
Show evidence (1 reference)
PMID:23104132 SUPPORT PRIMARY RESULT Model Organism
"cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks"
The knockout tests TOP2B contribution to the lesion.
Show evidence (1 reference)
PMID:23104132 SUPPORT PRIMARY RESULT Model Organism
"cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks"
The knockout tests TOP2B contribution to the lesion.
Show evidence (2 references)
PMID:23104132 SUPPORT PRIMARY RESULT Model Organism
"cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks"
The knockout tests TOP2B contribution to the lesion.
PMID:23104132 SUPPORT PRIMARY RESULT Model Organism
"cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure"
The abstract reports protection at the whole-heart clinical-model level.
Cardiac ABCB8 overexpression
Cardiac ABCB8 overexpression lowers mitochondrial iron and attenuates doxorubicin injury in acute and subacute mouse exposure protocols. The study also uses cardiac Abcb8 deletion, whose pre-existing cardiomyopathy complicates interpretation of drug-specific susceptibility.
Species
Mouse
Genotype
Cardiac ABCB8 transgene on a backcrossed C57BL/6J background
Publication
PMID:24382354
Pathograph links
Mitochondrial Iron Accumulation perturbs observes: organism Transgenic expression reduces mitochondrial iron before and after exposure.
Limitations: One founder line and relatively intensive short-duration doxorubicin protocols differ from repeated human cancer regimens. Prevention before exposure is not reversal of established chronic human cardiomyopathy.
Readouts
Mitochondrial iron in cardiac ABCB8 transgenic mice
Iron is lower in transgenic than nontransgenic hearts, including after drug exposure.
Direction: DECREASED
Show evidence (1 reference)
PMID:24382354 SUPPORT PRIMARY RESULT Model Organism
"ABCB8 TG mice displayed significantly lower mitochondrial iron levels than those observed in non-TG (NTG) animals both at baseline and after treatment with DOX"
The transgenic comparison directly measures the compartmental iron pool.
Show evidence (1 reference)
PMID:24382354 SUPPORT PRIMARY RESULT Model Organism
"ABCB8 TG mice displayed significantly lower mitochondrial iron levels than those observed in non-TG (NTG) animals both at baseline and after treatment with DOX"
The transgenic comparison directly measures the compartmental iron pool.
Show evidence (1 reference)
PMID:24382354 SUPPORT PRIMARY RESULT Model Organism
"ABCB8 TG mice displayed significantly lower mitochondrial iron levels than those observed in non-TG (NTG) animals both at baseline and after treatment with DOX"
The transgenic comparison directly measures the compartmental iron pool.
Heterozygous A-band titin-truncation mouse
Three weekly doxorubicin doses initially depress function in both genotypes; wild-type function returns to baseline while heterozygous mutants have persistent dysfunction through week 12. Fifteen mice per genotype were tested.
Species
Mouse
Genotype
Ttntv/+ heterozygous A-band truncation on C57BL/6N
Publication
PMID:30987448
Pathograph links
Reduced Ventricular Contractile Function partially recapitulates observes: organism The model reproduces sustained ventricular dysfunction after a defined drug stress.
Limitations: A single truncation and background do not represent every human TTN allele. Cardiac histology did not show a significant increase in fibrosis or apoptosis relative to untreated mice, so persistent functional impairment is not converted into a proved excess-cell-death mechanism.
Readouts
Ventricular function recovery after doxorubicin
Wild-type function returns to baseline by week 8 while titin-truncation function remains depressed through week 12.
Direction: ALTERED
Show evidence (1 reference)
PMID:30987448 SUPPORT PRIMARY RESULT Model Organism
"at week 8, LV function recovered to baseline in wild-type mice but remained depressed through week 12 in Ttntv/+ mice"
The measured recovery trajectories differ after doxorubicin.
Show evidence (2 references)
PMID:30987448 SUPPORT PRIMARY RESULT Model Organism
"at week 8, LV function recovered to baseline in wild-type mice but remained depressed through week 12 in Ttntv/+ mice"
The measured recovery trajectories differ after doxorubicin.
+ 1 more reference
Show evidence (1 reference)
PMID:30987448 SUPPORT PRIMARY RESULT Model Organism
"at week 8, LV function recovered to baseline in wild-type mice but remained depressed through week 12 in Ttntv/+ mice"
The measured recovery trajectories differ after doxorubicin.
{ }

Source YAML

click to show 
name: Anthracycline-Induced Cardiomyopathy
creation_date: '2026-09-01T14:00:00Z'
description: Anthracycline-induced cardiomyopathy is cardiac muscle dysfunction associated with exposure to agents such as doxorubicin, daunorubicin, epirubicin and idarubicin. Risk is related to cumulative exposure and modified by baseline cardiovascular disease, age, other cancer treatments and genetic susceptibility. Experimentally implicated pathways include TOP2B-associated DNA injury, altered mitochondrial biology and compartmental iron loading. Clinical expression ranges from asymptomatic ventricular dysfunction to heart failure, sometimes years after treatment. Recovery is possible; neither universal irreversibility nor one obligatory molecular pathway is established.
categories:
- Treatment Toxicity
- Cardiovascular Disorder
category: Complex
parents:
- Cardiomyopathy
disease_term:
  preferred_term: anthracycline-induced cardiomyopathy
  term:
    id: MONDO:0022653
    label: cardiomyopathy due to anthracyclines
updated_date: '2026-09-21T10:18:17Z'
review_notes: All six original cited sources were reviewed using the complete scientific body where available. Genuine full texts additionally cover mitochondrial iron experiments, modern cardio-oncology synthesis, pediatric dexrazoxane guidance and long-term survivor follow-up, and the applicable ESC 2022 guideline sections. The canonical TOP2B knockout, Cardinale recovery cohort and spironolactone trial remain abstract-limited after retrieval attempts. The DCM GeneReviews overview was consulted for definition and genetic context; it explicitly excludes acquired DCM from later evaluation, management and counseling sections, so these domains are supplied by anthracycline-specific guidance. Experimental concentrations, prevention designs and human cohort denominators are retained locally. No general disease frequency is inferred from selected exposed or cardiomyopathy cohorts. Arrhythmias can accompany anthracycline exposure or established heart failure, but this entry centers on myocardial dysfunction; it does not treat every acute rhythm toxicity as cardiomyopathy. Treatment drug classes and the liposomal carrier are explicitly annotated. The ESC guideline retains its complete, already
  audited PDF quotation source, with its canonical PMID, DOI and publisher record identified in the bibliography.
pathophysiology:
- name: Anthracycline-TOP2B-DNA Complex Formation
  biological_scale: MOLECULAR
  description: Anthracyclines interfere with TOP2B-associated DNA cleavage and religation in cardiomyocytes. The drug-enzyme-DNA complex is distinguished from the ensuing DNA lesion and cell death. TOP2B contributes to cardiac injury in experimental systems; its expression does not imply that all cardiac toxicity follows one obligatory pathway.
  evidence: &id029
  - reference: PMID:39479333
    reference_title: 'Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Anthracyclines target the Top2b-cleaved DNA complex, causing accumulation of double-strand DNA breaks and subsequent apoptosis.
    explanation: The mechanistic synthesis identifies the TOP2B-associated DNA complex and its downstream damage.
  role: trigger
  conforms_to: cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult
  cell_types: &id003
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: DNA Double-Strand Break Accumulation
    causal_link_type: DIRECT
    description: Interference with the TOP2B-DNA cleavage complex prevents normal resolution of enzyme-associated breaks.
    evidence:
    - reference: PMID:39479333
      reference_title: 'Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Anthracyclines target the Top2b-cleaved DNA complex, causing accumulation of double-strand DNA breaks and subsequent apoptosis.
      explanation: The review directly links the targeted complex to accumulated breaks.
  - target: Impaired Mitochondrial Biogenesis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: TOP2B-dependent transcriptome changes connect the initiating drug interaction to impaired mitochondrial biogenesis; individual transcriptional intermediates are not resolved in this entry.
    evidence: &id001
    - reference: PMID:23104132
      reference_title: Identification of the molecular basis of doxorubicin-induced cardiotoxicity.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation.
      explanation: The primary abstract reports transcription-associated impairment; detailed dosing and transcriptional mediators are not available in its cache.
  - target: Mitochondrial Structural Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: TOP2B knockdown attenuates the mitochondrial lesion, supporting a contribution through unresolved downstream mediators. Shared endpoints do not establish a strict sequence through every mapped mitochondrial process.
    evidence:
    - reference: PMID:40158615
      reference_title: SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: TOP2B knockdown preserves mitochondrial morphology and sarcomere structure
      explanation: Perturbation supports TOP2B involvement but not a serial ordering of the two structural lesions.
  - target: Sarcomere Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: TOP2B depletion attenuates sarcomere injury in culture; the downstream mediators remain unresolved.
    evidence:
    - reference: PMID:40158615
      reference_title: SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: TOP2B knockdown preserves mitochondrial morphology and sarcomere structure
      explanation: The intervention affects both readouts without ordering them.
  - target: Increased Reactive Oxygen Species
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: TOP2B-dependent transcriptome changes are associated with ROS formation in the mouse experiment. The source does not establish impaired biogenesis as the mediator of ROS, so these outcomes are parallel downstream branches.
    evidence: *id001
- name: DNA Double-Strand Break Accumulation
  biological_scale: MOLECULAR
  description: Persistent TOP2B-associated DNA lesions accumulate after doxorubicin exposure. Cardiomyocyte-specific Top2b deletion protects against these breaks in mice. TUNEL in the separate human cardiomyocyte culture study measures terminal fragmentation and is not used as a direct assay of the initiating double-strand break.
  evidence:
  - reference: PMID:23104132
    reference_title: Identification of the molecular basis of doxorubicin-induced cardiotoxicity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks
    explanation: The genetic mouse experiment implicates TOP2B in the initial DNA injury.
  downstream:
  - target: Cardiomyocyte Death
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Persistent DNA injury can engage downstream death responses; the mapped evidence does not isolate one necessary p53 or caspase sequence.
    evidence:
    - reference: PMID:39479333
      reference_title: 'Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Anthracyclines target the Top2b-cleaved DNA complex, causing accumulation of double-strand DNA breaks and subsequent apoptosis.
      explanation: The synthesis links accumulated DNA breaks to apoptosis through downstream signaling.
- name: Impaired Mitochondrial Biogenesis
  biological_scale: CELLULAR
  description: Doxorubicin-induced, TOP2B-dependent transcriptional changes impair mitochondrial biogenesis in the genetic mouse study. This process is separate from iron accumulation and ultrastructural injury; the later human siRNA culture study did not measure biogenesis or respiratory flux.
  evidence: *id001
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
- name: Reduced ABCB8 Expression
  biological_scale: MOLECULAR
  description: Doxorubicin reduces the abundance of the mitochondrial iron-export regulator ABCB8 in neonatal rat cardiomyocytes and mouse hearts. The data implicate regulation at the mRNA level; direct binding of doxorubicin to the ABCB8 promoter or a measured transport-blocking interaction is not established.
  evidence: &id030
  - reference: PMID:24382354
    reference_title: Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: DOX significantly reduced the mRNA and protein levels of ABCB8
    explanation: The culture and mouse expression data establish reduced abundance.
  - reference: PMID:24382354
    reference_title: Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: These results suggest that DOX regulates ABCB8 at the mRNA level and that this regulation is independent of cytotoxic effects of the drug.
    explanation: The experiment localizes the regulatory effect to mRNA-level expression rather than proving direct promoter binding.
  downstream:
  - target: Mitochondrial Iron Accumulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Lower ABCB8 abundance can reduce iron export and favor mitochondrial retention. Knockdown and overexpression support this route without proving the complete export machinery.
    evidence:
    - &id026
      reference: PMID:24382354
      reference_title: Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: In the presence of DOX, ABCB8 siRNA resulted in a fur- ther increase in mitochondrial iron levels
      explanation: ABCB8 depletion increases the mitochondrial iron measurement under doxorubicin exposure.
    - reference: PMID:24382354
      reference_title: Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron
      explanation: Gain of expression lowers the measured mitochondrial iron pool.
- name: Mitochondrial Iron Accumulation
  biological_scale: CELLULAR
  description: Doxorubicin exposure increases mitochondrial iron in cardiomyocyte cultures and mouse hearts. ABCB8 manipulation supports a contribution of impaired export. Human transplant explants show the same compartmental association, but the small end-stage series cannot establish temporal causation or a clinical iron-removal treatment effect.
  evidence:
  - &id002
    reference: PMID:24382354
    reference_title: Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS
    explanation: The culture and transgenic experiments test iron export as a modifiable process.
  - reference: PMID:24382354
    reference_title: Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function.
    explanation: The explant comparison is human tissue association, not an intervention trial.
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  downstream:
  - target: Increased Reactive Oxygen Species
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: An expanded mitochondrial iron pool can promote iron-dependent redox reactions. ABCB8 manipulation lowers both iron and oxidant readouts; these experiments do not resolve every reaction or exclude parallel sources.
    evidence:
    - *id002
  - target: Cardiomyocyte Death
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: ABCB8-dependent iron handling modifies culture injury, with oxidative and other mitochondrial intermediates unresolved.
    evidence:
    - &id005
      reference: PMID:24382354
      reference_title: Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: cell death, as assessed by MTS assay and TUNEL staining, was significantly higher after DOX treatment in response to ABCB8 silencing than in cells transfected with control siRNA
      explanation: The ABCB8 experiment supports an additional iron-associated injury route.
- name: Increased Reactive Oxygen Species
  biological_scale: MOLECULAR
  description: Anthracycline redox cycling and mitochondrial iron can increase reactive oxygen species. The iron and TOP2B-associated transcriptional branches can converge on oxidative stress. Probe-based culture readouts do not identify every radical species or show that oxidative injury is the sole human mechanism.
  evidence:
  - reference: PMID:28185035
    reference_title: Anthracycline Chemotherapy and Cardiotoxicity.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: ROS levels may also be increased by free cellular iron and potentiating ferrous-ferric cycling of molecular iron
    explanation: The review provides the chemical rationale for the iron-associated oxidant branch.
  - reference: PMID:40158615
    reference_title: SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Representative images (Fig. 7A) show a marked increase in mitochondrial ROS in Dox-treated hiPSC-CMs, which was reduced with Dex and TOP2B-KD interventions.
    explanation: The human culture study measures a mitochondrial oxidant-probe signal.
  biological_processes:
  - preferred_term: reactive oxygen species biosynthetic process
    term:
      id: GO:1903409
      label: reactive oxygen species biosynthetic process
  downstream:
  - target: Mitochondrial Structural Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Oxidative injury can damage mitochondrial structure; this synthesis does not make the simultaneous probe and TEM endpoints a mediator-specific epistasis test.
    evidence:
    - reference: PMID:28185035
      reference_title: Anthracycline Chemotherapy and Cardiotoxicity.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: The doxorubicin-iron complexes form toxic radical and reac- tive nitrogen species, resulting in increased nitrosative stress and mitochondrial dysfunction [18].
      explanation: The review connects iron-associated radical production to mitochondrial injury.
- name: Mitochondrial Structural Injury
  biological_scale: CELLULAR
  description: Doxorubicin-exposed human iPSC-derived cardiomyocytes develop swollen or fragmented mitochondria and disrupted cristae. TOP2B knockdown attenuates these changes. Ultrastructure is not treated as a direct measurement of ATP production, respiratory flux or complete functional restoration.
  evidence: &id004
  - reference: PMID:40158615
    reference_title: SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: TEM images (Fig. 7D) indicated fragmented and swollen mitochondria with disrupted cristae in Dox treated hiPSC-CMs, along with irregular sarcomere alignment.
    explanation: TEM resolves the mitochondrial lesion separately from the concurrent contractile-structure lesion.
  cell_types: *id003
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
- name: Sarcomere Disruption
  biological_scale: CELLULAR
  description: Irregular sarcomere alignment is a distinct ultrastructural lesion in doxorubicin-exposed human cardiomyocyte cultures. TOP2B knockdown partly preserves it. The study does not establish that mitochondrial structural injury necessarily occurs first or directly causes this lesion.
  evidence: *id004
  cell_types: *id003
  biological_processes:
  - preferred_term: sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
  downstream:
  - target: Reduced Ventricular Contractile Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Damage to the contractile apparatus may impair ventricular performance, but extrapolation from culture ultrastructure to patient ejection fraction is indirect.
    evidence: *id004
- name: Cardiomyocyte Death
  biological_scale: CELLULAR
  description: Loss of cardiomyocytes contributes to anthracycline injury. DNA damage and mitochondrial stress are experimentally implicated routes. TUNEL and viability assays support injury and death but do not establish a universal exclusive death program, or identify ferroptosis from iron accumulation alone.
  evidence:
  - reference: PMID:40158615
    reference_title: SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: TOP2B-KD resulted in a marked decrease in the number of TUNEL-positive cells
    explanation: TOP2B perturbation reduces terminal DNA-fragmentation-positive cells.
  - *id005
  cell_types: *id003
  downstream:
  - target: Ventricular Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cumulative myocyte injury can drive maladaptive chamber remodeling through incompletely resolved tissue responses; recovery remains possible.
    evidence:
    - reference: PMID:28185035
      reference_title: Anthracycline Chemotherapy and Cardiotoxicity.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: cardiotoxic vulnerability from the loss of myocytes during anthracycline exposure in childhood
      explanation: The review discusses myocyte loss as a source of later vulnerability.
- name: Ventricular Remodeling
  biological_scale: TISSUE
  description: Structural changes after myocardial injury can include chamber dilation and wall thinning. These changes vary with age, treatment and follow-up; pediatric survivors may develop a restrictive pattern. Remodeling is not assumed inevitable or irreversible.
  evidence: &id006
  - reference: PMID:39479333
    reference_title: 'Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Late onset cardiotoxicity, which becomes clinically evident more than 1 year after exposure, typically presents as hypokinetic and/or dilated cardiomyopathy with overt HF symptoms.
    explanation: The review describes a late structural and functional presentation.
  conforms_to: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
  locations: &id007
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  downstream:
  - target: Reduced Ventricular Contractile Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Maladaptive chamber geometry and tissue remodeling can reduce contractile performance; dysfunction can also precede marked dilation.
    evidence: *id006
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
    description: Ventricular dilation with hypokinetic function defines the dilated phenotype in affected patients.
    evidence: *id006
- name: Reduced Ventricular Contractile Function
  biological_scale: ORGANISM
  description: Anthracycline-associated left ventricular systolic dysfunction may be asymptomatic or present as heart failure. It can improve with treatment, remain impaired or emerge late. Loss of myocardium, contractile-structure injury and remodeling can contribute without a single demonstrated universal sequence.
  evidence: &id008
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Anthracycline-induced CTRCD is a dose-dependent and cumulative process of variable onset that may present with symptomatic or asymptomatic CTRCD.
    explanation: The guideline defines variable timing and clinical expression.
  conforms_to: cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction
  locations: *id007
  downstream:
  - target: Reduced left ventricular ejection fraction
    causal_link_type: DIRECT
    description: Reduced ventricular pump performance underlies this measurable or clinical expression; asymptomatic dysfunction need not progress to overt heart failure.
    evidence: *id008
  - target: Congestive heart failure
    causal_link_type: DIRECT
    description: Reduced ventricular pump performance underlies this measurable or clinical expression; asymptomatic dysfunction need not progress to overt heart failure.
    evidence: *id008
  - target: Dyspnea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Symptomatic cardiac dysfunction can produce this manifestation through hemodynamic or congestion-related intermediates. The clinical source does not measure each intermediate, and the finding is not specific for anthracycline injury.
    evidence: &id010
    - reference: PMID:26237429
      reference_title: A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: symptoms (dyspnea, orthopnea and/or fatigue) and/or signs (edema, hepatomegaly and/or rales)
      explanation: These manifestations form part of the source clinical case definition; the passage does not supply individual-feature prevalence.
  - target: Orthopnea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Symptomatic cardiac dysfunction can produce this manifestation through hemodynamic or congestion-related intermediates. The clinical source does not measure each intermediate, and the finding is not specific for anthracycline injury.
    evidence: &id011
    - reference: PMID:26237429
      reference_title: A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: symptoms (dyspnea, orthopnea and/or fatigue) and/or signs (edema, hepatomegaly and/or rales)
      explanation: These manifestations form part of the source clinical case definition; the passage does not supply individual-feature prevalence.
  - target: Fatigue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Symptomatic cardiac dysfunction can produce this manifestation through hemodynamic or congestion-related intermediates. The clinical source does not measure each intermediate, and the finding is not specific for anthracycline injury.
    evidence: &id012
    - reference: PMID:26237429
      reference_title: A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: symptoms (dyspnea, orthopnea and/or fatigue) and/or signs (edema, hepatomegaly and/or rales)
      explanation: These manifestations form part of the source clinical case definition; the passage does not supply individual-feature prevalence.
  - target: Hepatomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Symptomatic cardiac dysfunction can produce this manifestation through hemodynamic or congestion-related intermediates. The clinical source does not measure each intermediate, and the finding is not specific for anthracycline injury.
    evidence: &id013
    - reference: PMID:26237429
      reference_title: A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: symptoms (dyspnea, orthopnea and/or fatigue) and/or signs (edema, hepatomegaly and/or rales)
      explanation: These manifestations form part of the source clinical case definition; the passage does not supply individual-feature prevalence.
  - target: Pulmonary edema
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Symptomatic cardiac dysfunction can produce this manifestation through hemodynamic or congestion-related intermediates. The clinical source does not measure each intermediate, and the finding is not specific for anthracycline injury.
    evidence: &id009
    - reference: PMID:28185035
      reference_title: Anthracycline Chemotherapy and Cardiotoxicity.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: congestive heart failure (CHF), characterised by pulmonary oedema, fluid overload, and effort intolerance
      explanation: The review describes the clinical congestive syndrome.
  - target: Exercise intolerance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Symptomatic cardiac dysfunction can produce this manifestation through hemodynamic or congestion-related intermediates. The clinical source does not measure each intermediate, and the finding is not specific for anthracycline injury.
    evidence: *id009
  - target: Edema
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cardiac congestion and fluid retention can produce edema, with the intervening hemodynamics unresolved by the source case definition.
    evidence: &id014
    - reference: PMID:26237429
      reference_title: A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: symptoms (dyspnea, orthopnea and/or fatigue) and/or signs (edema, hepatomegaly and/or rales)
      explanation: The source names edema without an anatomical qualifier.
phenotypes:
- name: Reduced left ventricular ejection fraction
  description: Systolic dysfunction is a central measurable manifestation. It may initially be asymptomatic and can improve; mild cancer therapy-related dysfunction may instead have preserved ejection fraction with new strain or biomarker abnormalities.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: New LVEF reduction by ≥10 percentage points to an LVEF of 40–49%
    explanation: The guideline provides one moderate asymptomatic dysfunction criterion, rather than a universal threshold for all cardiac injury.
- name: Dilated cardiomyopathy
  description: Some patients develop a dilated, hypokinetic ventricular phenotype, including late presentations. It is not required for every stage of anthracycline-related dysfunction.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:39479333
    reference_title: 'Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Late onset cardiotoxicity, which becomes clinically evident more than 1 year after exposure, typically presents as hypokinetic and/or dilated cardiomyopathy with overt HF symptoms.
    explanation: The review describes the late dilated phenotype.
- name: Congestive heart failure
  description: Symptomatic pump failure can occur during treatment or later in survivorship, but asymptomatic dysfunction does not invariably progress to heart failure.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence: *id009
- name: Dyspnea
  description: Breathlessness can accompany symptomatic cardiac compromise.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence: *id010
- name: Orthopnea
  description: Positional breathlessness is a possible heart-failure manifestation.
  phenotype_term:
    preferred_term: Orthopnea
    term:
      id: HP:0012764
      label: Orthopnea
  evidence: *id011
- name: Fatigue
  description: Fatigue can accompany cardiac compromise but is nonspecific in cancer care.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence: *id012
- name: Hepatomegaly
  description: Hepatic enlargement may accompany clinical congestion; it is not specific for cardiac toxicity in a person with cancer.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence: *id013
- name: Pulmonary edema
  description: Pulmonary congestion can occur with overt congestive failure.
  phenotype_term:
    preferred_term: Pulmonary edema
    term:
      id: HP:0100598
      label: Pulmonary edema
  evidence: *id009
- name: Exercise intolerance
  description: Effort intolerance is described in clinical congestive failure; its presence and severity vary.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence: *id009
- name: Edema
  description: Edema is reported among signs used to recognize cardiac compromise; the cited case definition does not specify a distribution or a frequency.
  phenotype_term:
    preferred_term: Edema
    term:
      id: HP:0000969
      label: Edema
  evidence: *id014
genetic:
- name: RARG
  gene_term:
    preferred_term: RARG
    term:
      id: hgnc:9866
      label: RARG
  relationship_type: SUSCEPTIBILITY
  notes: RARG rs2229774 (p.Ser427Leu) was associated with cardiotoxicity after treatment for childhood cancer. The discovery and replication groups contained 280, 96 and 80 participants, with 73 cases among 456 in the combined selected sample. The reported adjusted per-allele odds ratio was 4.7, distinct from a carrier-versus-noncarrier estimate. Non-European replication was small and had no variant carriers among controls. HEK293T reporter and rat H9c2 transfection studies support altered receptor function and weaker Top2b repression; they are not patient-heart measurements or a validated treatment-selection test.
  evidence:
  - reference: PMID:26237429
    reference_title: A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT
    explanation: The childhood case-control study establishes a susceptibility association.
  - reference: PMID:26237429
    reference_title: A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: The significant 17% decrease in RARG activity conferred by the rs2229774 variant
    explanation: A transfected reporter assay measures partial functional alteration, not human clinical receptor activity.
- name: TTN
  gene_term:
    preferred_term: TTN
    term:
      id: hgnc:12403
      label: TTN
  relationship_type: SUSCEPTIBILITY
  notes: TTN truncating variants were present in 16/213 selected cancer therapy-related cardiomyopathy cases (7.5%); 90% had anthracycline exposure and some adults also received trastuzumab. This is neither population penetrance nor an anthracycline-only prevalence. TCGA comparator cardiac status and individual treatment exposure were not established. Adult carriers had more heart-failure admissions and atrial fibrillation and a lower mean final LVEF; recovery occurred in both groups and recovery occurrence was not significantly correlated with TTN status. A heterozygous A-band mouse model supports prolonged dysfunction after doxorubicin.
  evidence:
  - reference: PMID:30987448
    reference_title: Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: TTNtvs were identified in 16 of 213 CCM cases (7.5%)
    explanation: The numerator and denominator belong to selected mixed-treatment cases.
  - reference: PMID:30987448
    reference_title: Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Recovery occurred in both groups, although the final mean LVEF was more depressed in patients with TTNtvs
    explanation: The full body qualifies the abstract wording about impaired recovery.
  - reference: PMID:30987448
    reference_title: Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: A more ideal comparison group would have been patients treated with chemotherapy who did not develop cardiomyopathy.
    explanation: The authors acknowledge the comparator limitation.
- name: CBR3
  gene_term:
    preferred_term: CBR3
    term:
      id: hgnc:1549
      label: CBR3
  relationship_type: SUSCEPTIBILITY
  notes: In a matched study of 170 childhood-cancer survivors with cardiomyopathy and 317 controls, CBR3 rs1056892 (V244M) GG was associated with greater risk than GA/AA within the 1–250 mg/m² anthracycline-exposure stratum (OR 3.30, 95% CI 1.41–7.73). High-dose exposure was associated with disease in both genotype groups. Most participants were non-Hispanic White; 114 controls lacked echocardiography, and fatal cases were excluded by survivor ascertainment. This observational result does not establish a safe dose for any genotype, population penetrance, or benefit from genotype-guided prescribing. The later CELF4 study overlapped this cohort substantially and is not independent CBR3 replication. CBR1 rs9024 (1096G>A) was a candidate susceptibility variant in the same survivor study, but the full results found no overall association. The low/moderate-dose GG association was borderline before CBR3 adjustment (OR 3.29, P=.05) and nonsignificant after adjustment (OR 2.63, P=.11). CBR1 is recorded as an investigated candidate, not an established risk determinant. Proposed effects on alcohol-metabolite production are background from prior experiments and do not prove mediation of the observed
    clinical associations.
  evidence:
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3383117/?pdf=render
    reference_title: 'Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children&#x27;s Oncology Group - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: One hundred seventy patient cases with cardiomyopathy and 317 matched controls participated in this study.
    explanation: Defines the selected childhood-cancer survivor case-control sample.
  - reference: PMID:22124095
    reference_title: 'Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children''s Oncology Group.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006).
    explanation: The abstract supplies the within-exposure CBR3 comparison; the full body and Table 4 were also reviewed.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3383117/?pdf=render
    reference_title: 'Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children&#x27;s Oncology Group - PMC'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Prevalent case-control studies, by the nature of their design, exclude fatal end points from the patient case set.
    explanation: Survival selection can alter observed genotype-risk associations; this study does not measure lifetime penetrance.
- name: CELF4
  gene_term:
    preferred_term: CELF4
    term:
      id: hgnc:14015
      label: CELF4
  relationship_type: SUSCEPTIBILITY
  notes: A two-step genome-wide gene-by-dose analysis implicated rs1786814 in 331 non-Hispanic White childhood-cancer survivors after quality control (112 cases, 219 controls). No marginal SNP association passed the study threshold. The reported 10.16-fold odds ratio compares GG with >300 mg/m² exposure against GA/AA with ≤300 mg/m², changing both genotype and dose. Replication included 54 cases without controls and tested genotype-dose association, not the same disease-risk contrast. In 33 healthy heart samples, embryonic/adult TNNT2 isoform coexpression was observed in 19/21 GG versus 5/12 GA/AA samples. This supports a molecular association; neither variant perturbation nor anthracycline-exposed myocardial contractility was measured. Clinical prediction and treatment selection remain unvalidated.
  evidence:
  - reference: PMID:26811534
    reference_title: 'CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children''s Oncology Group Genome-Wide Association Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: No SNP was marginally associated with cardiomyopathy. However, SNP rs1786814 on the CELF4 gene passed the significance cutoff for gene-environment interaction (Pge = 1.14 × 10(-5)).
    explanation: The discovery result concerns gene-by-exposure interaction rather than a marginal genome-wide disease association.
  - reference: PMID:26811534
    reference_title: 'CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children''s Oncology Group Genome-Wide Association Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Compared with cases who had GA/AA genotype, the odds of cases who had the GG genotype being in the greater-than–300-mg/m2 versus the 300-mg/m2 –or-less anthracycline group were 5.09 times higher
    explanation: The replication comparison is explicitly restricted to cases and dose category.
  - reference: PMID:26811534
    reference_title: 'CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children''s Oncology Group Genome-Wide Association Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: 'The embryonic splicing variant of TNNT2 was found in 24 of the 33 heart samples and was more likely to coexist with the adult TNNT2 splicing variant in hearts homozygous for the high-risk rs1786814 genotype (GG: 19 (90.5%) of 21 samples; GA/AA: 5 (41.7%) of 12 samples; P = .005, Fisher’s exact test; Data Supplement).'
    explanation: Healthy-heart tissue associates genotype with isoform coexpression; it does not directly test a drug-injury mechanism.
progression:
- phase: Variable onset and clinical expression
  notes: Injury can become apparent during treatment, within the first year, or years later. The dose, age, coexisting cardiovascular disease and additional therapies modify risk. A closely monitored 2625-person cohort detected 226 cases (9%), 98% of them within the first year; this cohort observation does not exclude late disease or establish a general population incidence.
  evidence:
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Anthracycline-induced CTRCD is a dose-dependent and cumulative process of variable onset that may present with symptomatic or asymptomatic CTRCD.
    explanation: The guideline recognizes variable timing and symptom status.
  - reference: PMID:25948538
    reference_title: Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The overall incidence of cardiotoxicity was 9% (n=226).
    explanation: The estimate comes from the particular serial-monitoring cohort.
- phase: Recovery or persistent dysfunction
  notes: Anthracycline cardiomyopathy is not uniformly irreversible. In the serial-monitoring cohort, prompt heart-failure treatment was followed by full recovery in 11% and partial recovery in 71% of affected patients. These observational results lack a randomized untreated comparator and do not guarantee recovery. Childhood survivors can later develop a restrictive physiological pattern despite periods of compensated systolic function.
  evidence:
  - reference: PMID:25948538
    reference_title: Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Twenty-five (11%) patients had full recovery, and 160 (71%) patients had partial recovery.
    explanation: The cohort distinguishes return to baseline from partial improvement.
  - reference: PMID:28185035
    reference_title: Anthracycline Chemotherapy and Cardiotoxicity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: early dilated cardiomyopathy followed by a period of compensated systolic function and later restrictive physiology
    explanation: The review describes a pediatric restrictive trajectory.
biochemical:
- name: Cardiac troponin
  presence: INCREASED
  notes: A rise can indicate myocardial injury and contribute to surveillance, but must be interpreted with timing, renal function, infection and other causes. A single value does not prove anthracycline causation or irreversible cardiomyocyte loss. The hiPSC study measured cTnT transcript and does not validate a serum assay.
  evidence:
  - reference: PMID:39479333
    reference_title: 'Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Troponins, which are cardiac-specific circulating proteins, become indicative of myocardial injury when their levels exceed the 99th percentile in the general population.
    explanation: The clinical review describes this circulating biomarker and its interpretation.
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: an increase in biomarker level should be interpreted in the patient clinical context (cancer treatment timing and comorbidities).
    explanation: The guideline requires contextual interpretation rather than a standalone etiologic test.
- name: Natriuretic peptides
  presence: INCREASED
  notes: BNP or NT-proBNP can reflect myocardial wall stress and support heart-failure assessment. Predictive performance for future anthracycline dysfunction varies; renal function, body size, rhythm and therapy affect concentrations.
  evidence:
  - &id015
    reference: PMID:39479333
    reference_title: 'Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: NPs, including B-type natriuretic peptide and N-terminal pro–B-type natriuretic peptide (NT-proBNP), are cardiac hormones critical for diagnosis and managing HF.
    explanation: The clinical review describes this circulating biomarker and its interpretation.
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: an increase in biomarker level should be interpreted in the patient clinical context (cancer treatment timing and comorbidities).
    explanation: The guideline requires contextual interpretation rather than a standalone etiologic test.
  readouts:
  - target: Reduced Ventricular Contractile Function
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Higher values can accompany myocardial stress from dysfunction; this association is nonspecific and confounded.
    evidence:
    - *id015
diagnosis:
- name: Integrated clinical and cardiac assessment
  description: Evaluate new cardiac symptoms and signs in the context of anthracycline dose, timing, other cancer treatments and baseline cardiovascular disease. Integrate imaging and biomarkers and consider alternative cardiac or systemic explanations. Cancer therapy-related cardiac dysfunction includes subclinical injury and is broader than established symptomatic cardiomyopathy.
  evidence:
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: dysfunction includes new CV symptoms, new abnormalities in cardiac function on CV imaging
    explanation: The diagnosis integrates the clinical, imaging and biomarker picture.
- name: Echocardiography and global longitudinal strain
  description: Compare LVEF and GLS with baseline, using the same modality and strain vendor when possible. ESC asymptomatic severe dysfunction is a new LVEF below 40%; moderate dysfunction is a decline of at least 10 percentage points to 40–49%, or a smaller decline to that range with a new relative GLS fall over 15% or biomarker rise. Mild dysfunction requires LVEF at least 50% plus a new relative GLS fall over 15% and/or a biomarker rise. Symptomatic severity is graded clinically and is not interchangeable with these EF strata.
  evidence:
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Current definitions of CTRCD are based on a reduction of LVEF and/or relative changes in global longitudinal strain (GLS)
    explanation: The guideline uses functional change rather than a single universal EF threshold.
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: New LVEF reduction by ≥10 percentage points to an LVEF of 40–49%
    explanation: This is one of the moderate asymptomatic criteria.
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: to use the same vendor to analyse GLS during cancer treatment to accurately compare values over time.
    explanation: Consistent acquisition and analysis reduce measurement variability.
- name: Cardiac magnetic resonance when echocardiography is limited
  description: CMR can clarify ventricular function when echocardiographic images are inadequate or borderline and can characterize tissue when a specific alternative diagnosis is suspected. Tissue iron or fibrosis measurements do not by themselves establish anthracycline causation.
  evidence:
  - reference: PMID:39479333
    reference_title: 'Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: CMR is mainly used for evaluating LVEF when echocardiography is limited by a poor acoustic window or provides borderline values
    explanation: The review identifies an adjunctive clinical indication.
- name: Assessment of inherited cardiomyopathy susceptibility
  description: 'Family history and the cardiac phenotype may prompt a cardiomyopathy genetics assessment. RARG and TTN findings do not establish a universal predictive panel: ESC 2022 does not recommend routine genetic testing solely to assess cardiac-toxicity risk before cancer therapy. The DCM GeneReviews overview recognizes an emerging genetic contribution to chemotherapy-associated DCM but explicitly excludes acquired DCM from its later evaluation and counseling recommendations.'
  evidence:
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Routine use of genetic testing for the assessment of CTR-CVT risk prior to initiation of cancer therapy is not currently recommended.
    explanation: The guideline limits routine pre-treatment susceptibility testing.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/
    reference_title: Dilated Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: the clinical relevance of this information is currently undefined
    explanation: The DCM overview explicitly limits translation of chemotherapy-associated genetic findings.
- name: Risk-adapted cardiac surveillance
  description: Obtain baseline echocardiography before anthracyclines and reassess according to risk, cumulative exposure and new findings. ESC recommends an echocardiogram within 12 months after completion in all adults; high/very-high-risk patients require more frequent imaging and biomarkers. Continue risk-adapted survivorship follow-up because a normal early assessment does not eliminate late risk.
  evidence:
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: In all adults receiving anthracycline chemotherapy, an echocardiogram is recommended within 12 months after completing treatment.
    explanation: The guideline gives a general adult post-treatment assessment.
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: In high- and very high-risk patients, echocardiography is recommended every two cycles and within 3 months after completing treatment.
    explanation: More frequent imaging is reserved for the specified risk group.
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Lifelong sur- veillance for high-risk survivors is recommended.
    explanation: The survivorship section supports continued surveillance in high-risk survivors.
treatments:
- name: Dexrazoxane cardioprotection
  description: Dexrazoxane is considered before anthracycline administration for selected patients at high or very high cardiac-toxicity risk or requiring substantial cumulative exposure. ESC adult prevention guidance is broader than product-label eligibility and should not be read as a universal indication. The pediatric IGHG guideline makes a moderate recommendation when anticipated cumulative doxorubicin-equivalent exposure is at least 250 mg/m²; it makes no recommendation below that threshold because evidence is insufficient. Historical secondary-neoplasm concerns remain part of benefit-risk discussion, not proof that the drug causes such cancers. TOP2B-associated DNA damage and mitochondrial iron handling are proposed cardioprotective mechanisms, distinct from clinical proof of prevention. A later survivor follow-up analyzed 195 people from legacy trials, mostly originally randomized, with modest systolic-function differences after about 18 years. The prespecified structural measure did not differ significantly, and only 41% of potentially eligible survivors enrolled; this is incomplete protection, not proven elimination of lifetime heart-failure risk.
  evidence:
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Dexrazoxane should be considered in adult patients with cancer at high and very high CV toxicity risk when anthracycline chemotherapy is indicated.
    explanation: ESC recommends consideration for the specified adult risk group, rather than universal administration.
  - reference: PMID:36174614
    reference_title: 'Primary cardioprotection with dexrazoxane in patients with childhood cancer who are expected to receive anthracyclines: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: the benefits of dexrazoxane probably outweigh the risk of subsequent neoplasms when the cumulative doxorubicin or equivalent dose is at least 250 mg/m2 (moderate recommendation).
    explanation: The pediatric guideline weighs benefit and uncertain harm at the stated anticipated cumulative exposure.
  - reference: PMID:36174614
    reference_title: 'Primary cardioprotection with dexrazoxane in patients with childhood cancer who are expected to receive anthracyclines: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: No recommendation could be formulated for cumulative doxorubicin or equivalent doses of lower than 250 mg/m2
    explanation: Insufficient evidence below the threshold is not a contraindication.
  - reference: PMID:26598513
    reference_title: 'Cardioprotection and Second Malignant Neoplasms Associated With Dexrazoxane in Children Receiving Anthracycline Chemotherapy: A Systematic Review and Meta-Analysis.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: use in children has been hindered by lack of direct evidence of cardioprotection and concerns regarding second malignant neoplasms (SMNs).
    explanation: This historical synthesis provides context for the concern; newer guidance is used for the current recommendation.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC10448941/?pdf=render
    reference_title: Dexrazoxane and Long-Term Heart Function in Survivors of Childhood Cancer - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Univariate analyses did not reveal significant differences in the LV structure including the wall thickness-dimension ratio
    explanation: The prespecified structural outcome was not significantly different even though secondary functional measures favored dexrazoxane.
  - reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC10448941/?pdf=render
    reference_title: Dexrazoxane and Long-Term Heart Function in Survivors of Childhood Cancer - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We also were able to prospectively assess only 41% of potential participants.
    explanation: Incomplete participation limits generalizability of the long-term follow-up.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dexrazoxane
      term:
        id: CHEBI:50223
        label: (+)-dexrazoxane
  target_mechanisms:
  - target: DNA Double-Strand Break Accumulation
    treatment_effect: INHIBITS
    description: Dexrazoxane can reduce TOP2B-associated DNA damage; this mechanistic rationale is separate from patient selection and clinical efficacy.
    evidence:
    - reference: PMID:39479333
      reference_title: 'Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review.'
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: prevent DNA double-strand breaks induced by anthracyclines through topoisomerase IIβ
      explanation: The review summarizes the TOP2B-associated protective mechanism.
- name: Liposomal anthracycline substitution
  description: When oncologically appropriate, liposomal anthracyclines can reduce cardiotoxicity through altered distribution and are an ESC consideration for high or very high risk adults. Available formulations and indications differ by cancer. This is not proof of absent cardiac risk or equivalent efficacy in every malignancy.
  evidence:
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Liposomal anthracyclines should be considered in adult patients with cancer at high and very high CV toxicity risk when anthracycline chemotherapy is indicated.
    explanation: The guideline supports a risk- and regimen-dependent preventive choice.
  treatment_term:
    preferred_term: Liposomal anthracycline substitution
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: doxorubicin
      term:
        id: CHEBI:28748
        label: doxorubicin
  delivery_system:
    delivery_platform: LIPOSOME
  notes: Doxorubicin identifies a representative liposomal anthracycline discussed in the guideline. PEGylated and non-PEGylated products differ; this annotation does not make all formulations or cancer indications interchangeable.
- name: Heart-failure pharmacotherapy
  description: Treat symptomatic dysfunction or asymptomatic moderate/severe anthracycline-related dysfunction with guideline-based heart-failure therapy. ESC lists an ACE inhibitor/ARB or ARNI, beta-blocker, SGLT2 inhibitor and mineralocorticoid receptor antagonist as appropriate and tolerated, with titration and monitoring. This imports heart-failure management evidence rather than proving each drug reverses anthracycline DNA or mitochondrial injury.
  evidence: &id016
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Guideline-based HF therapy is recommended in patients who de- velop symptomatic CTRCD or asymptomatic moderate or severe CTRCD during anthracycline chemotherapy. The use of an ACE-I/ ARB or angiotensin receptor –neprilysin inhibitor, a beta-blocker, a sodium–glucose co-transporter 2 inhibitor, and a mineralocorticoid re- ceptor antagonist is recommended unless the drugs are contraindi- cated or not tolerated.
    explanation: The guideline names ACE inhibitor/ARB or ARNI, beta-blocker, SGLT2 inhibitor and mineralocorticoid-receptor antagonist therapy for symptomatic or moderate/severe asymptomatic dysfunction, subject to contraindications and tolerance.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE Inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: Angiotensin II Receptor Antagonist
      term:
        id: NCIT:C66930
        label: Angiotensin II Receptor Antagonist
    - preferred_term: Angiotensin Receptor-Neprilysin Inhibitor
      term:
        id: NCIT:C190796
        label: Angiotensin Receptor-Neprilysin Inhibitor
    - preferred_term: Beta-Adrenergic Antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: SGLT2 Inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
    - preferred_term: Aldosterone Receptor Antagonist
      term:
        id: NCIT:C101255
        label: Aldosterone Receptor Antagonist
  target_mechanisms:
  - target: Reduced Ventricular Contractile Function
    treatment_effect: INHIBITS
    description: This intervention addresses the indicated clinical process; the guidance does not establish reversal of each upstream molecular lesion.
    evidence: *id016
- name: Anthracycline interruption and individualized rechallenge
  description: Discontinue anthracyclines for severe symptomatic dysfunction; temporarily interrupt for moderate symptomatic or moderate/severe asymptomatic dysfunction. Mild symptomatic cases require multidisciplinary benefit-risk discussion. Mild asymptomatic dysfunction with preserved LVEF generally permits continued treatment with close monitoring and selected cardioprotection. Restarting after recovery requires an oncology-cardiology decision; dose minimization, liposomal formulation and dexrazoxane may be considered, with monitoring every 1–2 cycles. These measures do not guarantee safe rechallenge.
  evidence:
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Discontinuation of anthracycline chemotherapy is recommended in patients with cancer who develop severe symptomatic CTRCD.
    explanation: This recommendation concerns clinical HF severity, not EF alone.
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Temporary interruption of anthracycline chemotherapy and initiation of HF therapy is recommended in patients who develop asymptomatic moderate or severe CTRCD.
    explanation: The anthracycline rule differs from the HER2-targeted therapy continuation rule.
- name: Selected ACE inhibitor or ARB and beta-blocker cardioprotection
  description: Preventive neurohormonal therapy may be considered in adults at high or very high risk. For mild asymptomatic dysfunction during anthracyclines, ACE inhibitor/ARB and/or beta-blocker consideration is stronger for a significant GLS fall or troponin rise than for isolated natriuretic-peptide elevation. Avoid hypotension. Prevention trials predominantly measure LVEF and have not established a universal mortality or overt-HF benefit.
  evidence: &id017
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Asymptomatic patients who have LVEF ≥ 50% and who have developed a troponin elevation .ULN should be considered for ACE-I/ARB and/ or beta-blockers.
    explanation: The recommendation applies to this preserved-EF subgroup; the PDF represents the greater-than sign as a dot.
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: preventing LVEF reduction, but no statistical differences in the in- cidence of overt HF or other clinical outcomes were demonstrated
    explanation: The guideline distinguishes surrogate preservation from proven clinical-event benefit.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE Inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: Angiotensin II Receptor Antagonist
      term:
        id: NCIT:C66930
        label: Angiotensin II Receptor Antagonist
    - preferred_term: Beta-Adrenergic Antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
  target_mechanisms:
  - target: Reduced Ventricular Contractile Function
    treatment_effect: INHIBITS
    description: This intervention addresses the indicated clinical process; the guidance does not establish reversal of each upstream molecular lesion.
    evidence: *id017
- name: Spironolactone prevention evidence
  description: A small randomized study of 83 women with breast cancer tested concurrent spironolactone and reported preservation of LVEF and diastolic measures. A later network meta-analysis ranked its LVEF effect highly, but small indirect comparisons and risk of bias limit ranking-based claims. This is limited primary-prevention evidence, distinct from mineralocorticoid receptor antagonists as established guideline HF therapy; no clinical superiority or direct antifibrotic effect in these patients is inferred.
  evidence: &id018
  - reference: PMID:25410653
    reference_title: Protective effects of spironolactone against anthracycline-induced cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Eighty-three female patients who were diagnosed with breast cancer were included in the study. The study population was randomized into spironolactone and control groups.
    explanation: The primary trial defines its small breast-cancer population.
  - reference: PMID:25410653
    reference_title: Protective effects of spironolactone against anthracycline-induced cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: the interaction of LVEF decrease between groups was significantly lower in the spironolactone group than in the control group (P < 0.001).
    explanation: The endpoint is a ventricular-function comparison, not mortality.
  - reference: PMID:40970189
    reference_title: 'Pharmacological interventions to prevent cardiotoxicity in patients undergoing anthracycline-based chemotherapy: a network meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Spironolactone demonstrated the most significant improvement in (LVEF [MD = 12.10, 95% CI (7.50, 16.70)]
    explanation: The network estimate concerns LVEF; its ranking is not proof of the optimal patient treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: spironolactone
      term:
        id: CHEBI:9241
        label: spironolactone
  target_mechanisms:
  - target: Reduced Ventricular Contractile Function
    treatment_effect: INHIBITS
    description: This intervention addresses the indicated clinical process; the guidance does not establish reversal of each upstream molecular lesion.
    evidence: *id018
- name: Cardiovascular risk-factor management
  description: Assess and manage hypertension, diabetes, dyslipidemia, smoking and other modifiable risks before, during and after therapy. Coordinate oncology, cardiology and primary care; background risk and combined treatments modify vulnerability.
  evidence:
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Management of CVRF according to the 2021 ESC Guidelines on CVD prevention in clinical practice is recommended before,
    explanation: The guideline recommends ongoing risk-factor care, without assigning a molecular target.
- name: Exercise and cardiovascular rehabilitation
  description: Individualize aerobic activity and rehabilitation to cardiac status, cancer treatment and functional capacity. This supports cardiovascular health and recovery; it does not establish reversal of the molecular injury or replace HF therapy.
  evidence:
  - reference: PMID:39479333
    reference_title: 'Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Participating in exercise programs is known to have significant cardiac health benefits and is particularly important for cancer patients at risk of cardiotoxicity.
    explanation: The cardio-oncology review supports tailored exercise-based care.
- name: Atorvastatin prevention in selected lymphoma patients
  description: STOP-CA randomized 300 adults receiving anthracycline-based lymphoma treatment to atorvastatin 40 mg daily or placebo for 12 months. Atorvastatin reduced the prespecified LVEF-decline endpoint (13/150 versus 33/150), while incident heart failure over 24 months did not differ significantly. This supports a preventive option for selected patients with lymphoma; it does not establish benefit across all cancers, treatment of established cardiomyopathy, or mortality benefit.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: atorvastatin
      term:
        id: CHEBI:39548
        label: atorvastatin
  evidence:
  - &id019
    reference: PMID:37552303
    reference_title: 'Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002).
    explanation: The primary endpoint was a fall of at least 10 LVEF percentage points to below 55% at 12 months, not clinical heart failure.
  - &id031
    reference: PMID:37552303
    reference_title: 'Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26).
    explanation: The trial did not establish prevention of clinical heart failure; nonsignificance does not demonstrate equivalence.
  target_mechanisms:
  - target: Reduced Ventricular Contractile Function
    treatment_effect: INHIBITS
    description: Preventive treatment reduced the trial-defined LVEF-decline endpoint in the lymphoma study population; an upstream molecular mediator was not tested.
    evidence:
    - *id019
animal_models:
- name: Cardiomyocyte-specific Top2b deletion
  species: Mouse
  genotype: Cardiomyocyte-restricted Top2b knockout
  publication: PMID:23104132
  description: Cardiomyocyte-specific deletion protects mice against doxorubicin-associated DNA breaks, mitochondrial transcriptional changes and progressive heart failure.
  evidence:
  - &id020
    reference: PMID:23104132
    reference_title: Identification of the molecular basis of doxorubicin-induced cardiotoxicity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks
    explanation: The knockout tests TOP2B contribution to the lesion.
  - reference: PMID:23104132
    reference_title: Identification of the molecular basis of doxorubicin-induced cardiotoxicity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure
    explanation: The abstract reports protection at the whole-heart clinical-model level.
  modeled_mechanisms:
  - target: DNA Double-Strand Break Accumulation
    relationship: PERTURBS
    model_scale: ORGANISM
    description: Genetic deletion reduces the doxorubicin-associated DNA lesion.
    limitations: The canonical cache remains abstract-only despite retrieval attempts; strain, exact dosing and deletion efficiency are not imported. Genetic deletion is not a demonstrated clinically deliverable selective inhibitor.
    evidence:
    - *id020
    readouts:
    - name: Doxorubicin-associated DNA breaks
      target: DNA Double-Strand Break Accumulation
      direction: DECREASED
      description: Cardiomyocyte-specific Top2b deletion reduces the drug-associated DNA lesion.
      evidence:
      - *id020
- name: Cardiac ABCB8 overexpression
  species: Mouse
  genotype: Cardiac ABCB8 transgene on a backcrossed C57BL/6J background
  publication: PMID:24382354
  description: Cardiac ABCB8 overexpression lowers mitochondrial iron and attenuates doxorubicin injury in acute and subacute mouse exposure protocols. The study also uses cardiac Abcb8 deletion, whose pre-existing cardiomyopathy complicates interpretation of drug-specific susceptibility.
  evidence:
  - &id021
    reference: PMID:24382354
    reference_title: Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: ABCB8 TG mice displayed significantly lower mitochondrial iron levels than those observed in non-TG (NTG) animals both at baseline and after treatment with DOX
    explanation: The transgenic comparison directly measures the compartmental iron pool.
  modeled_mechanisms:
  - target: Mitochondrial Iron Accumulation
    relationship: PERTURBS
    model_scale: ORGANISM
    description: Transgenic expression reduces mitochondrial iron before and after exposure.
    limitations: One founder line and relatively intensive short-duration doxorubicin protocols differ from repeated human cancer regimens. Prevention before exposure is not reversal of established chronic human cardiomyopathy.
    evidence:
    - *id021
    readouts:
    - name: Mitochondrial iron in cardiac ABCB8 transgenic mice
      target: Mitochondrial Iron Accumulation
      direction: DECREASED
      description: Iron is lower in transgenic than nontransgenic hearts, including after drug exposure.
      evidence:
      - *id021
- name: Heterozygous A-band titin-truncation mouse
  species: Mouse
  genotype: Ttntv/+ heterozygous A-band truncation on C57BL/6N
  publication: PMID:30987448
  description: Three weekly doxorubicin doses initially depress function in both genotypes; wild-type function returns to baseline while heterozygous mutants have persistent dysfunction through week 12. Fifteen mice per genotype were tested.
  evidence:
  - &id022
    reference: PMID:30987448
    reference_title: Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: at week 8, LV function recovered to baseline in wild-type mice but remained depressed through week 12 in Ttntv/+ mice
    explanation: The measured recovery trajectories differ after doxorubicin.
  modeled_mechanisms:
  - target: Reduced Ventricular Contractile Function
    relationship: PARTIALLY_RECAPITULATES
    model_scale: ORGANISM
    description: The model reproduces sustained ventricular dysfunction after a defined drug stress.
    limitations: A single truncation and background do not represent every human TTN allele. Cardiac histology did not show a significant increase in fibrosis or apoptosis relative to untreated mice, so persistent functional impairment is not converted into a proved excess-cell-death mechanism.
    evidence:
    - *id022
    - reference: PMID:30987448
      reference_title: Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: Histological analysis of cardiac tissues from anthracycline-treated wild-type or Ttntv/+ mice were comparable and showed no significant increase in fibrosis or apoptosis in comparison with untreated mice.
      explanation: The negative histological result limits the mechanism assigned to persistent dysfunction.
    readouts:
    - name: Ventricular function recovery after doxorubicin
      target: Reduced Ventricular Contractile Function
      direction: ALTERED
      description: Wild-type function returns to baseline by week 8 while titin-truncation function remains depressed through week 12.
      evidence:
      - *id022
experimental_models:
- name: Commercial human iPSC-derived cardiomyocyte TOP2B knockdown
  experimental_model_type: OTHER
  description: Commercial CDI cardiomyocytes receive pooled TOP2B siRNAs or dexrazoxane pretreatment before 48-hour doxorubicin exposure. Knockdown improves several viability, electrical, oxidant-probe and ultrastructural readouts. It does not uniformly outperform dexrazoxane across assays or completely normalize calcium transients.
  evidence:
  - reference: PMID:40158615
    reference_title: SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: 'The hiPSC-CMs procured from CDI (Cat. #R1007, FUJIFILM Cellular Dynamics Inc.) were cultured according to the manufacturer’s protocol.'
    explanation: The system is a commercial culture, not an identified multi-patient cohort.
  - &id023
    reference: PMID:40158615
    reference_title: SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: TOP2B knockdown preserves mitochondrial morphology and sarcomere structure
    explanation: TEM shows attenuation of two structural lesions after siRNA pretreatment.
  - reference: PMID:40158615
    reference_title: SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Treatment with Dox, Dox + Dex, and Dox + TOP2B-KD resulted in a significant decrease in transient amplitude
    explanation: The calcium-amplitude defect persists in treated groups.
  modeled_mechanisms:
  - target: Mitochondrial Structural Injury
    relationship: PERTURBS
    model_scale: CELLULAR
    description: TOP2B knockdown attenuates the ultrastructural lesion.
    limitations: No direct ATP, oxygen-consumption or biogenesis assay is reported. Donor diversity is unspecified; pooled siRNAs lack a re-expression rescue. Pretreatment addresses acute prevention, not established cardiomyopathy.
    evidence: &id024
    - *id023
    readouts:
    - name: TEM structural preservation
      target: Mitochondrial Structural Injury
      direction: RESTORED
      description: TOP2B knockdown attenuates the structural abnormality relative to doxorubicin exposure alone; this is partial morphological preservation.
      evidence: *id024
  - target: Sarcomere Disruption
    relationship: PERTURBS
    model_scale: CELLULAR
    description: Knockdown preserves sarcomere alignment in the same culture experiment.
    limitations: Shared time-point preservation does not establish a mitochondrial-to-sarcomere causal sequence or whole-heart contractile recovery.
    evidence: &id025
    - *id023
    readouts:
    - name: TEM structural preservation
      target: Sarcomere Disruption
      direction: RESTORED
      description: TOP2B knockdown attenuates the structural abnormality relative to doxorubicin exposure alone; this is partial morphological preservation.
      evidence: *id025
  notes: MTT benefit exceeds the tested dexrazoxane condition whereas LDH reduction is comparable. cTnT is a transcript readout, not blood troponin. No cancer-cell killing, in-vivo delivery or long-term safety outcome establishes clinical superiority or preservation of antitumor efficacy.
- name: Neonatal rat cardiomyocyte iron-transport perturbation
  experimental_model_type: OTHER
  description: Doxorubicin preferentially accumulates in mitochondria in this culture system. Neonatal rat cardiomyocytes are exposed to doxorubicin with ABCB8 knockdown or overexpression. Compartmental iron, cellular oxidant probes, viability and TUNEL are assessed. Separate TOP2B and ABCB8 manipulations support parallel contributions to injury.
  evidence:
  - reference: PMID:24382354
    reference_title: Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: While ABCB8 siRNA did not affect baseline cellular ROS levels, it resulted in a significantly higher ROS after DOX treatment
    explanation: The culture perturbation changes the oxidant response after drug exposure.
  - reference: PMID:24382354
    reference_title: Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: cell death, as assessed by MTS assay and TUNEL staining, was significantly higher after DOX treatment in response to ABCB8 silencing than in cells transfected with control siRNA
    explanation: Iron-export perturbation changes cell-injury readouts.
  - reference: PMID:24382354
    reference_title: Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels.
    explanation: The observed co-occurrence is retained as experimental context without imposing a causal sequestration-to-iron arrow.
  modeled_mechanisms:
  - target: Mitochondrial Iron Accumulation
    relationship: PERTURBS
    model_scale: CELLULAR
    description: Manipulation of an iron-export regulator changes compartmental iron accumulation.
    limitations: Neonatal rat cultures and short high-concentration exposure differ from adult human myocardium. These assays do not identify ferroptosis specifically or establish clinical benefit of nonspecific chelation.
    evidence:
    - *id026
    readouts:
    - name: Mitochondrial iron after ABCB8 knockdown
      target: Mitochondrial Iron Accumulation
      direction: INCREASED
      description: Mitochondrial iron is higher with ABCB8 siRNA plus doxorubicin than with control siRNA plus drug.
      evidence:
      - *id026
  notes: Drug sequestration and iron loading are measured together, but the study does not selectively perturb sequestration to establish it as the mediator of iron accumulation.
- name: RARG Ser427Leu reporter and rat H9c2 transfection systems
  experimental_model_type: OTHER
  description: Wild-type and Ser427Leu human RARG are compared in a HEK293T retinoic-acid-response reporter and in rat H9c2 cells measuring Top2b repression. The variant shows partial functional alteration.
  evidence:
  - reference: PMID:26237429
    reference_title: A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: The significant 17% decrease in RARG activity conferred by the rs2229774 variant
    explanation: The reporter detects a partial allele-associated functional difference.
  notes: HEK293T cells retain endogenous retinoic-acid receptors, which complicates the size of the allele effect. H9c2 is a rat cell line, not a patient heart. The experiment does not quantify patient-specific TOP2B-DNA complexes or prove clinical utility of genotype-guided cardioprotection.
- name: Isolated titin-truncation mouse cardiomyocyte mechanics
  experimental_model_type: OTHER
  description: Cardiomyocytes isolated twelve weeks after doxorubicin exposure show depressed contractility in the heterozygous titin-truncation group compared with exposed wild-type and untreated controls.
  evidence:
  - &id027
    reference: PMID:30987448
    reference_title: Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: Cardiomyocytes from doxorubicin-treated Ttntv/+ mice had significantly depressed contractility
    explanation: Ex-vivo cellular mechanics corroborate persistent functional impairment.
  modeled_mechanisms:
  - target: Reduced Ventricular Contractile Function
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    description: Ex-vivo sarcomere mechanics provide a cellular correlate of the in-vivo functional phenotype.
    limitations: At least 52 measured cells per group are not 52 independent animals. The assay does not directly establish patient ventricular recovery or a universal TTN-mediated structural pathway.
    evidence: &id028
    - *id027
    readouts:
    - name: Isolated cardiomyocyte contractility
      target: Reduced Ventricular Contractile Function
      direction: DECREASED
      description: Measured cellular contractility is lower in drug-exposed titin-truncation cells than the specified control groups.
      evidence: *id028
environmental:
- name: Cumulative anthracycline chemotherapy exposure
  description: Therapeutic anthracycline exposure initiates cardiotoxic injury. Cumulative dose is important, but schedule, drug, coexposures and patient factors also matter; no single cumulative threshold guarantees safety.
  exposure_term:
    preferred_term: exposure to anthracycline chemotherapy
    term:
      id: ECTO:0000509
      label: exposure to drug
  exposure_classifications:
    hazard_agent_type:
    - classification_value: CHEMICAL
    exposure_route:
    - classification_value: PARENTERAL
    exposure_duration:
    - classification_value: INTERMITTENT
      notes: Commonly delivered in repeated treatment cycles; cumulative dose contributes to risk.
  influences_mechanisms:
  - target: Anthracycline-TOP2B-DNA Complex Formation
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: Drug exposure permits formation and stabilization of the TOP2B-associated DNA complex.
    evidence: *id029
  - target: Reduced ABCB8 Expression
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Doxorubicin reduces ABCB8 expression through incompletely resolved regulatory steps.
    evidence: *id030
  notes: Bound to the substance-level ECTO:0000509 (exposure to drug). ECTO was checked for an anthracycline- or doxorubicin-specific exposure class and none is bindable here; note that dismech validates ECTO against sqlite:obo:ecto, so a term resolving in OLS is not sufficient.
  evidence:
  - reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    reference_title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Anthracycline-induced CTRCD is a dose-dependent and cumulative process of variable onset that may present with symptomatic or asymptomatic CTRCD.
    explanation: The guideline links anthracycline exposure to dose-related cardiac dysfunction.
references:
- reference: PMID:39479333
  title: 'Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review.'
- reference: PMID:23104132
  title: Identification of the molecular basis of doxorubicin-induced cardiotoxicity.
- reference: PMID:40158615
  title: SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity.
- reference: PMID:24382354
  title: Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
- reference: PMID:28185035
  title: Anthracycline Chemotherapy and Cardiotoxicity.
- reference: url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
  title: https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
  findings:
  - statement: 'Full PDF of 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Canonical publication: PMID:36017568; DOI:10.1093/eurheartj/ehac244. Publisher record: https://academic.oup.com/eurheartj/article/43/41/4229/6673995. This generated PDF cache supplies the exact recommendation-table excerpts. The companion PMID record supplies bibliographic identity only: its current fetch is an institutional metadata page, not clinical full text.'
- reference: PMID:26237429
  title: A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.
- reference: PMID:30987448
  title: Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.
- reference: PMID:25948538
  title: Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/
  title: Dilated Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: PMID:36174614
  title: 'Primary cardioprotection with dexrazoxane in patients with childhood cancer who are expected to receive anthracyclines: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.'
- reference: PMID:26598513
  title: 'Cardioprotection and Second Malignant Neoplasms Associated With Dexrazoxane in Children Receiving Anthracycline Chemotherapy: A Systematic Review and Meta-Analysis.'
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC10448941/?pdf=render
  title: Dexrazoxane and Long-Term Heart Function in Survivors of Childhood Cancer - PMC
- reference: PMID:25410653
  title: Protective effects of spironolactone against anthracycline-induced cardiomyopathy.
- reference: PMID:40970189
  title: 'Pharmacological interventions to prevent cardiotoxicity in patients undergoing anthracycline-based chemotherapy: a network meta-analysis.'
- reference: PMID:36017568
  title: 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS).
  findings:
  - statement: Canonical bibliographic identity for the ESC 2022 guideline. The same publication is quoted from its generated complete PDF cache; this metadata-only cache is not used as evidence for clinical recommendations.
- reference: PMID:22124095
  title: 'Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children''s Oncology Group.'
  findings:
  - statement: Matched survivor study; full main body, tables and figures were additionally read from the separately cached PMC URL. The two records are views of the same paper, not independent evidence.
- reference: url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3383117/?pdf=render
  title: 'Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children&#x27;s Oncology Group - PMC'
  findings:
  - statement: Full scientific body of PMID:22124095. No independent causal or clinical validation is inferred from this additional full-text view.
- reference: PMID:26811534
  title: 'CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children''s Oncology Group Genome-Wide Association Study.'
  findings:
  - statement: Full main body, methods, tables and figures reviewed. Susceptibility interaction, case-only replication and healthy-tissue isoform association have distinct scopes.
- reference: PMID:37552303
  title: 'Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial.'
  findings:
  - statement: STOP-CA primary trial publication. The complete abstract was read; official full-text routes returned access challenges. Efficacy claims are limited to the reported endpoints.
- reference: clinicaltrials:NCT02943590
  title: STOP-CA (Statins TO Prevent the Cardiotoxicity From Anthracyclines)
  findings:
  - statement: Canonical registry summary for STOP-CA; the official API cache supplies status, design and results metadata.
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT02943590
  title: https://clinicaltrials.gov/api/v2/studies/NCT02943590
  findings:
  - statement: Official complete registry JSON, read in full on 2026-09-21. Some results fields mix percentage values with count labels; use the publication for outcome counts.
clinical_trials:
- name: NCT02943590
  phase: PHASE_II
  status: COMPLETED
  description: STOP-CA was a randomized, placebo-controlled trial of atorvastatin during anthracycline-based lymphoma treatment. The primary publication reports 300 randomized adults and a lower 12-month LVEF-decline endpoint with atorvastatin, without a significant difference in clinical heart failure over 24 months.
  notes: The official registry record was checked on 2026-09-21; status was COMPLETED, with actual completion in October 2023 and last posted update in May 2025. Patients with baseline LVEF below 50% or an existing statin indication were excluded. Registry results fields label some percentage values as participant counts; outcome denominators here come from the peer-reviewed publication. The full registry JSON and the publication abstract were read; attempts to retrieve the publication full body returned access challenges.
  evidence:
  - reference: clinicaltrials:NCT02943590
    reference_title: STOP-CA (Statins TO Prevent the Cardiotoxicity From Anthracyclines)
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: This research study will test whether atorvastatin, a drug commonly prescribed for reducing cholesterol levels, can protect the heart during chemotherapy with doxorubicin.
    explanation: The registry identifies the prevention question.
  - reference: url:https://clinicaltrials.gov/api/v2/studies/NCT02943590
    reference_title: https://clinicaltrials.gov/api/v2/studies/NCT02943590
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: 'STOP-CA (Statins TO Prevent the Cardiotoxicity From Anthracyclines)"},"statusModule":{"statusVerifiedDate":"2025-05","overallStatus":"COMPLETED"'
    explanation: The official API supplies the current registry status.
  - *id019
  - *id031
📚

References & Deep Research

References

22
PMID:39479333
Anthracycline Cardiotoxicity in Adult Cancer Patients: JACC: CardioOncology State-of-the-Art Review.
No top-level findings curated for this source.
PMID:23104132
Identification of the molecular basis of doxorubicin-induced cardiotoxicity.
No top-level findings curated for this source.
PMID:40158615
SiRNA-mediated knockdown of TOP2B protects hiPSC-derived cardiomyocytes from doxorubicin-induced toxicity.
No top-level findings curated for this source.
PMID:24382354
Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation.
No top-level findings curated for this source.
PMID:28185035
Anthracycline Chemotherapy and Cardiotoxicity.
No top-level findings curated for this source.
url:https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
https://cardio-onco.fr/wp-content/uploads/2023/06/ehac244.pdf
1 finding
Full PDF of 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Canonical publication: PMID:36017568; DOI:10.1093/eurheartj/ehac244. Publisher record: https://academic.oup.com/eurheartj/article/43/41/4229/6673995. This generated PDF cache supplies the exact recommendation-table excerpts. The companion PMID record supplies bibliographic identity only: its current fetch is an institutional metadata page, not clinical full text.
PMID:26237429
A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer.
No top-level findings curated for this source.
PMID:30987448
Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.
No top-level findings curated for this source.
PMID:25948538
Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/
Dilated Cardiomyopathy Overview - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.
PMID:36174614
Primary cardioprotection with dexrazoxane in patients with childhood cancer who are expected to receive anthracyclines: recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.
No top-level findings curated for this source.
PMID:26598513
Cardioprotection and Second Malignant Neoplasms Associated With Dexrazoxane in Children Receiving Anthracycline Chemotherapy: A Systematic Review and Meta-Analysis.
No top-level findings curated for this source.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC10448941/?pdf=render
Dexrazoxane and Long-Term Heart Function in Survivors of Childhood Cancer - PMC
No top-level findings curated for this source.
PMID:25410653
Protective effects of spironolactone against anthracycline-induced cardiomyopathy.
No top-level findings curated for this source.
PMID:40970189
Pharmacological interventions to prevent cardiotoxicity in patients undergoing anthracycline-based chemotherapy: a network meta-analysis.
No top-level findings curated for this source.
PMID:36017568
2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS).
1 finding
Canonical bibliographic identity for the ESC 2022 guideline. The same publication is quoted from its generated complete PDF cache; this metadata-only cache is not used as evidence for clinical recommendations.
PMID:22124095
Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes--a report from the Children's Oncology Group.
1 finding
Matched survivor study; full main body, tables and figures were additionally read from the separately cached PMC URL. The two records are views of the same paper, not independent evidence.
url:https://pmc.ncbi.nlm.nih.gov/articles/PMC3383117/?pdf=render
Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children&#x27;s Oncology Group - PMC
1 finding
Full scientific body of PMID:22124095. No independent causal or clinical validation is inferred from this additional full-text view.
PMID:26811534
CELF4 Variant and Anthracycline-Related Cardiomyopathy: A Children's Oncology Group Genome-Wide Association Study.
1 finding
Full main body, methods, tables and figures reviewed. Susceptibility interaction, case-only replication and healthy-tissue isoform association have distinct scopes.
PMID:37552303
Atorvastatin for Anthracycline-Associated Cardiac Dysfunction: The STOP-CA Randomized Clinical Trial.
1 finding
STOP-CA primary trial publication. The complete abstract was read; official full-text routes returned access challenges. Efficacy claims are limited to the reported endpoints.
clinicaltrials:NCT02943590
STOP-CA (Statins TO Prevent the Cardiotoxicity From Anthracyclines)
1 finding
Canonical registry summary for STOP-CA; the official API cache supplies status, design and results metadata.
url:https://clinicaltrials.gov/api/v2/studies/NCT02943590
https://clinicaltrials.gov/api/v2/studies/NCT02943590
1 finding
Official complete registry JSON, read in full on 2026-09-21. Some results fields mix percentage values with count labels; use the publication for outcome counts.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review anthracycline cardiomyopathy mechanisms and risk-adapted care · 2026-09-21T10:21:43Z · View source

Comprehensive review of the original entry and matching deep research against all six original cited sources, using genuine full scientific bodies where available. Recovered the TTN study as canonical full XML, mitochondrial iron experiments, the 2024 clinical review, pediatric dexrazoxane guidance, the full ESC 2022 guideline and long-term childhood-survivor dexrazoxane follow-up. Consulted the full DCM GeneReviews context; its explicit exclusion of acquired DCM prevents importing nonsyndromic genetic-management recommendations. Canonical TOP2B knockout, Cardinale recovery and spironolactone trial records remain abstract-limited after retrieval attempts; failed CAPTCHA or metadata-only pages were excluded. Rebuilt the graph into eleven atomic processes, separating TOP2B/DNA injury, mitochondrial biogenesis, ABCB8/iron handling, oxidants, mitochondrial and sarcomere structure, cell death, remodeling and contractile impairment. Removed the unsupported serial TOP2B-to-iron and mitochondrial-to-sarcomere routes and universal irreversibility. Added clinical phenotypes, biomarker interpretation, diagnostic criteria, progression and risk-adapted prevention, HF management, interruption/rechallenge and surveillance. Corrected RARG functional evidence to cell experiments, qualified selected TTN cohort denominators and recovery findings, and retained limited spironolactone prevention evidence without clinical ranking claims. Added three animal and four culture models with actual readouts and translation limits. Updated the existing node-class example for this disorder's renamed contractile-function node. Independent bounded peer review covered the TOP2B culture paper and applicable ESC care recommendations; the final independent topology/model integration check removed unproven sequestration-to-iron and biogenesis-to-ROS mediation arrows while preserving the measured outcomes as context and parallel branches. Authoritative validation passes schema, live ontology and 128/128 evidence snippets; all 25 additional guards and whole-KB node-class example checks pass. History and final formatting hooks are checked before publication. No reference cache was hand-edited and the frozen dataset accession cache was neither read nor changed.

Create Anthracycline-Induced Cardiomyopathy conforming to cardiomyopathy_maladaptive_remodeling · 2026-09-01T16:29:42Z · View source

New entry for the archetypal dose-limiting cardiotoxicity of cytotoxic cancer therapy, absent from the KB and explicitly named as a use case in the cardiomyopathy_maladaptive_remodeling module's own description. The entry turns on the isoform distinction, which is what makes the toxicity mechanistically interesting rather than merely dose-related. Proliferating tumour cells express topoisomerase II-alpha, which is the antitumour target; quiescent cardiomyocytes express topoisomerase II-beta instead, and disruption of that isoform is what injures the heart. The causal evidence is loss-of-function: silencing TOP2B in human iPSC-derived cardiomyocytes reduces doxorubicin-induced apoptosis and preserves mitochondrial and sarcomere ultrastructure. That experiment is also what licenses modelling mitochondrial and sarcomere injury as a node DOWNSTREAM of the trigger rather than as a parallel consequence, since removing the upstream lesion preserves both. Three pathophysiology nodes, two conforming to the module (Primary Cardiomyocyte Insult, Progressive Contractile Dysfunction). The exposure is wired in with influences_mechanisms and carries exposure_classifications recording that the route is parenteral and the duration intermittent, with risk driven by cumulative rather than per-cycle dose. Dexrazoxane is joined to the trigger node with INHIBITS, since it acts on the initiating injury rather than on established remodelling. The exposure binds the substance-level ECTO:0000509 (exposure to drug), with a notes line recording that dismech validates ECTO against sqlite:obo:ecto, so a term resolving in OLS is not sufficient to bind here. That constraint was established the hard way on PR 10366 earlier today and is recorded so the next curator does not repeat the round trip. Deep research was run with claude_code and is committed as provenance. No quote from it was curated; all six evidence snippets were independently sourced from PubMed and pre-verified against the local cache before being written, and all reference_title values were generated from cache rather than typed. Validated with just validate-disorders (batched sweep CI runs), just count-verified-snippets (8/8), just check-duplicate-keys, and a graph build showing 4 edges, no integrity issues, and the exposure and treatment both joined.

Claude Code ▸
Anthracycline-Induced Cardiomyopathy — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-opus-5[1m] 12 citations 2026-09-01T12:24:20.696101

Anthracycline-Induced Cardiomyopathy — Comprehensive Research Report

Prepared: 2026-09-01 · Target MONDO: MONDO:0022653 (cardiomyopathy due to anthracyclines) · Category: Complex / acquired drug-toxicity cardiomyopathy

Read-me first — a framing note that matters for KB modeling. This is not a Mendelian disease with a causal gene. It is an exposure-initiated cardiomyopathy: the drug is the cause, and the genome is a set of dials on how hard the drug lands. Every "genetic" section below therefore describes susceptibility modifiers, not causal variants, and the etiologic root node of the pathograph should be the anthracycline exposure itself. Modeling this the other way round (gene → disease) inverts the whole mechanism.

1. Disease Information

1.1 Overview

Anthracycline-induced cardiomyopathy (AIC) is an acquired, dose-dependent cardiomyopathy caused by exposure to anthracycline chemotherapeutics — doxorubicin, daunorubicin, epirubicin, idarubicin — and the structurally related anthraquinone mitoxantrone. It presents as progressive left ventricular systolic dysfunction that may remain asymptomatic (detectable only by imaging or biomarkers) or progress to overt dilated-phenotype heart failure. It is the archetypal "side effect as mechanism" entity in cardio-oncology.

The clinical importance is not marginal. Anthracyclines remain first-line for lymphomas, acute leukaemias, breast cancer, and soft-tissue sarcomas six decades after their introduction:

"Since their introduction in the 1960s, anthracyclines have been a significant breakthrough in oncology... Although new-generation targeted drugs and cellular therapies are revolutionizing contemporary oncology, anthracyclines remain the cornerstone of treatment for lymphomas, acute leukemias, and soft tissue sarcomas. However, their clinical application is limited by a dose-dependent cardiotoxicity that can reduce cardiac performance and eventually lead to overt heart failure." — Camilli et al., JACC CardioOncology 2024 (PMID:39479333), state-of-the-art review

1.2 Identifiers

Resource Identifier Label
MONDO MONDO:0022653 cardiomyopathy due to anthracyclines (verified via OLS4)
SNOMED CT 880042006 Dilated cardiomyopathy caused by anthracycline (disorder)
UMLS / MedGen C5437452 Dilated cardiomyopathy caused by anthracycline
MONDO parent MONDO:0004994 cardiomyopathy
SNOMED parent 72972005 Dilated cardiomyopathy caused by drug (disorder)
ICD-10-CM I42.7 Cardiomyopathy due to drug and external agent (+ T45.1X5A adverse effect of antineoplastic drugs)
ICD-11 BC43.4 / BC43 region (cardiomyopathy due to drug) with external-cause extension
MeSH D066126 (Cardiotoxicity); D004317 (Doxorubicin); D002311 (Cardiomyopathies)
OMIM Not applicable — no Mendelian OMIM entry; this is an acquired toxicity
Orphanet No dedicated ORPHA disorder code; check ORPHA: structured cache before asserting one

Modeling note: ICD-10/ICD-11 assignments above are the conventional coding practice and should be confirmed against a coding authority before being committed as mappings — they are the weakest-verified identifiers in this table.

1.3 Synonyms and alternative names

  • Anthracycline cardiotoxicity (ACT); anthracycline-induced cardiotoxicity (AIC)
  • Doxorubicin-induced cardiomyopathy (DIC); doxorubicin cardiotoxicity
  • Adriamycin cardiomyopathy (historic trade-name usage)
  • Chemotherapy-induced cardiomyopathy (broader; not synonymous — includes trastuzumab, VEGF-inhibitor, and proteasome-inhibitor toxicity)
  • Cancer therapy-related cardiac dysfunction (CTRCD) — the umbrella term adopted by ESC/IC-OS, of which AIC is one cause. Do not treat CTRCD and AIC as exact matches; skos:broadMatch is the honest relation.

1.4 Data provenance character

Evidence is drawn from both aggregated disease-level resources and individual-patient sources, and the two disagree systematically:

  • Prospective single-institution cohorts with protocolized echo (e.g., Cardinale 2015, n=2,625) capture asymptomatic dysfunction and yield ~9% incidence.
  • Retrospective trial re-analysis (Swain 2003) and survivorship registries (Childhood Cancer Survivor Study, DCOG-LATER, St Jude Lifetime) capture symptomatic/late events at long latency.
  • EHR/registry disproportionality data (VigiBase) capture reported adverse events, heavily under-ascertained for asymptomatic disease.

Incidence figures are therefore not comparable across sources without knowing the case definition. This is the single most important caveat for any epidemiology annotation in this entry.

2. Etiology

2.1 Primary causal factor

Exposure to an anthracycline or anthraquinone antineoplastic agent. The relationship is dose-dependent and, in its established form, largely irreversible at the level of cardiomyocyte loss.

Suggested ECTO/CHEBI grounding for the exposure node:

Agent CHEBI Status
doxorubicin CHEBI:28748 verified (label: doxorubicin)
daunorubicin CHEBI:41977 verified
epirubicin CHEBI:47898 verified — canonical label is 4'-epidoxorubicin, use preferred_term: epirubicin
idarubicin CHEBI:42068 verified
mitoxantrone CHEBI:50729 verified

2.2 Dose as the dominant risk factor

Swain's re-analysis of three prospective phase III trials remains the reference dose-response curve in adults:

"Analysis indicated that an estimated cumulative 26% of patients would experience doxorubicin-related CHF at a cumulative dose of 550 mg/m(2)." — Swain SM et al., Cancer 2003;97(11):2869-79 (PMID:12767102)

and, crucially, that the older 7%-at-550-mg/m² figure was an underestimate:

"Doxorubicin-related CHF occurs with greater frequency and at a lower cumulative dose than previously reported. These findings further indicate that LVEF is not an accurate predictor of CHF in patients who receive doxorubicin." (ibid.)

In childhood cancer survivors the dose-response begins far lower than the traditional "safe threshold" implied:

"A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m(2): reference; 1 to 100 mg/m(2): odds ratio [OR], 1.65; 101 to 150 mg/m(2): OR, 3.85; 151 to 200 mg/m(2): OR, 3.69; 201 to 250 mg/m(2): OR, 7.23; 251 to 300 mg/m(2): OR, 23.47; > 300 mg/m(2): OR, 27.59; P(trend) < .001)." — Blanco JG et al., J Clin Oncol 2012 (PMID:22124095)

Agent-specific dose equivalence was re-derived from 28,423 pooled survivors, overturning the hematologic-toxicity-based conversion factors that treatment protocols had used:

"Relative to doxorubicin, the equivalence ratios were 0.6 (95% CI, 0.4-1.0) for daunorubicin, 0.8 (95% CI, 0.5-2.8) for epirubicin, and 10.5 (95% CI, 6.2-19.1) for mitoxantrone." — Feijen EAM et al., JAMA Oncol 2019;5(6):864-871 (PMID:30703192)

"the current hematologic-based doxorubicin dose equivalency of mitoxantrone (4:1) appeared to significantly underestimate the association of mitoxantrone with long-term cardiomyopathy risk." (ibid.)

This is a high-value, under-modeled fact: mitoxantrone is roughly 10× doxorubicin for late cardiomyopathy, not 4×.

2.3 Non-genetic (clinical/environmental) risk factors

Assembled from the HFA-ICOS baseline risk proforma and its validation, the ESC 2022 guideline, and the JACC state-of-the-art review:

  • Cumulative anthracycline dose (dominant, continuous)
  • Prior anthracycline or other cardiotoxic cancer therapy
  • Mediastinal/chest radiotherapy, especially ≥15 Gy cardiac dose — Mulrooney reports cardiac radiation ≥1500 cGy "increased the relative hazard of congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities by twofold to sixfold" (PMID:19996459)
  • Concurrent HER2-targeted therapy (trastuzumab) — sequential/concurrent exposure is synergistic
  • Age at exposure — bimodal: very young children and older adults. Swain: "Age appeared to be an important risk factor for doxorubicin-related CHF after a cumulative dose of 400 mg/m(2), with older patients (age > 65 years) showing a greater incidence of CHF compared with younger patients" (PMID:12767102)
  • Female sex — higher risk in paediatric cohorts; also the group with greater dexrazoxane benefit (Lipshultz 2010)
  • Pre-existing cardiovascular disease, reduced baseline LVEF, hypertension, diabetes, obesity, chronic kidney disease
  • Elevated baseline cardiac biomarkers (troponin, natriuretic peptides)
  • Smoking, sedentary behaviour (HFA-ICOS lifestyle domain)
  • Bolus vs. prolonged-infusion administration — bolus schedules deliver higher peak myocardial concentration and carry higher risk

Baseline risk stratification is now validated. In the CARDIOTOX registry (NCT02039622), n=1,066:

"According to the HFA-ICOS criteria, 571 patients (53.6%) were classified as low risk, 333 (31.2%) as moderate risk, 152 (14.3%) as high risk, and 10 (0.9%) as very high risk... Incidence rates of symptomatic or moderate to severe symptomatic CTRCD and all-cause mortality significantly increased with HFA-ICOS score [hazard ratio 28.74, 95% confidence interval (CI) 9.33-88.5; P < .001...]" — Rivero-Santana B et al., Eur Heart J 2025;46(3):273-284 (PMID:39106857)

2.4 Protective factors

Genetic protective alleles. The variant alleles of the carbonyl-reductase SNPs behave protectively at low-to-moderate dose:

"Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m(2)) did not increase the risk of cardiomyopathy." — Blanco 2012 (PMID:22124095)

Similarly for CELF4: "among patients with the A allele, cardiomyopathy was infrequent and not dose related" (PMID:26811534).

Pharmacological/behavioural protection — see §12–13. Briefly: dexrazoxane, liposomal formulation, statins, ACE inhibitors/ARBs, and (emerging) SGLT2 inhibitors.

2.5 Gene–environment interaction

This disease is the textbook GxE case, and the CELF4 finding was explicitly framed that way — the SNP showed no marginal association, only an interaction with dose:

"No SNP was marginally associated with cardiomyopathy. However, SNP rs1786814 on the CELF4 gene passed the significance cutoff for gene-environment interaction (Pge = 1.14 × 10(-5))... among those exposed to greater than 300 mg/m(2) of anthracyclines, the rs1786814 GG genotype conferred a 10.2-fold (95% CI, 3.8- to 27.3-fold; P < .001) increased risk of cardiomyopathy compared with those who had GA/AA genotypes and anthracycline exposure of 300 mg/m(2) or less." — Wang X et al., J Clin Oncol 2016 (PMID:26811534)

Modeling implication: a genotype node with no edge to the exposure node misrepresents this. The correct pathograph shape is exposure → mechanism, with genotype as a modifier edge onto the exposure→mechanism link, not a parallel initiating cause.

3. Phenotypes

3.1 Cardiac structural and functional phenotypes

Phenotype HP term Type Notes
Dilated cardiomyopathy HP:0001644 Dilated cardiomyopathy ✓cached Structural The established late phenotype
Cardiomyopathy (generic) HP:0001638 Cardiomyopathy ✓ Structural Parent term
Reduced left ventricular ejection fraction HP:0012664 Reduced left ventricular ejection fraction ✓ Functional/imaging The defining CTRCD criterion
Congestive heart failure HP:0001635 Congestive heart failure ✓ Clinical syndrome Symptomatic endpoint
Restrictive cardiomyopathy HP:0001723 Restrictive cardiomyopathy ✓ Structural Paediatric survivors, late; less common
Myocardial fibrosis HP:0001685 Myocardial fibrosis ✓ Histopathological Detected by CMR LGE/ECV and biopsy
Left ventricular hypertrophy (inadequate wall growth in children) HP:0001712 ✓ Structural In paediatric survivors the lesion is often failure of wall thickness to grow, i.e. reduced LV wall thickness — verify a better HP term before binding
Cardiogenic shock HP:0030149 ✓ Severe/late "very severe" CTRCD
Sudden cardiac death HP:0001645 ✓ Terminal event Late survivorship

3.2 Arrhythmic and electrophysiological phenotypes

Phenotype HP term
Arrhythmia HP:0011675 ✓
Sinus tachycardia HP:0011703 ✓
Supraventricular tachycardia HP:0004755 ✓
Atrial fibrillation HP:0005110 ✓
Atrial flutter HP:0004749 ✓
Ventricular tachycardia HP:0004756 ✓
Ventricular arrhythmia HP:0004308 ✓
Prolonged QT interval HP:0001657 ✓
Abnormal EKG HP:0003115 ✓ — non-specific ST/T changes and reduced QRS voltage are classic acute findings

3.3 Symptoms and signs of heart failure

Phenotype HP term
Dyspnea HP:0002094 ✓
Exertional dyspnea HP:0002875 ✓
Orthopnea HP:0012764 ✓
Fatigue HP:0012378 ✓
Asthenia HP:0025406 ✓
Palpitations HP:0001962 ✓
Syncope HP:0001279 ✓
Peripheral edema HP:0012398 ✓
Elevated jugular venous pressure HP:0030848 ✓
Hepatomegaly HP:0002240 ✓
Ascites HP:0001541 ✓
Pleural effusion HP:0002202 ✓
Pericardial effusion HP:0001698 ✓ (acute pericarditis-myocarditis syndrome)

3.4 Laboratory abnormalities

Phenotype HP term LOINC
Increased circulating troponin I concentration HP:0410173 ✓ LOINC 10839-9 (Troponin I, serum)
Increased circulating troponin T concentration HP:0410174 ✓ LOINC 67151-1 (hs-cTnT)
Increased circulating brain natriuretic peptide concentration HP:0033534 ✓ LOINC 33762-6 (NT-proBNP); 30934-4 (BNP)

LOINC codes above are the conventional ones and should be confirmed before binding — they were not machine-verified in this pass.

3.5 Onset, severity, progression, frequency

Three classical temporal forms (a taxonomy that Cardinale's data partly dismantled — see §8):

Form Timing Character Frequency
Acute Within days of infusion Transient arrhythmia, ECG changes, rarely myopericarditis <1%; usually reversible
Early-onset chronic <1 year after therapy Progressive LV dysfunction, often asymptomatic at detection The bulk of cases
Late-onset chronic >1 year, up to decades Dilated/restrictive cardiomyopathy in survivors Cumulative incidence rises to 30 years

Frequency of asymptomatic vs symptomatic disease, from the RARG GWAS background:

"Anthracyclines are used in over 50% of childhood cancer treatment protocols, but their clinical usefulness is limited by anthracycline-induced cardiotoxicity (ACT) manifesting as asymptomatic cardiac dysfunction and congestive heart failure in up to 57% and 16% of patients, respectively." — Aminkeng F et al., Nat Genet 2015 (PMID:26237429)

Severity grading — ESC 2022 CTRCD. These are the operative severity categories and should be modeled as a stages/severity axis rather than as separate phenotypes:

Asymptomatic: - Mild: "LVEF ≥50% and decline in GLS >15% and/or new rise in cardiac biomarkers" - Moderate: "new decrease in LVEF by 10% to a LVEF of 40% to 49%" - Severe: "new decrease in LVEF to <40%"

Symptomatic: - Mild: "mild HF symptoms, no intensification of therapy required" - Moderate: "required intensification of diuretic agents and HF therapy" - Severe: "hospitalization for HF" - Very severe: "HF requiring inotropic or mechanical support and consideration of transplantation"

— as summarized in Camilli et al. 2024 (PMID:39479333), from Lyon AR et al., Eur Heart J 2022;43(41):4229-4361 (PMID:36017568)

3.6 Quality of life

No AIC-specific QoL instrument exists. Reported impacts, per phenotype: - Symptomatic HF — measured with KCCQ, MLHFQ, and generic EQ-5D/SF-36; scores track NYHA class rather than aetiology. - Asymptomatic dysfunction — by definition no direct QoL decrement, but drives lifelong surveillance burden, insurance/employment consequences, and anxiety in survivors. - Treatment truncation — an under-measured harm: cardiotoxicity that forces early discontinuation of curative-intent chemotherapy imposes oncologic as well as cardiac cost. - Childhood cancer survivors carry the burden across decades; CCSS data (PMID:19996459) show cumulative cardiac incidence still climbing 30 years out.

4. Genetic / Molecular Information

There are no causal genes. Everything in this section is susceptibility, modifier, or pharmacogenomic. Model with relationship_type: SUSCEPTIBILITY or MODIFIER, never CAUSATIVE.

4.1 Susceptibility loci — replicated

Gene HGNC (verified via HGNC REST) Variant Effect Evidence
RARG hgnc:9866 rs2229774 (p.Ser427Leu), nonsynonymous ~4.7× increased risk; derepresses TOP2B PMID:26237429, PMID:34525346
CBR3 hgnc:1549 V244M (rs1056892), G allele Homozygous G → risk at low/moderate dose PMID:22124095
CBR1 hgnc:1548 1096G>A Variant A allele protective at low dose PMID:22124095
CELF4 hgnc:14015 rs1786814, GG genotype 10.2× risk at >300 mg/m²; GxE only PMID:26811534
TTN hgnc:12403 Truncating variants (TTNtv) 7.5% of CCM cases vs 1.1% TCGA PMID:30987448
RAC2 hgnc:9802 — Functionally validated as modulating DIC susceptibility JACC CardioOncol 2024 functional-validation study (verify PMID before citing)
SLC28A3 hgnc:16484 rs7853758 Protective in CPNDS candidate-gene work Verify PMID before binding
UGT1A6 hgnc:12538 *4 allele Risk-increasing Verify PMID before binding
HAS3 hgnc:4820 rs2232228 Modifies risk at high dose Verify PMID before binding

The RARG result is the mechanistically deepest, because the variant was traced to the same effector as the core mechanism:

"We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT (P = 5.9 × 10(-8), odds ratio (95% confidence interval) = 4.7 (2.7-8.3)). This variant alters RARG function, leading to derepression of the key ACT genetic determinant Top2b, and provides new insight into the pathophysiology of this severe adverse drug reaction." — Aminkeng 2015 (PMID:26237429)

and was then confirmed in patient-derived cells with a candidate therapy attached:

"We determine that the mechanism of this RARG variant effect is mediated via suppression of topoisomerase 2β (TOP2B) expression and activation of the cardioprotective extracellular regulated kinase (ERK) pathway. We use patient-specific hiPSC-CMs as a drug discovery platform, determining that the RARG agonist CD1530 attenuates DIC" — Magdy T et al., Cell Stem Cell 2021;28(12):2076-2089 (PMID:34525346)

4.2 The rare-variant / latent-cardiomyopathy hypothesis

Garcia-Pavia's finding reframes a fraction of AIC as unmasked latent inherited cardiomyopathy:

"Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants (P=7.36e-08), 0.7% of healthy volunteers (P=3.42e-06), and 0.6% of the reference population (P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation (P=0.003) and impaired myocardial recovery (P=0.03) than those without." — Garcia-Pavia P et al., Circulation 2019 (PMID:30987448)

"Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type (P=0.0004 and P<0.002, respectively)." (ibid.)

Other sarcomeric/cytoskeletal genes on the sequenced panel — MYH7 (hgnc:7577), LMNA (hgnc:6636), BAG3 (hgnc:939) — are plausible in the same frame but individually underpowered.

4.3 Variant classification, frequency, origin

  • Classification: These are risk alleles, not ACMG pathogenic variants. rs2229774, rs1786814, CBR3 V244M are common polymorphisms and would be classified benign/VUS by ACMG criteria for Mendelian disease — that framework simply does not apply. TTNtvs are the exception: individually they may be classified pathogenic/likely pathogenic for DCM in ClinVar, and here act as a susceptibility background.
  • Allele frequency: All the GWAS/candidate SNPs above are common (MAF typically >5%) in gnomAD; TTNtv carrier frequency in unselected populations is ~0.5–1.1% per the comparison cohorts above.
  • Origin: Germline. Somatic variation is not implicated.
  • Functional consequence: RARG p.Ser427Leu — loss of repressive function on TOP2B (a de-repression, i.e. functionally hypomorphic for the receptor, hypermorphic for the target). CBR1/CBR3 — altered enzyme activity changing the rate of anthracycline → alcohol-metabolite conversion. CELF4 — altered TNNT2 splicing regulation. TTNtv — haploinsufficiency/poison-peptide effect on sarcomere reserve.

4.4 The CELF4 → TNNT2 splicing mechanism

Unusually for a GWAS hit, a splicing mechanism was proposed and partly tested in human hearts:

"CUG-BP and ETR-3-like factor proteins control developmentally regulated splicing of TNNT2, the gene that encodes for cardiac troponin T (cTnT), a biomarker of myocardial injury. Coexistence of more than one cTnT variant results in a temporally split myofilament response to calcium, which causes decreased contractility. Analysis of TNNT2 splicing variants in healthy human hearts suggested an association between the rs1786814 GG genotype and coexistence of more than one TNNT2 splicing variant (90.5% GG v 41.7% GA/AA; P = .005)." — Wang 2016 (PMID:26811534) — TNNT2 = hgnc:11949 ✓cached

4.5 Epigenetic information

  • Nrf2 (NFE2L2, HGNC:7782) → HMOX1 (HGNC:5013) transcriptional axis is a demonstrated transcriptional, not strictly epigenetic, driver of iron liberation (Fang 2019, below).
  • Circulating miRNAs are the most active current biomarker/epigenetic-regulation area; a 2024 state-of-the-art review catalogues candidates: "circulating miRNAs exhibit resistance to degradation and offer a direct pathomechanistic link" — Boen HM et al., JACC CardioOncol 2024;6(2):183-199 (PMID:38774014). Frequently reported candidates include miR-1, miR-34a, miR-208a/b, miR-133b, miR-146a; none is clinically validated.
  • TOP2B–SMYD1 interaction: a 2026 report describes TOP2B binding SMYD1, a muscle-restricted histone methyltransferase whose mutations independently cause human cardiomyopathy — a genuinely epigenetic arm of the mechanism (Wang Q et al., Cancer Res Commun 2026, PMID:42102394). New and unreplicated; treat as EMERGING.
  • DNA methylation and histone-modification profiling in AIC is exploratory; no ENCODE/Roadmap-level resource is disease-specific.

4.6 Chromosomal abnormalities

Not applicable. No aneuploidy, translocation, or CNV association is established for AIC.

5. Environmental Information

5.1 The exposure itself

This is the etiologic root. Model as an environmental[] entry with influences_mechanisms and environmental_effect: TRIGGERS, targeting the systemic-exposure pathophysiology node.

  • Route: intravenous (bolus or continuous infusion). Infusion duration is a modifiable determinant of peak myocardial concentration.
  • Dose metric: cumulative mg/m² doxorubicin-equivalent, with the Feijen equivalence ratios (PMID:30703192) as the conversion.
  • ECTO: Search ECTO for an anthracycline/doxorubicin exposure term before binding. If none exists at adequate specificity, follow the repository's "no term beats a bad one" rule — leave term: off, keep the free-text preferred_term, and record the search in notes:. Do not stretch a generic "exposure to drug" term.

5.2 Co-exposures that modify risk

  • Thoracic/mediastinal ionizing radiation — additive to synergistic (Mulrooney, PMID:19996459)
  • Trastuzumab and other HER2-targeted agents — sequential exposure amplifies dysfunction; the mechanistic rationale is loss of the NRG1/ERBB2 cardiomyocyte repair pathway while anthracycline damage is accruing
  • Cyclophosphamide, taxanes — commonly co-administered; taxanes alter doxorubicin pharmacokinetics
  • Mitoxantrone used in multiple sclerosis — a non-oncologic exposure route that is easy to miss

5.3 Lifestyle factors

  • Sedentary behaviour, obesity, smoking, hypertension, diabetes — all in the HFA-ICOS proforma
  • Exercise during and after treatment is under investigation as protective; evidence is mechanistically attractive and clinically not yet definitive

5.4 Infectious agents

Not applicable. No infectious aetiology.

6. Mechanism / Pathophysiology

6.1 The causal chain — ordered

Present in this order in the pathograph. Every step names what it causes next; inference is flagged.

  1. Intravenous anthracycline administration leads to systemic anthracycline exposure and myocardial drug accumulation. Cardiomyocytes are particularly exposed because doxorubicin concentrates in mitochondria, of which cardiac muscle has an unusually high fraction by volume. (Demonstrated — Ichikawa, PMID:24382354)

  2. Myocardial drug accumulation branches into three coupled arms:

Arm A — the topoisomerase-IIβ arm (the dominant, best-evidenced initiating lesion).

2A. Doxorubicin intercalates into cardiomyocyte DNA and forms a ternary Top2β–DNA–drug cleavage complex. TOP2A, the antitumour target, is not expressed in terminally differentiated cardiomyocytes; TOP2B is, throughout the cell cycle including in quiescent cells. (Demonstrated)

2A.1 The trapped complex results in DNA double-strand breaks (GO:0006302 double-strand break repair ✓cached, as the countervailing process).

2A.2 Top2β-dependent transcriptome remodelling leads to defective mitochondrial biogenesis — specifically, downregulation of PGC-1α (PPARGC1A) and PGC-1β and their downstream oxidative-phosphorylation programme.

2A.3 Defective mitochondrial biogenesis results in reactive oxygen species formation, which feeds Arm B.

"Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIβ) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase-IIβ in cardiomyocytes." — Zhang S et al., Nat Med 2012;18(11):1639-42 (PMID:23104132) · evidence_source: MODEL_ORGANISM

Arm B — the iron / redox / ferroptosis arm.

2B. Doxorubicin concentrates inside mitochondria and chelates iron; simultaneously, Nrf2-mediated upregulation of heme oxygenase-1 degrades heme and results in systemic non-heme iron release.

"Administering DOX to mice induced cardiomyopathy with a rapid, systemic accumulation of nonheme iron via heme degradation by Nrf2-mediated up-regulation of Hmox1, which effect was abolished in Nrf2-deficent mice. Conversely, zinc protoporphyrin IX, an Hmox1 antagonist, protected the DOX-treated mice, suggesting free iron released on heme degradation is necessary and sufficient to induce cardiac injury." — Fang X et al., PNAS 2019 (PMID:30692261) · evidence_source: MODEL_ORGANISM

2B.1 Mitochondrial iron accumulation leads to Fenton-chemistry ROS generation and lipid peroxidation of mitochondrial membranes.

"Given that ferroptosis is driven by damage to lipid membranes, we further investigated and found that excess free iron accumulated in mitochondria and caused lipid peroxidation on its membrane. Mitochondria-targeted antioxidant MitoTEMPO significantly rescued DOX cardiomyopathy, supporting oxidative damage of mitochondria as a major mechanism in ferroptosis-induced heart damage." (ibid.)

2B.2 Concurrent GPX4 downregulation removes the enzymatic brake on lipid peroxidation, resulting in mitochondria-dependent ferroptosis (GO:0097707 ferroptosis ✓cached).

"we show that DOX downregulated glutathione peroxidase 4 (GPx4) and induced excessive lipid peroxidation through DOX-Fe2+ complex in mitochondria, leading to mitochondria-dependent ferroptosis; we also show that mitochondria-dependent ferroptosis is a major cause of DOX cardiotoxicity." — Tadokoro T et al., JCI Insight 2020 (PMID:32376803) · evidence_source: MODEL_ORGANISM

2B.3 The human-tissue anchor for this arm — the one observation that is not model-organism-only:

"hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function." — Ichikawa Y et al., J Clin Invest 2014;124(2):617-30 (PMID:24382354) · evidence_source: HUMAN_CLINICAL

Arm C — the metabolite arm.

2C. Cytosolic carbonyl reductases CBR1/CBR3 reduce doxorubicin to doxorubicinol, a C-13 alcohol metabolite that is a poor antitumour agent but a potent inhibitor of cardiac ion pumps (SERCA2a/ATP2A2 HGNC:812, Na⁺/K⁺-ATPase) and of mitochondrial F₀F₁-ATPase. (Mechanism inferred from enzymology and the CBR1/CBR3 genetic association; the direct in vivo human causal step is not demonstrated.)

  1. Convergence. ROS, DNA damage, mitochondrial failure, and ion-pump inhibition converge on cardiomyocyte energetic failure and impaired excitation–contraction coupling (GO:0060048 cardiac muscle contraction ✓, GO:0034614 cellular response to reactive oxygen species ✓).

  2. Sarcomeric and cytoskeletal disruption — myofibrillar loss and sarcomere disarray (GO:0045214 sarcomere organization ✓). Titin haploinsufficiency amplifies this step, which is why TTNtv carriers show "sustained contractile dysfunction" (PMID:30987448).

  3. Regulated cardiomyocyte death — ferroptosis is now argued to be the predominant form, with apoptosis (GO:0006915 ✓), necroptosis, and dysregulated autophagy (GO:0006914 ✓) contributing. Because adult cardiomyocytes are terminally differentiated, this loss is irreversible — the defining reason the disease progresses.

  4. Cardiomyocyte loss leads to compensatory hypertrophy of surviving myocytes, cardiac fibroblast activation, and replacement fibrosis (HP:0001685; CL:0002548 fibroblast of cardiac tissue ✓).

  5. Fibrosis + myocyte loss result in adverse LV remodelling — chamber dilatation, wall thinning, and falling ejection fraction. This is the point where the disease becomes detectable by GLS, then by LVEF.

  6. Adverse remodelling leads to clinical heart failure, arrhythmia, and, at the extreme, cardiogenic shock and death.

  7. Branch — the surveillance/reversibility branch. Between steps 6 and 8 there is a therapeutic window in which neurohormonal blockade produces substantial functional recovery (see §11). Beyond it, recovery falls off sharply. This branch is what makes early detection a mechanistic, not merely a logistic, question.

6.2 Molecular pathways

  • DNA topoisomerase type II activity — GO:0003918 DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity (verified via OLS4); the relevant enzyme is TOP2B (hgnc:11990, verified)
  • DNA damage response / DSB repair — GO:0006302 ✓; ATM–p53 signalling downstream
  • PGC-1α/β mitochondrial biogenesis programme — via PPARGC1A/B; KEGG hsa04714, Reactome R-HSA-1592230
  • Nrf2–ARE antioxidant response — NFE2L2 (HGNC:7782) → HMOX1 (HGNC:5013); paradoxically injurious here because HMOX1 induction liberates free iron
  • Ferroptosis pathway — GPX4 (HGNC:4556), ACSL4, system x_c⁻; KEGG hsa04216
  • Iron homeostasis — ABCB8 (HGNC:49) mitochondrial iron export; note GO:0055072 is obsolete — use GO:0006879 intracellular iron ion homeostasis (verified via OLS4)
  • Retinoic-acid receptor signalling — RARG (hgnc:9866) → TOP2B transcriptional repression
  • ERK/MAPK — cardioprotective; suppressed in RARG-variant cardiomyocytes (PMID:34525346)
  • Neuregulin-1/ERBB2 cardiomyocyte survival — the pathway trastuzumab blocks, explaining anthracycline–trastuzumab synergy
  • NLRP3 inflammasome / IL-1β — sterile inflammation amplifying injury; increasingly reported, not yet definitive

6.3 Cellular processes

Process GO term Status
Ferroptosis GO:0097707 ✓cached Now argued dominant
Apoptotic process GO:0006915 ✓ Established, modifier: INCREASED
Autophagy GO:0006914 ✓ Dysregulated (both blocked flux and excess initiation reported)
Response to oxidative stress GO:0006979 ✓ Established
Cellular response to reactive oxygen species GO:0034614 ✓ Established
Mitochondrion organization GO:0007005 ✓ modifier: DECREASED (biogenesis defect)
Double-strand break repair GO:0006302 ✓ Overwhelmed
Cellular senescence GO:0090398 ✓ Reported in cardiac fibroblasts and endothelium
Sarcomere organization GO:0045214 ✓ modifier: DECREASED
Cardiac muscle contraction GO:0060048 ✓ modifier: DECREASED
Intracellular iron ion homeostasis GO:0006879 (verified) modifier: DECREASED / disrupted

6.4 Protein dysfunction

  • TOP2B — not misfolded; trapped as a covalent cleavage complex on DNA. This is a poisoned-enzyme mechanism, closer to a gain of toxic function than to loss of function, and should be modeled with Descriptor.modifier on the process rather than functional_impact_category (no host variant is required).
  • GPX4 — downregulated protein abundance, loss of peroxidase activity
  • SERCA2a (ATP2A2) — inhibited by doxorubicinol; impaired calcium reuptake
  • Titin — truncated in the TTNtv subgroup, reducing sarcomeric reserve
  • Mitochondrial complexes I/III — sites of doxorubicin one-electron redox cycling generating superoxide
  • ABCB8 — capacity-limited mitochondrial iron export; overexpression is protective in mice

6.5 Metabolic changes

  • Shift away from fatty-acid β-oxidation toward glycolysis (the fetal metabolic programme of failing myocardium)
  • Reduced oxidative phosphorylation capacity and ATP output
  • Depleted reduced glutathione; NADPH consumption by redox cycling
  • Accumulation of oxidized phospholipid species (the ferroptosis lipidomic signature — hydroperoxy-PE species)
  • Cardiac creatine/phosphocreatine depletion

6.6 Immune system involvement

Sterile inflammation rather than autoimmunity. DAMPs released from dying cardiomyocytes activate resident and recruited macrophages (CL:0000763 myeloid cell ✓, or a cardiac macrophage term); NLRP3-inflammasome activation and IL-1β/IL-6 elevation are reported. No autoantibody or immunodeficiency component. This is a secondary amplifier, not an initiator — place it downstream in the pathograph.

6.7 Tissue damage mechanisms

Oxidative stress, iron-catalysed lipid peroxidation, DNA double-strand breakage, mitochondrial permeability transition, myocyte necrosis/ferroptosis, and replacement fibrosis. Ischaemia is not a primary mechanism — coronary arteries are typically spared, which distinguishes AIC from ischaemic cardiomyopathy at biopsy and on CMR.

6.8 Molecular profiling

  • Transcriptomics: anthracyclines produce a shared cardiomyocyte gene-expression response across TOP2-inhibiting agents, suggesting a common transcriptional signature rather than agent-specific programmes (see PMC10927150 / the associated bioRxiv preprint; verify the published PMID before citing). GEO holds multiple hiPSC-CM doxorubicin exposure series — search doxorubicin cardiomyocyte in GEO and triage for relevance before recording any datasets: accession (relevance triage is mandatory; resolution is not relevance).
  • Proteomics: PRIDE/ProteomeXchange hold doxorubicin-treated cardiomyocyte and murine heart datasets; no consensus signature.
  • Metabolomics/lipidomics: oxidized phosphatidylethanolamine species are the mechanistically anchored lipidomic readout (LIPID MAPS); acylcarnitine accumulation reflects the β-oxidation block.
  • Single-cell: cardiac macrophage, fibroblast, and endothelial responses have been profiled in murine DIC; human single-cell AIC data are sparse.
  • Functional genomics: hiPSC-CM CRISPR and pharmacogenomic screens (Burridge/Magdy programme) are the productive platform; DepMap is not informative for a non-cancer cardiac phenotype.

7. Anatomical Structures Affected

7.1 Organ level

  • Primary: heart — UBERON:0000948 heart ✓cached
  • Predominant chamber: left ventricle — UBERON:0002084 heart left ventricle ✓; myocardium UBERON:0002349 ✓; left ventricle myocardium UBERON:0006566 ✓
  • Right ventricle: involved, and increasingly recognized as an early site; historically under-imaged
  • Secondary organ involvement (all consequences of heart failure, not direct toxicity): lungs (congestion, pleural effusion), liver (congestive hepatopathy), kidneys (cardiorenal syndrome), skeletal muscle (deconditioning)
  • Body systems: cardiovascular (primary); respiratory, hepatic, renal (secondary)

7.2 Tissue and cell level

Structure Term
Cardiac muscle tissue UBERON:0001133 ✓
Cardiac muscle cell (the primary target) CL:0000746 cardiac muscle cell ✓
Cardiac fibroblast (fibrotic response) CL:0002548 fibroblast of cardiac tissue ✓
Endothelial cell (microvascular injury) CL:0000115 endothelial cell ✓
Endocardial cell CL:0002350 ✓
Myeloid cell / cardiac macrophage CL:0000763 ✓
Vascular smooth muscle cell CL:0000359 ✓

Cardiac progenitor/stem cell depletion is a proposed additional mechanism, particularly relevant to the paediatric phenotype where the heart still needs to grow. Treat as EMERGING.

7.3 Subcellular level (GO Cellular Component)

  • Mitochondrion (GO:0005739) — the central compartment: drug concentration, iron accumulation, lipid peroxidation, biogenesis failure
  • Nucleus (GO:0005634) — TOP2B cleavage complexes, DNA DSBs
  • Sarcomere (GO:0030017) / myofibril (GO:0030016) — structural disarray
  • Sarcoplasmic reticulum (GO:0016529) — SERCA2a inhibition, calcium mishandling
  • Mitochondrial inner membrane (GO:0005743) — site of lipid peroxidation and ETC redox cycling

These GO CC IDs are the standard ones but were not machine-verified in this pass; confirm before binding.

7.4 Localization and laterality

Global and biventricular, not regional. This is diagnostically important: a regional wall-motion abnormality argues for coronary disease rather than AIC. On CMR, diffuse extracellular volume expansion without an infarct-pattern late-gadolinium-enhancement territory is the expected picture.

8. Temporal Development

8.1 Onset

  • Age: any — from infancy (paediatric oncology) to the ninth decade. Bimodal risk peaks in very young children and adults >65.
  • Pattern: predominantly insidious and asymptomatic at onset. Acute onset (arrhythmia, myopericarditis within days) is rare.

8.2 The timing revision — the single most consequential recent finding

The classical acute / early-chronic / late-chronic trichotomy is substantially wrong about when the injury declares itself. In the largest prospective protocolized-echo cohort (n=2,625, median follow-up 5.2 years):

"The overall incidence of cardiotoxicity was 9% (n=226). The median time elapsed between the end of chemotherapy and cardiotoxicity development was 3.5 (quartile 1 to quartile 3, 3-6) months. In 98% of cases (n=221), cardiotoxicity occurred within the first year." — Cardinale D et al., Circulation 2015;131(22):1981-8 (PMID:25948538)

"Three types of anthracycline-induced cardiotoxicities are currently recognized: acute, early-onset chronic, and late-onset chronic. However, data supporting this classification are lacking." (ibid.)

The reconciliation with survivorship data is that "late-onset" cardiomyopathy is largely early subclinical injury that was never looked for, plus the additional stress of somatic growth and ageing on a depleted myocyte pool. Both facts are true and belong in the entry: injury is early, manifestation can be decades later.

8.3 Progression and stages

Map to the ESC CTRCD severity ladder (§3.5) as stages: 1. Subclinical injury — troponin rise, GLS decline >15% relative, LVEF preserved ≥50% 2. Mild asymptomatic CTRCD — as above, formally graded 3. Moderate asymptomatic CTRCD — LVEF 40–49% 4. Severe asymptomatic CTRCD — LVEF <40% 5. Symptomatic HF — mild → moderate → severe (hospitalization) → very severe (inotropes/MCS/transplant)

Rate: variable. Most decline occurs within 12 months of the last dose; thereafter slow progression or plateau, with a second late slope in long-term survivors.

Course: progressive rather than relapsing–remitting; the paediatric course can be biphasic (early dysfunction, apparent stabilization, late deterioration around growth spurts and pregnancy).

Duration: chronic and lifelong once established.

8.4 Remission and recovery

Treatment-induced, and steeply time-dependent. Cardinale's recovery data are the key numbers:

"Twenty-five (11%) patients had full recovery, and 160 (71%) patients had partial recovery." — PMID:25948538

"Most cardiotoxicity after anthracycline-containing therapy occurs within the first year and is associated with anthracycline dose and LVEF at the end of treatment. Early detection and prompt therapy of cardiotoxicity appear crucial for substantial recovery of cardiac function." (ibid.)

Spontaneous remission without therapy is uncommon.

8.5 Critical periods

  • During and immediately after chemotherapy — the window for primary prevention (dexrazoxane, liposomal formulation, statin, ACEi/ARB)
  • First 12 months post-treatment — the window where nearly all incident dysfunction appears and where prompt HF therapy yields recovery
  • Adolescent growth spurt and pregnancy in childhood-cancer survivors — periods of increased haemodynamic demand that unmask latent dysfunction

9. Inheritance and Population

9.1 Epidemiology

There is no single prevalence figure, and reporting one without its case definition is misleading. Anchor points:

Population / definition Figure Source
Prospective cohort, LVEF decline >10 points to <50%, adults 9% overall incidence Cardinale 2015, PMID:25948538
Doxorubicin 550 mg/m², clinical CHF, adults 26% estimated cumulative Swain 2003, PMID:12767102
Doxorubicin 400 mg/m², clinical CHF, adults ~5% (widely cited from the same dataset) Swain 2003
Childhood cancer protocols, asymptomatic dysfunction up to 57% Aminkeng 2015, PMID:26237429
Childhood cancer protocols, congestive heart failure up to 16% Aminkeng 2015, PMID:26237429
Meta-analysis, LVEF decline at median 9 y 6% overt, 18% subclinical cited in Camilli 2024, PMID:39479333
CCSS survivors vs siblings, CHF HR 5.9 (95% CI 3.4–9.6) Mulrooney 2009, PMID:19996459
CARDIOTOX registry, any CTRCD incl. mild asymptomatic 67.3% (n=718/1066) Rivero-Santana 2025, PMID:39106857

That last row deserves emphasis — under the ESC 2022 definition, which counts a >15% relative GLS decline as mild CTRCD, two-thirds of anthracycline-treated patients meet criteria. The definition, not the biology, moved. Any prevalence record here must carry measure_type and a notes: line naming the case definition, or it will be uninterpretable.

Suggested structured record shape:

prevalence:
- population: Adults receiving anthracycline-containing chemotherapy (prospective cohort, Italy)
  measure_type: PERIOD_PREVALENCE
  prevalence_class: COMMON
  rate_per_100000: 9000.0
  notes: >-
    9% incidence of LVEF decline >10 absolute points to <50% over median 5.2 years;
    98% of events within the first year. Not comparable with ESC-2022 CTRCD rates,
    which include mild asymptomatic GLS-defined cases.

9.2 Inheritance

Not a heritable disease. Do not populate inheritance: with a Mendelian mode. If an inheritance block is used at all, HP:0010982 Polygenic inheritance with relationship_type: SUSCEPTIBILITY gene typing is the only defensible framing, and even that is a stretch — the susceptibility architecture is a handful of common variants plus a rare-variant tail, acting only in the presence of exposure.

  • Penetrance / expressivity / anticipation / mosaicism / founder effects / consanguinity / carrier frequency: Not applicable.
  • The one partial exception is the TTNtv subgroup, where a genuinely inherited, autosomal-dominant DCM predisposition is unmasked by exposure. Model that as a MODIFIER/SUSCEPTIBILITY genetic entry with a discussions note, not as an inheritance mode for AIC.

9.3 Population demographics

  • Affected populations: anyone exposed. Ancestry-specific risk-allele frequencies differ (the RARG GWAS replicated in both European and non-European cohorts — 96 European and 80 non-European replication patients), but population-level differences in AIC risk are driven mainly by differences in treatment protocols and access to surveillance.
  • Geographic distribution: worldwide, tracking anthracycline use. No endemic pattern.
  • Sex ratio: In paediatric cohorts, female sex is a risk factor and girls derive greater dexrazoxane benefit (PMID:20850381). In the adult CARDIOTOX validation cohort, 81.9% were women — but that reflects the breast-cancer-heavy case mix, not a sex-specific susceptibility. Do not read a sex ratio out of a cohort's cancer distribution.
  • Age distribution: bimodal risk (young children, adults ≥65); the CARDIOTOX cohort mean age was 54 ± 14 years with 24.5% ≥65.

10. Diagnostics

10.1 Imaging — the diagnostic backbone

Modality Role NCIT
Transthoracic echocardiography with 3D LVEF and GLS First-line, serial Search NCIT for Echocardiography; not verified this pass
Global longitudinal strain (GLS) Earliest routine functional marker; >15% relative decline defines mild CTRCD —
Cardiac MRI Reference standard for LVEF; T1 mapping/ECV quantifies diffuse fibrosis and oedema; used when echo is non-diagnostic —
MUGA / radionuclide ventriculography Historic; reproducible LVEF, but radiation and no strain — largely superseded —
CT Only for coronary exclusion —

The SUCCOUR trial tested whether GLS should drive therapy rather than merely detect injury:

"In this international, multicenter, prospective, randomized controlled trial, 331 anthracycline-treated patients with another heart failure risk factor were randomly allocated to CPT initiation guided by either ≥12% relative reduction in GLS (n = 166) or >10% absolute reduction of LVEF (n = 165)." — Thavendiranathan P et al., J Am Coll Cardiol 2021;77(4):392-401 (PMID:33220426); 3-year follow-up: Negishi T et al., JACC Cardiovasc Imaging 2023 (PMID:36435732)

10.2 Biomarkers

  • Cardiac troponin I / T (including high-sensitivity assays) — the earliest signal of injury and the best-validated risk stratifier:

"TnI release pattern after high-dose chemotherapy identifies patients at different risks of cardiac events in the 3 years thereafter." — Cardinale D et al., Circulation 2004;109(22):2749-54 (PMID:15148277)

"In the TnI-/- group, no significant reduction in ejection fraction was observed during the follow-up, and there was a very low incidence of cardiac events (1%). In contrast, a greater incidence of cardiac events occurred in TnI-positive patients, particularly in the TnI(+/+) group (84% versus 37% in the TnI+/- group; P<0.001)." (ibid.)

Note the study's threshold was ≥0.08 ng/mL on a contemporary-generation assay — do not carry that cut-point forward to a high-sensitivity assay.

  • Natriuretic peptides (BNP, NT-proBNP) — ESC recommends baseline measurement if they are to be used in follow-up.
  • Circulating miRNAs — investigational; reviewed in PMID:38774014. Not clinically actionable.
  • Emerging plasma panels in childhood survivors — Leerink JM et al., J Am Heart Assoc 2022 (PMID:35861824).

10.3 Electrophysiology

12-lead ECG at baseline and during surveillance: sinus tachycardia, non-specific ST/T changes, reduced QRS voltage, QTc prolongation, and (late) conduction disease. ECG is neither sensitive nor specific for AIC and is used for arrhythmia detection and as a red flag, not for diagnosis.

10.4 Biopsy and pathology

  • Endomyocardial biopsy — NCIT:C51674 Endomyocardial Biopsy ✓cached. Historically the gold standard, using the Billingham grading scale (0 to 3, scoring myofibrillar loss, cytoplasmic vacuolization of cardiomyocytes, and myocyte necrosis on electron microscopy). Now rarely performed: it is invasive, samples the right ventricle, and has been displaced by strain and CMR. Retain it as a differential-diagnosis tool when myocarditis or infiltrative disease is in play.
  • Characteristic histopathology: myocyte vacuolization ("adria cells"), myofibrillar dropout, interstitial and perivascular fibrosis, absence of significant inflammatory infiltrate (which is what distinguishes it from myocarditis), and on EM, distended sarcoplasmic reticulum and swollen mitochondria.

10.5 Genetic testing

  • No diagnostic genetic test exists for AIC. Genotype is not part of any guideline diagnostic pathway.
  • Cardiomyopathy gene panel has an emerging risk-stratification role, given the TTNtv finding (PMID:30987448). ClinGen-curated DCM panels (TTN, LMNA, MYH7, BAG3, RBM20, FLNC, DSP, etc.) are the relevant gene set. This is not yet standard of care; frame it as a discussions / KNOWLEDGE_GAP item.
  • Pharmacogenomic genotyping (RARG, CBR3, SLC28A3, UGT1A6) — CPNDS has proposed clinical recommendations; not in CPIC guidelines and not in the FDA Table of Pharmacogenomic Biomarkers as of this writing. Check PharmGKB for current level-of-evidence assignments before asserting clinical actionability.
  • WGS/WES, CMA, karyotyping, FISH, mtDNA testing, repeat-expansion testing: not applicable.

10.6 Clinical criteria

ESC 2022 / IC-OS CTRCD definitions (§3.5) are the operative diagnostic criteria (PMID:36017568). ASCO's 2017 survivorship guideline (PMID:27918725) covers monitoring in adult survivors.

10.7 Differential diagnosis

Alternative Distinguishing features
Ischaemic cardiomyopathy Regional wall-motion abnormality; subendocardial/transmural LGE in a coronary territory; obstructive CAD on angiography. AIC is global.
Trastuzumab-mediated cardiac dysfunction Typically reversible on drug cessation, non-dose-dependent, no myocyte necrosis. Distinguishing the two in a patient who got both is often impossible and is a genuine knowledge gap.
Immune checkpoint inhibitor myocarditis Fulminant course, marked troponin elevation, lymphocytic infiltrate on biopsy, conduction disease.
Familial/genetic DCM Family history, earlier onset relative to exposure, causative variant. Note the overlap: TTNtv carriers sit in both categories.
Peripartum cardiomyopathy Temporal relation to pregnancy; a real confounder in young survivors.
Radiation-induced heart disease Pericardial constriction, valvular thickening, coronary ostial disease, conduction disease. Frequently co-occurs rather than being an alternative.
Cardiac amyloidosis / infiltrative disease Increased wall thickness with low voltage, apical-sparing strain pattern, characteristic CMR.
Takotsubo / stress cardiomyopathy Apical ballooning, rapid recovery.
Sepsis- or thyrotoxicosis-related cardiomyopathy Reversible, systemic trigger identifiable.

10.8 Screening

  • Baseline risk assessment before the first dose — HFA-ICOS proforma (validated: PMID:39106857). Baseline echo with GLS plus troponin and natriuretic peptide in anyone who will be followed with them.
  • On-treatment surveillance — frequency by risk tier; high/very-high risk patients get echo/biomarkers before alternate cycles and at cumulative-dose milestones.
  • Post-treatment — echo at end of therapy and at 12 months is the highest-yield schedule, since 98% of events fall in the first year (PMID:25948538).
  • Long-term survivorship — lifelong periodic echo per Children's Oncology Group / IGHG survivorship guidelines, risk-stratified on cumulative dose and chest radiation.
  • Cascade/carrier screening: not applicable, except that a TTNtv found incidentally has family implications.

11. Outcome / Prognosis

11.1 Survival and mortality

  • AIC is a leading non-cancer cause of death in long-term cancer survivors. Historical series of established, untreated anthracycline cardiomyopathy reported ~50% 2-year mortality — a figure that predates modern HF therapy and should be cited as historical, not current.
  • CCSS: survivors were "significantly more likely than siblings to report congestive heart failure (hazard ratio (HR) 5.9, 95% confidence interval 3.4 to 9.6; P<0.001)" and "The cumulative incidence of adverse cardiac outcomes in cancer survivors continued to increase up to 30 years after diagnosis" (PMID:19996459).
  • CARDIOTOX: "A total of 197 patients (18.4%) died" over median 54.8 months, with mortality rising steeply across HFA-ICOS strata (HR 7.43 for very high risk) (PMID:39106857).

11.2 Recovery potential — the most actionable prognostic fact

Recovery is common if therapy starts early, and this is the central argument for surveillance: 11% full and 71% partial recovery when HF therapy was initiated at detection (PMID:25948538). Recovery probability falls sharply with time from LVEF decline to treatment initiation.

Modeling note: this makes "time from detection to therapy" a legitimate prognostic factor node, not merely a process metric.

11.3 Morbidity, disability, quality of life

Chronic heart failure with its full functional burden: exercise limitation, recurrent hospitalization, polypharmacy, device therapy, and — in the paediatric survivor population — a decades-long trajectory interacting with growth, pregnancy, and other late effects. QoL measured with generic instruments (EQ-5D, SF-36, PROMIS) and HF-specific tools (KCCQ, MLHFQ); no AIC-specific instrument.

11.4 Complications

Progressive HF; atrial and ventricular arrhythmia; thromboembolism from a dilated, poorly contracting ventricle; secondary mitral regurgitation; pulmonary hypertension; cardiorenal syndrome; sudden cardiac death; and — the oncologic complication that is easy to overlook — curtailment of curative cancer therapy.

11.5 Prognostic factors and biomarkers

  • Cumulative anthracycline dose (dose-equivalent adjusted)
  • End-of-chemotherapy LVEF — "end-chemotherapy LVEF (hazard ratio, 1.37; 95% confidence interval, 1.33-1.42 for each percent unit decrement) and cumulative doxorubicin dose (hazard ratio, 1.09; 95% confidence interval, 1.04-1.15 for each 50 mg/m(2) increment) were independent correlates of cardiotoxicity" (PMID:25948538)
  • Troponin release pattern — persistent elevation (TnI+/+) carries an 84% cardiac-event rate (PMID:15148277)
  • Baseline HFA-ICOS risk category (PMID:39106857)
  • Time from LVEF decline to HF therapy initiation
  • Concomitant chest radiotherapy
  • Age, sex, pre-existing cardiovascular disease
  • Genotype: TTNtv carriers show "impaired myocardial recovery (P=0.03)" (PMID:30987448) — a genotype→prognosis edge worth modeling explicitly
  • CMR ECV / late gadolinium enhancement burden (emerging)

12. Treatment

12.1 Established heart-failure pharmacotherapy (treatment of established AIC)

Guideline-directed medical therapy for HFrEF applies without modification. All are treatment_term: NCIT:C15986 Pharmacotherapy ✓cached, with therapeutic_agent carrying the drug and therapeutic_modality: SMALL_MOLECULE (or MONOCLONAL_ANTIBODY where relevant).

Class Example agent CHEBI Verified?
ACE inhibitor enalapril CHEBI:4784 ✓cached
ARB candesartan CHEBI:3347 verified via OLS4
Beta blocker (non-selective, antioxidant) carvedilol CHEBI:3441 ✓cached
MRA spironolactone CHEBI:9241 ✓cached
SGLT2 inhibitor empagliflozin / dapagliflozin CHEBI:82720 / CHEBI:85078 ✓cached
ARNI sacubitril/valsartan look up before binding not verified
Loop diuretic furosemide look up before binding not verified

12.2 Primary prevention — cardioprotective strategies

Dexrazoxane — the only agent licensed specifically for this indication. CHEBI:50223 (label (+)-dexrazoxane, verified) / NCIT:C1333 Dexrazoxane (verified). Mechanism: EDTA-analogue iron chelation plus catalytic-cycle inhibition of TOP2B — note that both arms of the core mechanism are addressed, which is why it works.

Cochrane, 13 RCTs, 2,521 participants:

"In adults, moderate-quality evidence showed that there was less clinical heart failure with the use of dexrazoxane (risk ratio (RR) 0.22, 95% confidence interval (CI) 0.11 to 0.43; 7 studies, 1221 adults). In children, we identified no difference in clinical heart failure risk between treatment groups (RR 0.20, 95% CI 0.01 to 4.19; 3 studies, 885 children; low-quality evidence)." — de Baat EC et al., Cochrane Database Syst Rev 2022;9:CD014638 (PMID:36162822)

"Overall survival (OS) was reported in adults and overall mortality in children. The meta-analyses of both outcomes showed no difference between treatment groups (hazard ratio (HR) 1.04, 95% 0.88 to 1.23; 4 studies; moderate-quality evidence...)" (ibid.) — i.e., the historical concern that dexrazoxane blunts antitumour efficacy is not supported.

Long-term paediatric follow-up:

"Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys." — Lipshultz SE et al., Lancet Oncol 2010;11(10):950-61 (PMID:20850381)

Regulatory label restricts use to metastatic breast cancer beyond 300 mg/m² cumulative doxorubicin, which is narrower than the evidence supports — a live practice/label mismatch worth recording in notes:.

Liposomal doxorubicin — reformulation reduces myocardial delivery while preserving tumour delivery via the EPR effect. "In five trials comparing liposomal doxorubicin (LD) with conventional doxorubicin, LD reduced the risk of clinical heart failure (OR 0.18, 0.08–0.38) and subclinical heart failure (RR 0.31, 0.20–0.48)" (meta-analysis; verify the PMID for the specific systematic review before citing — candidates surfaced include PMID:41084073). Formally recommended by ESC for CTRCD prevention (PMID:36017568).

Statins. STOP-CA is the strongest randomized evidence:

"The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4)." — Neilan TG et al., JAMA 2023;330(6):528-536 (PMID:37552303) · NCT02943590

"There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26)." (ibid.)

That second quote is the honest limitation and should be curated alongside the first: the trial moved an imaging endpoint, not a clinical heart-failure endpoint. Curate as SUPPORT with directness: INDIRECT for any claim about preventing heart failure.

Neurohormonal prophylaxis. PRADA:

"The overall decline in LVEF was 2.6 (95% CI 1.5, 3.8) percentage points in the placebo group and 0.8 (95% CI −0.4, 1.9) in the candesartan group in the intention-to-treat analysis (P-value for between-group difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed." — Gulati G et al., Eur Heart J 2016;37(21):1671-80 (PMID:26903532) · a 2.6-point vs 0.8-point difference is real but small; do not over-claim it.

Administration-schedule modification — prolonged infusion rather than bolus; dose capping.

SGLT2 inhibitors — emerging. EMPACARD-PILOT (PMID:39237985) and the PROTECT trial (dapagliflozin; registered 2024-03-19) are the active programme; observational data suggest benefit. Curate as EMERGING with a discussions knowledge-gap entry, not as established therapy.

12.3 Advanced and device therapy

  • Cardiac resynchronization therapy — NCIT:C80436 ✓cached — for eligible patients with wide QRS
  • ICD for primary/secondary arrhythmic prevention
  • Mechanical circulatory support (LVAD) as bridge or destination
  • Heart transplantation — NCIT:C15246 Heart Transplantation ✓cached — feasible in cancer survivors with adequate oncologic remission duration; AIC is a recognized transplant indication
  • Gene, cell, RNA-based, and targeted therapies: none approved. Investigational: TOP2B antisense oligonucleotide (ASO-18) reported cardioprotective versus dexrazoxane in a mouse AIC model (PMID:42102394 — 2026, preclinical, unreplicated); RARG agonist CD1530 (PMID:34525346 — hiPSC-CM and mouse); ferroptosis inhibitors (ferrostatin-1, MitoTEMPO) preclinical only.

12.4 Supportive and rehabilitative

  • Sodium and fluid management, symptom-directed diuresis — NCIT:C15747 Supportive Care ✓cached
  • Cardiac rehabilitation / structured exercise training — increasingly recommended both during and after therapy; therapeutic_modality: BEHAVIORAL
  • Cardiovascular risk-factor management (BP, lipids, glycaemia, smoking cessation)

12.5 Pharmacogenomics

No CPIC guideline and no FDA pharmacogenomic labelling for anthracyclines as of this writing. CPNDS has published RARG/SLC28A3/UGT1A6 recommendations. Verify current PharmGKB level-of-evidence assignments before asserting any actionable genotype-guided recommendation — this is exactly the kind of claim that ages badly.

12.6 Treatment algorithm

  1. Baseline HFA-ICOS risk stratification + echo with GLS + troponin/NP
  2. Risk-adapted primary prevention: dexrazoxane and/or liposomal formulation and/or dose capping for high/very-high risk; consider statin
  3. On-treatment surveillance at risk-adapted intervals
  4. On detection of CTRCD: grade by ESC criteria; start ACEi/ARB + beta blocker (carvedilol) promptly; do not wait for symptoms
  5. Multidisciplinary cardio-oncology decision on continuing versus modifying versus stopping anthracycline — a genuine risk-benefit trade, since stopping curative chemotherapy has its own mortality
  6. Escalate to full GDMT (add MRA, SGLT2i, ARNI) for established HFrEF
  7. Device therapy, MCS, transplant for refractory disease
  8. Lifelong survivorship surveillance

13. Prevention

13.1 Primary prevention (preventing the cardiomyopathy)

  • Avoid the exposure where an equally effective non-anthracycline regimen exists — the only fully effective prevention, and increasingly available in breast cancer
  • Cumulative dose limitation, using cardiotoxicity-calibrated equivalence ratios (PMID:30703192) rather than hematologic-toxicity ratios
  • Dexrazoxane in high-risk patients (PMID:36162822, PMID:20850381)
  • Liposomal formulation (ESC-recommended)
  • Prolonged infusion rather than bolus
  • Atorvastatin 40 mg daily for 12 months in lymphoma patients (PMID:37552303)
  • Candesartan during adjuvant therapy (PMID:26903532)
  • Pre-treatment cardiovascular risk-factor optimization — BP, lipids, glycaemia, weight, smoking
  • Minimize concurrent cardiac radiation dose — modern conformal/proton techniques

13.2 Secondary prevention (early detection, treat before symptoms)

This is where the field's leverage is. The evidence chain — troponin identifies subclinical injury (PMID:15148277) → GLS identifies functional decline before LVEF (PMID:33220426) → early HF therapy yields 82% partial-or-full recovery (PMID:25948538) — is the strongest argument in cardio-oncology and should be modeled as an explicit causal chain in the entry, not as three unrelated diagnostic facts.

13.3 Tertiary prevention

Full GDMT, arrhythmia management, anticoagulation where indicated, cardiac rehabilitation, avoidance of further cardiotoxic exposure (including re-challenge and additional chest radiation), pregnancy counselling in female survivors, and lifelong surveillance.

13.4 Risk stratification

The HFA-ICOS baseline proforma is the validated instrument (PMID:39106857), available as a calculator. Genotype is not yet part of any validated risk model — an explicit knowledge gap.

13.5 Immunization, genetic counselling, public health

  • Immunization: not applicable to AIC as such; routine vaccination is standard supportive care for immunosuppressed oncology patients.
  • Genetic counselling: not routine. Becomes relevant only when a TTNtv or other DCM-associated variant is identified, at which point cascade testing of relatives follows standard inherited-cardiomyopathy practice.
  • Public health / environmental interventions: not applicable — the exposure is a prescribed therapeutic, so the "environmental intervention" is prescribing policy and formulary choice.

14. Other Species / Natural Disease

14.1 Taxonomy

Species NCBI Taxon Relevance
Homo sapiens NCBITaxon:9606 Primary
Canis lupus familiaris NCBITaxon:9615 Naturally occurring — dogs treated for lymphoma/sarcoma develop AIC
Felis catus NCBITaxon:9685 Occasional veterinary oncology use
Mus musculus NCBITaxon:10090 Principal experimental model
Rattus norvegicus NCBITaxon:10116 Chronic-dosing model
Danio rerio NCBITaxon:7955 Screening model
Oryctolagus cuniculus NCBITaxon:9986 Classic chronic cardiomyopathy model

Taxon IDs above are the standard ones; verify against the cache/ncbitaxon cache before binding.

14.2 Natural disease in other species

This is genuinely a naturally occurring veterinary disease, not merely an induced model — dogs receiving anthracycline chemotherapy for canine multicentric lymphoma develop the same entity:

"An 8-year-old, castrated, mixed-breed dog was diagnosed with multicentric lymphoma and received multi-agent chemotherapy... After third-line chemotherapy with epirubicin, the patient was diagnosed with dilated cardiomyopathy. The total cumulative doses of doxorubicin, mitoxantrone, and epirubicin were 125, 8, and 125 mg/m2, respectively." — Tagawa M et al., Open Vet J 2021;11(1):6-10 (PMID:33898277) · evidence_source: MODEL_ORGANISM (per repository convention, veterinary observations grade as MODEL_ORGANISM)

"Further studies are required to establish prevention and management strategies for dogs receiving potentially cardiotoxic therapies, such as anthracyclines." (ibid.)

Veterinary relevance is real and practical: canine lymphoma is one of the most common canine malignancies, doxorubicin is standard of care, and dose limits (~180–240 mg/m² cumulative in dogs) are set by cardiotoxicity. Doberman Pinschers and other breeds with a genetic DCM predisposition are considered higher risk — a natural analogue of the human TTNtv finding. Check VBO for breed identifiers if breed-specific curation is wanted; check OMIA for canine DCM entries.

14.3 Comparative biology

  • Conservation: TOP2B, GPX4, ABCB8, and the mitochondrial biogenesis machinery are broadly conserved across mammals; the core mechanism is not human-specific.
  • Orthologues: mouse Top2b, Gpx4, Abcb8, Rarg, Cbr1/Cbr3, Celf4, Ttn — all have one-to-one human orthologues (Alliance of Genome Resources / HomoloGene).
  • Comparative pathology: the murine and canine lesions both show myocyte vacuolization, myofibrillar loss, and interstitial fibrosis — the same Billingham-type picture as human biopsies.
  • Difference to flag: rodent hearts have a much higher basal heart rate and different calcium-handling kinetics, so contractile-phenotype timing does not translate directly.

14.4 Transmission

Not applicable — no zoonotic or cross-species transmission. Cross-species susceptibility to the same drug is universal among mammals.

15. Model Organisms

15.1 In vivo models

Model Design Fidelity Limitations
Acute high-dose murine DIC (single 15–20 mg/kg i.p. doxorubicin) Rapid LV dysfunction over 5–14 days PARTIALLY_RECAPITULATES Supraclinical dose; substantial systemic toxicity and weight loss confound the cardiac phenotype; does not model the chronic human course
Chronic low-dose murine DIC (repeated 3–5 mg/kg weekly, cumulative ~20–25 mg/kg) Progressive dilated phenotype over weeks RECAPITULATES — closest to human Long, expensive; strain-dependent (C57BL/6 relatively resistant vs. BALB/c)
Cardiomyocyte-specific Top2b knockout (Top2b^fl/fl; Myh6-Cre) The mechanistic proof model RESCUES the phenotype A loss-of-target model, not a disease model; tells you the target, not the natural history — PMID:23104132
ABCB8-overexpressing transgenic mouse Mitochondrial iron export RESCUES — PMID:24382354 Overexpression is supraphysiological
Gpx4 Tg and heterodeletion mice Bidirectional ferroptosis test RESCUES / worsens respectively — PMID:32376803 Same caveat
Ripk3^−/−, Mlkl^−/−, Fadd^−/−Mlkl^−/− mice Apoptosis/necroptosis-defective backgrounds, isolating ferroptosis RECAPITULATES ferroptotic death — PMID:30692261 Compound knockouts have their own baseline phenotypes
Nrf2-deficient mice Tests the HMOX1/iron arm FAILS_TO_RECAPITULATE (protected) — PMID:30692261 Nrf2 loss has broad pleiotropic effects
TTNtv rat/mouse + anthracycline Genotype × exposure interaction RECAPITULATES the human genotype effect — PMID:30987448 —
Rabbit chronic model Weekly doxorubicin, classic CHF model RECAPITULATES Cost; limited genetic tools
Zebrafish Larval and adult doxorubicin exposure PARTIALLY_RECAPITULATES Cardiomyocytes regenerate in zebrafish — which is precisely the property human hearts lack, so translational validity for the irreversibility of the human disease is poor. This is a HUMAN_MODEL_MISMATCH, not just a limitation
Naturally occurring canine AIC Client-owned dogs on anthracycline chemotherapy RECAPITULATES — spontaneous, outbred, clinically monitored — PMID:33898277 Case-series level evidence; no controlled dosing

15.2 In vitro / non-animal models (NAMs)

Patient-specific hiPSC-derived cardiomyocytes are the standout platform, because they reproduce individual susceptibility, not just the class effect:

"hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production." — Burridge PW et al., Nat Med 2016;22(5):547-56 (PMID:27089514) · evidence_source: IN_VITRO

"Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC." (ibid.)

And they function as a drug-discovery platform for genotype-matched cardioprotection (PMID:34525346, CD1530 for RARG carriers).

Other in vitro systems: - Neonatal rat ventricular myocytes (NRVM) — the historical workhorse; immature and proliferative, poor fidelity for a terminally differentiated phenotype - H9c2 rat cardiomyoblast line — convenient, low fidelity; not a cardiomyocyte - AC16 human cardiomyocyte line — immortalized, limited fidelity - Engineered heart tissue / cardiac organoids and organ-chips — force-generating 3D constructs with better maturation; the direction of travel for NAM-based cardiotoxicity screening - Isolated adult cardiomyocytes and ex vivo Langendorff-perfused hearts — good for acute contractile and calcium readouts

15.3 Model characteristics — what is and is not captured

Recapitulated well: myocyte vacuolization and myofibrillar loss; LV systolic dysfunction; mitochondrial iron accumulation; ferroptotic death; TOP2B dependence; genotype-specific susceptibility (hiPSC-CM).

Not captured: - The decades-long latency of human late-onset disease — no model runs that long - Cumulative-dose scaling — murine mg/kg regimens do not map cleanly onto human mg/m² cumulative exposure - Co-exposure complexity — real patients get radiation, trastuzumab, taxanes, and cyclophosphamide - Comorbidity background — models are young, healthy, and inbred; patients are older with hypertension, diabetes, and CKD - hiPSC-CM maturity — these cells are fetal-like in metabolism, sarcomere organization, and electrophysiology, which limits inference about a terminally differentiated adult myocyte. Model this explicitly as a HUMAN_MODEL_MISMATCH discussion rather than burying it in limitations prose.

15.4 Resources

MGI, RGD, ZFIN, Alliance of Genome Resources, IMPC/KOMP (for Top2b, Gpx4, Abcb8, Rarg alleles), IMSR/JAX for strain availability, Cellosaurus for H9c2/AC16, and the Stanford Cardiovascular Institute and Northwestern Center for Pharmacogenomics hiPSC-CM biobanks.

Knowledge Gaps and Open Questions

Worth curating as discussions entries with kind: KNOWLEDGE_GAP or HUMAN_MODEL_MISMATCH:

  1. Are the ESC-2022 mild-CTRCD cases the same disease as clinical AIC? Two-thirds of treated patients now meet criteria (PMID:39106857). Whether GLS-defined mild dysfunction predicts clinical heart failure, or is a reversible physiological perturbation, is unresolved — and it determines whether a very large number of people should be treated.
  2. Statins move imaging endpoints but not heart-failure endpoints. STOP-CA was explicit: "There was no difference in the rates of incident heart failure between study groups" (PMID:37552303). Whether the surrogate translates is untested.
  3. Should genotype enter clinical risk models? TTNtv has a strong effect and no place in any guideline pathway.
  4. Distinguishing anthracycline from trastuzumab injury in patients who received both is currently impossible clinically, and blurs the aetiology of a large fraction of breast-cancer CTRCD.
  5. Why is dexrazoxane's label narrower than its evidence? Cochrane finds RR 0.22 for clinical HF in adults with no survival penalty (PMID:36162822), yet approval is restricted to metastatic breast cancer beyond 300 mg/m².
  6. Ferroptosis inhibition has never been tested in humans, despite being the mechanism with the strongest recent preclinical support and a human-tissue anchor (PMID:24382354).
  7. hiPSC-CM immaturity as a translational limit on the entire pharmacogenomic-screening programme (HUMAN_MODEL_MISMATCH).
  8. Zebrafish cardiac regeneration makes that model structurally unable to test the property that defines the human disease (HUMAN_MODEL_MISMATCH).
  9. SGLT2 inhibitors — mechanistically attractive, observationally supported, awaiting PROTECT and its siblings.

Verification Status of Identifiers in This Report

Because a plausible-but-wrong CURIE passes most automated checks, here is what was actually verified in this pass:

Machine-verified against the local term caches (cache/*/terms.csv): all HP terms in §3; CL:0000746, CL:0002548, CL:0000115, CL:0002350, CL:0000763, CL:0000359; UBERON:0000948, UBERON:0001133, UBERON:0002084, UBERON:0002349, UBERON:0006566; GO:0006302, GO:0006914, GO:0006915, GO:0006979, GO:0007005, GO:0034614, GO:0045214, GO:0060048, GO:0090398, GO:0097707; CHEBI:28748, CHEBI:41977, CHEBI:42068, CHEBI:3441, CHEBI:4784, CHEBI:9241, CHEBI:39548, CHEBI:82720, CHEBI:85078, CHEBI:18248, CHEBI:29033; NCIT:C15632, NCIT:C15986, NCIT:C15747, NCIT:C15246, NCIT:C51674, NCIT:C80436, NCIT:C456; hgnc:12403, hgnc:11949, hgnc:9802, hgnc:7577, hgnc:6636, hgnc:939, hgnc:11180, hgnc:1516, hgnc:2874, hgnc:7876, hgnc:10484, hgnc:4886.

Verified live via OLS4 or the HGNC REST API: MONDO:0022653; CHEBI:47898, CHEBI:50223, CHEBI:50729, CHEBI:3347; NCIT:C1333; GO:0003918, GO:0006879; HGNC:11990 (TOP2B), HGNC:9866 (RARG), HGNC:1548 (CBR1), HGNC:1549 (CBR3), HGNC:14015 (CELF4), HGNC:4556 (GPX4), HGNC:49 (ABCB8), HGNC:16484 (SLC28A3), HGNC:12538 (UGT1A6), HGNC:4820 (HAS3), HGNC:7782 (NFE2L2), HGNC:5013 (HMOX1), HGNC:812 (ATP2A2), HGNC:11989 (TOP2A).

Explicitly flagged as NOT verified in this pass — look them up before binding: all ICD-10/ICD-11 codes; all LOINC codes; all GO Cellular Component IDs in §7.3; all NCBITaxon IDs in §14.1; the NCIT terms for echocardiography, CMR, and MUGA; ECTO exposure terms.

One obsolescence caught: GO:0055072 is recorded in the local cache as obsolete iron ion homeostasis. Use GO:0006879 intracellular iron ion homeostasis instead.

Two PMIDs cited from search-engine summaries only, not fetched abstracts — verify before use as evidence: the JACC CardioOncology 2024 functional-validation study naming RAC2, and the liposomal-doxorubicin systematic review (PMID:41084073 is the likely match). The SLC28A3, UGT1A6, and HAS3 associations in §4.1 are reported without a fetched primary citation and need one.

Key References

PMID Citation Role
23104132 Zhang S et al. Nat Med 2012;18(11):1639-42 TOP2B is the mechanistic target
24382354 Ichikawa Y et al. J Clin Invest 2014;124(2):617-30 Mitochondrial iron; human tissue anchor
30692261 Fang X et al. PNAS 2019 Ferroptosis; Nrf2–HMOX1 iron release
32376803 Tadokoro T et al. JCI Insight 2020 GPX4 and mitochondria-dependent ferroptosis
26237429 Aminkeng F et al. Nat Genet 2015;47(9):1079-84 RARG rs2229774 GWAS
34525346 Magdy T et al. Cell Stem Cell 2021;28(12):2076-2089 RARG mechanism + CD1530
26811534 Wang X et al. J Clin Oncol 2016 CELF4 gene–environment interaction
22124095 Blanco JG et al. J Clin Oncol 2012 CBR1/CBR3; low-dose risk
30987448 Garcia-Pavia P et al. Circulation 2019 TTN truncating variants
27089514 Burridge PW et al. Nat Med 2016;22(5):547-56 Patient-specific hiPSC-CM platform
12767102 Swain SM et al. Cancer 2003;97(11):2869-79 Adult dose–response
30703192 Feijen EAM et al. JAMA Oncol 2019;5(6):864-871 Cardiotoxicity dose-equivalence ratios
25948538 Cardinale D et al. Circulation 2015;131(22):1981-8 Timing, incidence, recovery
15148277 Cardinale D et al. Circulation 2004;109(22):2749-54 Troponin risk stratification
19996459 Mulrooney DA et al. BMJ 2009;339:b4606 CCSS long-term cardiac outcomes
36017568 Lyon AR et al. Eur Heart J 2022;43(41):4229-4361 ESC 2022 cardio-oncology guideline
39106857 Rivero-Santana B et al. Eur Heart J 2025;46(3):273-284 HFA-ICOS risk score validation
27918725 Armenian SH et al. J Clin Oncol 2017 ASCO survivorship guideline
36162822 de Baat EC et al. Cochrane Database Syst Rev 2022;9:CD014638 Dexrazoxane meta-analysis
20850381 Lipshultz SE et al. Lancet Oncol 2010;11(10):950-61 Dexrazoxane long-term paediatric
37552303 Neilan TG et al. JAMA 2023;330(6):528-536 STOP-CA atorvastatin RCT
26903532 Gulati G et al. Eur Heart J 2016;37(21):1671-80 PRADA candesartan/metoprolol
33220426 Thavendiranathan P et al. J Am Coll Cardiol 2021;77(4):392-401 SUCCOUR GLS-guided therapy
36435732 Negishi T et al. JACC Cardiovasc Imaging 2023 SUCCOUR 3-year results
39479333 Camilli M et al. JACC CardioOncol 2024;6(5):655-677 State-of-the-art review
38774014 Boen HM et al. JACC CardioOncol 2024;6(2):183-199 Circulating miRNA biomarkers
33898277 Tagawa M et al. Open Vet J 2021;11(1):6-10 Naturally occurring canine AIC
42102394 Wang Q et al. Cancer Res Commun 2026 TOP2B–SMYD1; ASO-18 (preclinical, new)
39237985 EMPACARD-PILOT SGLT2 inhibitor pilot

Sources (web): - ESC 2022 Guidelines on cardio-oncology — European Heart Journal - Anthracycline Cardiotoxicity in Adult Cancer Patients — JACC: CardioOncology (PMC11520218) - STOP-CA Randomized Clinical Trial — JAMA - HFA-ICOS risk score validation — PubMed - Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation — JCI - Identification of the molecular basis of doxorubicin-induced cardiotoxicity — Nature Medicine - A coding variant in RARG confers susceptibility — Nature Genetics - Genetics of Anthracycline-Associated Cardiotoxicity — Frontiers in Cardiovascular Medicine - Novel Mechanism of and Therapeutic Approach for Anthracycline-Induced Cardiotoxicity — Cancer Research Communications - Efficacy and cardiovascular safety of liposomal doxorubicin — Cardio-Oncology - PROTECT trial (dapagliflozin) rationale and design — Cardio-Oncology - MONDO:0022653 — EBI OLS4

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 36
Resolved 36
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 9
Quoted claims found in source 8
Quoted claims not found in source 1
References weighed for topical relevance 36
On topic 29
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:41084073 (abstract only): "In five trials comparing liposomal doxorubicin (LD) with conventional doxorubicin, LD reduced the risk of clinical heart failure (OR 0.18, 0.08–0.38) and subclinical heart failure (RR 0.31, 0.20–0.48)"
  • closest text in source: "Nine studies compared LD with conventional doxorubicin and three with epirubicin"