Heart Failure

Complex MONDO:0005252 Show in embeddings browser Cardiovascular Disease

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

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5
Pathophys.
6
Phenotypes
2
Gaps
3
Genes
8
Medical Actions
3
Subtypes
6
References
2
Deep Research
🏷

Classifications

Harrison's Chapter
CARDIOVASCULAR
◆

Subtypes

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

Comorbidities

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

Discussions and Knowledge Gaps

2
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
⚙

Pathophysiology

5
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
Show evidence (2 references)
PMID:33432192 PARTIAL
"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
"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
Show evidence (3 references)
PMID:37895150 SUPPORT
"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
"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.
PMID:33432192 NO_EVIDENCE
"This multiorgan involvement makes HFpEF difficult to model in experimental animals because the condition is not simply cardiac hypertrophy and hypertension with abnormal myocardial relaxation."
This highlights the complexity of neurohormonal effects extending beyond the heart to multiple organ systems in heart failure pathophysiology.
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
Show evidence (3 references)
PMID:40892534 SUPPORT
"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 PARTIAL
"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 PARTIAL
"Lilrb4a alleviates cardiac dysfunction and ISO-induced arrhythmogenic remodeling associated with cardiac fibrosis and inflammation through the regulation of NF-κB signaling and MAPK signaling activation."
This identifies specific signaling pathways (NF-κB and MAPK) involved in cardiac remodeling and fibrosis, demonstrating the molecular mechanisms underlying structural changes.
Fluid Retention
Impaired sodium excretion leads to volume overload, causing pulmonary and peripheral edema. Results from reduced renal perfusion and neurohormonal activation.
Show evidence (2 references)
PMID:36769308 PARTIAL
"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.
PMID:36769308 NO_EVIDENCE
"As the worsening of renal function has an undeniably negative impact on the outcomes in patients with HF, searching for new treatment strategies and identification of biomarkers is necessary."
This emphasizes the critical role of renal dysfunction in heart failure pathophysiology and outcomes, supporting the mechanism of fluid retention through impaired kidney function.
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
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.
●

Phenotypes

6
Cardiovascular 1
Cardiomegaly FREQUENT Cardiomegaly HP:0001640
Show evidence (1 reference)
PMID:38636927 PARTIAL
"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 Peripheral edema HP:0012398
Show evidence (1 reference)
PMID:36769308 PARTIAL
"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 Dyspnea HP:0002094
Show evidence (1 reference)
PMID:40892534 PARTIAL
"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 Orthopnea HP:0012764
Dyspnea when lying flat
Constitutional 2
Fatigue VERY_FREQUENT Fatigue HP:0012378
Exercise Intolerance VERY_FREQUENT Exercise intolerance HP:0003546
Show evidence (1 reference)
PMID:40892534 SUPPORT
"Myocardial fibrosis and its surrogate changes in LV structure and geometry lead to functional impairments such as increased diastolic stiffness and elevated filling pressures and are associated with reduced exercise tolerance and poor prognosis in patients with HFpEF."
Exercise intolerance in heart failure is directly caused by increased diastolic stiffness and elevated filling pressures from myocardial fibrosis and structural remodeling.
🧬

Genetic Associations

3
TTN (Causative)
MYH7 (Causative)
LMNA (Causative)
💊

Medical Actions

8
ACE Inhibitors/ARBs
Action: Pharmacotherapy NCIT:C15986
Neurohormonal blockade, reduce mortality in HFrEF.
Beta Blockers
Action: Pharmacotherapy NCIT:C15986
Reduce heart rate and reverse remodeling in HFrEF.
ARNI (Sacubitril/Valsartan)
Action: Pharmacotherapy NCIT:C15986
Combined neprilysin inhibitor and ARB, superior to ACE inhibitors.
SGLT2 Inhibitors
Action: Pharmacotherapy NCIT:C15986
Reduce hospitalizations and mortality across HF spectrum.
Mineralocorticoid Receptor Antagonists
Action: Pharmacotherapy NCIT:C15986
Spironolactone or eplerenone for additional neurohormonal blockade.
Diuretics
Action: Pharmacotherapy NCIT:C15986
Manage fluid overload and congestion symptoms.
Cardiac Resynchronization Therapy
Action: Cardiac Resynchronization Therapy NCIT:C80436
For patients with wide QRS and reduced EF.
Implantable Cardioverter-Defibrillator
Action: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
Prevents sudden cardiac death in high-risk patients.
🌍

Environmental Factors

4
Hypertension
Major cause of heart failure
Coronary Artery Disease
Leading cause of HFrEF
Alcohol Abuse
Can cause alcoholic cardiomyopathy
Obesity
Risk factor for HFpEF
🔬

Biochemical Markers

2
BNP/NT-proBNP (Elevated)
Context: Diagnostic and prognostic biomarker
Show evidence (1 reference)
PMID:37895150 SUPPORT
"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
{ }

Source YAML

click to show 
name: Heart Failure
creation_date: '2025-12-18T17:01:35Z'
updated_date: '2026-02-17T21:53:14Z'
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
disease_term:
  preferred_term: heart failure
  term:
    id: MONDO:0005252
    label: heart failure
has_subtypes:
- name: Heart Failure with Reduced Ejection Fraction (HFrEF)
  description: Left ventricular ejection fraction less than 40%, systolic
    dysfunction predominates.
- name: Heart Failure with Preserved Ejection Fraction (HFpEF)
  description: Left ventricular ejection fraction 50% or greater, diastolic
    dysfunction predominates.
- name: Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)
  description: Left ventricular ejection fraction 41-49%, intermediate
    phenotype.
pathophysiology:
- name: Myocardial Contractile Dysfunction
  description: >
    Reduced cardiac output due to impaired ventricular contraction (systolic dysfunction)
    or relaxation (diastolic dysfunction). The heart cannot meet metabolic demands.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac Contraction
    term:
      id: GO:0060047
      label: heart contraction
  evidence:
  - reference: PMID:33432192
    reference_title: "Cellular and molecular pathobiology of heart failure with preserved ejection fraction."
    supports: PARTIAL
    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
    snippet: "Myocardial fibrosis and its surrogate changes in LV structure and geometry
      lead to functional impairments such as increased diastolic stiffness and elevated
      filling pressures and are associated with reduced exercise tolerance and poor
      prognosis in patients with HFpEF."
    explanation: This demonstrates how structural changes lead to diastolic
      dysfunction and impaired cardiac output, supporting the mechanism of
      contractile dysfunction in heart failure.
- name: Neurohormonal Activation
  description: >
    Compensatory activation of RAAS and sympathetic nervous system initially
    maintains cardiac output but leads to maladaptive remodeling, sodium
    retention, and progressive dysfunction.
  biological_processes:
  - preferred_term: RAAS Activation
    term:
      id: GO:0002018
      label: renin-angiotensin regulation of aldosterone production
  evidence:
  - reference: PMID:37895150
    reference_title: "Neurohumoral Activation in Heart Failure."
    supports: SUPPORT
    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
    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.
  - reference: PMID:33432192
    reference_title: "Cellular and molecular pathobiology of heart failure with preserved ejection fraction."
    supports: NO_EVIDENCE
    snippet: "This multiorgan involvement makes HFpEF difficult to model in experimental
      animals because the condition is not simply cardiac hypertrophy and hypertension
      with abnormal myocardial relaxation."
    explanation: This highlights the complexity of neurohormonal effects
      extending beyond the heart to multiple organ systems in heart failure
      pathophysiology.
- 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
    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: PARTIAL
    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: PARTIAL
    snippet: "Lilrb4a alleviates cardiac dysfunction and ISO-induced arrhythmogenic
      remodeling associated with cardiac fibrosis and inflammation through the regulation
      of NF-κB signaling and MAPK signaling activation."
    explanation: This identifies specific signaling pathways (NF-κB and MAPK)
      involved in cardiac remodeling and fibrosis, demonstrating the molecular
      mechanisms underlying structural changes.
- name: Fluid Retention
  description: >
    Impaired sodium excretion leads to volume overload, causing pulmonary
    and peripheral edema. Results from reduced renal perfusion and
    neurohormonal activation.
  evidence:
  - reference: PMID:36769308
    reference_title: "Chronic Kidney Disease as a Comorbidity in Heart Failure."
    supports: PARTIAL
    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.
  - reference: PMID:36769308
    reference_title: "Chronic Kidney Disease as a Comorbidity in Heart Failure."
    supports: NO_EVIDENCE
    snippet: "As the worsening of renal function has an undeniably negative impact
      on the outcomes in patients with HF, searching for new treatment strategies
      and identification of biomarkers is necessary."
    explanation: This emphasizes the critical role of renal dysfunction in heart
      failure pathophysiology and outcomes, supporting the mechanism of fluid
      retention through impaired kidney function.
- name: Lipoprotein(a)-Driven Coronary Microvascular Dysfunction
  description: >
    Lipoprotein(a) [Lp(a)], a genetically determined cardiovascular risk factor,
    promotes coronary microvascular dysfunction through endothelial dysfunction,
    oxidative stress, inflammatory activation, and microvascular remodeling. Lp(a)
    carries oxidized phospholipids and exhibits antifibrinolytic properties that
    distinctly drive microvascular disease independent of epicardial coronary
    atherosclerosis, with particular relevance to HFpEF pathogenesis.
  cell_types:
  - preferred_term: Endothelial Cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: Vascular Smooth Muscle Cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: Oxidative Stress Response
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  - preferred_term: Vascular Remodeling
    term:
      id: GO:0001974
      label: blood vessel remodeling
    modifier: ABNORMAL
  - preferred_term: Microthrombotic Events
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  evidence:
  - reference: PMID:41936813
    reference_title: "The role of lipoprotein(a) in coronary microvascular dysfunction: Mechanistic pathways, clinical evidence, and therapeutic perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lp(a) exhibits unique structural and biological properties, including the antifibrinolytic effects of apolipoprotein(a) and carriage of oxidized phospholipids, which promote endothelial dysfunction, oxidative stress, inflammatory activation, microvascular remodeling, and microthrombotic susceptibility-key processes implicated in CMD pathophysiology."
    explanation: This directly supports the mechanism of Lp(a)-driven endothelial dysfunction and oxidative stress in coronary microvascular disease.
  - reference: PMID:41936813
    reference_title: "The role of lipoprotein(a) in coronary microvascular dysfunction: Mechanistic pathways, clinical evidence, and therapeutic perspectives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lp(a)], a genetically determined and causal cardiovascular risk factor, has been extensively studied in epicardial coronary atherosclerosis; however, its role in the coronary microcirculation has received comparatively limited attention."
    explanation: This establishes the distinction between Lp(a)'s well-characterized role in macrovascular atherosclerosis versus its emerging role in microvascular dysfunction specifically relevant to heart failure pathophysiology.
discussions:
- discussion_id: gap_lpa_microvascular_vs_macrovascular_mechanism
  prompt: >-
    What are the distinct mechanistic pathways by which lipoprotein(a) drives
    coronary microvascular dysfunction (CMD) as opposed to its well-characterized
    role in epicardial macrovascular atherosclerosis, and what are the biomarker
    and disease-modifying therapeutic implications for heart failure (especially HFpEF)?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Lipoprotein(a)-Driven Coronary Microvascular Dysfunction
  rationale: >-
    Lp(a)'s unique structural properties — antifibrinolytic apolipoprotein(a) and
    carriage of oxidized phospholipids — promote endothelial dysfunction, oxidative
    stress, inflammatory activation, microvascular remodeling, and microthrombotic
    susceptibility. These mechanisms are extensively characterized in epicardial
    coronary atherosclerosis (macrovascular disease), but Lp(a)'s contribution to the
    coronary microcirculation has received comparatively limited attention. Observational
    studies link elevated Lp(a) to impaired coronary flow reserve, yet the microvascular-specific
    pathways remain poorly delineated and no disease-modifying therapies targeting Lp(a) in CMD exist.
  notes: "Seeded from PMID:41936813 — The role of lipoprotein(a) in coronary microvascular dysfunction: Mechanistic pathways, clinical evidence, and therapeutic perspectives"
- discussion_id: gap_pyroptosis_hfpef_dapagliflozin_mechanism
  prompt: >-
    Is pyroptosis (via the AIM2/Caspase-1/GSDMD inflammasome pathway) a primary driver
    of HFpEF pathophysiology or a secondary inflammatory consequence of diastolic
    dysfunction and ventricular remodeling? What is the human clinical relevance of
    AIM2/Caspase-1/GSDMD pathway dysregulation in HFpEF, and does dapagliflozin's
    therapeutic benefit in HFpEF arise primarily through pyroptosis attenuation or
    through other complementary mechanisms?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Ventricular Remodeling
  rationale: >-
    Preclinical evidence (PMID:42246167) demonstrates that dapagliflozin alleviates
    HFpEF symptoms and decreases myocardial pyroptosis in a mouse model through
    AIM2/Caspase-1/GSDMD axis regulation. Pyroptosis is a pro-inflammatory form of
    programmed cell death that induces inflammatory amplification and contributes to
    cardiovascular disease. However, the mechanistic hierarchy remains unclear: whether
    AIM2-inflammasome activation is a primary pathophysiological driver of HFpEF (and
    thus should be added as a core pathophysiology node) versus a secondary consequence
    of the established mechanisms (myocardial contractile dysfunction, neurohormonal
    activation, ventricular remodeling, diastolic dysfunction). Furthermore, the human
    clinical significance of this pathway in HFpEF remains to be determined — the
    evidence is primarily from mouse cardiomyocyte and animal models, and whether
    AIM2/Caspase-1/GSDMD dysregulation is a targetable therapeutic mechanism in human
    HFpEF patients requires human tissue validation and clinical trial evidence.
  proposed_experiments:
  - experiment_id: exp_hfpef_aim2_pyroptosis_human_tissue
    name: AIM2/Caspase-1/GSDMD pathway activation and pyroptosis quantification in HFpEF patient cardiac tissue
    description: >-
      Quantify AIM2 protein, active Caspase-1, GSDMD proteolysis, and pyroptosis markers
      (e.g., released IL-1β, IL-18) in cardiac tissue from HFpEF patients (endomyocardial
      biopsies or cardiac explants undergoing transplantation) compared to age-matched
      controls without heart failure. Correlate AIM2/Caspase-1/GSDMD activation with
      biomarkers of diastolic dysfunction and ventricular stiffness to determine whether
      pathway dysregulation is primary or secondary.
  - experiment_id: exp_hfpef_ipsc_cardiomyocyte_pyroptosis_dapagliflozin
    name: Dose-response validation of dapagliflozin on AIM2/Caspase-1/GSDMD pyroptosis in human iPSC-derived cardiomyocytes under diastolic stress
    description: >-
      Establish human iPSC-derived cardiomyocyte models of diastolic dysfunction stress
      (diastolic calcium handling impairment, passive stiffness elevation) and measure
      baseline AIM2/Caspase-1/GSDMD activation and pyroptosis rates. Apply dapagliflozin
      in a dose-response manner and quantify pyroptosis attenuation, mechanism of action
      (direct AIM2 inhibition vs. indirect via restored calcium handling), and whether
      dapagliflozin's benefit is AIM2-dependent (using AIM2 knockdown or Caspase-1
      inhibitors like VX-765 to block downstream pyroptosis execution).
  - experiment_id: exp_hfpef_dapagliflozin_trial_pyroptosis_biomarker
    name: Biomarker-driven clinical trial subset analysis correlating pyroptosis pathway activation with dapagliflozin response in HFpEF
    description: >-
      In a prospective HFpEF cohort treated with dapagliflozin, measure baseline circulating
      pyroptosis biomarkers (cleaved Caspase-1, IL-1β, IL-18, or GSDMD-N terminal fragment)
      and cardiac imaging of diastolic dysfunction and myocardial stiffness. Stratify
      patients by baseline AIM2/Caspase-1 activation status and assess whether high-baseline
      pyroptosis correlates with enhanced dapagliflozin treatment response (echocardiographic
      improvement in ejection fraction, diastolic parameters, or symptom relief) and
      whether post-treatment pyroptosis attenuation predicts clinical benefit.
  notes: "Seeded from PMID:42246167 — Dapagliflozin alleviates heart failure with preserved ejection fraction potentially by regulating the AIM2/caspase-1/GSDMD pathway and attenuating pyroptosis"
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: PARTIAL
    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: PARTIAL
    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
    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: PARTIAL
    snippet: "In the isoproterenol (ISO)-induced animal model, it is often accompanied
      by myocardial hypertrophy, fibrosis, and inflammation."
    explanation: Cardiomegaly in heart failure results from myocardial
      hypertrophy, which is a structural adaptation to increased workload and
      sympathetic activation.
biochemical:
- name: BNP/NT-proBNP
  presence: Elevated
  context: Diagnostic and prognostic biomarker
  evidence:
  - reference: PMID:37895150
    reference_title: "Neurohumoral Activation in Heart Failure."
    supports: SUPPORT
    snippet: "There are biomarkers of activation of these neurohormonal pathways,
      such as the natriuretic peptides, catecholamine levels and neprilysin and various
      newer ones, which may be employed to better understand the mechanisms of HF
      drugs and also aid in defining the subgroups of patients who might benefit from
      specific therapies."
    explanation: BNP and NT-proBNP are natriuretic peptides that serve as
      biomarkers of neurohormonal activation in heart failure, useful for
      diagnosis and therapeutic guidance.
- name: Troponin
  presence: Elevated
  context: May be chronically elevated in heart failure
genetic:
- name: TTN
  association: Causative
  notes: Titin mutations cause dilated cardiomyopathy
- name: MYH7
  association: Causative
  notes: Causes hypertrophic and dilated cardiomyopathy
- name: LMNA
  association: Causative
  notes: Lamin A/C mutations cause cardiomyopathy
environmental:
- name: Hypertension
  notes: Major cause of heart failure
- name: Coronary Artery Disease
  notes: Leading cause of HFrEF
- name: Alcohol Abuse
  notes: Can cause alcoholic cardiomyopathy
- name: Obesity
  notes: Risk factor for HFpEF
treatments:
- name: ACE Inhibitors/ARBs
  description: Neurohormonal blockade, reduce mortality in HFrEF.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Beta Blockers
  description: Reduce heart rate and reverse remodeling in HFrEF.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: ARNI (Sacubitril/Valsartan)
  description: Combined neprilysin inhibitor and ARB, superior to ACE
    inhibitors.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: SGLT2 Inhibitors
  description: Reduce hospitalizations and mortality across HF spectrum.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Mineralocorticoid Receptor Antagonists
  description: Spironolactone or eplerenone for additional neurohormonal
    blockade.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Diuretics
  description: Manage fluid overload and congestion symptoms.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Cardiac Resynchronization Therapy
  description: For patients with wide QRS and reduced EF.
  treatment_term:
    preferred_term: Cardiac Resynchronization Therapy
    term:
      id: NCIT:C80436
      label: Cardiac Resynchronization Therapy
- name: Implantable Cardioverter-Defibrillator
  description: Prevents sudden cardiac death in high-risk patients.
  treatment_term:
    preferred_term: Implantable Cardioverter-Defibrillator Placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
datasets:
references:
- reference: DOI:10.1038/s41569-020-00480-6
  title: Cellular and molecular pathobiology of heart failure with preserved
    ejection fraction
  findings: []
- reference: DOI:10.1038/s41569-024-01067-1
  title: Pathophysiological insights into HFpEF from studies of human cardiac
    tissue
  findings: []
- reference: DOI:10.1101/2025.04.02.646923
  title: Deciphering human heart failure with preserved ejection fraction
    (HFpEF) at single cell resolution
  findings: []
- reference: DOI:10.1186/s12933-025-02774-w
  title: 'Cardiometabolic heart failure with preserved ejection fraction: from molecular
    signatures to personalized treatment'
  findings: []
- reference: DOI:10.3390/cells14050324
  title: Molecular Mechanisms Underlying Heart Failure and Their Therapeutic
    Potential
  findings: []
- reference: DOI:10.53846/goediss-10367
  title: Mechanistic differences in mouse models of heart failure with preserved
    ejection fraction
  findings: []
📚

References & Deep Research

References

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

Deep Research

2
Disorder ▸

Disorder

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

Key Pathophysiology Nodes

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

Citation Inventory (for evidence mapping)

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

Disease Pathophysiology Research Report

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References

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