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Classifications

Harrison's Part

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Subtypes

3

Heart Failure with Reduced Ejection Fraction (HFrEF)

Left ventricular ejection fraction 40% or less, 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

Respiratory Syncytial Virus Infection <-> Heart Failure

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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.

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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

Cardiac Contraction GO:0060047

Computational models

CircAdapt par-75 imaging-based left-ventricular digital twin DIGITAL TWIN MATLAB; CircAdapt C++ model solver; dynamic multi-swarm particle swarm optimization Personalized activation delays and active and passive myocardial material properties reproduce regional strain and cavity-volume measurements and yield regional myocardial work distributions.

Downstream

Neurohormonal Activation Falling cardiac output and effective arterial underfilling unload the arterial baroreceptors and reduce renal perfusion, which is the stimulus that switches on the sympathetic nervous system and the renin-angiotensin-aldosterone system in heart failure.

Exercise Intolerance The failing ventricle cannot augment stroke volume and cardiac output to meet the metabolic demand of exertion, which is the proximate cause of the reduced exercise capacity that defines functional class.

Fatigue Inadequate cardiac output limits oxygen delivery to skeletal muscle and other tissues at rest and on mild exertion, producing the persistent tiredness characteristic of the syndrome.

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

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.

Ventricular Remodeling Sustained sympathetic and RAAS signalling drives the maladaptive hypertrophic and fibrotic growth programme in the ventricle, converting an initially compensatory response into progressive structural remodelling.

Fluid Retention Angiotensin II and aldosterone promote renal sodium and water reabsorption and arginine vasopressin promotes free-water retention, which is the neurohormonal route to volume overload in heart failure.

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

Cardiac Remodeling GO:0060420

Computational models

CircAdapt virtual-pacing CRT response twin DIGITAL TWIN CircAdapt cardiovascular mechanics model Virtual biventricular pacing alters septal-to-lateral work distribution; the simulated acute mechanical response is compared with the patient's subsequent reduction in left-ventricular end-systolic volume.

Downstream

Myocardial Contractile Dysfunction Hypertrophy, chamber dilatation and interstitial fibrosis increase diastolic stiffness and degrade systolic performance, so the structural response that was initially compensatory ends up worsening pump function. This closes the self-reinforcing loop that drives progression of the syndrome.

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.

Downstream

Dyspnea Volume overload raises left atrial and pulmonary venous pressure, driving fluid into the pulmonary interstitium and alveoli and producing the cardinal breathlessness of heart failure.

Orthopnea In the recumbent position the retained volume redistributes from the splanchnic and lower-body reservoirs to the thorax, raising pulmonary capillary pressure further and producing breathlessness on lying flat.

Peripheral Edema Systemic venous congestion from the expanded extracellular volume raises capillary hydrostatic pressure in dependent tissues, driving interstitial fluid accumulation.

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

TGF-beta-Smad profibrotic signalling in cardiac fibroblasts GO:0007179 ↑ INCREASED NADPH oxidase-derived oxidative stress GO:0042554 ↑ INCREASED NO-cGMP-PKG braking of fibroblast activation GO:0038060 ↓ DECREASED mineralocorticoid receptor signalling GO:0031959 ↑ 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

intracellular regeneration of active cortisol from cortisone GO:0008211 ↑ INCREASED

11beta-HSD1 reductase activity regenerating cortisol GO:0070524 ↑ INCREASED glucocorticoid receptor-driven profibrotic transcription GO:0004883 ↑ 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 cardiac endothelial cell CL:0010008

ESR1 hgnc:3467 ESR2 hgnc:3468

oestrogen receptor signalling in myocardium and coronary endothelium GO:0030520 ↓ DECREASED

nuclear oestrogen receptor activity in cardiac fibroblasts and coronary endothelium GO:0030284 ↓ 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 (3 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.

PMID:20810711 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"In the hearts of ovariectomized female mice, cardiac hypertrophy and fibrosis were induced by AngII infusion and prevented by E2 administration to wild type but not ERβ knockout rodents."

Grounds the ESR2 descriptor on this node and its direction. Ovariectomy is the experimental counterpart of the oestrogen withdrawal upstream, and the antifibrotic effect of restoring oestradiol depends on an intact oestrogen receptor beta gene, so the lost signal runs through the ESR2 product. Graded INDIRECT because the model is angiotensin II-induced fibrosis in mice rather than human HFpEF myocardium.

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 Vascular Smooth Muscle Cell CL:0000359

Oxidative Stress Response GO:0006979 ↑ INCREASED Vascular Remodeling GO:0001974 ⚠ ABNORMAL Microthrombotic Events GO:0007596 ↑ INCREASED

Downstream

Myocardial Contractile Dysfunction Impaired coronary microvascular vasodilator reserve limits subendocardial perfusion during increased demand, which is the route by which Lp(a)-driven microvascular disease is proposed to contribute to the diastolic and systolic impairment of HFpEF.

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.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

6

Cardiovascular 1

Cardiomegaly FREQUENT HP:0001640

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

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

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

Dyspnea when lying flat

Constitutional 2

Fatigue VERY_FREQUENT HP:0012378

Exercise Intolerance VERY_FREQUENT HP:0003546

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.

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Genetic Associations

3

TTN (Causative)

Gene: TTN hgnc:12403 gene page

Show evidence (1 reference)

CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2025-05-30T160000.000Z SUPPORT Other

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 gene page

Show evidence (1 reference)

CGGV:assertion_4ec27d4f-70ea-4c6a-ad67-d6260ecadcde-2025-05-30T160000.000Z SUPPORT Other

ClinGen classifies the MYH7-dilated cardiomyopathy relationship as definitive, establishing a sarcomeric-cardiomyopathy route to heart failure.

LMNA (Causative)

Gene: LMNA hgnc:6636 gene page

Show evidence (1 reference)

CGGV:assertion_132ea1ec-caa9-409a-8670-3edb2ec9c889-2025-05-30T160000.000Z SUPPORT Other

ClinGen classifies the LMNA-dilated cardiomyopathy relationship as definitive; LMNA cardiomyopathy progresses to heart failure and carries genotype-specific device indications.

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Medical Actions

8

ACE Inhibitors/ARBs

Action: Pharmacotherapy NCIT:C15986

Agent: ACE inhibitor NCIT:C247 angiotensin II receptor antagonist NCIT:C66930

Neurohormonal blockade, reduce mortality in HFrEF.

Mechanism Target:

INHIBITS Neurohormonal Activation — ACE inhibition and AT1 receptor blockade interrupt the renin-angiotensin-aldosterone arm of the neurohormonal response, which is the mechanism by which they slow progression rather than merely relieve symptoms.

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: Pharmacotherapy NCIT:C15986

Agent: beta-adrenergic antagonist NCIT:C29576

Reduce heart rate and reverse remodeling in HFrEF.

Mechanism Target:

INHIBITS Neurohormonal Activation — Beta-adrenergic blockade interrupts the sympathetic arm of the neurohormonal response, lowering heart rate and myocardial oxygen demand.

INHIBITS Ventricular Remodeling — By removing the chronic adrenergic drive to the hypertrophic and fibrotic growth programme, beta blockade produces the reverse remodelling and recovery of ejection fraction described for this treatment.

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: Pharmacotherapy NCIT:C15986

Agent: sacubitril CHEBI:134714 valsartan CHEBI:9927

Combined neprilysin inhibitor and ARB, superior to ACE inhibitors.

Mechanism Target:

MODULATES Neurohormonal Activation — The combination blocks the AT1 receptor while neprilysin inhibition raises circulating natriuretic peptides, so it simultaneously suppresses the vasoconstrictor-antinatriuretic arm and augments the vasodilator-natriuretic arm of the same neurohormonal node.

SGLT2 Inhibitors

Action: Pharmacotherapy NCIT:C15986

Agent: SGLT2 inhibitor NCIT:C98083

Reduce hospitalizations and mortality across HF spectrum.

Mechanism Target:

INHIBITS Fluid Retention — Blocking proximal tubular sodium-glucose cotransport produces natriuresis and osmotic diuresis, reducing plasma and interstitial volume. This is the best-characterised of the several proposed mechanisms for this class and is not asserted here to be the whole explanation for its outcome benefit.

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: Pharmacotherapy NCIT:C15986

Agent: spironolactone CHEBI:9241 eplerenone CHEBI:31547 finerenone CHEBI:747008

Platform: Small molecule

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: Pharmacotherapy NCIT:C15986

Manage fluid overload and congestion symptoms.

Mechanism Target:

INHIBITS Fluid Retention — Loop and thiazide diuretics block renal tubular sodium reabsorption, relieving the volume overload that produces congestion. This is symptomatic decongestion and does not act on the upstream neurohormonal or remodelling nodes.

Cardiac Resynchronization Therapy

Action: Cardiac Resynchronization Therapy NCIT:C80436

For patients with wide QRS and reduced EF.

Mechanism Target:

RESTORES Myocardial Contractile Dysfunction — Biventricular pacing recoordinates the mechanically dyssynchronous contraction produced by left bundle branch block, improving stroke volume from the same myocardium and permitting reverse remodelling.

Implantable Cardioverter-Defibrillator

Action: Implantable Cardioverter-Defibrillator Placement 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.

Mechanism Target:

TRIGGERS Ventricular Remodeling — Chronic arterial pressure overload is the afterload stimulus that initiates concentric hypertrophy and interstitial fibrosis in the left ventricle, the structural substrate on which the heart failure syndrome develops.

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.

Mechanism Target:

TRIGGERS Myocardial Contractile Dysfunction — Epicardial coronary obstruction causes myocardial infarction and chronic ischaemia, and the resulting loss of viable contractile myocardium through necrosis and scar formation is the dominant route to reduced ejection fraction in this entry.

Alcohol Abuse

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.

Mechanism Target:

TRIGGERS Myocardial Contractile Dysfunction — Sustained excessive ethanol intake depresses myocardial contractility directly and can produce a dilated cardiomyopathy, giving a route into the heart failure syndrome that is independent of hypertension and coronary disease.

Show evidence (1 reference)

PMID:20308914 SUPPORT DIRECT 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 that chronic excessive intake leads to chronic cardiac dysfunction and can cause dilated cardiomyopathy, which is contractile dysfunction at this node.

🔬

Biochemical Markers

2

BNP/NT-proBNP (Elevated)

Context: Diagnostic and prognostic biomarker

Pathograph Readouts

Readout Of Neurohormonal Activation Positive Diagnostic

Natriuretic peptide release from the myocardium in response to increased wall stress is one arm of the neurohormonal response, so the circulating level reports on the activation state of that node.

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

Pathograph Readouts

Correlates With Myocardial Contractile Dysfunction Positive Prognostic

Chronic low-grade troponin release reflects ongoing cardiomyocyte injury in the failing ventricle and tracks with the severity of pump dysfunction, without being a specific measure of it.

🔬

Diagnosis

1

Echocardiography (Left Ventricular Ejection Fraction)

Left ventricular ejection fraction, measured by echocardiography, is the parameter on which the clinical classification of heart failure rests: the disease is subtyped as reduced, mildly reduced, or preserved ejection fraction (the `has_subtypes` HFrEF/HFmrEF/HFpEF rows), and the three bands recorded here are that classification's own numeric boundaries.

echocardiography NCIT:C16525

left ventricular ejection fraction LOINC:10230-1

Reference Ranges

Left ventricular Ejection fraction (Adults with an incident primary diagnosis of heart failure, manually reviewed Danish hospital cohort, 2021-2024 (as applied by PMID:42614974); the same three-tier boundaries are the ones this entry's `has_subtypes` HFrEF/HFmrEF/HFpEF rows describe in prose.)

Heart Failure with Reduced Ejection Fraction (HFrEF) (< 41 %) Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF) (41–50 %) Heart Failure with Preserved Ejection Fraction (HFpEF) (≥ 50 %)

Heart Failure with Reduced Ejection Fraction (HFrEF): LVEF 40% or below; systolic dysfunction predominates.

Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF): LVEF 41-49%; an intermediate phenotype.

Heart Failure with Preserved Ejection Fraction (HFpEF): LVEF 50% or above; diastolic dysfunction predominates and the ejection fraction itself is not reduced.

The cited cohort states the boundaries as a single sentence ("HFrEF was defined as left ventricular ejection fraction (LVEF) <=40%, HFmrEF as 41-49%, and HFpEF as >=50%"). The bands below partition the scale as half-open intervals that share boundary values, so the HFrEF/HFmrEF split is placed at 41 (HFrEF < 41%, i.e. <=40% at whole-percent resolution) rather than at 40, the same half-open convention the Osteoporosis entry's WHO T-score bands document. This is the classification scheme's own operational definition rather than a specific guideline document's text, because a search of the cached references in this entry for a quotable restatement of the ACC/AHA/HFSA or ESC numeric boundaries themselves (rather than a result that merely mentions "HFrEF"/"HFpEF" in passing) returned none; the cohort study's methods section was the first source found stating all three boundaries together in one quotable sentence.

Show evidence (1 reference)

PMID:42614974 SUPPORT BACKGROUND Human Clinical

"HFrEF was defined as left ventricular ejection fraction (LVEF) ≤40%, HFmrEF as 41-49%, and HFpEF as ≥50%."

States the three LVEF boundaries that define HFrEF, HFmrEF and HFpEF, reproduced below as interpretation bands.

📊

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.

🧮

Computational Models

2

CircAdapt par-75 imaging-based left-ventricular digital twin MATLAB scripts and CircAdapt P-struct MAT files MATLAB; CircAdapt C++ model solver; dynamic multi-swarm particle swarm optimization DIGITAL_TWIN

A patient-specific closed-loop heart-and-circulation model calibrated to left-ventricular cavity volume, regional longitudinal strain, and strain-rate measurements. Sensitivity and identifiability analysis reduces the CircAdapt MultiPatch personalization problem to 75 reproducibly estimable parameters.

Repository ↗ PMID:38741182

Variable	Model ID	Unit
Cardiac output Global cardiac output estimated during digital-twin personalization.	`q0`	L/min
Global left-ventricular activation duration Duration of mechanical activation across the left ventricle.	`dT`	ms
Regional mechanical activation delay Segment-specific mechanical activation timing relative to the reference wall.	`DT`	ms
Left-ventricular cavity volume Time-varying cavity volume used as a patient-specific calibration target.	`VLV`	mL
Regional longitudinal strain Segmental deformation trace used to calibrate and assess the twin.	`strain`	percent

Pathograph links

Myocardial Contractile Dysfunction measures fidelity: moderate Personalized activation delays and active and passive myocardial material properties reproduce regional strain and cavity-volume measurements and yield regional myocardial work distributions.

Limitations: Only seven participants had HFrEF with LBBB; the remaining six had prior myocardial infarction without HFrEF (LVEF 50 ± 3%). The inferred constitutive parameters are model-dependent, and activation delay was non-identifiable in hypocontractile segments.

Readouts

Regional left-ventricular strain and cavity-volume fit

Interpretation: A composite mean-squared error quantifies agreement between each twin and the patient's regional strain, strain-rate, and cavity-volume traces.

Show evidence (1 reference)

PMID:38741182 SUPPORT Computational

"This reduced subset produced patient-resembling DTs ( χ 2 < 2.2), while septal-to-lateral wall workload imbalance was higher for the LBBB-only DTs than for the MI-only DTs (p < 0.05)."

Reports the fit threshold achieved by the identifiable 75-parameter subset and its disease-substrate readout.

Septal-to-lateral myocardial workload imbalance

Direction: INCREASED

Interpretation: Positive work difference reflects inefficient lateral-wall loading relative to the septum in dyssynchronous LBBB-associated heart failure.

Show evidence (1 reference)

PMID:38741182 SUPPORT Computational

"Workload imbalance was significantly higher for the LBBB-only DTs than for the MI-only DTs (p < 0.05) but there was no significant difference between LBBB-only and LBBB-MI DTs."

Supports the direction of the modeled workload-imbalance readout while preserving the negative combined-substrate comparison.

Show evidence (1 reference)

PMID:38741182 SUPPORT Computational

"Furthermore, the model is able to simulate regional mechanics at the same spatial scale as current non-invasive strain imaging technologies and at low computational cost."

Establishes that CircAdapt resolves the regional mechanics used to personalize the imaging-based twins at an appropriate scale.

Findings

Reducing the personalization problem from 270 to 75 parameters improved minimum parameter reproducibility from ICC 0.01 to 0.83 while retaining patient-resembling fits below a composite error of 2.2.

Show evidence (1 reference)

PMID:38741182 SUPPORT Computational

"A subset of 270 parameters remained after MSM which produced high-quality DTs of all patients ( χ 2 < 1.6), but minimum parameter reproducibility was poor ( ICC min = 0.01). Iterative reduction yielded a reproducible ( ICC min = 0.83) subset of 75 parameters, including cardiac output,..."

Reports the central identifiability result and the physiological content retained in the reduced parameter set.

Notes

Repository inspected at commit dc4fc2b69cbbd5f51ff4976b9ded20dedd9b7a51 (2024-05-07). It contains the MATLAB sensitivity, Sobol, diaphony, and DMS-PSO scripts plus reference CircAdapt P-structs, but no license, automated tests, patient measurement files, or bundled CircAdapt solver. Execution was not attempted because neither MATLAB nor Octave is installed and the scripts require a separately placed CircAdapt C++ checkout and non-public patient data.

Show evidence (1 reference)

PMID:38741182 SUPPORT Computational

"To this end, we included seven patients with heart failure with reduced ejection fraction (HFrEF) and LBBB"

Establishes direct evaluation in the HFrEF population represented by this disorder entry.

CircAdapt virtual-pacing CRT response twin Patient-specific simulation workflow curated from the publication CircAdapt cardiovascular mechanics model DIGITAL_TWIN

Forty-five echocardiography-personalized CircAdapt models of patients with dyssynchronous HFrEF. Each twin simulates biventricular pacing using the patient's atrioventricular delay and lead location, then relates acute changes in regional myocardial work to six-month reverse remodeling.

PMID:38288616

Variable	Model ID	Unit	Ontology Mappings	Phenotype Thresholds
Septal-to-lateral myocardial work difference Digital-twin-derived difference in myocardial work between the lateral wall and septum.	`MWLW-S,DT`	relative work
Maximum left-ventricular pressure-rise rate Simulated acute hemodynamic response to biventricular pacing.	`dP/dtmax,DT`	mmHg/s

Pathograph links

Ventricular Remodeling perturbs fidelity: moderate Virtual biventricular pacing alters septal-to-lateral work distribution; the simulated acute mechanical response is compared with the patient's subsequent reduction in left-ventricular end-systolic volume.

Limitations: The study is retrospective, includes only 45 CRT recipients with wide QRS and LVEF at or below 35%, and reports association rather than prospective treatment-selection benefit. The exact analysis code and patient inputs were not deposited with the paper.

Readouts

Virtual pacing-induced septal-to-lateral work redistribution

Direction: DECREASED

Interpretation: A larger reduction in workload imbalance represents greater acute mechanical recoordination and was associated with more reverse remodeling.

Show evidence (1 reference)

PMID:38288616 SUPPORT Computational

"The DT's baseline MWLW-S,DT and virtual pacing-induced ΔMWLW-S,DT were both significantly associated with the real patient's reverse remodelling ΔLVESV (r = -0.60, P < 0.001 and r = 0.62, P < 0.001, respectively), while correlation between ΔdP/dtmax,DT and ΔLVESV was considerably weaker (r =..."

Quantifies the association between virtual work redistribution and observed six-month reverse remodeling, including the weaker hemodynamic comparator.

Show evidence (1 reference)

PMID:38288616 SUPPORT Computational

"Biventricular pacing was then simulated using patient-specific atrioventricular delay and lead location."

Establishes that the model performs a patient-specific pacing perturbation rather than only measuring baseline physiology.

Findings

Virtual pacing-induced work redistribution correlated with real six-month LV end-systolic-volume change at r = 0.62, whereas simulated pressure-rise response correlated more weakly at r = -0.34.

Show evidence (1 reference)

PMID:38288616 SUPPORT Computational

"The DT's baseline MWLW-S,DT and virtual pacing-induced ΔMWLW-S,DT were both significantly associated with the real patient's reverse remodelling ΔLVESV (r = -0.60, P < 0.001 and r = 0.62, P < 0.001, respectively), while correlation between ΔdP/dtmax,DT and ΔLVESV was considerably weaker (r =..."

Preserves both the principal predictive association and the weaker alternative readout.

Curated directly from the paper because no exact code deposit for the 45-patient virtual-pacing analysis was identified. The public Koopsen2024ParameterSubsetReduction repository above documents a closely related CircAdapt personalization framework from the same group, but it is not claimed as the implementation of this CRT study.

Show evidence (1 reference)

PMID:38288616 SUPPORT Computational

"A previously developed algorithm was used to generate 45 DTs by personalizing the CircAdapt model to each patient's baseline measurements."

Establishes cohort size and patient-specific calibration of the CircAdapt models.

{ }

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 40% or less, 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.
  downstream:
  - target: Neurohormonal Activation
    description: >-
      Falling cardiac output and effective arterial underfilling unload the
      arterial baroreceptors and reduce renal perfusion, which is the stimulus
      that switches on the sympathetic nervous system and the
      renin-angiotensin-aldosterone system in heart failure.
  - target: Exercise Intolerance
    description: >-
      The failing ventricle cannot augment stroke volume and cardiac output to
      meet the metabolic demand of exertion, which is the proximate cause of the
      reduced exercise capacity that defines functional class.
  - target: Fatigue
    description: >-
      Inadequate cardiac output limits oxygen delivery to skeletal muscle and
      other tissues at rest and on mild exertion, producing the persistent
      tiredness characteristic of the syndrome.
- 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.
  - target: Ventricular Remodeling
    description: >-
      Sustained sympathetic and RAAS signalling drives the maladaptive
      hypertrophic and fibrotic growth programme in the ventricle, converting an
      initially compensatory response into progressive structural remodelling.
  - target: Fluid Retention
    description: >-
      Angiotensin II and aldosterone promote renal sodium and water reabsorption
      and arginine vasopressin promotes free-water retention, which is the
      neurohormonal route to volume overload in heart failure.
- 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.
  downstream:
  - target: Myocardial Contractile Dysfunction
    description: >-
      Hypertrophy, chamber dilatation and interstitial fibrosis increase
      diastolic stiffness and degrade systolic performance, so the structural
      response that was initially compensatory ends up worsening pump function.
      This closes the self-reinforcing loop that drives progression of the
      syndrome.
- 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.
  downstream:
  - target: Dyspnea
    description: >-
      Volume overload raises left atrial and pulmonary venous pressure, driving
      fluid into the pulmonary interstitium and alveoli and producing the
      cardinal breathlessness of heart failure.
  - target: Orthopnea
    description: >-
      In the recumbent position the retained volume redistributes from the
      splanchnic and lower-body reservoirs to the thorax, raising pulmonary
      capillary pressure further and producing breathlessness on lying flat.
  - target: Peripheral Edema
    description: >-
      Systemic venous congestion from the expanded extracellular volume raises
      capillary hydrostatic pressure in dependent tissues, driving interstitial
      fluid accumulation.
- 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
  - preferred_term: cardiac endothelial cell
    description: >-
      The second cell the node names. Oestrogen upregulates endothelial nitric
      oxide synthase in the cardiac endothelium, and that arm is lost together
      with the fibroblast one. Bound at the cardiac level because the cited
      review names endothelial nitric oxide synthase without localizing it to
      the coronary arteries.
    term:
      id: CL:0010008
      label: cardiac endothelial cell
  genes:
  - preferred_term: ESR1
    description: >-
      The gene encoding oestrogen receptor alpha, one of the two receptors
      through which the cited review has oestrogen suppressing fibroblast
      proliferation and upregulating endothelial nitric oxide synthase; it is
      the unliganded state of that receptor after menopause that this node
      models, not a variant in the gene.
    term:
      id: hgnc:3467
      label: ESR1
  - preferred_term: ESR2
    description: >-
      The gene encoding oestrogen receptor beta, the receptor the cited review
      assigns the brake on TGF-beta/CTGF-mediated collagen transcription in
      cardiac fibroblasts and that the cited ovariectomy model shows is
      required for oestradiol to prevent cardiac fibrosis. Bound alongside
      ESR1 because the two paralogues carry distinct arms of the lost signal.
    term:
      id: hgnc:3468
      label: ESR2
  molecular_functions:
  - preferred_term: nuclear oestrogen receptor activity in cardiac fibroblasts and coronary endothelium
    modifier: DECREASED
    description: >-
      Receptor occupancy falls with circulating oestrogen after menopause; the
      receptors themselves are intact, so the activity is reduced rather than
      absent or altered. The term names the receptor's own molecular function
      and is not a claim that the lost signal is genomic only: in the cited
      study the ERbeta antifibrotic effect on cultured cardiac fibroblasts runs
      through cAMP and protein kinase A, a membrane-initiated route of the same
      receptor.
    term:
      id: GO:0030284
      label: nuclear estrogen receptor activity
  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.
  - reference: PMID:20810711
    reference_title: "Estrogen receptor-beta prevents cardiac fibrosis."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    evidence_source: MODEL_ORGANISM
    snippet: "In the hearts of ovariectomized female mice, cardiac hypertrophy and fibrosis were induced by AngII infusion and prevented by E2 administration to wild type but not ERβ knockout rodents."
    explanation: >-
      Grounds the ESR2 descriptor on this node and its direction. Ovariectomy
      is the experimental counterpart of the oestrogen withdrawal upstream, and
      the antifibrotic effect of restoring oestradiol depends on an intact
      oestrogen receptor beta gene, so the lost signal runs through the ESR2
      product. Graded INDIRECT because the model is angiotensin II-induced
      fibrosis in mice rather than human HFpEF myocardium.
  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.
  downstream:
  - target: Myocardial Contractile Dysfunction
    description: >-
      Impaired coronary microvascular vasodilator reserve limits subendocardial
      perfusion during increased demand, which is the route by which Lp(a)-driven
      microvascular disease is proposed to contribute to the diastolic and
      systolic impairment of HFpEF.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced coronary flow reserve and subendocardial ischaemia
    - Myocardial nitrosative stress and titin hypophosphorylation
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.
  reports_on:
  - target: Ventricular Remodeling
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    description: >-
      An enlarged cardiac silhouette on chest radiography or an increased chamber
      volume on echocardiography is the imaging readout of the chamber dilatation
      and hypertrophy that constitute ventricular remodelling.
    interpretation: >-
      Cardiomegaly is measured rather than experienced, so it is modelled as an
      observational readout of the remodelling node rather than as a causal
      consequence of it.
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.
  readouts:
  - target: Neurohormonal Activation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    description: >-
      Natriuretic peptide release from the myocardium in response to increased
      wall stress is one arm of the neurohormonal response, so the circulating
      level reports on the activation state of that node.
- name: Troponin
  presence: Elevated
  context: May be chronically elevated in heart failure
  readouts:
  - target: Myocardial Contractile Dysfunction
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    description: >-
      Chronic low-grade troponin release reflects ongoing cardiomyocyte injury in
      the failing ventricle and tracks with the severity of pump dysfunction,
      without being a specific measure of it.
diagnosis:
- name: Echocardiography (Left Ventricular Ejection Fraction)
  description: >-
    Left ventricular ejection fraction, measured by echocardiography, is the
    parameter on which the clinical classification of heart failure rests: the
    disease is subtyped as reduced, mildly reduced, or preserved ejection
    fraction (the `has_subtypes` HFrEF/HFmrEF/HFpEF rows), and the three bands
    recorded here are that classification's own numeric boundaries.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  measurements:
  - preferred_term: left ventricular ejection fraction
    term:
      id: LOINC:10230-1
      label: Left ventricular Ejection fraction
  reference_ranges:
  - loinc_term:
      id: LOINC:10230-1
      label: Left ventricular Ejection fraction
    unit: '%'
    population: >-
      Adults with an incident primary diagnosis of heart failure, manually
      reviewed Danish hospital cohort, 2021-2024 (as applied by PMID:42614974);
      the same three-tier boundaries are the ones this entry's `has_subtypes`
      HFrEF/HFmrEF/HFpEF rows describe in prose.
    notes: >-
      The cited cohort states the boundaries as a single sentence ("HFrEF was
      defined as left ventricular ejection fraction (LVEF) <=40%, HFmrEF as
      41-49%, and HFpEF as >=50%"). The bands below partition the scale as
      half-open intervals that share boundary values, so the HFrEF/HFmrEF
      split is placed at 41 (HFrEF < 41%, i.e. <=40% at whole-percent
      resolution) rather than at 40, the same half-open convention the
      Osteoporosis entry's WHO T-score bands document. This is the
      classification scheme's own operational definition rather than a
      specific guideline document's text, because a search of the cached
      references in this entry for a quotable restatement of the ACC/AHA/HFSA
      or ESC numeric boundaries themselves (rather than a result that merely
      mentions "HFrEF"/"HFpEF" in passing) returned none; the cohort study's
      methods section was the first source found stating all three boundaries
      together in one quotable sentence.
    evidence:
    - reference: PMID:42614974
      reference_title: "Heart Failure Phenotypes Across Age Groups in the Danish Administrative Registers."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "HFrEF was defined as left ventricular ejection fraction (LVEF) ≤40%, HFmrEF as 41-49%, and HFpEF as ≥50%."
      explanation: States the three LVEF boundaries that define HFrEF, HFmrEF and HFpEF, reproduced below as interpretation bands.
    interpretation_bands:
    - name: Heart Failure with Reduced Ejection Fraction (HFrEF)
      upper_bound: 41
      unit: '%'
      abnormal_flag: LOW
      interpretation: LVEF 40% or below; systolic dysfunction predominates.
    - name: Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)
      lower_bound: 41
      upper_bound: 50
      unit: '%'
      abnormal_flag: LOW
      interpretation: LVEF 41-49%; an intermediate phenotype.
    - name: Heart Failure with Preserved Ejection Fraction (HFpEF)
      lower_bound: 50
      unit: '%'
      abnormal_flag: NORMAL
      interpretation: >-
        LVEF 50% or above; diastolic dysfunction predominates and the ejection
        fraction itself is not reduced.
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.
computational_models:
- name: CircAdapt par-75 imaging-based left-ventricular digital twin
  description: >-
    A patient-specific closed-loop heart-and-circulation model calibrated to
    left-ventricular cavity volume, regional longitudinal strain, and strain-rate
    measurements. Sensitivity and identifiability analysis reduces the CircAdapt
    MultiPatch personalization problem to 75 reproducibly estimable parameters.
  model_type: DIGITAL_TWIN
  repository_url: https://github.com/CircAdapt/Koopsen2024ParameterSubsetReduction
  model_id: GitHub:CircAdapt/Koopsen2024ParameterSubsetReduction@dc4fc2b69cbbd5f51ff4976b9ded20dedd9b7a51
  model_software: MATLAB; CircAdapt C++ model solver; dynamic multi-swarm particle swarm optimization
  model_format: MATLAB scripts and CircAdapt P-struct MAT files
  publication: PMID:38741182
  modeled_mechanisms:
  - target: Myocardial Contractile Dysfunction
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Personalized activation delays and active and passive myocardial material
      properties reproduce regional strain and cavity-volume measurements and
      yield regional myocardial work distributions.
    limitations: >-
      Only seven participants had HFrEF with LBBB; the remaining six had prior
      myocardial infarction without HFrEF (LVEF 50 ± 3%). The inferred
      constitutive parameters are model-dependent, and activation delay was
      non-identifiable in hypocontractile segments.
    readouts:
    - name: Regional left-ventricular strain and cavity-volume fit
      target: Myocardial Contractile Dysfunction
      interpretation: >-
        A composite mean-squared error quantifies agreement between each twin and
        the patient's regional strain, strain-rate, and cavity-volume traces.
      evidence:
      - reference: PMID:38741182
        reference_title: "Parameter subset reduction for imaging-based digital twin generation of patients with left ventricular mechanical discoordination."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "This reduced subset produced patient-resembling DTs (  χ 2   < 2.2), while septal-to-lateral wall workload imbalance was higher for the LBBB-only DTs than for the MI-only DTs (p < 0.05)."
        explanation: Reports the fit threshold achieved by the identifiable 75-parameter subset and its disease-substrate readout.
    - name: Septal-to-lateral myocardial workload imbalance
      target: Myocardial Contractile Dysfunction
      direction: INCREASED
      interpretation: >-
        Positive work difference reflects inefficient lateral-wall loading
        relative to the septum in dyssynchronous LBBB-associated heart failure.
      evidence:
      - reference: PMID:38741182
        reference_title: "Parameter subset reduction for imaging-based digital twin generation of patients with left ventricular mechanical discoordination."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "Workload imbalance was significantly higher for the LBBB-only DTs than for the MI-only DTs (p < 0.05) but there was no significant difference between LBBB-only and LBBB-MI DTs."
        explanation: Supports the direction of the modeled workload-imbalance readout while preserving the negative combined-substrate comparison.
    evidence:
    - reference: PMID:38741182
      reference_title: "Parameter subset reduction for imaging-based digital twin generation of patients with left ventricular mechanical discoordination."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "Furthermore, the model is able to simulate regional mechanics at the same spatial scale as current non-invasive strain imaging technologies and at low computational cost."
      explanation: Establishes that CircAdapt resolves the regional mechanics used to personalize the imaging-based twins at an appropriate scale.
  variables:
  - name: Cardiac output
    dataset_identifier: q0
    description: Global cardiac output estimated during digital-twin personalization.
    unit: L/min
  - name: Global left-ventricular activation duration
    dataset_identifier: dT
    description: Duration of mechanical activation across the left ventricle.
    unit: ms
  - name: Regional mechanical activation delay
    dataset_identifier: DT
    description: Segment-specific mechanical activation timing relative to the reference wall.
    unit: ms
  - name: Left-ventricular cavity volume
    dataset_identifier: VLV
    description: Time-varying cavity volume used as a patient-specific calibration target.
    unit: mL
  - name: Regional longitudinal strain
    dataset_identifier: strain
    description: Segmental deformation trace used to calibrate and assess the twin.
    unit: percent
  findings:
  - statement: Reducing the personalization problem from 270 to 75 parameters improved minimum parameter reproducibility from ICC 0.01 to 0.83 while retaining patient-resembling fits below a composite error of 2.2.
    evidence:
    - reference: PMID:38741182
      reference_title: "Parameter subset reduction for imaging-based digital twin generation of patients with left ventricular mechanical discoordination."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "A subset of 270 parameters remained after MSM which produced high-quality DTs of all patients (  χ 2   < 1.6), but minimum parameter reproducibility was poor (  ICC min    = 0.01). Iterative reduction yielded a reproducible (  ICC min    = 0.83) subset of 75 parameters, including cardiac output, global LV activation duration, regional mechanical activation delay, and regional LV myocardial constitutive properties."
      explanation: Reports the central identifiability result and the physiological content retained in the reduced parameter set.
  evidence:
  - reference: PMID:38741182
    reference_title: "Parameter subset reduction for imaging-based digital twin generation of patients with left ventricular mechanical discoordination."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "To this end, we included seven patients with heart failure with reduced ejection fraction (HFrEF) and LBBB"
    explanation: Establishes direct evaluation in the HFrEF population represented by this disorder entry.
  notes: >-
    Repository inspected at commit dc4fc2b69cbbd5f51ff4976b9ded20dedd9b7a51
    (2024-05-07). It contains the MATLAB sensitivity, Sobol, diaphony, and
    DMS-PSO scripts plus reference CircAdapt P-structs, but no license, automated
    tests, patient measurement files, or bundled CircAdapt solver. Execution was
    not attempted because neither MATLAB nor Octave is installed and the scripts
    require a separately placed CircAdapt C++ checkout and non-public patient data.
- name: CircAdapt virtual-pacing CRT response twin
  description: >-
    Forty-five echocardiography-personalized CircAdapt models of patients with
    dyssynchronous HFrEF. Each twin simulates biventricular pacing using the
    patient's atrioventricular delay and lead location, then relates acute changes
    in regional myocardial work to six-month reverse remodeling.
  model_type: DIGITAL_TWIN
  model_id: CircAdapt-CRT-45
  model_software: CircAdapt cardiovascular mechanics model
  model_format: Patient-specific simulation workflow curated from the publication
  publication: PMID:38288616
  modeled_mechanisms:
  - target: Ventricular Remodeling
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Virtual biventricular pacing alters septal-to-lateral work distribution;
      the simulated acute mechanical response is compared with the patient's
      subsequent reduction in left-ventricular end-systolic volume.
    limitations: >-
      The study is retrospective, includes only 45 CRT recipients with wide QRS
      and LVEF at or below 35%, and reports association rather than prospective
      treatment-selection benefit. The exact analysis code and patient inputs
      were not deposited with the paper.
    readouts:
    - name: Virtual pacing-induced septal-to-lateral work redistribution
      target: Ventricular Remodeling
      direction: DECREASED
      interpretation: >-
        A larger reduction in workload imbalance represents greater acute
        mechanical recoordination and was associated with more reverse remodeling.
      evidence:
      - reference: PMID:38288616
        reference_title: "Virtual pacing of a patient's digital twin to predict left ventricular reverse remodelling after cardiac resynchronization therapy."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "The DT's baseline MWLW-S,DT and virtual pacing-induced ΔMWLW-S,DT were both significantly associated with the real patient's reverse remodelling ΔLVESV (r = -0.60, P < 0.001 and r = 0.62, P < 0.001, respectively), while correlation between ΔdP/dtmax,DT and ΔLVESV was considerably weaker (r = -0.34, P = 0.02)."
        explanation: Quantifies the association between virtual work redistribution and observed six-month reverse remodeling, including the weaker hemodynamic comparator.
    evidence:
    - reference: PMID:38288616
      reference_title: "Virtual pacing of a patient's digital twin to predict left ventricular reverse remodelling after cardiac resynchronization therapy."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "Biventricular pacing was then simulated using patient-specific atrioventricular delay and lead location."
      explanation: Establishes that the model performs a patient-specific pacing perturbation rather than only measuring baseline physiology.
  variables:
  - name: Septal-to-lateral myocardial work difference
    dataset_identifier: MWLW-S,DT
    description: Digital-twin-derived difference in myocardial work between the lateral wall and septum.
    unit: relative work
  - name: Maximum left-ventricular pressure-rise rate
    dataset_identifier: dP/dtmax,DT
    description: Simulated acute hemodynamic response to biventricular pacing.
    unit: mmHg/s
  findings:
  - statement: Virtual pacing-induced work redistribution correlated with real six-month LV end-systolic-volume change at r = 0.62, whereas simulated pressure-rise response correlated more weakly at r = -0.34.
    evidence:
    - reference: PMID:38288616
      reference_title: "Virtual pacing of a patient's digital twin to predict left ventricular reverse remodelling after cardiac resynchronization therapy."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "The DT's baseline MWLW-S,DT and virtual pacing-induced ΔMWLW-S,DT were both significantly associated with the real patient's reverse remodelling ΔLVESV (r = -0.60, P < 0.001 and r = 0.62, P < 0.001, respectively), while correlation between ΔdP/dtmax,DT and ΔLVESV was considerably weaker (r = -0.34, P = 0.02)."
      explanation: Preserves both the principal predictive association and the weaker alternative readout.
  evidence:
  - reference: PMID:38288616
    reference_title: "Virtual pacing of a patient's digital twin to predict left ventricular reverse remodelling after cardiac resynchronization therapy."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "A previously developed algorithm was used to generate 45 DTs by personalizing the CircAdapt model to each patient's baseline measurements."
    explanation: Establishes cohort size and patient-specific calibration of the CircAdapt models.
  notes: >-
    Curated directly from the paper because no exact code deposit for the
    45-patient virtual-pacing analysis was identified. The public
    Koopsen2024ParameterSubsetReduction repository above documents a closely
    related CircAdapt personalization framework from the same group, but it is
    not claimed as the implementation of this CRT study.
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.
  influences_mechanisms:
  - target: Ventricular Remodeling
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Chronic arterial pressure overload is the afterload stimulus that initiates
      concentric hypertrophy and interstitial fibrosis in the left ventricle, the
      structural substrate on which the heart failure syndrome develops.
- 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.
  influences_mechanisms:
  - target: Myocardial Contractile Dysfunction
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Epicardial coronary obstruction causes myocardial infarction and chronic
      ischaemia, and the resulting loss of viable contractile myocardium through
      necrosis and scar formation is the dominant route to reduced ejection
      fraction in this entry.
- 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.
  influences_mechanisms:
  - target: Myocardial Contractile Dysfunction
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Sustained excessive ethanol intake depresses myocardial contractility
      directly and can produce a dilated cardiomyopathy, giving a route into the
      heart failure syndrome that is independent of hypertension and coronary
      disease.
    evidence:
    - reference: PMID:20308914
      reference_title: "Alcoholic cardiomyopathy."
      supports: SUPPORT
      directness: DIRECT
      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 that chronic excessive intake leads to chronic cardiac dysfunction and can cause dilated cardiomyopathy, which is contractile dysfunction at this node.
treatments:
- name: ACE Inhibitors/ARBs
  description: Neurohormonal blockade, reduce mortality in HFrEF.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: angiotensin II receptor antagonist
      term:
        id: NCIT:C66930
        label: Angiotensin II Receptor Antagonist
  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.
  target_mechanisms:
  - target: Neurohormonal Activation
    treatment_effect: INHIBITS
    description: >-
      ACE inhibition and AT1 receptor blockade interrupt the
      renin-angiotensin-aldosterone arm of the neurohormonal response, which is
      the mechanism by which they slow progression rather than merely relieve
      symptoms.
- name: Beta Blockers
  description: Reduce heart rate and reverse remodeling in HFrEF.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-adrenergic antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
  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.
  target_mechanisms:
  - target: Neurohormonal Activation
    treatment_effect: INHIBITS
    description: >-
      Beta-adrenergic blockade interrupts the sympathetic arm of the
      neurohormonal response, lowering heart rate and myocardial oxygen demand.
  - target: Ventricular Remodeling
    treatment_effect: INHIBITS
    description: >-
      By removing the chronic adrenergic drive to the hypertrophic and fibrotic
      growth programme, beta blockade produces the reverse remodelling and
      recovery of ejection fraction described for this treatment.
- 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
    therapeutic_agent:
    - preferred_term: sacubitril
      term:
        id: CHEBI:134714
        label: sacubitril
    - preferred_term: valsartan
      term:
        id: CHEBI:9927
        label: valsartan
  target_mechanisms:
  - target: Neurohormonal Activation
    treatment_effect: MODULATES
    description: >-
      The combination blocks the AT1 receptor while neprilysin inhibition raises
      circulating natriuretic peptides, so it simultaneously suppresses the
      vasoconstrictor-antinatriuretic arm and augments the vasodilator-natriuretic
      arm of the same neurohormonal node.
- name: SGLT2 Inhibitors
  description: Reduce hospitalizations and mortality across HF spectrum.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: SGLT2 inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
  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.
  target_mechanisms:
  - target: Fluid Retention
    treatment_effect: INHIBITS
    description: >-
      Blocking proximal tubular sodium-glucose cotransport produces natriuresis
      and osmotic diuresis, reducing plasma and interstitial volume. This is the
      best-characterised of the several proposed mechanisms for this class and is
      not asserted here to be the whole explanation for its outcome benefit.
- 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
  target_mechanisms:
  - target: Fluid Retention
    treatment_effect: INHIBITS
    description: >-
      Loop and thiazide diuretics block renal tubular sodium reabsorption,
      relieving the volume overload that produces congestion. This is
      symptomatic decongestion and does not act on the upstream neurohormonal
      or remodelling nodes.
- 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
  target_mechanisms:
  - target: Myocardial Contractile Dysfunction
    treatment_effect: RESTORES
    description: >-
      Biventricular pacing recoordinates the mechanically dyssynchronous
      contraction produced by left bundle branch block, improving stroke volume
      from the same myocardium and permitting reverse remodelling.
- 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: []

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References & Deep Research