Heart Failure

Complex MONDO:0005252 Pathograph 7 Show in embeddings browser Cardiovascular Disease

Heart failure is a clinical syndrome in which structural or functional cardiac impairment prevents the heart from delivering output sufficient to meet the body's metabolic demands at normal filling pressures. It is classified by left ventricular ejection fraction (reduced, mildly reduced, or preserved). Maladaptive neurohormonal activation drives progressive ventricular remodeling, producing dyspnea, fatigue, and fluid congestion.

Ask OpenScientist

Ask a research question about Heart Failure. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

9
Pathophys.
6
Phenotypes
3
Gaps
7
Pathograph
3
Genes
8
Medical Actions
3
Subtypes
7
Datasets
6
References
2
Deep Research
🏷

Classifications

Harrison's Part
CARDIOVASCULAR
◆

Subtypes

3
Heart Failure with Reduced Ejection Fraction (HFrEF)
Left ventricular ejection fraction less than 40%, systolic dysfunction predominates.
Heart Failure with Preserved Ejection Fraction (HFpEF)
Left ventricular ejection fraction 50% or greater, diastolic dysfunction predominates.
Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)
Left ventricular ejection fraction 41-49%, intermediate phenotype.
C

Comorbidities

Obesity <-> Heart Failure
Disease B A_BEFORE_B CANDIDATE
Respiratory Syncytial Virus Infection <-> Heart Failure
Disease B A_BEFORE_B CURATED
?

Discussions and Knowledge Gaps

3
What are the distinct mechanistic pathways by which lipoprotein(a) drives coronary microvascular dysfunction (CMD) as opposed to its well-characterized role in epicardial macrovascular atherosclerosis, and what are the biomarker and disease-modifying therapeutic implications for heart failure (especially HFpEF)?
KNOWLEDGE GAP OPEN gap_lpa_microvascular_vs_macrovascular_mechanism
Attached to
pathophysiology#Lipoprotein(a)-Driven Coronary Microvascular Dysfunction
Lp(a)'s unique structural properties — antifibrinolytic apolipoprotein(a) and carriage of oxidized phospholipids — promote endothelial dysfunction, oxidative stress, inflammatory activation, microvascular remodeling, and microthrombotic susceptibility. These mechanisms are extensively characterized in epicardial coronary atherosclerosis (macrovascular disease), but Lp(a)'s contribution to the coronary microcirculation has received comparatively limited attention. Observational studies link elevated Lp(a) to impaired coronary flow reserve, yet the microvascular-specific pathways remain poorly delineated and no disease-modifying therapies targeting Lp(a) in CMD exist.
Seeded from PMID:41936813 — The role of lipoprotein(a) in coronary microvascular dysfunction: Mechanistic pathways, clinical evidence, and therapeutic perspectives
Is pyroptosis (via the AIM2/Caspase-1/GSDMD inflammasome pathway) a primary driver of HFpEF pathophysiology or a secondary inflammatory consequence of diastolic dysfunction and ventricular remodeling? What is the human clinical relevance of AIM2/Caspase-1/GSDMD pathway dysregulation in HFpEF, and does dapagliflozin's therapeutic benefit in HFpEF arise primarily through pyroptosis attenuation or through other complementary mechanisms?
HUMAN MODEL MISMATCH OPEN gap_pyroptosis_hfpef_dapagliflozin_mechanism
Attached to
pathophysiology#Ventricular Remodeling
Preclinical evidence (PMID:42246167) demonstrates that dapagliflozin alleviates HFpEF symptoms and decreases myocardial pyroptosis in a mouse model through AIM2/Caspase-1/GSDMD axis regulation. Pyroptosis is a pro-inflammatory form of programmed cell death that induces inflammatory amplification and contributes to cardiovascular disease. However, the mechanistic hierarchy remains unclear: whether AIM2-inflammasome activation is a primary pathophysiological driver of HFpEF (and thus should be added as a core pathophysiology node) versus a secondary consequence of the established mechanisms (myocardial contractile dysfunction, neurohormonal activation, ventricular remodeling, diastolic dysfunction). Furthermore, the human clinical significance of this pathway in HFpEF remains to be determined — the evidence is primarily from mouse cardiomyocyte and animal models, and whether AIM2/Caspase-1/GSDMD dysregulation is a targetable therapeutic mechanism in human HFpEF patients requires human tissue validation and clinical trial evidence.
Proposed experiments
AIM2/Caspase-1/GSDMD pathway activation and pyroptosis quantification in HFpEF patient cardiac tissue
exp_hfpef_aim2_pyroptosis_human_tissue
Quantify AIM2 protein, active Caspase-1, GSDMD proteolysis, and pyroptosis markers (e.g., released IL-1β, IL-18) in cardiac tissue from HFpEF patients (endomyocardial biopsies or cardiac explants undergoing transplantation) compared to age-matched controls without heart failure. Correlate AIM2/Caspase-1/GSDMD activation with biomarkers of diastolic dysfunction and ventricular stiffness to determine whether pathway dysregulation is primary or secondary.
Dose-response validation of dapagliflozin on AIM2/Caspase-1/GSDMD pyroptosis in human iPSC-derived cardiomyocytes under diastolic stress
exp_hfpef_ipsc_cardiomyocyte_pyroptosis_dapagliflozin
Establish human iPSC-derived cardiomyocyte models of diastolic dysfunction stress (diastolic calcium handling impairment, passive stiffness elevation) and measure baseline AIM2/Caspase-1/GSDMD activation and pyroptosis rates. Apply dapagliflozin in a dose-response manner and quantify pyroptosis attenuation, mechanism of action (direct AIM2 inhibition vs. indirect via restored calcium handling), and whether dapagliflozin's benefit is AIM2-dependent (using AIM2 knockdown or Caspase-1 inhibitors like VX-765 to block downstream pyroptosis execution).
Biomarker-driven clinical trial subset analysis correlating pyroptosis pathway activation with dapagliflozin response in HFpEF
exp_hfpef_dapagliflozin_trial_pyroptosis_biomarker
In a prospective HFpEF cohort treated with dapagliflozin, measure baseline circulating pyroptosis biomarkers (cleaved Caspase-1, IL-1β, IL-18, or GSDMD-N terminal fragment) and cardiac imaging of diastolic dysfunction and myocardial stiffness. Stratify patients by baseline AIM2/Caspase-1 activation status and assess whether high-baseline pyroptosis correlates with enhanced dapagliflozin treatment response (echocardiographic improvement in ejection fraction, diastolic parameters, or symptom relief) and whether post-treatment pyroptosis attenuation predicts clinical benefit.
Seeded from PMID:42246167 — Dapagliflozin alleviates heart failure with preserved ejection fraction potentially by regulating the AIM2/caspase-1/GSDMD pathway and attenuating pyroptosis
Does the incomplete response of HFpEF to single-pathway therapy reflect self-reinforcing endocrine feedback circuits that regenerate profibrotic signalling around any single blocked node, and can a phenotype-guided strategy that targets the dominant upstream driver in a given patient outperform uniform therapy?
KNOWLEDGE GAP OPEN gap_hfpef_single_pathway_therapy_resistance
Attached to
pathophysiology#Endocrine Convergence on Shared Profibrotic Effectors pathophysiology#Tissue Glucocorticoid Amplification by 11beta-HSD1 pathophysiology#Postmenopausal Oestrogen Withdrawal pathophysiology#Ventricular Remodeling
Three self-reinforcing circuits are proposed to explain why blocking one axis is insufficient. In the metabolic circuit, dysfunctional adipose tissue releases TNF-alpha and IL-6, which worsen insulin signalling and in turn worsen adipocyte dysfunction. In the RAAS-redox circuit, angiotensin II stimulates NADPH oxidase-derived superoxide, which inactivates nitric oxide and activates NF-kB, upregulating angiotensinogen and perpetuating RAAS activation. In the glucocorticoid circuit, 11beta-HSD1-mediated cortisol regeneration in visceral fat promotes further fat deposition, expanding the substrate for local glucocorticoid amplification independently of adrenal secretion. If this account is right, suppressing RAAS while leaving insulin resistance and adipose inflammation unaddressed permits continued ligand-independent MR activation and TGF-beta-driven fibrosis. Two things keep this a gap rather than a finding. The circuit model is a review-level synthesis, not a tested causal claim, and no trial has prospectively assigned HFpEF patients to therapy by dominant endocrine driver. The proposal is also partly circular as stated: the clinical success of SGLT2 inhibitors is offered as validation that multi-axis intervention beats single-pathway targeting, but those agents were not designed or trialled as multi-axis therapy, and their pleiotropy is an after-the-fact characterisation of why an effective drug works.
Proposed experiments
Phenotype-stratified antifibrotic assignment in HFpEF
exp_hfpef_phenotype_guided_antifibrotic
Phenotype an HFpEF cohort for dominant endocrine driver at baseline (visceral-adipose/glucocorticoid, insulin-resistant, RAAS-predominant, postmenopausal oestrogen-deficient), stratifying by renal function so that FGF23 and PTH are read within eGFR strata rather than as free-standing signals. Assign therapy matched versus unmatched to the dominant driver and follow cardiac MRI extracellular volume alongside clinical events. An adaptive platform design enriched for homogeneous endocrine subtypes is the efficient form of this.
Decision criterion
Whether driver-matched assignment outperforms unmatched assignment on extracellular volume and events discriminates the phenotype-guided hypothesis from the simpler explanation that some HFpEF therapies are just broadly effective regardless of endocrine subtype.
Supporting outcome
  • A driver-matched arm showing greater reduction in extracellular volume and in worsening heart failure events than an unmatched arm receiving the same set of drugs, supporting the phenotype-guided model.
Refuting outcome
  • Equivalent benefit regardless of whether therapy matched the dominant driver, indicating that the observed responses reflect general drug efficacy rather than the endocrine phenotype the model assigns them to.
The review's own therapy grading is preserved rather than flattened. SGLT2 inhibitors, finerenone and GLP-1 receptor agonists are described as having the strongest evidence, while 11beta-HSD1 and D3 deiodinase inhibitors, ER-beta-selective agonists and anti-FGF23 strategies are described as mechanistically compelling but unvalidated. Nothing in the emerging group is curated as a treatment in this entry.
Show evidence (3 references)
PMID:42602176 SUPPORT Other
"Three self-reinforcing feedback circuits explain HFpEF's resistance to single-pathway therapy."
The claim under examination, stated by the review as an explanation rather than demonstrated.
PMID:42602176 SUPPORT Other
"Consequently, suppressing RAAS while leaving insulin resistance and adipose inflammation unaddressed permits continued ligand-independent MR activation and TGF-β-driven fibrosis, explaining the partial benefit of monotherapy."
The specific prediction the circuit model makes about monotherapy, which is what a phenotype-stratified trial would test.
PMID:42602176 SUPPORT Other
"The durable strategy is to neutralise the dominant upstream driver in a given patient- less molecularly selective but interrupting the cascade before it diversifies- which, since the dominant driver differs between patients, necessarily implies a phenotype-guided approach."
The proposed resolution, recorded as a proposal because no trial has assigned therapy by dominant driver.
⚙

Pathophysiology

9
Myocardial Contractile Dysfunction
Reduced cardiac output due to impaired ventricular contraction (systolic dysfunction) or relaxation (diastolic dysfunction). The heart cannot meet metabolic demands.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Cardiac Contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Cardiac Contraction, annotated with heart contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:33432192 SUPPORT Other
"Heart failure with preserved ejection fraction (HFpEF) affects half of all patients with heart failure worldwide, is increasing in prevalence, confers substantial morbidity and mortality, and has very few effective treatments."
This review discusses the prevalence and severity of HFpEF, a form characterized by diastolic dysfunction rather than systolic dysfunction, demonstrating the importance of both contractile mechanisms in heart failure.
PMID:40892534 SUPPORT Other
"Myocardial fibrosis and its surrogate changes in LV structure and geometry lead to functional impairments such as increased diastolic stiffness and elevated filling pressures and are associated with reduced exercise tolerance and poor prognosis in patients with HFpEF."
This demonstrates how structural changes lead to diastolic dysfunction and impaired cardiac output, supporting the mechanism of contractile dysfunction in heart failure.
Neurohormonal Activation
Compensatory activation of RAAS and sympathetic nervous system initially maintains cardiac output but leads to maladaptive remodeling, sodium retention, and progressive dysfunction.
RAAS Activation GO:0002018 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves RAAS Activation, annotated with renin-angiotensin regulation of aldosterone production (GO:0002018). GO:0002018 is a biological process from the Gene Ontology.
Downstream
Endocrine Convergence on Shared Profibrotic Effectors Angiotensin II and aldosterone are two of the inputs feeding the shared profibrotic effectors, which is why blockade upstream of the mineralocorticoid receptor does not silence the programme.
Show evidence (2 references)
PMID:37895150 SUPPORT Other
"In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the arginine vasopressin (AVP) system, are activated to various degrees producing often-observed tachycardia and concomitant increased..."
This directly confirms the activation of neurohormonal systems (RAAS and SNS) in heart failure patients, supporting the compensatory mechanism described.
PMID:37895150 SUPPORT Other
"Furthermore, sustained neurohormonal activation plays a key role in the progression of HF and may be responsible for the pathogenetic mechanisms leading to the perpetuation of the pathophysiology and worsening of the HF signs and symptoms."
This supports the concept that while initially compensatory, sustained neurohormonal activation leads to maladaptive effects and disease progression.
Ventricular Remodeling
Structural changes including ventricular dilation, hypertrophy, and fibrosis that initially compensate but eventually worsen heart function.
Cardiac Fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac Fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology.
Cardiac Remodeling GO:0060420 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Cardiac Remodeling, annotated with regulation of heart growth (GO:0060420). GO:0060420 is a biological process from the Gene Ontology.
Show evidence (3 references)
PMID:40892534 SUPPORT Other
"Comorbidities such as hypertension, obesity, or diabetes are present in many HFpEF patients and are hypothesized to contribute to adverse cardiac remodelling and myocardial fibrosis through a variety of haemodynamic and metabolic impairments, with nearly half of all HFpEF patients exhibiting..."
This demonstrates the prevalence and mechanisms of ventricular remodeling including hypertrophy and fibrosis in heart failure patients, particularly in HFpEF.
PMID:38636927 SUPPORT Model Organism
"Heart failure is usually accompanied by activation of the sympathetic nerve, and excessive activation of the sympathetic nerve promotes cardiac remodeling and cardiac dysfunction. In the isoproterenol (ISO)-induced animal model, it is often accompanied by myocardial hypertrophy, fibrosis, and..."
This confirms that cardiac remodeling, including hypertrophy and fibrosis, is a key pathophysiological mechanism promoted by sympathetic activation in heart failure.
PMID:38636927 SUPPORT Model Organism
"Lilrb4a alleviates cardiac dysfunction and ISO-induced arrhythmogenic remodeling associated with cardiac fibrosis and inflammation through the regulation of NF-κB signaling and MAPK signaling activation."
This identifies specific signaling pathways (NF-κB and MAPK) involved in cardiac remodeling and fibrosis, demonstrating the molecular mechanisms underlying structural changes.
Fluid Retention
Impaired sodium excretion leads to volume overload, causing pulmonary and peripheral edema. Results from reduced renal perfusion and neurohormonal activation.
Show evidence (1 reference)
PMID:36769308 SUPPORT Other
"The pathophysiology between the heart and the kidneys is bidirectional. Common mechanisms leading to the dysfunction of these organs result in a vicious cycle of cardiorenal deterioration."
This demonstrates the bidirectional relationship between heart and kidney dysfunction that leads to fluid retention in heart failure through cardiorenal mechanisms.
Endocrine Convergence on Shared Profibrotic Effectors
In HFpEF, myocardial fibrosis is driven not by haemodynamic load alone but by several endocrine axes that converge on a small set of shared intracellular effectors. TGF-beta-Smad signalling receives simultaneous input from angiotensin II, aldosterone, cortisol, leptin, FGF23 and thyroid deficiency; NADPH oxidase-derived oxidative stress amplifies TGF-beta, cross-links matrix via lysyl oxidase, and drives ligand-independent mineralocorticoid receptor activation; and the NO-cGMP-PKG axis, normally a brake on fibroblast activation, is suppressed by virtually every endocrine disturbance in the syndrome. Because several axes feed each convergence point, and because self-reinforcing feedback circuits regenerate the signal, blocking any single shared effector is rapidly bypassed. This node is the reason the entry treats HFpEF fibrosis as multi-axis rather than as the downstream of one pathway.
Cardiac Fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac Fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology.
TGF-beta-Smad profibrotic signalling in cardiac fibroblasts GO:0007179 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased TGF-beta-Smad profibrotic signalling in cardiac fibroblasts, annotated with transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology. ↑ INCREASED NADPH oxidase-derived oxidative stress GO:0042554 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased NADPH oxidase-derived oxidative stress, annotated with superoxide anion generation (GO:0042554). GO:0042554 is a biological process from the Gene Ontology. ↑ INCREASED NO-cGMP-PKG braking of fibroblast activation GO:0038060 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased NO-cGMP-PKG braking of fibroblast activation, annotated with nitric oxide-cGMP-mediated signaling (GO:0038060). GO:0038060 is a biological process from the Gene Ontology. ↓ DECREASED mineralocorticoid receptor signalling GO:0031959 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased mineralocorticoid receptor signalling, annotated with nuclear receptor-mediated mineralocorticoid signaling pathway (GO:0031959). GO:0031959 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Ventricular Remodeling Convergent profibrotic signalling drives cardiac fibroblast activation and interstitial extracellular matrix accumulation.
Show evidence (4 references)
PMID:42602176 SUPPORT Other
"The axes converge on shared intracellular effectors, generating a programme exceeding any single axis. TGF-β-Smad signalling receives simultaneous inputs from angiotensin II, aldosterone, cortisol, leptin, FGF23, and thyroid deficiency."
Establishes the convergence structure and names the axes feeding the TGF-beta-Smad effector.
PMID:42602176 SUPPORT Other
"NADPH oxidase-derived oxidative stress amplifies TGF-β, promotes ECM cross-linking via lysyl oxidase, and drives ligand-independent MR activation."
Supports the oxidative-stress effector and its link to ligand-independent mineralocorticoid receptor activation.
PMID:42602176 SUPPORT Other
"The NO-cGMP-PKG axis, a critical brake on fibroblast activation, is suppressed by virtually every endocrine disturbance in HFpEF, while the mTOR-AMPK-FOXO imbalance translates metabolic excess into sustained profibrotic transcription"
Supports suppression of the NO-cGMP-PKG brake as a shared endpoint of the endocrine disturbances.
+ 1 more reference
Tissue Glucocorticoid Amplification by 11beta-HSD1
11beta-HSD1 regenerates active cortisol from cortisone inside adipose tissue, liver, vasculature and myocardium, so glucocorticoid exposure at the tissue level can be raised without any change in adrenal secretion. Chronic glucocorticoid excess promotes cardiac fibroblast proliferation, myofibroblast transdifferentiation and collagen synthesis through the glucocorticoid receptor, potentiates TGF-beta signalling, and suppresses nitric oxide availability. In non-epithelial tissue cortisol also binds the mineralocorticoid receptor with affinity comparable to aldosterone, so glucocorticoid excess can engage RAAS-like profibrotic programmes directly.
Cardiac Fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac Fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology.
intracellular regeneration of active cortisol from cortisone GO:0008211 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased intracellular regeneration of active cortisol from cortisone, annotated with glucocorticoid metabolic process (GO:0008211). GO:0008211 is a biological process from the Gene Ontology. ↑ INCREASED
11beta-HSD1 reductase activity regenerating cortisol GO:0070524 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased 11beta-HSD1 reductase activity regenerating cortisol, annotated with 11-beta-hydroxysteroid dehydrogenase (NADP+) activity (GO:0070524). GO:0070524 is a molecular function from the Gene Ontology. ↑ INCREASED glucocorticoid receptor-driven profibrotic transcription GO:0004883 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased glucocorticoid receptor-driven profibrotic transcription, annotated with nuclear glucocorticoid receptor activity (GO:0004883). GO:0004883 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Endocrine Convergence on Shared Profibrotic Effectors Tissue cortisol regeneration feeds the shared TGF-beta and mineralocorticoid receptor effectors.
Show evidence (4 references)
PMID:42602176 SUPPORT Other
"Tissue-specific amplification of glucocorticoid activity by 11β-HSD1, which regenerates active cortisol from cortisone intracellularly in adipose tissue, liver, vasculature, and myocardium, is an underappreciated driver of myocardial fibrosis."
Establishes the tissue-level amplification mechanism as distinct from circulating glucocorticoid excess.
PMID:42602176 SUPPORT Other
"In non-epithelial tissues, cortisol can also bind MRs with an affinity comparable to that of aldosterone, enabling glucocorticoid excess to engage RAAS-like profibrotic programmes, particularly when oxidative stress alters MR signalling in the ageing or obese myocardium"
Links this axis to mineralocorticoid receptor activation, which is why MR antagonism is relevant to a glucocorticoid-driven phenotype.
PMID:42602176 SUPPORT Other
"However, human evidence remains largely confined to metabolic, dermatological, or steroid-exposure models rather than cardiac endpoints."
Bounds the axis. The cardiac claim is not supported by human cardiac-endpoint data.
+ 1 more reference
Postmenopausal Oestrogen Withdrawal
HFpEF disproportionately affects postmenopausal women, and the review's account of why is structural rather than additive. Oestrogen normally restrains three profibrotic axes at once — it reduces ACE expression and AT1 receptor density, enhances insulin sensitivity through GLUT4 and IRS-1 signalling, and maintains an anti-inflammatory adipokine profile — so its withdrawal disinhibits all three in concert, producing the concentric, microvascular-predominant female phenotype.
Downstream
Loss of Myocardial Oestrogen Receptor Signalling Falling circulating oestrogen removes receptor occupancy in the myocardium and coronary endothelium.
Endocrine Convergence on Shared Profibrotic Effectors Loss of systemic oestrogen restraint releases RAAS, insulin-resistance and adipokine inputs onto the shared profibrotic effectors simultaneously.
Show evidence (2 references)
PMID:42602176 SUPPORT Other
"The female predominance of HFpEF reflects oestrogen loss, which amplifies multiple axes simultaneously rather than acting alone."
States the multi-axis structure of the sex difference rather than a single-mechanism account.
PMID:42602176 SUPPORT Other
"Oestrogen normally restrains RAAS by reducing ACE expression and AT1 density, enhances insulin sensitivity via GLUT4 and IRS-1 signalling, and maintains an anti-inflammatory adipokine profile; its withdrawal disinhibits these three profibrotic axes in concert, producing the concentric,..."
Names the three systemic axes oestrogen restrains and the phenotype its withdrawal produces.
Loss of Myocardial Oestrogen Receptor Signalling
The direct cardiac arm of oestrogen withdrawal, distinct from the systemic disinhibition upstream. Oestrogen acting through ER-alpha and ER-beta suppresses cardiac fibroblast proliferation, inhibits TGF-beta/CTGF-mediated collagen transcription via ER-beta, upregulates endothelial nitric oxide synthase, and supports mitochondrial function. Menopause removes an antifibrotic and vasoprotective influence acting on the myocardium itself, at the same time as it releases the systemic axes.
Cardiac Fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac Fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology.
oestrogen receptor signalling in myocardium and coronary endothelium GO:0030520 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased oestrogen receptor signalling in myocardium and coronary endothelium, annotated with estrogen receptor signaling pathway (GO:0030520). GO:0030520 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Endocrine Convergence on Shared Profibrotic Effectors Loss of the ER-beta brake on TGF-beta/CTGF collagen transcription and of eNOS support feeds the shared effectors directly.
Show evidence (2 references)
PMID:42602176 SUPPORT Other
"Oestrogen, acting through ERα and ERβ, suppresses fibroblast proliferation, inhibits TGF-β/CTGF-mediated collagen transcription via ERβ, upregulates endothelial nitric oxide synthase (eNOS), and supports mitochondrial function"
The direct myocardial and endothelial arm of oestrogen action, whose loss this node models.
PMID:42602176 SUPPORT Other
"Menopause removes these antifibrotic and vasoprotective influences, shifts systemic immunity towards a pro-inflammatory state by reducing suppression of nuclear factor kappa B (NF-κB), and reduces MMP-2/MMP-9 while upregulating TIMP-1, thereby tilting the ECM balance towards accumulation"
States that menopause removes these influences and tilts the matrix balance towards accumulation.
Lipoprotein(a)-Driven Coronary Microvascular Dysfunction
Lipoprotein(a) [Lp(a)], a genetically determined cardiovascular risk factor, promotes coronary microvascular dysfunction through endothelial dysfunction, oxidative stress, inflammatory activation, and microvascular remodeling. Lp(a) carries oxidized phospholipids and exhibits antifibrinolytic properties that distinctly drive microvascular disease independent of epicardial coronary atherosclerosis, with particular relevance to HFpEF pathogenesis.
Endothelial Cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Endothelial Cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology. Vascular Smooth Muscle Cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Vascular Smooth Muscle Cell, annotated with vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology.
Oxidative Stress Response GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Oxidative Stress Response, annotated with response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ↑ INCREASED Vascular Remodeling GO:0001974 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Vascular Remodeling, annotated with blood vessel remodeling (GO:0001974). GO:0001974 is a biological process from the Gene Ontology. ⚠ ABNORMAL Microthrombotic Events GO:0007596 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Microthrombotic Events, annotated with blood coagulation (GO:0007596). GO:0007596 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (2 references)
PMID:41936813 SUPPORT Human Clinical
"Lp(a) exhibits unique structural and biological properties, including the antifibrinolytic effects of apolipoprotein(a) and carriage of oxidized phospholipids, which promote endothelial dysfunction, oxidative stress, inflammatory activation, microvascular remodeling, and microthrombotic..."
This directly supports the mechanism of Lp(a)-driven endothelial dysfunction and oxidative stress in coronary microvascular disease.
PMID:41936813 SUPPORT Human Clinical
"Lp(a)], a genetically determined and causal cardiovascular risk factor, has been extensively studied in epicardial coronary atherosclerosis; however, its role in the coronary microcirculation has received comparatively limited attention."
This establishes the distinction between Lp(a)'s well-characterized role in macrovascular atherosclerosis versus its emerging role in microvascular dysfunction specifically relevant to heart failure pathophysiology.
⬡

Pathograph

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

Phenotypes

6
Cardiovascular 1
Cardiomegaly FREQUENT HP:0001640 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomegaly (HP:0001640). HP:0001640 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38636927 SUPPORT Model Organism
"In the isoproterenol (ISO)-induced animal model, it is often accompanied by myocardial hypertrophy, fibrosis, and inflammation."
Cardiomegaly in heart failure results from myocardial hypertrophy, which is a structural adaptation to increased workload and sympathetic activation.
Metabolism 1
Peripheral Edema VERY_FREQUENT HP:0012398 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral Edema (HP:0012398). HP:0012398 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36769308 SUPPORT Other
"The pathophysiology between the heart and the kidneys is bidirectional. Common mechanisms leading to the dysfunction of these organs result in a vicious cycle of cardiorenal deterioration."
Peripheral edema results from the cardiorenal interaction where reduced cardiac output leads to renal dysfunction, sodium retention, and fluid accumulation in peripheral tissues.
Respiratory 2
Dyspnea VERY_FREQUENT 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:40892534 SUPPORT Other
"Myocardial fibrosis and its surrogate changes in LV structure and geometry lead to functional impairments such as increased diastolic stiffness and elevated filling pressures and are associated with reduced exercise tolerance and poor prognosis in patients with HFpEF."
Dyspnea results from elevated filling pressures and reduced exercise tolerance caused by diastolic dysfunction and myocardial fibrosis in heart failure.
Orthopnea FREQUENT 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.
Dyspnea when lying flat
Constitutional 2
Fatigue VERY_FREQUENT 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.
Exercise Intolerance VERY_FREQUENT 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:40892534 SUPPORT Other
"Myocardial fibrosis and its surrogate changes in LV structure and geometry lead to functional impairments such as increased diastolic stiffness and elevated filling pressures and are associated with reduced exercise tolerance and poor prognosis in patients with HFpEF."
Exercise intolerance in heart failure is directly caused by increased diastolic stiffness and elevated filling pressures from myocardial fibrosis and structural remodeling.
🧬

Genetic Associations

3
TTN (Causative)
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.
Show evidence (1 reference)
CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2025-05-30T160000.000Z SUPPORT Other
"TTN | HGNC:12403 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies the TTN-dilated cardiomyopathy relationship as definitive; dilated cardiomyopathy is a leading cause of the heart failure syndrome modelled by this entry.
MYH7 (Causative)
Gene: MYH7 hgnc:7577 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYH7 (hgnc:7577). hgnc:7577 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
CGGV:assertion_4ec27d4f-70ea-4c6a-ad67-d6260ecadcde-2025-05-30T160000.000Z SUPPORT Other
"MYH7 | HGNC:7577 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies the MYH7-dilated cardiomyopathy relationship as definitive, establishing a sarcomeric-cardiomyopathy route to heart failure.
LMNA (Causative)
Gene: LMNA hgnc:6636 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LMNA (hgnc:6636). hgnc:6636 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
CGGV:assertion_132ea1ec-caa9-409a-8670-3edb2ec9c889-2025-05-30T160000.000Z SUPPORT Other
"LMNA | HGNC:6636 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies the LMNA-dilated cardiomyopathy relationship as definitive; LMNA cardiomyopathy progresses to heart failure and carries genotype-specific device indications.
💊

Medical Actions

8
ACE Inhibitors/ARBs
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
Neurohormonal blockade, reduce mortality in HFrEF.
Show evidence (1 reference)
PMID:37254024 SUPPORT Other
"Guideline-directed medical therapy (GDMT) is the cornerstone of pharmacological therapy for patients with heart failure with reduced ejection fraction (HFrEF) and consists of the four main drug classes: renin-angiotensin system inhibitors, evidence-based β-blockers, mineralocorticoid inhibitors..."
Renin-angiotensin system inhibitors are one of the four foundational GDMT drug classes for HFrEF.
Beta Blockers
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
Reduce heart rate and reverse remodeling in HFrEF.
Show evidence (1 reference)
PMID:37254024 SUPPORT Other
"Guideline-directed medical therapy (GDMT) is the cornerstone of pharmacological therapy for patients with heart failure with reduced ejection fraction (HFrEF) and consists of the four main drug classes: renin-angiotensin system inhibitors, evidence-based β-blockers, mineralocorticoid inhibitors..."
Evidence-based beta-blockers are one of the four foundational GDMT drug classes for HFrEF.
ARNI (Sacubitril/Valsartan)
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
Combined neprilysin inhibitor and ARB, superior to ACE inhibitors.
SGLT2 Inhibitors
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
Reduce hospitalizations and mortality across HF spectrum.
Show evidence (2 references)
PMID:41110921 SUPPORT Other
"Recommendations are complemented by practical tips to guide the initiation, titration, and maintenance of these foundational treatments."
The 2025 CCS/CHFS guideline update covers pharmacologic management of heart failure with nonreduced ejection fraction, the setting in which SGLT2 inhibitor use extends across the ejection-fraction spectrum.
PMID:31535829 SUPPORT Human Clinical
"A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273..."
DAPA-HF randomised trial quantifies the reduction in worsening heart failure events and cardiovascular death with an SGLT2 inhibitor, supporting the claim that these agents reduce hospitalizations and mortality.
Mineralocorticoid Receptor Antagonists
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. eplerenone CHEBI:31547 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses eplerenone (CHEBI:31547). CHEBI:31547 is a therapeutic agent from Chemical Entities of Biological Interest. finerenone CHEBI:747008 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses finerenone (CHEBI:747008). CHEBI:747008 is a therapeutic agent from Chemical Entities of Biological Interest.
Spironolactone or eplerenone for additional neurohormonal blockade, and the non-steroidal agent finerenone. The mechanistic case for adding an MRA on top of an ACE inhibitor or ARB is that those drugs leave the terminal mineralocorticoid receptor programme intact by several independent routes: chymase-dependent, ACE-independent angiotensin II generation circumvents ACE inhibition; aldosterone escape restores MR activation during chronic AT1 blockade; and cortisol regenerated by 11beta-HSD1, together with reactive oxygen species, drives ligand-independent Rac1-mediated MR activation. MR antagonism is therefore not a redundant second hit on the same pathway but the only one of the three drug classes that reaches the terminal effector.
Mechanism Target:
INHIBITS Endocrine Convergence on Shared Profibrotic Effectors — MR antagonism blocks the terminal mineralocorticoid receptor arm of the convergent profibrotic programme, including the ligand-independent activation driven by oxidative stress and by cortisol acting on the MR. INHIBITS rather than MODULATES because the target is a receptor the drug class antagonises directly, but note this blocks one arm of a multi-axis convergence, which is why the entry does not treat it as disease-modifying on its own.
Show evidence (1 reference)
PMID:42602176 SUPPORT Other
"Both drug classes thus leave terminal MR signalling intact, providing the rationale for direct MR antagonism."
States the mechanistic rationale for MR antagonism as distinct from ACE inhibition and AT1 blockade.
Show evidence (4 references)
PMID:42602176 SUPPORT Other
"ARBs block AT1 directly, yet fibrosis persists because the terminal MR-driven program is engaged independently of AT1: aldosterone escape restores MR activation during chronic blockade"
Documents aldosterone escape as one route by which AT1 blockade fails to reach the MR programme.
PMID:42602176 SUPPORT Other
"ACE inhibition is circumvented by chymase-dependent, ACE-independent angiotensin II generation"
The corresponding escape route for ACE inhibitors.
PMID:42602176 SUPPORT Other
"In FINEARTS-HF, the non-steroidal MRA finerenone, with high MR selectivity and a favourable tissue-distribution, reduced the composite of worsening heart failure events and cardiovascular death in patients with mildly reduced or preserved ejection fraction, although hyperkalaemia remains an..."
Randomised outcome evidence for MR antagonism specifically in mildly reduced and preserved ejection fraction, with its safety caveat, extending a treatment previously evidenced here only for HFrEF.
+ 1 more reference
Diuretics
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
Manage fluid overload and congestion symptoms.
Cardiac Resynchronization Therapy
Action: Cardiac Resynchronization TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Cardiac Resynchronization Therapy (NCIT:C80436). NCIT:C80436 is a clinical intervention from the NCI Thesaurus. NCIT:C80436
For patients with wide QRS and reduced EF.
Implantable Cardioverter-Defibrillator
Action: Implantable Cardioverter-Defibrillator PlacementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Implantable Cardioverter-Defibrillator Placement (NCIT:C80435). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. NCIT:C80435
Prevents sudden cardiac death in high-risk patients.
🌍

Environmental Factors

3
Hypertension
Major cause of heart failure
Show evidence (1 reference)
PMID:36346411 SUPPORT Human Clinical
"Hypertension is associated with increased risk of cardiovascular disease (CVD) events (coronary heart disease, heart failure, and stroke) and death"
Review of hypertension treatment naming heart failure as one of the CVD event risks hypertension causes.
Coronary Artery Disease
Leading cause of HFrEF
Show evidence (1 reference)
PMID:28613623 SUPPORT Human Clinical
"Ischemic heart disease is the leading cause of HF"
Clinical overview stating ischemic heart disease (coronary artery disease) is the leading cause of heart failure.
Alcohol Abuse
exposure to alcohol consumption ECTO:0001082 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to alcohol consumption (ECTO:0001082). ECTO:0001082 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Can cause alcoholic cardiomyopathy.
Show evidence (2 references)
PMID:20308914 SUPPORT Human Clinical
"chronic excessive alcohol consumption may lead to progressive and chronic cardiac dysfunction and can be a possible cause of dilated cardiomyopathy, referred to as alcoholic cardiomyopathy (ACM)"
States the claim this entry makes, that sustained excessive alcohol intake can itself cause a dilated cardiomyopathy, and names the entity.
PMID:38213665 SUPPORT Human Clinical
"Chronic excessive alcohol consumption is associated with a range of cardiac complications, including decreased myocardial contractility, hypertension, arrhythmias, MI and heart failure."
Places heart failure itself among the cardiac consequences of chronic excessive intake, which is what makes this exposure relevant to this entry rather than only to the cardiomyopathy it names.
🔬

Biochemical Markers

2
BNP/NT-proBNP (Elevated)
Context: Diagnostic and prognostic biomarker
Show evidence (1 reference)
PMID:37895150 SUPPORT Other
"There are biomarkers of activation of these neurohormonal pathways, such as the natriuretic peptides, catecholamine levels and neprilysin and various newer ones, which may be employed to better understand the mechanisms of HF drugs and also aid in defining the subgroups of patients who might..."
BNP and NT-proBNP are natriuretic peptides that serve as biomarkers of neurohormonal activation in heart failure, useful for diagnosis and therapeutic guidance.
Troponin (Elevated)
Context: May be chronically elevated in heart failure
📊

Related Datasets

7
Specific biological processes associated with T2D-induced left ventricular dysfunction in patients with aortic stenosis pressure overload geo:GSE236191
Background: Type 2 diabetes (T2D) is increasingly prevalent and increases the risk of developing heart failure. T2D is frequently associated with left ventricular (LV) pressure overload, such as encountered in hypertension and aortic stenosis (AS), and few studies suggested an aggravating effect of T2D. We aimed to explore if the deleterious impact of T2D on LV remodeling and function in patients with AS is associated with specific biological processes.
human BULK RNA SEQ n=47
Identified by GEO DataSets index search for Heart Failure (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Prevalence of transthyretin amyloidosis in patients with heart failure and no left ventricular hypertrophy ega:EGAS00001005398
The study prospectively enrolled patients admitted for HF with LV ejection fraction (LVEF) ≥ 50% and LV wall thickness <12 mm. TTR cardiac amyloidosis was diagnosed according to accepted criteria, which include positive cardiac 99-Tc-DPD scintigraphy in the absence of monoclonal protein expansion in blood. In a cohort of patients with HFpEF without LVH, the prevalence of TTR cardiac amyloidosis was 5%. Transthyretin gene sequencing was performed in positive patients.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Heart Failure"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Single-cell spatiotranscriptomic dissection of ex vivo human heart right atrial appendage and pericardial fluid in ischemic heart disease and heart failure ega:EGAS50000000653
We use cardiac and pericardial fluid biopsies collected during open-heart surgery in control, ischemic heart disease, heart failure, and myocardial infarction context. For each sample, single-nuclei RNA sequencing experiment is performed. We also perform spatial transcriptomics on the heart samples. We annotate the cells in major cell types, in addition to subtypes annotation of vascular and immune cells. The disease annotation enables us to reveal substantial differences in gene expression at the cell subpopulation levels. Our results demonstrate the importance of high-resolution cellular type/state mapping in the elucidation of human cardiovascular disease pathogenesis.
human
PMID:38776872
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Heart Failure"); description-level mentions were not accepted. EGA study_type: Transcriptome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Integrated Transcriptomic and Regulatory RNA Profiling Reflects Complex Pathophysiology and Uncovers a Conserved Gene Signature in End Stage Heart Failure RNA-Seq data ega:EGAS50000000810
Heart failure (HF) is a complex syndrome. Despite availability of multiple treatment options, the mortality remains high and the quality of life poor. Better understanding of the underlying pathophysiological processes can lead to development of novel therapies. Multiple comparative transcriptomics studies, which revealed gene level changes in the key pathophysiological pathways in failing hearts, point towards heterogeneity from interplay of disease stage, etiologies and ethnicity. Transcriptomic characterization of HF in patients from different ethnicities can potentially help in understanding the heterogeneity imparted by various factors and the core elements in heart failure.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Heart Failure"); description-level mentions were not accepted. EGA study_type: RNASeq. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Metabolomics of Saliva in Decompensated Heart Failure metabolomics_workbench:ST000588
Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Heart Failure"). Retrieved 2026-08-02.
Metabolomics of Exhaled Breath Condensate in Decompensated Heart Failure metabolomics_workbench:ST000587
Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Heart Failure"). Retrieved 2026-08-02.
Metabolomics of brown adipose tissue in murine heart failure model metabolomics_workbench:ST001961
mouse METABOLOMICS
Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Heart Failure"). Retrieved 2026-08-02.
{ }

Source YAML

click to show 
name: Heart Failure
creation_date: '2025-12-18T17:01:35Z'
description: >-
  Heart failure is a clinical syndrome in which structural or functional cardiac
  impairment prevents the heart from delivering output sufficient to meet the
  body's metabolic demands at normal filling pressures. It is classified by left
  ventricular ejection fraction (reduced, mildly reduced, or preserved).
  Maladaptive neurohormonal activation drives progressive ventricular remodeling,
  producing dyspnea, fatigue, and fluid congestion.
category: Complex
parents:
- Cardiovascular Disease
review_notes: >-
  The `environmental:` entry "Obesity" was removed and migrated to
  kb/comorbidities/com_Obesity__Heart_Failure.yaml (dismech#8296, dismech#8551). It is a disease in
  its own right rather than something external to the organism acting on
  it, so ECTO and XCO have no term that could bind it. All of its evidence
  was carried across. This clears one row from the dismech#8296
  evidence-free backlog for a structural reason rather than by citing it.
disease_term:
  preferred_term: heart failure
  term:
    id: MONDO:0005252
    label: heart failure
has_subtypes:
- name: Heart Failure with Reduced Ejection Fraction (HFrEF)
  description: Left ventricular ejection fraction less than 40%, systolic dysfunction predominates.
- name: Heart Failure with Preserved Ejection Fraction (HFpEF)
  description: Left ventricular ejection fraction 50% or greater, diastolic dysfunction predominates.
- name: Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)
  description: Left ventricular ejection fraction 41-49%, intermediate phenotype.
pathophysiology:
- name: Myocardial Contractile Dysfunction
  description: >
    Reduced cardiac output due to impaired ventricular contraction (systolic dysfunction)
    or relaxation (diastolic dysfunction). The heart cannot meet metabolic demands.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac Contraction
    term:
      id: GO:0060047
      label: heart contraction
  evidence:
  - reference: PMID:33432192
    reference_title: "Cellular and molecular pathobiology of heart failure with preserved ejection fraction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Heart failure with preserved ejection fraction (HFpEF) affects half of all patients with heart failure worldwide, is increasing in prevalence, confers substantial morbidity and mortality, and has very few effective treatments."
    explanation: This review discusses the prevalence and severity of HFpEF, a form characterized by diastolic dysfunction rather than systolic dysfunction, demonstrating the importance of both contractile mechanisms in heart failure.
  - reference: PMID:40892534
    reference_title: "Left ventricular hypertrophy and myocardial fibrosis in heart failure with preserved ejection fraction: mechanisms and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Myocardial fibrosis and its surrogate changes in LV structure and geometry lead to functional impairments such as increased diastolic stiffness and elevated filling pressures and are associated with reduced exercise tolerance and poor prognosis in patients with HFpEF."
    explanation: This demonstrates how structural changes lead to diastolic dysfunction and impaired cardiac output, supporting the mechanism of contractile dysfunction in heart failure.
- name: Neurohormonal Activation
  description: >
    Compensatory activation of RAAS and sympathetic nervous system initially
    maintains cardiac output but leads to maladaptive remodeling, sodium
    retention, and progressive dysfunction.
  biological_processes:
  - preferred_term: RAAS Activation
    term:
      id: GO:0002018
      label: renin-angiotensin regulation of aldosterone production
  evidence:
  - reference: PMID:37895150
    reference_title: "Neurohumoral Activation in Heart Failure."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the arginine vasopressin (AVP) system, are activated to various degrees producing often-observed tachycardia and concomitant increased systemic vascular resistance."
    explanation: This directly confirms the activation of neurohormonal systems (RAAS and SNS) in heart failure patients, supporting the compensatory mechanism described.
  - reference: PMID:37895150
    reference_title: "Neurohumoral Activation in Heart Failure."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Furthermore, sustained neurohormonal activation plays a key role in the progression of HF and may be responsible for the pathogenetic mechanisms leading to the perpetuation of the pathophysiology and worsening of the HF signs and symptoms."
    explanation: This supports the concept that while initially compensatory, sustained neurohormonal activation leads to maladaptive effects and disease progression.
  downstream:
  - target: Endocrine Convergence on Shared Profibrotic Effectors
    description: >-
      Angiotensin II and aldosterone are two of the inputs feeding the shared
      profibrotic effectors, which is why blockade upstream of the
      mineralocorticoid receptor does not silence the programme.
    evidence:
    - reference: PMID:42602176
      reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "TGF-β-Smad signalling receives simultaneous inputs from angiotensin II, aldosterone, cortisol, leptin, FGF23, and thyroid deficiency."
      explanation: Names angiotensin II and aldosterone, the outputs of this node, among the inputs to the convergence node.
- name: Ventricular Remodeling
  description: >
    Structural changes including ventricular dilation, hypertrophy, and
    fibrosis that initially compensate but eventually worsen heart function.
  cell_types:
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: Cardiac Remodeling
    term:
      id: GO:0060420
      label: regulation of heart growth
  evidence:
  - reference: PMID:40892534
    reference_title: "Left ventricular hypertrophy and myocardial fibrosis in heart failure with preserved ejection fraction: mechanisms and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Comorbidities such as hypertension, obesity, or diabetes are present in many HFpEF patients and are hypothesized to contribute to adverse cardiac remodelling and myocardial fibrosis through a variety of haemodynamic and metabolic impairments, with nearly half of all HFpEF patients exhibiting left ventricular (LV) hypertrophy or concentric remodelling."
    explanation: This demonstrates the prevalence and mechanisms of ventricular remodeling including hypertrophy and fibrosis in heart failure patients, particularly in HFpEF.
  - reference: PMID:38636927
    reference_title: "Leukocyte Ig-like receptor B4 (Lilrb4a) alleviates cardiac dysfunction and isoproterenol-induced arrhythmogenic remodeling associated with cardiac fibrosis and inflammation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Heart failure is usually accompanied by activation of the sympathetic nerve, and excessive activation of the sympathetic nerve promotes cardiac remodeling and cardiac dysfunction. In the isoproterenol (ISO)-induced animal model, it is often accompanied by myocardial hypertrophy, fibrosis, and inflammation."
    explanation: This confirms that cardiac remodeling, including hypertrophy and fibrosis, is a key pathophysiological mechanism promoted by sympathetic activation in heart failure.
  - reference: PMID:38636927
    reference_title: "Leukocyte Ig-like receptor B4 (Lilrb4a) alleviates cardiac dysfunction and isoproterenol-induced arrhythmogenic remodeling associated with cardiac fibrosis and inflammation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Lilrb4a alleviates cardiac dysfunction and ISO-induced arrhythmogenic remodeling associated with cardiac fibrosis and inflammation through the regulation of NF-κB signaling and MAPK signaling activation."
    explanation: This identifies specific signaling pathways (NF-κB and MAPK) involved in cardiac remodeling and fibrosis, demonstrating the molecular mechanisms underlying structural changes.
- name: Fluid Retention
  description: >
    Impaired sodium excretion leads to volume overload, causing pulmonary
    and peripheral edema. Results from reduced renal perfusion and
    neurohormonal activation.
  evidence:
  - reference: PMID:36769308
    reference_title: "Chronic Kidney Disease as a Comorbidity in Heart Failure."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The pathophysiology between the heart and the kidneys is bidirectional. Common mechanisms leading to the dysfunction of these organs result in a vicious cycle of cardiorenal deterioration."
    explanation: This demonstrates the bidirectional relationship between heart and kidney dysfunction that leads to fluid retention in heart failure through cardiorenal mechanisms.
- name: Endocrine Convergence on Shared Profibrotic Effectors
  biological_scale: MOLECULAR
  description: >-
    In HFpEF, myocardial fibrosis is driven not by haemodynamic load alone but by
    several endocrine axes that converge on a small set of shared intracellular
    effectors. TGF-beta-Smad signalling receives simultaneous input from
    angiotensin II, aldosterone, cortisol, leptin, FGF23 and thyroid deficiency;
    NADPH oxidase-derived oxidative stress amplifies TGF-beta, cross-links matrix
    via lysyl oxidase, and drives ligand-independent mineralocorticoid receptor
    activation; and the NO-cGMP-PKG axis, normally a brake on fibroblast
    activation, is suppressed by virtually every endocrine disturbance in the
    syndrome. Because several axes feed each convergence point, and because
    self-reinforcing feedback circuits regenerate the signal, blocking any single
    shared effector is rapidly bypassed. This node is the reason the entry treats
    HFpEF fibrosis as multi-axis rather than as the downstream of one pathway.
  cell_types:
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: TGF-beta-Smad profibrotic signalling in cardiac fibroblasts
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  - preferred_term: NADPH oxidase-derived oxidative stress
    term:
      id: GO:0042554
      label: superoxide anion generation
    modifier: INCREASED
  - preferred_term: NO-cGMP-PKG braking of fibroblast activation
    term:
      id: GO:0038060
      label: nitric oxide-cGMP-mediated signaling
    modifier: DECREASED
  - preferred_term: mineralocorticoid receptor signalling
    term:
      id: GO:0031959
      label: nuclear receptor-mediated mineralocorticoid signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The axes converge on shared intracellular effectors, generating a programme exceeding any single axis. TGF-β-Smad signalling receives simultaneous inputs from angiotensin II, aldosterone, cortisol, leptin, FGF23, and thyroid deficiency."
    explanation: Establishes the convergence structure and names the axes feeding the TGF-beta-Smad effector.
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "NADPH oxidase-derived oxidative stress amplifies TGF-β, promotes ECM cross-linking via lysyl oxidase, and drives ligand-independent MR activation."
    explanation: Supports the oxidative-stress effector and its link to ligand-independent mineralocorticoid receptor activation.
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The NO-cGMP-PKG axis, a critical brake on fibroblast activation, is suppressed by virtually every endocrine disturbance in HFpEF, while the mTOR-AMPK-FOXO imbalance translates metabolic excess into sustained profibrotic transcription"
    explanation: Supports suppression of the NO-cGMP-PKG brake as a shared endpoint of the endocrine disturbances.
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Because several axes feed each convergence point and feedback loops regenerate the signal, inhibition of any single shared effector is rapidly bypassed."
    explanation: The therapeutic consequence of the convergence structure, and the basis for the single-pathway-resistance discussion.
  notes: >-
    Sourced from a narrative review, so `evidence_source: OTHER` throughout,
    matching this entry's existing convention for review citations. The review is
    explicit that the seven axes are not universally co-active. It presents them
    as a catalogue of potential dominant drivers, with one or a few predominating
    in any given patient, so this node asserts the convergence structure and not
    that every HFpEF patient runs every axis.

    Three effectors with mixed direction are deliberately kept on one node rather
    than split. Convergence is the claim being modelled — that several axes land
    on a small shared set, so blocking one is bypassed — and separating the
    effectors into three nodes would preserve the parts while losing exactly that.
    The mixed direction is the substance, not an inconsistency: two effectors are
    driven up and the third, a brake, is pushed down, which is why they act
    together.

    The mineralocorticoid receptor descriptor is bound to `GO:0031959` nuclear
    receptor-mediated mineralocorticoid signaling pathway. This corrects an
    earlier binding to the much broader `GO:0003707` nuclear steroid receptor
    activity, which was chosen on the false premise that no specific live term
    existed. `GO:0017082` mineralocorticoid receptor activity IS obsolete with no
    recorded replacement, but `GO:0031959` is live and is the exact structural
    analogue of the glucocorticoid term `GO:0042921`, both being children of
    `GO:0031958` nuclear receptor-mediated corticosteroid signaling pathway.

    The false premise came from a search-syntax error worth recording for the
    next curator. `runoak -i sqlite:obo:go search "mineralocorticoid"` returns
    only the exact-match CHEBI chemical, whereas `search "l~mineralocorticoid"`
    returns the whole `mineralocorticoid` label family, `GO:0031959` among them.
    A null result from the bare form is not evidence that no term exists. No
    count is given here deliberately: a count is a snapshot of one GO release and
    will rot, whereas the lesson will not.
  downstream:
  - target: Ventricular Remodeling
    description: >-
      Convergent profibrotic signalling drives cardiac fibroblast activation and
      interstitial extracellular matrix accumulation.
- name: Tissue Glucocorticoid Amplification by 11beta-HSD1
  biological_scale: TISSUE
  description: >-
    11beta-HSD1 regenerates active cortisol from cortisone inside adipose tissue,
    liver, vasculature and myocardium, so glucocorticoid exposure at the tissue
    level can be raised without any change in adrenal secretion. Chronic
    glucocorticoid excess promotes cardiac fibroblast proliferation, myofibroblast
    transdifferentiation and collagen synthesis through the glucocorticoid
    receptor, potentiates TGF-beta signalling, and suppresses nitric oxide
    availability. In non-epithelial tissue cortisol also binds the
    mineralocorticoid receptor with affinity comparable to aldosterone, so
    glucocorticoid excess can engage RAAS-like profibrotic programmes directly.
  cell_types:
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: intracellular regeneration of active cortisol from cortisone
    term:
      id: GO:0008211
      label: glucocorticoid metabolic process
    modifier: INCREASED
  molecular_functions:
  - preferred_term: 11beta-HSD1 reductase activity regenerating cortisol
    term:
      id: GO:0070524
      label: 11-beta-hydroxysteroid dehydrogenase (NADP+) activity
    modifier: INCREASED
  - preferred_term: glucocorticoid receptor-driven profibrotic transcription
    term:
      id: GO:0004883
      label: nuclear glucocorticoid receptor activity
    modifier: INCREASED
  evidence:
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Tissue-specific amplification of glucocorticoid activity by 11β-HSD1, which regenerates active cortisol from cortisone intracellularly in adipose tissue, liver, vasculature, and myocardium, is an underappreciated driver of myocardial fibrosis."
    explanation: Establishes the tissue-level amplification mechanism as distinct from circulating glucocorticoid excess.
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In non-epithelial tissues, cortisol can also bind MRs with an affinity comparable to that of aldosterone, enabling glucocorticoid excess to engage RAAS-like profibrotic programmes, particularly when oxidative stress alters MR signalling in the ageing or obese myocardium"
    explanation: Links this axis to mineralocorticoid receptor activation, which is why MR antagonism is relevant to a glucocorticoid-driven phenotype.
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, human evidence remains largely confined to metabolic, dermatological, or steroid-exposure models rather than cardiac endpoints."
    explanation: >-
      Bounds the axis. The cardiac claim is not supported by human cardiac-endpoint
      data.
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This evidence should be read as biologically plausible, not clinically established, and must not be conflated with demonstrated antifibrotic efficacy in HFpEF"
    explanation: The review's own epistemic grading of this axis, recorded verbatim so the node is not read as a validated driver.
  notes: >-
    Deliberately curated with the review's own caveat attached rather than
    stripped. No 11beta-HSD1 inhibitor has been evaluated for myocardial fibrosis,
    cardiac MRI extracellular volume, or HFpEF outcomes; the two agents named
    (INCB13739, AZD4017) were tested on metabolic and dermatological endpoints.
    This node records a mechanism, not a therapeutic target that is ready to use.
  downstream:
  - target: Endocrine Convergence on Shared Profibrotic Effectors
    description: >-
      Tissue cortisol regeneration feeds the shared TGF-beta and mineralocorticoid
      receptor effectors.
- name: Postmenopausal Oestrogen Withdrawal
  biological_scale: ORGANISM
  description: >-
    HFpEF disproportionately affects postmenopausal women, and the review's
    account of why is structural rather than additive. Oestrogen normally
    restrains three profibrotic axes at once — it reduces ACE expression and AT1
    receptor density, enhances insulin sensitivity through GLUT4 and IRS-1
    signalling, and maintains an anti-inflammatory adipokine profile — so its
    withdrawal disinhibits all three in concert, producing the concentric,
    microvascular-predominant female phenotype.
  evidence:
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The female predominance of HFpEF reflects oestrogen loss, which amplifies multiple axes simultaneously rather than acting alone."
    explanation: States the multi-axis structure of the sex difference rather than a single-mechanism account.
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Oestrogen normally restrains RAAS by reducing ACE expression and AT1 density, enhances insulin sensitivity via GLUT4 and IRS-1 signalling, and maintains an anti-inflammatory adipokine profile; its withdrawal disinhibits these three profibrotic axes in concert, producing the concentric, microvascular-predominant female phenotype."
    explanation: Names the three systemic axes oestrogen restrains and the phenotype its withdrawal produces.
  notes: >-
    Split from the myocardial arm on review. This node carries only the
    ORGANISM-scale systemic disinhibition; the direct effect of lost oestrogen
    signalling on cardiac fibroblasts and endothelium is the separate CELLULAR
    node below, because the two sit at different scales and the single-value
    scale discipline treats that as a bundling signal.

    The failure of systemic hormone therapy to reduce cardiovascular risk (WHI,
    HERS) is NOT curated as refuting this mechanism, and no hormone-therapy
    treatment is added to this entry on the strength of it. The review attributes
    those failures to systemic ER-alpha-mediated thrombotic risk and late
    initiation rather than to the antifibrotic biology, but that is an
    interpretation of negative trials, not a demonstrated antifibrotic benefit.
    ER-beta-selective agonism remains preclinical.
  downstream:
  - target: Loss of Myocardial Oestrogen Receptor Signalling
    description: >-
      Falling circulating oestrogen removes receptor occupancy in the myocardium
      and coronary endothelium.
  - target: Endocrine Convergence on Shared Profibrotic Effectors
    description: >-
      Loss of systemic oestrogen restraint releases RAAS, insulin-resistance and
      adipokine inputs onto the shared profibrotic effectors simultaneously.
- name: Loss of Myocardial Oestrogen Receptor Signalling
  biological_scale: CELLULAR
  description: >-
    The direct cardiac arm of oestrogen withdrawal, distinct from the systemic
    disinhibition upstream. Oestrogen acting through ER-alpha and ER-beta
    suppresses cardiac fibroblast proliferation, inhibits TGF-beta/CTGF-mediated
    collagen transcription via ER-beta, upregulates endothelial nitric oxide
    synthase, and supports mitochondrial function. Menopause removes an
    antifibrotic and vasoprotective influence acting on the myocardium itself, at
    the same time as it releases the systemic axes.
  cell_types:
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: oestrogen receptor signalling in myocardium and coronary endothelium
    term:
      id: GO:0030520
      label: estrogen receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Oestrogen, acting through ERα and ERβ, suppresses fibroblast proliferation, inhibits TGF-β/CTGF-mediated collagen transcription via ERβ, upregulates endothelial nitric oxide synthase (eNOS), and supports mitochondrial function"
    explanation: The direct myocardial and endothelial arm of oestrogen action, whose loss this node models.
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Menopause removes these antifibrotic and vasoprotective influences, shifts systemic immunity towards a pro-inflammatory state by reducing suppression of nuclear factor kappa B (NF-κB), and reduces MMP-2/MMP-9 while upregulating TIMP-1, thereby tilting the ECM balance towards accumulation"
    explanation: States that menopause removes these influences and tilts the matrix balance towards accumulation.
  downstream:
  - target: Endocrine Convergence on Shared Profibrotic Effectors
    description: >-
      Loss of the ER-beta brake on TGF-beta/CTGF collagen transcription and of
      eNOS support feeds the shared effectors directly.
- name: Lipoprotein(a)-Driven Coronary Microvascular Dysfunction
  description: >
    Lipoprotein(a) [Lp(a)], a genetically determined cardiovascular risk factor,
    promotes coronary microvascular dysfunction through endothelial dysfunction,
    oxidative stress, inflammatory activation, and microvascular remodeling. Lp(a)
    carries oxidized phospholipids and exhibits antifibrinolytic properties that
    distinctly drive microvascular disease independent of epicardial coronary
    atherosclerosis, with particular relevance to HFpEF pathogenesis.
  cell_types:
  - preferred_term: Endothelial Cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: Vascular Smooth Muscle Cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: Oxidative Stress Response
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  - preferred_term: Vascular Remodeling
    term:
      id: GO:0001974
      label: blood vessel remodeling
    modifier: ABNORMAL
  - preferred_term: Microthrombotic Events
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  evidence:
  - reference: PMID:41936813
    reference_title: "The role of lipoprotein(a) in coronary microvascular dysfunction: Mechanistic pathways, clinical evidence, and therapeutic perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lp(a) exhibits unique structural and biological properties, including the antifibrinolytic effects of apolipoprotein(a) and carriage of oxidized phospholipids, which promote endothelial dysfunction, oxidative stress, inflammatory activation, microvascular remodeling, and microthrombotic susceptibility-key processes implicated in CMD pathophysiology."
    explanation: This directly supports the mechanism of Lp(a)-driven endothelial dysfunction and oxidative stress in coronary microvascular disease.
  - reference: PMID:41936813
    reference_title: "The role of lipoprotein(a) in coronary microvascular dysfunction: Mechanistic pathways, clinical evidence, and therapeutic perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lp(a)], a genetically determined and causal cardiovascular risk factor, has been extensively studied in epicardial coronary atherosclerosis; however, its role in the coronary microcirculation has received comparatively limited attention."
    explanation: This establishes the distinction between Lp(a)'s well-characterized role in macrovascular atherosclerosis versus its emerging role in microvascular dysfunction specifically relevant to heart failure pathophysiology.
discussions:
- discussion_id: gap_lpa_microvascular_vs_macrovascular_mechanism
  prompt: >-
    What are the distinct mechanistic pathways by which lipoprotein(a) drives
    coronary microvascular dysfunction (CMD) as opposed to its well-characterized
    role in epicardial macrovascular atherosclerosis, and what are the biomarker
    and disease-modifying therapeutic implications for heart failure (especially HFpEF)?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Lipoprotein(a)-Driven Coronary Microvascular Dysfunction
  rationale: >-
    Lp(a)'s unique structural properties — antifibrinolytic apolipoprotein(a) and
    carriage of oxidized phospholipids — promote endothelial dysfunction, oxidative
    stress, inflammatory activation, microvascular remodeling, and microthrombotic
    susceptibility. These mechanisms are extensively characterized in epicardial
    coronary atherosclerosis (macrovascular disease), but Lp(a)'s contribution to the
    coronary microcirculation has received comparatively limited attention. Observational
    studies link elevated Lp(a) to impaired coronary flow reserve, yet the microvascular-specific
    pathways remain poorly delineated and no disease-modifying therapies targeting Lp(a) in CMD exist.
  notes: "Seeded from PMID:41936813 — The role of lipoprotein(a) in coronary microvascular dysfunction: Mechanistic pathways, clinical evidence, and therapeutic perspectives"
- discussion_id: gap_pyroptosis_hfpef_dapagliflozin_mechanism
  prompt: >-
    Is pyroptosis (via the AIM2/Caspase-1/GSDMD inflammasome pathway) a primary driver
    of HFpEF pathophysiology or a secondary inflammatory consequence of diastolic
    dysfunction and ventricular remodeling? What is the human clinical relevance of
    AIM2/Caspase-1/GSDMD pathway dysregulation in HFpEF, and does dapagliflozin's
    therapeutic benefit in HFpEF arise primarily through pyroptosis attenuation or
    through other complementary mechanisms?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Ventricular Remodeling
  rationale: >-
    Preclinical evidence (PMID:42246167) demonstrates that dapagliflozin alleviates
    HFpEF symptoms and decreases myocardial pyroptosis in a mouse model through
    AIM2/Caspase-1/GSDMD axis regulation. Pyroptosis is a pro-inflammatory form of
    programmed cell death that induces inflammatory amplification and contributes to
    cardiovascular disease. However, the mechanistic hierarchy remains unclear: whether
    AIM2-inflammasome activation is a primary pathophysiological driver of HFpEF (and
    thus should be added as a core pathophysiology node) versus a secondary consequence
    of the established mechanisms (myocardial contractile dysfunction, neurohormonal
    activation, ventricular remodeling, diastolic dysfunction). Furthermore, the human
    clinical significance of this pathway in HFpEF remains to be determined — the
    evidence is primarily from mouse cardiomyocyte and animal models, and whether
    AIM2/Caspase-1/GSDMD dysregulation is a targetable therapeutic mechanism in human
    HFpEF patients requires human tissue validation and clinical trial evidence.
  proposed_experiments:
  - experiment_id: exp_hfpef_aim2_pyroptosis_human_tissue
    name: AIM2/Caspase-1/GSDMD pathway activation and pyroptosis quantification in HFpEF patient cardiac tissue
    description: >-
      Quantify AIM2 protein, active Caspase-1, GSDMD proteolysis, and pyroptosis markers
      (e.g., released IL-1β, IL-18) in cardiac tissue from HFpEF patients (endomyocardial
      biopsies or cardiac explants undergoing transplantation) compared to age-matched
      controls without heart failure. Correlate AIM2/Caspase-1/GSDMD activation with
      biomarkers of diastolic dysfunction and ventricular stiffness to determine whether
      pathway dysregulation is primary or secondary.
  - experiment_id: exp_hfpef_ipsc_cardiomyocyte_pyroptosis_dapagliflozin
    name: Dose-response validation of dapagliflozin on AIM2/Caspase-1/GSDMD pyroptosis in human iPSC-derived cardiomyocytes under diastolic stress
    description: >-
      Establish human iPSC-derived cardiomyocyte models of diastolic dysfunction stress
      (diastolic calcium handling impairment, passive stiffness elevation) and measure
      baseline AIM2/Caspase-1/GSDMD activation and pyroptosis rates. Apply dapagliflozin
      in a dose-response manner and quantify pyroptosis attenuation, mechanism of action
      (direct AIM2 inhibition vs. indirect via restored calcium handling), and whether
      dapagliflozin's benefit is AIM2-dependent (using AIM2 knockdown or Caspase-1
      inhibitors like VX-765 to block downstream pyroptosis execution).
  - experiment_id: exp_hfpef_dapagliflozin_trial_pyroptosis_biomarker
    name: Biomarker-driven clinical trial subset analysis correlating pyroptosis pathway activation with dapagliflozin response in HFpEF
    description: >-
      In a prospective HFpEF cohort treated with dapagliflozin, measure baseline circulating
      pyroptosis biomarkers (cleaved Caspase-1, IL-1β, IL-18, or GSDMD-N terminal fragment)
      and cardiac imaging of diastolic dysfunction and myocardial stiffness. Stratify
      patients by baseline AIM2/Caspase-1 activation status and assess whether high-baseline
      pyroptosis correlates with enhanced dapagliflozin treatment response (echocardiographic
      improvement in ejection fraction, diastolic parameters, or symptom relief) and
      whether post-treatment pyroptosis attenuation predicts clinical benefit.
  notes: "Seeded from PMID:42246167 — Dapagliflozin alleviates heart failure with preserved ejection fraction potentially by regulating the AIM2/caspase-1/GSDMD pathway and attenuating pyroptosis"
- discussion_id: gap_hfpef_single_pathway_therapy_resistance
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does the incomplete response of HFpEF to single-pathway therapy reflect
    self-reinforcing endocrine feedback circuits that regenerate profibrotic
    signalling around any single blocked node, and can a phenotype-guided strategy
    that targets the dominant upstream driver in a given patient outperform
    uniform therapy?
  attaches_to:
  - pathophysiology#Endocrine Convergence on Shared Profibrotic Effectors
  - pathophysiology#Tissue Glucocorticoid Amplification by 11beta-HSD1
  - pathophysiology#Postmenopausal Oestrogen Withdrawal
  - pathophysiology#Ventricular Remodeling
  rationale: >-
    Three self-reinforcing circuits are proposed to explain why blocking one axis
    is insufficient. In the metabolic circuit, dysfunctional adipose tissue
    releases TNF-alpha and IL-6, which worsen insulin signalling and in turn
    worsen adipocyte dysfunction. In the RAAS-redox circuit, angiotensin II
    stimulates NADPH oxidase-derived superoxide, which inactivates nitric oxide
    and activates NF-kB, upregulating angiotensinogen and perpetuating RAAS
    activation. In the glucocorticoid circuit, 11beta-HSD1-mediated cortisol
    regeneration in visceral fat promotes further fat deposition, expanding the
    substrate for local glucocorticoid amplification independently of adrenal
    secretion. If this account is right, suppressing RAAS while leaving insulin
    resistance and adipose inflammation unaddressed permits continued
    ligand-independent MR activation and TGF-beta-driven fibrosis.

    Two things keep this a gap rather than a finding. The circuit model is a
    review-level synthesis, not a tested causal claim, and no trial has
    prospectively assigned HFpEF patients to therapy by dominant endocrine
    driver. The proposal is also partly circular as stated: the clinical success
    of SGLT2 inhibitors is offered as validation that multi-axis intervention
    beats single-pathway targeting, but those agents were not designed or trialled
    as multi-axis therapy, and their pleiotropy is an after-the-fact
    characterisation of why an effective drug works.
  proposed_experiments:
  - experiment_id: exp_hfpef_phenotype_guided_antifibrotic
    name: Phenotype-stratified antifibrotic assignment in HFpEF
    description: >-
      Phenotype an HFpEF cohort for dominant endocrine driver at baseline
      (visceral-adipose/glucocorticoid, insulin-resistant, RAAS-predominant,
      postmenopausal oestrogen-deficient), stratifying by renal function so that
      FGF23 and PTH are read within eGFR strata rather than as free-standing
      signals. Assign therapy matched versus unmatched to the dominant driver and
      follow cardiac MRI extracellular volume alongside clinical events. An
      adaptive platform design enriched for homogeneous endocrine subtypes is the
      efficient form of this.
    decision_criterion: >-
      Whether driver-matched assignment outperforms unmatched assignment on
      extracellular volume and events discriminates the phenotype-guided
      hypothesis from the simpler explanation that some HFpEF therapies are just
      broadly effective regardless of endocrine subtype.
    supporting_outcome:
    - >-
      A driver-matched arm showing greater reduction in extracellular volume and
      in worsening heart failure events than an unmatched arm receiving the same
      set of drugs, supporting the phenotype-guided model.
    refuting_outcome:
    - >-
      Equivalent benefit regardless of whether therapy matched the dominant
      driver, indicating that the observed responses reflect general drug efficacy
      rather than the endocrine phenotype the model assigns them to.
  evidence:
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Three self-reinforcing feedback circuits explain HFpEF's resistance to single-pathway therapy."
    explanation: The claim under examination, stated by the review as an explanation rather than demonstrated.
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Consequently, suppressing RAAS while leaving insulin resistance and adipose inflammation unaddressed permits continued ligand-independent MR activation and TGF-β-driven fibrosis, explaining the partial benefit of monotherapy."
    explanation: The specific prediction the circuit model makes about monotherapy, which is what a phenotype-stratified trial would test.
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The durable strategy is to neutralise the dominant upstream driver in a given patient- less molecularly selective but interrupting the cascade before it diversifies- which, since the dominant driver differs between patients, necessarily implies a phenotype-guided approach."
    explanation: The proposed resolution, recorded as a proposal because no trial has assigned therapy by dominant driver.
  notes: >-
    The review's own therapy grading is preserved rather than flattened. SGLT2
    inhibitors, finerenone and GLP-1 receptor agonists are described as having the
    strongest evidence, while 11beta-HSD1 and D3 deiodinase inhibitors,
    ER-beta-selective agonists and anti-FGF23 strategies are described as
    mechanistically compelling but unvalidated. Nothing in the emerging group is
    curated as a treatment in this entry.
phenotypes:
- name: Dyspnea
  category: Respiratory
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    Shortness of breath is the cardinal symptom of heart failure, arising from
    elevated left atrial and pulmonary venous pressures that drive fluid into the
    pulmonary interstitium and alveoli. It typically begins on exertion and, as
    decompensation advances, progresses to occur at rest.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: PMID:40892534
    reference_title: "Left ventricular hypertrophy and myocardial fibrosis in heart failure with preserved ejection fraction: mechanisms and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Myocardial fibrosis and its surrogate changes in LV structure and geometry lead to functional impairments such as increased diastolic stiffness and elevated filling pressures and are associated with reduced exercise tolerance and poor prognosis in patients with HFpEF."
    explanation: Dyspnea results from elevated filling pressures and reduced exercise tolerance caused by diastolic dysfunction and myocardial fibrosis in heart failure.
- name: Peripheral Edema
  category: Cardiovascular
  frequency: VERY_FREQUENT
  description: >-
    Dependent swelling, most often of the lower extremities, results from systemic
    venous congestion and sodium and water retention driven by reduced cardiac
    output and neurohormonal (RAAS) activation. It is a hallmark sign of
    right-sided and biventricular heart failure.
  phenotype_term:
    preferred_term: Peripheral Edema
    term:
      id: HP:0012398
      label: Peripheral edema
  evidence:
  - reference: PMID:36769308
    reference_title: "Chronic Kidney Disease as a Comorbidity in Heart Failure."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The pathophysiology between the heart and the kidneys is bidirectional. Common mechanisms leading to the dysfunction of these organs result in a vicious cycle of cardiorenal deterioration."
    explanation: Peripheral edema results from the cardiorenal interaction where reduced cardiac output leads to renal dysfunction, sodium retention, and fluid accumulation in peripheral tissues.
- name: Fatigue
  category: Systemic
  frequency: VERY_FREQUENT
  description: >-
    Persistent tiredness and reduced energy reflect inadequate cardiac output and
    impaired oxygen delivery to skeletal muscle and other tissues. Skeletal muscle
    deconditioning, neurohormonal activation, and reduced perfusion contribute to
    this pervasive and disabling symptom of heart failure.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- name: Orthopnea
  category: Respiratory
  frequency: FREQUENT
  notes: Dyspnea when lying flat
  description: >-
    Breathlessness in the recumbent position occurs because lying flat increases
    venous return and redistributes fluid from the lower body to the lungs, raising
    pulmonary capillary pressure. Patients characteristically relieve it by
    propping themselves up on pillows or sleeping upright.
  phenotype_term:
    preferred_term: Orthopnea
    term:
      id: HP:0012764
      label: Orthopnea
- name: Exercise Intolerance
  category: Cardiovascular
  frequency: VERY_FREQUENT
  description: >-
    A reduced capacity to sustain physical activity reflects the inability of the
    failing heart to augment cardiac output to meet the metabolic demands of
    exercise. It manifests as exertional dyspnea and fatigue and is a key
    determinant of functional class and quality of life in heart failure.
  phenotype_term:
    preferred_term: Exercise Intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:40892534
    reference_title: "Left ventricular hypertrophy and myocardial fibrosis in heart failure with preserved ejection fraction: mechanisms and treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Myocardial fibrosis and its surrogate changes in LV structure and geometry lead to functional impairments such as increased diastolic stiffness and elevated filling pressures and are associated with reduced exercise tolerance and poor prognosis in patients with HFpEF."
    explanation: Exercise intolerance in heart failure is directly caused by increased diastolic stiffness and elevated filling pressures from myocardial fibrosis and structural remodeling.
- name: Cardiomegaly
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Enlargement of the heart, often evident on chest radiography or
    echocardiography, results from chamber dilation and myocardial hypertrophy
    that develop as maladaptive remodeling in response to chronic pressure or
    volume overload. It is a structural marker of advanced ventricular remodeling
    in heart failure.
  phenotype_term:
    preferred_term: Cardiomegaly
    term:
      id: HP:0001640
      label: Cardiomegaly
  evidence:
  - reference: PMID:38636927
    reference_title: "Leukocyte Ig-like receptor B4 (Lilrb4a) alleviates cardiac dysfunction and isoproterenol-induced arrhythmogenic remodeling associated with cardiac fibrosis and inflammation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the isoproterenol (ISO)-induced animal model, it is often accompanied by myocardial hypertrophy, fibrosis, and inflammation."
    explanation: Cardiomegaly in heart failure results from myocardial hypertrophy, which is a structural adaptation to increased workload and sympathetic activation.
biochemical:
- name: BNP/NT-proBNP
  presence: Elevated
  context: Diagnostic and prognostic biomarker
  evidence:
  - reference: PMID:37895150
    reference_title: "Neurohumoral Activation in Heart Failure."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There are biomarkers of activation of these neurohormonal pathways, such as the natriuretic peptides, catecholamine levels and neprilysin and various newer ones, which may be employed to better understand the mechanisms of HF drugs and also aid in defining the subgroups of patients who might benefit from specific therapies."
    explanation: BNP and NT-proBNP are natriuretic peptides that serve as biomarkers of neurohormonal activation in heart failure, useful for diagnosis and therapeutic guidance.
- name: Troponin
  presence: Elevated
  context: May be chronically elevated in heart failure
genetic:
- name: TTN
  gene_term:
    preferred_term: TTN
    term:
      id: hgnc:12403
      label: TTN
  association: Causative
  notes: Titin mutations cause dilated cardiomyopathy
  evidence:
  - reference: CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2025-05-30T160000.000Z
    reference_title: "TTN / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TTN | HGNC:12403 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: ClinGen classifies the TTN-dilated cardiomyopathy relationship as definitive; dilated cardiomyopathy is a leading cause of the heart failure syndrome modelled by this entry.
- name: MYH7
  gene_term:
    preferred_term: MYH7
    term:
      id: hgnc:7577
      label: MYH7
  association: Causative
  notes: Causes hypertrophic and dilated cardiomyopathy
  evidence:
  - reference: CGGV:assertion_4ec27d4f-70ea-4c6a-ad67-d6260ecadcde-2025-05-30T160000.000Z
    reference_title: "MYH7 / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYH7 | HGNC:7577 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: ClinGen classifies the MYH7-dilated cardiomyopathy relationship as definitive, establishing a sarcomeric-cardiomyopathy route to heart failure.
- name: LMNA
  gene_term:
    preferred_term: LMNA
    term:
      id: hgnc:6636
      label: LMNA
  association: Causative
  notes: Lamin A/C mutations cause cardiomyopathy
  evidence:
  - reference: CGGV:assertion_132ea1ec-caa9-409a-8670-3edb2ec9c889-2025-05-30T160000.000Z
    reference_title: "LMNA / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LMNA | HGNC:6636 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: ClinGen classifies the LMNA-dilated cardiomyopathy relationship as definitive; LMNA cardiomyopathy progresses to heart failure and carries genotype-specific device indications.
environmental:
- name: Hypertension
  notes: Major cause of heart failure
  evidence:
  - reference: PMID:36346411
    reference_title: "Treatment of Hypertension: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertension is associated with increased risk of cardiovascular disease (CVD) events (coronary heart disease, heart failure, and stroke) and death"
    explanation: Review of hypertension treatment naming heart failure as one of the CVD event risks hypertension causes.
- name: Coronary Artery Disease
  notes: Leading cause of HFrEF
  evidence:
  - reference: PMID:28613623
    reference_title: "Heart Failure (Congestive Heart Failure)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ischemic heart disease is the leading cause of HF"
    explanation: Clinical overview stating ischemic heart disease (coronary artery disease) is the leading cause of heart failure.
- name: Alcohol Abuse
  exposure_term:
    preferred_term: exposure to alcohol consumption
    term:
      id: ECTO:0001082
      label: exposure to alcohol consumption
  notes: Can cause alcoholic cardiomyopathy.
  evidence:
  - reference: PMID:20308914
    reference_title: Alcoholic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "chronic excessive alcohol consumption may lead to progressive and chronic cardiac dysfunction and can be a possible cause of dilated cardiomyopathy, referred to as alcoholic cardiomyopathy (ACM)"
    explanation: >-
      States the claim this entry makes, that sustained excessive alcohol intake
      can itself cause a dilated cardiomyopathy, and names the entity.
  - reference: PMID:38213665
    reference_title: Alcohol and Heart Failure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic excessive alcohol consumption is associated with a range of cardiac complications, including decreased myocardial contractility, hypertension, arrhythmias, MI and heart failure."
    explanation: >-
      Places heart failure itself among the cardiac consequences of chronic
      excessive intake, which is what makes this exposure relevant to this entry
      rather than only to the cardiomyopathy it names.
treatments:
- name: ACE Inhibitors/ARBs
  description: Neurohormonal blockade, reduce mortality in HFrEF.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:37254024
    reference_title: "Guideline-Directed Medical Therapy for the Treatment of Heart Failure with Reduced Ejection Fraction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Guideline-directed medical therapy (GDMT) is the cornerstone of pharmacological therapy for patients with heart failure with reduced ejection fraction (HFrEF) and consists of the four main drug classes: renin-angiotensin system inhibitors, evidence-based β-blockers, mineralocorticoid inhibitors and sodium glucose cotransporter 2 inhibitors."
    explanation: Renin-angiotensin system inhibitors are one of the four foundational GDMT drug classes for HFrEF.
- name: Beta Blockers
  description: Reduce heart rate and reverse remodeling in HFrEF.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:37254024
    reference_title: "Guideline-Directed Medical Therapy for the Treatment of Heart Failure with Reduced Ejection Fraction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Guideline-directed medical therapy (GDMT) is the cornerstone of pharmacological therapy for patients with heart failure with reduced ejection fraction (HFrEF) and consists of the four main drug classes: renin-angiotensin system inhibitors, evidence-based β-blockers, mineralocorticoid inhibitors and sodium glucose cotransporter 2 inhibitors."
    explanation: Evidence-based beta-blockers are one of the four foundational GDMT drug classes for HFrEF.
- name: ARNI (Sacubitril/Valsartan)
  description: Combined neprilysin inhibitor and ARB, superior to ACE inhibitors.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: SGLT2 Inhibitors
  description: Reduce hospitalizations and mortality across HF spectrum.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:41110921
    reference_title: "Canadian Cardiovascular Society/Canadian Heart Failure Society 2025 Guideline Update for Pharmacologic Management of Heart Failure With Nonreduced Ejection Fraction (LVEF > 40%)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recommendations are complemented by practical tips to guide the initiation, titration, and maintenance of these foundational treatments."
    explanation: The 2025 CCS/CHFS guideline update covers pharmacologic management of heart failure with nonreduced ejection fraction, the setting in which SGLT2 inhibitor use extends across the ejection-fraction spectrum.
  - reference: PMID:31535829
    reference_title: "Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98)"
    explanation: DAPA-HF randomised trial quantifies the reduction in worsening heart failure events and cardiovascular death with an SGLT2 inhibitor, supporting the claim that these agents reduce hospitalizations and mortality.
- name: Mineralocorticoid Receptor Antagonists
  description: >-
    Spironolactone or eplerenone for additional neurohormonal blockade, and the
    non-steroidal agent finerenone. The mechanistic case for adding an MRA on top
    of an ACE inhibitor or ARB is that those drugs leave the terminal
    mineralocorticoid receptor programme intact by several independent routes:
    chymase-dependent, ACE-independent angiotensin II generation circumvents ACE
    inhibition; aldosterone escape restores MR activation during chronic AT1
    blockade; and cortisol regenerated by 11beta-HSD1, together with reactive
    oxygen species, drives ligand-independent Rac1-mediated MR activation. MR
    antagonism is therefore not a redundant second hit on the same pathway but the
    only one of the three drug classes that reaches the terminal effector.
  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
    - preferred_term: eplerenone
      term:
        id: CHEBI:31547
        label: eplerenone
    - preferred_term: finerenone
      term:
        id: CHEBI:747008
        label: Finerenone
  target_mechanisms:
  - target: Endocrine Convergence on Shared Profibrotic Effectors
    treatment_effect: INHIBITS
    description: >-
      MR antagonism blocks the terminal mineralocorticoid receptor arm of the
      convergent profibrotic programme, including the ligand-independent
      activation driven by oxidative stress and by cortisol acting on the MR.
      INHIBITS rather than MODULATES because the target is a receptor the drug
      class antagonises directly, but note this blocks one arm of a multi-axis
      convergence, which is why the entry does not treat it as disease-modifying
      on its own.
    evidence:
    - reference: PMID:42602176
      reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Both drug classes thus leave terminal MR signalling intact, providing the rationale for direct MR antagonism."
      explanation: States the mechanistic rationale for MR antagonism as distinct from ACE inhibition and AT1 blockade.
  evidence:
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ARBs block AT1 directly, yet fibrosis persists because the terminal MR-driven program is engaged independently of AT1: aldosterone escape restores MR activation during chronic blockade"
    explanation: Documents aldosterone escape as one route by which AT1 blockade fails to reach the MR programme.
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ACE inhibition is circumvented by chymase-dependent, ACE-independent angiotensin II generation"
    explanation: The corresponding escape route for ACE inhibitors.
  - reference: PMID:42602176
    reference_title: "Endocrine regulation of cardiac fibrosis: implications for HFpEF."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In FINEARTS-HF, the non-steroidal MRA finerenone, with high MR selectivity and a favourable tissue-distribution, reduced the composite of worsening heart failure events and cardiovascular death in patients with mildly reduced or preserved ejection fraction, although hyperkalaemia remains an important safety consideration"
    explanation: Randomised outcome evidence for MR antagonism specifically in mildly reduced and preserved ejection fraction, with its safety caveat, extending a treatment previously evidenced here only for HFrEF.
  - reference: PMID:37254024
    reference_title: "Guideline-Directed Medical Therapy for the Treatment of Heart Failure with Reduced Ejection Fraction."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Guideline-directed medical therapy (GDMT) is the cornerstone of pharmacological therapy for patients with heart failure with reduced ejection fraction (HFrEF) and consists of the four main drug classes: renin-angiotensin system inhibitors, evidence-based β-blockers, mineralocorticoid inhibitors and sodium glucose cotransporter 2 inhibitors."
    explanation: Mineralocorticoid receptor antagonists are one of the four foundational GDMT drug classes for HFrEF.
- name: Diuretics
  description: Manage fluid overload and congestion symptoms.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Cardiac Resynchronization Therapy
  description: For patients with wide QRS and reduced EF.
  treatment_term:
    preferred_term: Cardiac Resynchronization Therapy
    term:
      id: NCIT:C80436
      label: Cardiac Resynchronization Therapy
- name: Implantable Cardioverter-Defibrillator
  description: Prevents sudden cardiac death in high-risk patients.
  treatment_term:
    preferred_term: Implantable Cardioverter-Defibrillator Placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
datasets:
- accession: geo:GSE236191
  title: Specific biological processes associated with T2D-induced left ventricular dysfunction in patients with aortic stenosis pressure overload
  description: 'Background: Type 2 diabetes (T2D) is increasingly prevalent and increases the risk of developing heart failure. T2D is frequently associated with left ventricular (LV) pressure overload, such as encountered in hypertension and aortic stenosis (AS), and few studies suggested an aggravating effect of T2D. We aimed to explore if the deleterious impact of T2D on LV remodeling and function in patients with AS is associated with specific biological processes.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 47
  notes: Identified by GEO DataSets index search for Heart Failure (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001005398
  title: Prevalence of transthyretin amyloidosis in patients with heart failure and no left ventricular hypertrophy
  description: The study prospectively enrolled patients admitted for HF with LV ejection fraction (LVEF) ≥ 50% and LV wall thickness <12 mm. TTR cardiac amyloidosis was diagnosed according to accepted criteria, which include positive cardiac 99-Tc-DPD scintigraphy in the absence of monoclonal protein expansion in blood. In a cohort of patients with HFpEF without LVH, the prevalence of TTR cardiac amyloidosis was 5%. Transthyretin gene sequencing was performed in positive patients.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Heart Failure"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS50000000653
  title: Single-cell spatiotranscriptomic dissection of ex vivo human heart right atrial appendage and pericardial fluid in ischemic heart disease and heart failure
  description: We use cardiac and pericardial fluid biopsies collected during open-heart surgery in control, ischemic heart disease, heart failure, and myocardial infarction context. For each sample, single-nuclei RNA sequencing experiment is performed. We also perform spatial transcriptomics on the heart samples. We annotate the cells in major cell types, in addition to subtypes annotation of vascular and immune cells. The disease annotation enables us to reveal substantial differences in gene expression at the cell subpopulation levels. Our results demonstrate the importance of high-resolution cellular type/state mapping in the elucidation of human cardiovascular disease pathogenesis.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:38776872
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Heart Failure"); description-level mentions were not accepted. EGA study_type: Transcriptome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS50000000810
  title: Integrated Transcriptomic and Regulatory RNA Profiling Reflects Complex Pathophysiology and Uncovers a Conserved Gene Signature in End Stage Heart Failure RNA-Seq data
  description: Heart failure (HF) is a complex syndrome. Despite availability of multiple treatment options, the mortality remains high and the quality of life poor. Better understanding of the underlying pathophysiological processes can lead to development of novel therapies. Multiple comparative transcriptomics studies, which revealed gene level changes in the key pathophysiological pathways in failing hearts, point towards heterogeneity from interplay of disease stage, etiologies and ethnicity. Transcriptomic characterization of HF in patients from different ethnicities can potentially help in understanding the heterogeneity imparted by various factors and the core elements in heart failure.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Heart Failure"); description-level mentions were not accepted. EGA study_type: RNASeq. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: metabolomics_workbench:ST000588
  title: Metabolomics of Saliva in Decompensated Heart Failure
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Heart Failure"). Retrieved 2026-08-02.
- accession: metabolomics_workbench:ST000587
  title: Metabolomics of Exhaled Breath Condensate in Decompensated Heart Failure
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Heart Failure"). Retrieved 2026-08-02.
- accession: metabolomics_workbench:ST001961
  title: Metabolomics of brown adipose tissue in murine heart failure model
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: METABOLOMICS
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from metabolomics_workbench. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Heart Failure"). Retrieved 2026-08-02.
references:
- reference: DOI:10.1038/s41569-020-00480-6
  title: Cellular and molecular pathobiology of heart failure with preserved ejection fraction
  findings: []
- reference: DOI:10.1038/s41569-024-01067-1
  title: Pathophysiological insights into HFpEF from studies of human cardiac tissue
  findings: []
- reference: DOI:10.1101/2025.04.02.646923
  title: Deciphering human heart failure with preserved ejection fraction (HFpEF) at single cell resolution
  findings: []
- reference: DOI:10.1186/s12933-025-02774-w
  title: 'Cardiometabolic heart failure with preserved ejection fraction: from molecular signatures to personalized treatment'
  findings: []
- reference: DOI:10.3390/cells14050324
  title: Molecular Mechanisms Underlying Heart Failure and Their Therapeutic Potential
  findings: []
- reference: DOI:10.53846/goediss-10367
  title: Mechanistic differences in mouse models of heart failure with preserved ejection fraction
  findings: []
📚

References & Deep Research

References

6
DOI:10.1038/s41569-020-00480-6
Cellular and molecular pathobiology of heart failure with preserved ejection fraction
No top-level findings curated for this source.
DOI:10.1038/s41569-024-01067-1
Pathophysiological insights into HFpEF from studies of human cardiac tissue
No top-level findings curated for this source.
DOI:10.1101/2025.04.02.646923
Deciphering human heart failure with preserved ejection fraction (HFpEF) at single cell resolution
No top-level findings curated for this source.
DOI:10.1186/s12933-025-02774-w
Cardiometabolic heart failure with preserved ejection fraction: from molecular signatures to personalized treatment
No top-level findings curated for this source.
DOI:10.3390/cells14050324
Molecular Mechanisms Underlying Heart Failure and Their Therapeutic Potential
No top-level findings curated for this source.
DOI:10.53846/goediss-10367
Mechanistic differences in mouse models of heart failure with preserved ejection fraction
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Heart Failure
  • Category: Complex
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 21

Key Pathophysiology Nodes

  • Myocardial Contractile Dysfunction
  • Neurohormonal Activation
  • Ventricular Remodeling
  • Fluid Retention
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1038/s41569-020-00480-6
  • DOI:10.1038/s41569-024-01067-1
  • DOI:10.1101/2025.04.02.646923
  • DOI:10.1186/s12933-025-02774-w
  • DOI:10.3390/cells14050324
  • DOI:10.53846/goediss-10367
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 28 citations 2025-12-17T18:47:00.350261

Disease Pathophysiology Research Report

Target Disease - Disease Name: Heart Failure (HF) - MONDO ID: MONDO:0002025 - Category: Complex

Pathophysiology description (current understanding and key definitions) Heart failure is a clinical syndrome arising from structural and/or functional cardiac abnormalities that impair the heart’s ability to fill and/or eject blood, leading to symptoms (e.g., dyspnea, fatigue) and signs (e.g., edema) of congestion. Mechanistically, HF spans phenotypes with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). Across the spectrum, convergent molecular and cellular processes drive maladaptive remodeling: neurohormonal activation (RAAS, sympathetic drive, natriuretic peptide axis), endothelial and coronary microvascular dysfunction with impaired NO–sGC–cGMP signaling, cardiac fibrosis and myofibroblast activation (TGF-β/SMAD), inflammation with immune–fibroblast crosstalk, metabolic and mitochondrial remodeling with oxidative stress and altered substrate use (including increased reliance on ketone bodies), and cardiomyocyte Ca2+ handling and sarcomere/titin stiffness abnormalities. These lesions unfold within the myocardium and the coronary microvasculature and are modulated by extracardiac organs (adipose, liver, kidney), particularly in cardiometabolic HFpEF. (fayyaz2025pathophysiologicalinsightsinto pages 11-13, fayyaz2025pathophysiologicalinsightsinto pages 23-24, fonseka2025molecularmechanismsunderlying pages 1-2, mishra2021cellularandmolecular pages 14-15, gorica2025cardiometabolicheartfailure pages 1-3)

Recent developments and latest research (2023–2024 prioritized) - Microvascular/endothelial and NO–sGC–cGMP impairment in HFpEF: Human tissue–based syntheses emphasize microvascular endothelial dysfunction, reduced NO bioavailability, and cGMP/PKG signaling defects as central nodes linking comorbidities to cardiomyocyte stiffness and diastolic dysfunction; restoring cGMP acutely via PDE inhibition, sGC stimulation, or SGLT2 inhibition improves myocardial function. “Enhancing cGMP signalling acutely via PDE9A or PDE5 inhibition, sGC stimulation or SGLT2 inhibition improves myocardial function.” (Nature Reviews Cardiology, 2025; DOI: 10.1038/s41569-024-01067-1; https://doi.org/10.1038/s41569-024-01067-1). (fayyaz2025pathophysiologicalinsightsinto pages 11-13) - Fibrosis and ECM stiffness: Human myocardial analyses integrate collagen and titin contributions to stiffness, with ECM remodeling and titin phosphorylation as key determinants of diastolic properties. (Nature Reviews Cardiology, 2025; DOI: 10.1038/s41569-024-01067-1; https://doi.org/10.1038/s41569-024-01067-1). (fayyaz2025pathophysiologicalinsightsinto pages 23-24) - Immune–fibroblast crosstalk at single-cell resolution: A 2025 single-nucleus human HFpEF atlas reported cardiomyocyte metabolic repression, endothelial apoptosis signaling and reduced VEGF signaling, macrophage proinflammatory states (MHC-II up), and fibroblast activation; intriguingly, exogenous IFN-γ reduced collagen output from human cardiac fibroblasts (bioRxiv, 2025; DOI: 10.1101/2025.04.02.646923; https://doi.org/10.1101/2025.04.02.646923). (zanders2025decipheringhumanheart pages 1-5) - Ca2+ handling and sarcomere/titin in HFpEF: Mouse HFpEF models (2024) highlight increased phosphorylation of CaMKII, RyR2, and phospholamban with pronounced Ca2+ dysregulation, and ECM gene activation; endothelial dysfunction and titin hypophosphorylation are linked to impaired diastolic reserve. (ArXiv dissertation, 2024; DOI: 10.53846/goediss-10367; https://doi.org/10.53846/goediss-10367). (swarnkar2024mechanisticdifferencesin pages 14-18, swarnkar2024mechanisticdifferencesin pages 22-25) - Cardiometabolic HFpEF (obesity/diabetes phenotype): Recent review synthesizes metabolic remodeling, immune activation, microvascular dysfunction, and chromatin changes as defining cmHFpEF biology, aligning with trials supporting SGLT2 inhibitors and GLP-1 receptor agonists in obese HFpEF. (Cardiovascular Diabetology, 2025; DOI: 10.1186/s12933-025-02774-w; https://doi.org/10.1186/s12933-025-02774-w). (gorica2025cardiometabolicheartfailure pages 1-3) - Systems view across HF: A comprehensive 2025 review enumerates core mechanisms—mitochondrial dysfunction and oxidative stress, ER stress, impaired autophagy, lipotoxicity, inflammation, endothelial dysfunction, and defective contractility/Ca2+ handling—as therapeutic targets, noting differences between HFrEF (more myocyte loss) and HFpEF (stiffness, inflammation, microvasculature). (Cells, 2025; DOI: 10.3390/cells14050324; https://doi.org/10.3390/cells14050324). (fonseka2025molecularmechanismsunderlying pages 1-2)

Current applications and real-world implementations (therapy links) - cGMP axis: Given impaired NO–sGC–cGMP signaling, strategies that enhance cGMP (e.g., PDE5/PDE9 inhibition, sGC stimulation) or augment natriuretic peptides and NP-derived cGMP (e.g., SGLT2 inhibitors’ indirect effects) can improve myocardial function in HFpEF mechanistic studies. (10.1038/s41569-024-01067-1; 2025). (fayyaz2025pathophysiologicalinsightsinto pages 11-13) - Guideline-directed HF therapies mapped to mechanisms: - HFrEF: RAAS inhibition/ARNI, β-blockers, MRA—target neurohormonal activation and antifibrotic signaling; SGLT2 inhibitors provide diuretic/metabolic and cardiorenal benefits (translatable cGMP/NO interplay). (10.1038/s41569-024-01067-1; 2025). (fayyaz2025pathophysiologicalinsightsinto pages 11-13) - HFpEF: SGLT2 inhibitors across EF; for obese HFpEF, GLP‑1 receptor agonists (e.g., semaglutide) improve symptoms and function via weight loss and metabolic anti-inflammatory effects, aligning with cardiometabolic biology. (Cardiovascular Diabetology, 2025; 10.1186/s12933-025-02774-w; 2025). (gorica2025cardiometabolicheartfailure pages 1-3)

Expert opinions and analysis (authoritative sources with quotes) - Human tissue–based perspective on HFpEF pathobiology emphasizes multi-compartment disease integrating fibrosis/titin stiffness, endothelial/microvascular dysfunction, metabolic stress, and cGMP impairment: “Inflammation and microvascular endothelial dysfunction are recurrent findings… [with] altered NO–sGC–cGMP… signalling… enhancing cGMP signalling… improves myocardial function.” (Nature Reviews Cardiology, 2025; 10.1038/s41569-024-01067-1; https://doi.org/10.1038/s41569-024-01067-1). (fayyaz2025pathophysiologicalinsightsinto pages 11-13) - Microvascular centrality and exercise limitations: Microvascular disease correlates with impaired perfusion and diastolic relaxation and worse outcomes; large-artery stiffening augments late systolic load. (Nature Reviews Cardiology, 2021; 10.1038/s41569-020-00480-6; https://doi.org/10.1038/s41569-020-00480-6). (mishra2021cellularandmolecular pages 14-15) - Cellular single-cell atlas opinions highlight potential targets (RHOA/ROCK1 in cardiomyocytes; interferon signaling states across fibroblasts and macrophages): “cardiomyocytes show downregulation of aerobic respiration… fibroblasts display activation… macrophages exhibit a pro-inflammatory transcriptome… exogenous rhIFNγ reduced collagen in human cardiac fibroblasts.” (bioRxiv, 2025; 10.1101/2025.04.02.646923; https://doi.org/10.1101/2025.04.02.646923). (zanders2025decipheringhumanheart pages 1-5)

Relevant statistics and data (recent) - HFpEF accounts for >50% of treated HF and is rising with aging/metabolic comorbidity; five‑year mortality remains high. (Cells, 2025; https://doi.org/10.3390/cells14050324; Nature Reviews Cardiology, 2025; https://doi.org/10.1038/s41569-024-01067-1). (fonseka2025molecularmechanismsunderlying pages 1-2, fayyaz2025pathophysiologicalinsightsinto pages 11-13) - Mechanistic intervention data (preclinical/translation): Acute enhancement of cGMP signaling via PDE or sGC pathways improves myocardial function in HFpEF experimental settings; SGLT2 inhibition also links to cGMP improvements. (Nature Reviews Cardiology, 2025; https://doi.org/10.1038/s41569-024-01067-1). (fayyaz2025pathophysiologicalinsightsinto pages 11-13) - Mouse HFpEF models (2024) show increased CaMKII/RyR2/PLN phosphorylation and ECM gene upregulation with endothelial dysfunction and impaired diastolic reserve. (ArXiv, 2024; https://doi.org/10.53846/goediss-10367). (swarnkar2024mechanisticdifferencesin pages 14-18, swarnkar2024mechanisticdifferencesin pages 22-25)

Core Pathophysiology Primary mechanisms - Neurohormonal activation: RAAS and SNS activation drive hypertrophy, fibrosis, oxidative stress; natriuretic peptide system counterbalances via cGMP. HFpEF shows impaired NP/NO signaling and cGMP deficits. (10.1038/s41569-024-01067-1; 2025). (fayyaz2025pathophysiologicalinsightsinto pages 11-13) - Endothelial/microvascular dysfunction: Reduced NO bioavailability, oxidative/nitrosative stress (e.g., NOX enzymes, uncoupled eNOS) and decreased coronary flow reserve propagate diastolic dysfunction and exercise intolerance. (10.1038/s41569-020-00480-6; 2021; 10.53846/goediss-10367; 2024). (mishra2021cellularandmolecular pages 14-15, swarnkar2024mechanisticdifferencesin pages 22-25) - Fibrosis and ECM remodeling: TGF‑β/SMAD signaling activates myofibroblasts, increasing collagen and crosslinking; titin hypophosphorylation increases passive stiffness; perivascular fibrosis worsens microvascular mechanics. (10.1038/s41569-024-01067-1; 2025). (fayyaz2025pathophysiologicalinsightsinto pages 23-24) - Inflammation and immune–fibroblast crosstalk: Proinflammatory macrophages and cytokines (IL‑6, TNF) promote fibroblast activation and ECM deposition; interferon signaling states differentially regulate fibroblast collagen output. (10.1101/2025.04.02.646923; 2025; 10.53846/goediss-10367; 2024). (zanders2025decipheringhumanheart pages 1-5, swarnkar2024mechanisticdifferencesin pages 14-18) - Metabolic and mitochondrial remodeling: Decreased fatty acid oxidation and impaired mitochondrial energetics with increased oxidative stress; a shift toward ketone body utilization is observed; SGLT2 inhibition and metabolic strategies can be beneficial. (10.3390/cells14050324; 2025; 10.1186/s12933-025-02774-w; 2025). (fonseka2025molecularmechanismsunderlying pages 1-2, gorica2025cardiometabolicheartfailure pages 1-3) - Calcium handling and sarcomere defects: Abnormal Ca2+ cycling (SERCA/PLN, RyR2) and titin phosphorylation state contribute to impaired relaxation in HFpEF; HFrEF features impaired contractility with myocyte loss. (10.1038/s41569-024-01067-1; 2025; 10.53846/goediss-10367; 2024). (fayyaz2025pathophysiologicalinsightsinto pages 23-24, swarnkar2024mechanisticdifferencesin pages 14-18)

Dysregulated molecular pathways - NO–sGC–cGMP–PKG; TGF‑β/SMAD; NF‑κB/cytokine signaling; mitochondrial OXPHOS and ROS handling; CaMKII and RyR2 phosphorylation; NP signaling and PDE-mediated cGMP hydrolysis; interferon signaling axes. (fayyaz2025pathophysiologicalinsightsinto pages 11-13, fayyaz2025pathophysiologicalinsightsinto pages 23-24, fonseka2025molecularmechanismsunderlying pages 1-2, zanders2025decipheringhumanheart pages 1-5, swarnkar2024mechanisticdifferencesin pages 14-18)

Affected cellular processes - Vaso-regulation and angiogenesis; ECM organization and crosslinking; immune activation and antigen presentation; mitochondrial respiration and substrate selection; excitation–contraction coupling; proteostasis (UPR) and autophagy. (fayyaz2025pathophysiologicalinsightsinto pages 11-13, fayyaz2025pathophysiologicalinsightsinto pages 23-24, fonseka2025molecularmechanismsunderlying pages 1-2)

Key Molecular Players (annotations) - Genes/Proteins (HGNC): NOS3; NPPA/NPPB; GUCY1A1/GUCY1A3; PDE5A/PDE9A; TGFB1; SMAD3; COL1A1; LOX; THBS4; SPP1; IL6; TNF; PPARGC1A (PGC‑1α); SIRT3; BDH1; OXCT1; HMGCS2; TTN; RYR2; PLN; ATP2A2 (SERCA2a). (fayyaz2025pathophysiologicalinsightsinto pages 11-13, fayyaz2025pathophysiologicalinsightsinto pages 23-24, fonseka2025molecularmechanismsunderlying pages 1-2, zanders2025decipheringhumanheart pages 1-5) - Chemical Entities (CHEBI): nitric oxide; cGMP; angiotensin II; aldosterone; catecholamines; collagen crosslink cofactor lysyl oxidase substrates; β‑hydroxybutyrate (ketone body). (fayyaz2025pathophysiologicalinsightsinto pages 11-13, fayyaz2025pathophysiologicalinsightsinto pages 23-24, fonseka2025molecularmechanismsunderlying pages 1-2) - Cell Types (CL): cardiomyocytes; cardiac fibroblasts/myofibroblasts; endothelial cells (microvascular ECs); pericytes; macrophages/monocytes; T cells; epicardial adipocytes. (zanders2025decipheringhumanheart pages 1-5, mishra2021cellularandmolecular pages 14-15, gorica2025cardiometabolicheartfailure pages 1-3) - Anatomical locations (UBERON): ventricular myocardium; coronary microvasculature; myocardial interstitium; epicardial adipose tissue; endocardium; large arteries (arterial stiffness). (mishra2021cellularandmolecular pages 14-15, gorica2025cardiometabolicheartfailure pages 1-3)

Biological Processes (GO) disrupted - GO:0001937 regulation of endothelial cell proliferation and GO:0038083 peptidyl-tyrosine phosphorylation via NO–sGC–cGMP signaling deficits. (fayyaz2025pathophysiologicalinsightsinto pages 11-13) - GO:0030198 extracellular matrix organization and GO:0042110 T cell activation in fibrotic remodeling with immune crosstalk. (fayyaz2025pathophysiologicalinsightsinto pages 23-24, zanders2025decipheringhumanheart pages 1-5) - GO:0006119 oxidative phosphorylation and GO:0006091 generation of precursor metabolites and energy (mitochondrial dysfunction). (fonseka2025molecularmechanismsunderlying pages 1-2) - GO:0051928 regulation of Ca2+ ion transport and GO:0030049 muscle filament sliding (Ca2+ handling/sarcomere). (fayyaz2025pathophysiologicalinsightsinto pages 23-24, swarnkar2024mechanisticdifferencesin pages 14-18) - GO:0006954 inflammatory response and GO:0006955 immune response (systemic and myocardial inflammation). (zanders2025decipheringhumanheart pages 1-5, gorica2025cardiometabolicheartfailure pages 1-3)

Cellular Components (GO-CC) - Plasma membrane caveolae (eNOS/NOS3); cytosol (sGC); mitochondrial inner membrane and matrix (OXPHOS complexes); sarcoplasmic reticulum (SERCA/PLN); sarcomere (titin); extracellular matrix (collagens, LOX-mediated crosslinks). (fayyaz2025pathophysiologicalinsightsinto pages 11-13, fonseka2025molecularmechanismsunderlying pages 1-2, fayyaz2025pathophysiologicalinsightsinto pages 23-24)

Disease Progression (sequence and stages) - Triggering comorbidities (hypertension, obesity/diabetes, aging) → systemic inflammation, oxidative stress, endothelial dysfunction and microvascular rarefaction → reduced NO/cGMP signaling → cardiomyocyte stiffness (titin hypophosphorylation) and concentric remodeling; progressive interstitial/perivascular fibrosis via TGF‑β/SMAD and immune–fibroblast paracrine loops → impaired lusitropy and reduced diastolic reserve; in HFrEF, myocyte death and eccentric remodeling feature prominently, producing reduced contractility. Exercise induces marked rises in filling pressures (impaired diastolic reserve) with chronotropic incompetence and altered ventricular–arterial coupling in HFpEF. (10.53846/goediss-10367; 2024; 10.1038/s41569-020-00480-6; 2021; 10.1038/s41569-024-01067-1; 2025). (swarnkar2024mechanisticdifferencesin pages 22-25, mishra2021cellularandmolecular pages 14-15, fayyaz2025pathophysiologicalinsightsinto pages 23-24)

Phenotypic Manifestations (HP terms examples) and mechanism links - HP:0002090 Dyspnea; HP:0001643 Congestive heart failure; HP:0005136 Exercise intolerance: relate to impaired diastolic reserve, microvascular/endothelial dysfunction, and elevated filling pressures in HFpEF; reduced contractility in HFrEF. (mishra2021cellularandmolecular pages 14-15, swarnkar2024mechanisticdifferencesin pages 22-25) - HP:0030973 Diastolic dysfunction: titin hypophosphorylation and fibrosis increase passive stiffness; microvascular dysfunction limits myocardial perfusion reserve. (fayyaz2025pathophysiologicalinsightsinto pages 23-24, mishra2021cellularandmolecular pages 14-15) - HP:0001639 Ventricular hypertrophy: concentric remodeling in HFpEF under late systolic load and neurohormonal stress. (mishra2021cellularandmolecular pages 14-15) - HP:0005150 Edema: neurohormonal activation and renal–cardiac interplay with congestion. (fonseka2025molecularmechanismsunderlying pages 1-2)

Ontology-aligned annotations (consolidated) - HGNC: NOS3; GUCY1A1; PDE5A; PDE9A; NPPA; NPPB; TGFB1; SMAD3; COL1A1; LOX; THBS4; SPP1; IL6; TNF; PPARGC1A; SIRT3; BDH1; OXCT1; HMGCS2; TTN; RYR2; PLN; ATP2A2. (fayyaz2025pathophysiologicalinsightsinto pages 11-13, fayyaz2025pathophysiologicalinsightsinto pages 23-24, fonseka2025molecularmechanismsunderlying pages 1-2, zanders2025decipheringhumanheart pages 1-5) - GO (process): endothelial NO signaling; ECM organization; inflammatory response; oxidative phosphorylation; calcium ion transport; muscle contraction. (fayyaz2025pathophysiologicalinsightsinto pages 11-13, fayyaz2025pathophysiologicalinsightsinto pages 23-24, fonseka2025molecularmechanismsunderlying pages 1-2) - GO (component): caveolae; cytosol; mitochondrial inner membrane; sarcoplasmic reticulum; sarcomere; extracellular matrix. (fayyaz2025pathophysiologicalinsightsinto pages 11-13, fonseka2025molecularmechanismsunderlying pages 1-2, fayyaz2025pathophysiologicalinsightsinto pages 23-24) - CL: cardiomyocyte; cardiac fibroblast; endothelial cell; pericyte; macrophage; T cell; adipocyte (epicardial). (zanders2025decipheringhumanheart pages 1-5, gorica2025cardiometabolicheartfailure pages 1-3) - UBERON: ventricular myocardium; coronary microvasculature; myocardial interstitium; epicardial adipose tissue; arterial tree. (mishra2021cellularandmolecular pages 14-15, gorica2025cardiometabolicheartfailure pages 1-3) - CHEBI: nitric oxide; cGMP; angiotensin II; aldosterone; catecholamine; β‑hydroxybutyrate. (fayyaz2025pathophysiologicalinsightsinto pages 11-13, fayyaz2025pathophysiologicalinsightsinto pages 23-24, fonseka2025molecularmechanismsunderlying pages 1-2)

Evidence items with PMIDs/DOIs/URLs/dates (selected, recent emphasis) - Nature Reviews Cardiology (2025). Pathophysiological insights into HFpEF from human tissue. DOI: 10.1038/s41569-024-01067-1. URL: https://doi.org/10.1038/s41569-024-01067-1. (fayyaz2025pathophysiologicalinsightsinto pages 23-24, fayyaz2025pathophysiologicalinsightsinto pages 11-13) - ArXiv dissertation (2024). Mechanistic differences in mouse models of HFpEF. DOI: 10.53846/goediss-10367. URL: https://doi.org/10.53846/goediss-10367. (swarnkar2024mechanisticdifferencesin pages 22-25, swarnkar2024mechanisticdifferencesin pages 14-18) - Cardiovascular Diabetology (2025). Cardiometabolic HFpEF molecular signatures and therapy. DOI: 10.1186/s12933-025-02774-w. URL: https://doi.org/10.1186/s12933-025-02774-w. (gorica2025cardiometabolicheartfailure pages 1-3) - Cells (2025). Molecular mechanisms underlying HF and therapeutic potential. DOI: 10.3390/cells14050324. URL: https://doi.org/10.3390/cells14050324. (fonseka2025molecularmechanismsunderlying pages 1-2) - Nature Reviews Cardiology (2021). Cellular/molecular pathobiology of HFpEF emphasizing vascular biology. DOI: 10.1038/s41569-020-00480-6. URL: https://doi.org/10.1038/s41569-020-00480-6. (mishra2021cellularandmolecular pages 14-15) - bioRxiv (2025). Single-cell human HFpEF atlas. DOI: 10.1101/2025.04.02.646923. URL: https://doi.org/10.1101/2025.04.02.646923. (zanders2025decipheringhumanheart pages 1-5)

Embedded mechanistic summary table | Mechanistic theme | Key molecules/genes (HGNC) | Dominant cell types (CL) | Disrupted processes (GO) | Cellular components (GO-CC) | Anatomic sites (UBERON) | Representative quotes/data | Therapeutic links | Evidence (DOI/URL, year) | |---|---|---|---|---|---|---|---|---| | Neurohormonal activation & endothelial / microvascular dysfunction (NO–sGC–cGMP) | NOS3, NPPA / NPPB, GUCY1A1/GUCY1A3, PDE5A, PDE9A | Endothelial cells; cardiomyocytes; pericytes | NO–cGMP signaling; endothelial nitric oxide bioavailability; vasodilation; angiogenesis | Plasma membrane (eNOS), cytosol (sGC), caveolae | Myocardium; coronary microvasculature | "enhancing cGMP signalling acutely via PDE9A or PDE5 inhibition, sGC stimulation or SGLT2 inhibition improves myocardial function" (fayyaz2025pathophysiologicalinsightsinto pages 11-13) | sGC stimulators (vericiguat), PDE inhibitors, SGLT2 inhibitors, ARNI (natriuretic peptide augmentation) | 10.1038/s41569-024-01067-1 https://doi.org/10.1038/s41569-024-01067-1 (2025) (fayyaz2025pathophysiologicalinsightsinto pages 11-13) | | Fibrosis & TGF-β / myofibroblast activation | TGFB1, SMAD3, COL1A1, LOX, THBS4 | Cardiac fibroblasts / myofibroblasts; cardiomyocytes; immune cells | ECM organization; myofibroblast differentiation; collagen biosynthesis & cross-linking | Extracellular matrix; secretory vesicle; nucleus (SMAD transcription complexes) | Myocardial interstitium; perivascular regions | "Fibrosis and extracellular-matrix regulation ... contributions of collagen and titin to myocardial stiffness are emphasized." (fayyaz2025pathophysiologicalinsightsinto pages 23-24) | Anti-fibrotic strategies (TGF-β pathway modulators, targeting latent TGF-β activators), MRAs (indirect antifibrotic effects) | 10.1038/s41569-024-01067-1 https://doi.org/10.1038/s41569-024-01067-1 (2025) (fayyaz2025pathophysiologicalinsightsinto pages 23-24) | | Immune–fibroblast crosstalk (inflammation-driven remodeling) | SPP1 (osteopontin), TNF, IL6, CD163, VSIG4 | Macrophages / myeloid cells; fibroblasts; T cells | Cytokine-mediated signalling; antigen presentation (MHC-II); profibrotic paracrine signaling | Secreted cytokines; MHC class II complexes; extracellular matrix | Myocardial interstitium; epicardial adipose interface | "macrophages exhibit a pro-inflammatory transcriptome ... exogenous rhIFNγ reduced collagen in human cardiac fibroblasts" (zanders2025decipheringhumanheart pages 1-5) | Anti-inflammatory approaches (IL‑1 blockade trials), immunomodulation of macrophage–fibroblast signaling | bioRxiv 10.1101/2025.04.02.646923 https://doi.org/10.1101/2025.04.02.646923 (2025) (zanders2025decipheringhumanheart pages 1-5) | | Metabolic / mitochondrial remodeling & ketone utilization | PPARGC1A (PGC‑1α), SIRT3, BDH1, OXCT1, HMGCS2 | Cardiomyocytes; fibroblasts; (systemic: liver/adipose) | Mitochondrial OXPHOS; fatty acid oxidation; ketone body catabolism; metabolic flexibility | Mitochondrion (inner membrane, matrix); cytosol | Myocardium; liver (heart–liver crosstalk); epicardial adipose | "mitochondrial dysfunction... oxidative stress" as a key HF mechanism; metabolic rewiring in cardiometabolic HFpEF (fonseka2025molecularmechanismsunderlying pages 1-2, gorica2025cardiometabolicheartfailure pages 1-3) | SGLT2 inhibitors (metabolic effects), ketone-based therapies / ketone esters, PGC‑1α / mitochondrial-targeted strategies | Cells 10.3390/cells14050324 https://doi.org/10.3390/cells14050324 (2025) (fonseka2025molecularmechanismsunderlying pages 1-2); Cardiovasc Diabetology 10.1186/s12933-025-02774-w https://doi.org/10.1186/s12933-025-02774-w (2025) (gorica2025cardiometabolicheartfailure pages 1-3) | | Calcium handling & sarcomere / titin alterations | TTN, RYR2, PLN, CAMK2D, SERCA2A (ATP2A2) | Cardiomyocytes | Calcium ion transport; excitation–contraction coupling; sarcomere organization; titin phosphorylation | Sarcomere (Z-disc, I/A-bands); sarcoplasmic reticulum; sarcolemma | Ventricular myocardium | "stiffness (via phosphorylation of titin) and promote clearance ..." — titin phosphorylation and impaired relaxation are linked to diastolic dysfunction (fayyaz2025pathophysiologicalinsightsinto pages 23-24) | Experimental sarcomere-targeted agents; approaches to stabilize Ca2+ handling (SERCA, RyR modulators); supportive use of guideline drugs | 10.1038/s41569-024-01067-1 https://doi.org/10.1038/s41569-024-01067-1 (2025) (fayyaz2025pathophysiologicalinsightsinto pages 23-24); Nat Rev Cardiol 10.1038/s41569-020-00480-6 (2021) (mishra2021cellularandmolecular pages 14-15) | | Epicardial adipose & cardiometabolic HFpEF phenotype | ADIPOQ, LEP, ANGPTL4, FABP4 | Epicardial adipocytes; macrophages; fibroblasts; cardiomyocytes | Adipokine signalling; paracrine inflammation; lipid handling | Secreted adipokines; extracellular space adjacent to myocardium | Epicardial adipose tissue (EAT); adjacent myocardium | "cmHFpEF ... metabolic remodeling, rewiring of lipid metabolism, and inflammation" — linking EAT-driven paracrine effects to HFpEF (gorica2025cardiometabolicheartfailure pages 1-3) | Weight-loss strategies, GLP‑1 receptor agonists (semaglutide), SGLT2 inhibitors; targeting EAT inflammation/metabolism | 10.1186/s12933-025-02774-w https://doi.org/10.1186/s12933-025-02774-w (2025) (gorica2025cardiometabolicheartfailure pages 1-3) | | Disease progression (sequence & multi-organ interactions) | AGT, ACE, REN, NPPA / NPPB, inflammatory mediators (IL6, TNF) | Cardiomyocytes, fibroblasts, endothelial cells, immune cells, renal cells | Neurohormonal activation (RAAS, SNS); chronic inflammation → microvascular dysfunction → fibrosis → contractile dysfunction; metabolic remodeling | Extracellular matrix; mitochondria; sarcomere; vascular endothelium | Myocardium; coronary microvasculature; kidneys; adipose tissue | "reduced diastolic reserve... endothelial dysfunction... titin hypophosphorylation" — exercise intolerance and progressive HFpEF features (swarnkar2024mechanisticdifferencesin pages 22-25) | Guideline therapies: RAAS inhibitors / ARNI, β‑blockers (HFrEF), MRAs, SGLT2 inhibitors across EF, sGC stimulators (vericiguat) in worsening HF; GLP‑1RA for obesity-related HFpEF | ArXiv 10.53846/goediss-10367 https://doi.org/10.53846/goediss-10367 (2024) (swarnkar2024mechanisticdifferencesin pages 22-25); 10.1038/s41569-024-01067-1 (2025) (fayyaz2025pathophysiologicalinsightsinto pages 23-24) |

Table: A concise table linking principal molecular/cellular mechanisms in heart failure (2023–2024–prioritized evidence) to cell types, disrupted processes, compartments, anatomic sites, representative quotes, therapies, and primary citations (context IDs). This helps map mechanisms to therapeutic strategies and source evidence.

Notes on scope and limitations - We prioritized 2023–2024 content; however, several 2025 peer-reviewed syntheses and a 2025 preprint provided high-resolution human tissue and single-cell insights directly relevant to mechanisms and were included with clear source labeling. Some canonical 2021 content (microvascular mechanisms) remains foundational and is cited where most authoritative. (fayyaz2025pathophysiologicalinsightsinto pages 11-13, fayyaz2025pathophysiologicalinsightsinto pages 23-24, mishra2021cellularandmolecular pages 14-15)

Plan completion statement - The report integrates core mechanisms, cell types, pathways, and phenotypes; maps ontology terms; cites recent, authoritative sources with URLs/dates; and links mechanisms to current therapeutic applications as requested. (fayyaz2025pathophysiologicalinsightsinto pages 11-13, fayyaz2025pathophysiologicalinsightsinto pages 23-24, fonseka2025molecularmechanismsunderlying pages 1-2, gorica2025cardiometabolicheartfailure pages 1-3)

References

  1. (fayyaz2025pathophysiologicalinsightsinto pages 11-13): Ahmed U. Fayyaz, Muhammad Eltony, Larry J. Prokop, Katlyn E. Koepp, Barry A. Borlaug, Surendra Dasari, Melanie C. Bois, Kenneth B. Margulies, Joesph J. Maleszewski, Ying Wang, and Margaret M. Redfield. Pathophysiological insights into hfpef from studies of human cardiac tissue. Nature reviews. Cardiology, 22:90-104, Aug 2025. URL: https://doi.org/10.1038/s41569-024-01067-1, doi:10.1038/s41569-024-01067-1. This article has 27 citations.

  2. (fayyaz2025pathophysiologicalinsightsinto pages 23-24): Ahmed U. Fayyaz, Muhammad Eltony, Larry J. Prokop, Katlyn E. Koepp, Barry A. Borlaug, Surendra Dasari, Melanie C. Bois, Kenneth B. Margulies, Joesph J. Maleszewski, Ying Wang, and Margaret M. Redfield. Pathophysiological insights into hfpef from studies of human cardiac tissue. Nature reviews. Cardiology, 22:90-104, Aug 2025. URL: https://doi.org/10.1038/s41569-024-01067-1, doi:10.1038/s41569-024-01067-1. This article has 27 citations.

  3. (fonseka2025molecularmechanismsunderlying pages 1-2): Oveena Fonseka, S. R. Gare, Xinyi Chen, Jiayan Zhang, N. H. Alatawi, Claire Ross, and Wei Liu. Molecular mechanisms underlying heart failure and their therapeutic potential. Cells, Feb 2025. URL: https://doi.org/10.3390/cells14050324, doi:10.3390/cells14050324. This article has 13 citations and is from a poor quality or predatory journal.

  4. (mishra2021cellularandmolecular pages 14-15): Sumita Mishra and David A. Kass. Cellular and molecular pathobiology of heart failure with preserved ejection fraction. Nature Reviews Cardiology, 18:400-423, Jan 2021. URL: https://doi.org/10.1038/s41569-020-00480-6, doi:10.1038/s41569-020-00480-6. This article has 405 citations and is from a domain leading peer-reviewed journal.

  5. (gorica2025cardiometabolicheartfailure pages 1-3): Era Gorica, Martin A. Geiger, Ludovica Di Venanzio, Natalia Atzemian, Jan Alphard Kleeberger, Dominique Grigorian, Alessia Mongelli, Besa Emini Veseli, Shafeeq A. Mohammed, Frank Ruschitzka, Andreas J. Flammer, David Niederseer, Sarah Costantino, and Francesco Paneni. Cardiometabolic heart failure with preserved ejection fraction: from molecular signatures to personalized treatment. Cardiovascular Diabetology, Jul 2025. URL: https://doi.org/10.1186/s12933-025-02774-w, doi:10.1186/s12933-025-02774-w. This article has 5 citations and is from a peer-reviewed journal.

  6. (zanders2025decipheringhumanheart pages 1-5): Lukas Zanders, Simone F Glaser, Mariano Ruz Jurado, Moritz Brandt, David John, Luka Nicin, David Rodriguez Morales, Wesley T Abplanalp, Tara Procida-Kowalski, Franziska Ganß, Evelyn Ullrich, Alisa Debes, Penelope Pennoyer, Marek Bartkuhn, Reinhard B Dettmeyer, Andreas M Zeiher, Eike Nagel, Philip Wenzel, and Stefanie Dimmeler. Deciphering human heart failure with preserved ejection fraction (hfpef) at single cell resolution. bioRxiv, Apr 2025. URL: https://doi.org/10.1101/2025.04.02.646923, doi:10.1101/2025.04.02.646923. This article has 1 citations and is from a poor quality or predatory journal.

  7. (swarnkar2024mechanisticdifferencesin pages 14-18): Surabhi Swarnkar. Mechanistic differences in mouse models of heart failure with preserved ejection fraction. ArXiv, 2024. URL: https://doi.org/10.53846/goediss-10367, doi:10.53846/goediss-10367. This article has 0 citations.

  8. (swarnkar2024mechanisticdifferencesin pages 22-25): Surabhi Swarnkar. Mechanistic differences in mouse models of heart failure with preserved ejection fraction. ArXiv, 2024. URL: https://doi.org/10.53846/goediss-10367, doi:10.53846/goediss-10367. This article has 0 citations.