Animedix

Heart Failure (I50.9)

Modern heart failure (HF) is now understood not as a single hemodynamic disorder but as a systems-level syndrome driven by maladaptive neurohormonal activation, inflammatory signaling, metabolic reprogramming, and structural remodeling. Chronic activation of the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system promotes fibrosis, apoptosis, and adverse ventricular remodeling—mechanisms directly targeted by ACE inhibitors, ARBs, mineralocorticoid receptor antagonists, and angiotensin receptor–neprilysin inhibition (ARNI). The introduction of SGLT2 inhibitors has reframed HF as a cardiometabolic disease, implicating myocardial energetics, sodium–hydrogen exchange, and renal–cardiac cross-talk in disease progression. In parallel, dysregulated cyclic GMP–PKG signaling, impaired nitric oxide bioavailability, mitochondrial dysfunction, and calcium-handling abnormalities (including SERCA2a and ryanodine receptor instability) are active therapeutic nodes under investigation. Inflammation and fibrosis pathways—TGF-β, NLRP3 inflammasome, galectin-3—along with microvascular dysfunction and titin hypophosphorylation are particularly relevant in HFpEF, where precision phenotyping is guiding subtype-specific interventions. Emerging approaches include myosin modulators that directly alter sarcomere contractility, gene and RNA-based therapies targeting maladaptive remodeling, device-based neuromodulation, and AI-driven phenomapping to match patients with mechanistically aligned treatments. Collectively, contemporary HF management reflects a shift from purely symptomatic relief toward temporally targeted modulation of interconnected molecular circuits that govern myocardial structure, energetics, and rhythm.

Causes

Heart failure (HF) arises from a heterogeneous set of primary insults that converge on impaired ventricular filling and/or contractility. In industrialized nations, the dominant etiologies are ischemic heart disease—particularly prior myocardial infarction leading to scar formation and adverse remodeling—and long-standing hypertension, which drives concentric hypertrophy and diastolic dysfunction. Cardiomyopathies contribute substantially, including genetic dilated and hypertrophic forms, toxin-mediated injury (e.g., alcohol, anthracyclines), viral myocarditis, and infiltrative diseases such as amyloidosis. Valvular heart disease produces chronic pressure or volume overload, while persistent tachyarrhythmias can induce a reversible tachycardia-mediated cardiomyopathy. Metabolic disorders—including diabetes, obesity, and chronic kidney disease—promote systemic inflammation, endothelial dysfunction, and myocardial fibrosis, particularly in HFpEF phenotypes. Less common but clinically important causes include congenital heart disease, peripartum cardiomyopathy, and high-output states. Across these diverse triggers, the unifying theme is structural and molecular remodeling of the myocardium that exceeds compensatory reserve, ultimately leading to symptomatic pump failure.

Pathophysiology

The pathophysiology of heart failure (HF) reflects a progressive failure of compensatory mechanisms that initially preserve cardiac output but ultimately drive maladaptive remodeling. A primary reduction in effective forward flow—whether from systolic dysfunction, diastolic stiffness, or both—triggers neurohormonal activation, including upregulation of the renin–angiotensin–aldosterone system and sympathetic nervous system. While acutely adaptive, chronic activation promotes vasoconstriction, sodium retention, myocardial hypertrophy, apoptosis, and interstitial fibrosis. At the cellular level, impaired calcium cycling (reduced SERCA2a activity, ryanodine receptor leak), mitochondrial energetic deficits, oxidative stress, and altered substrate utilization diminish contractile efficiency. Elevated wall stress stimulates mechanotransduction pathways that further activate profibrotic signaling (e.g., TGF-β), extracellular matrix deposition, and ventricular dilation or stiffening. In HF with reduced ejection fraction (HFrEF), progressive chamber dilation and contractile impairment dominate, whereas in HF with preserved ejection fraction (HFpEF), microvascular inflammation, endothelial dysfunction, and titin hypophosphorylation contribute to increased myocardial stiffness and impaired relaxation. Ultimately, the interplay between hemodynamic load, neurohormonal signaling, metabolic dysfunction, and structural remodeling establishes a self-reinforcing cycle of declining cardiac performance and systemic congestion.

Clinical features

Heart failure (HF) typically presents with symptoms reflecting impaired forward cardiac output and elevated filling pressures. Patients commonly report exertional dyspnea, orthopnea, and paroxysmal nocturnal dyspnea due to pulmonary congestion, along with fatigue and reduced exercise tolerance from diminished systemic perfusion. Peripheral edema, abdominal distension, and early satiety arise from venous congestion and right-sided involvement. On examination, clinicians may observe elevated jugular venous pressure, pulmonary crackles, an S3 gallop (in HFrEF), peripheral pitting edema, hepatomegaly, and, in advanced cases, cachexia. HFpEF often presents more subtly, with exertional intolerance and preserved ejection fraction on imaging despite elevated filling pressures. Acute decompensated heart failure may manifest as rapid weight gain, worsening dyspnea, hypoxia, and fluid overload, whereas chronic HF may show a more insidious decline in functional capacity. Overall, the clinical picture reflects the balance between congestion and hypoperfusion, shaped by the underlying phenotype and comorbidities.

Diagnosis

The diagnosis of heart failure (HF) integrates clinical assessment with objective evidence of structural or functional cardiac abnormality. Evaluation begins with a history of dyspnea, fatigue, or fluid retention and a physical examination demonstrating signs of congestion or hypoperfusion. Measurement of natriuretic peptides (BNP or NT-proBNP) provides biochemical support, as elevated levels reflect myocardial wall stress and correlate with filling pressures. Echocardiography is central, allowing quantification of left ventricular ejection fraction, chamber size, wall thickness, diastolic function, valvular disease, and estimates of pulmonary pressures—thereby distinguishing HFrEF from HFpEF and other phenotypes. Additional testing may include electrocardiography for rhythm and ischemic changes, chest radiography for pulmonary congestion or cardiomegaly, and cardiac MRI for tissue characterization (fibrosis, infiltration, myocarditis). In selected cases, coronary angiography, stress testing, or right heart catheterization clarifies ischemic burden or hemodynamics. Contemporary diagnostic strategy increasingly incorporates phenotyping based on imaging, biomarkers, and comorbidity profiling to align patients with mechanism-targeted therapies rather than relying solely on ejection fraction thresholds.

Mechanism of action videos

Clinical trials

  • A Longitudinal Cohort Study to Evaluate Cardiovascular Risk Factors and Disease in Haiti
  • A Safety, Tolerability, and Biomarker Trial of VS-041 in Participants With Heart Failure With Preserved Ejection Fraction (HFpEF)
  • Focus on Levels of Awareness and Perceptions Regarding hsCRP in Identifying Systemic Inflammation in ASCVD, CKD and Heart Failure Management
  • Feasibility Study of the Supira System in Patients Undergoing High-Risk Percutaneous Coronary Intervention (HRPCI) Who May Benefit From Mechanical Circulatory Support Beyond the PCI Procedure
  • A Phase 2, Multicenter, Double-blind, Extension Study to Evaluate the Effects of Sotatercept for the Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension (Cpc-PH) Due to Heart Failure With Preserved Ejection Fraction (HFpEF)
  • Vericiguat's Effects on Reverse Remodeling Indices: Pathophysiologic Approach to Treatment of Heart Failure With Reduced Ejection Fraction
  • Palliative Care Learning Laboratory
  • Biventricular Remodeling in Transcatheter Tricuspid Valve Replacement
  • Observation of Clinical Routine Care for Heart Failure Patients Implanted With BIOTRONIK CRT Devices
  • Cardiovascular Kidney and Metaboolic (CKM) Health Assessment and Patient Empowerment in chROnic Disease Using a Health Coach INtervention ModEl: A Randomized Clinical Trial
  • Restrictive Versus Liberal Fluid Intake in Acute Decompensated Heart Failure: a Randomized Trial
  • A Phase 3 Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Maridebart Cafraglutide on Mortality and Morbidity in Participants Living With Heart Failure With Preserved or Mildly Reduced Ejection Fraction and Obesity (MARITIME-HF)
  • A Phase 3, Single-arm, Open-label Extension Study to Evaluate the Safety of Finerenone in Addition to Standard of Care, in Pediatric Heart Failure Patients, From Birth to 18 Years of Age, With Left Ventricular Systolic Dysfunction (LVSD)
  • The Impact of Comprehensive Post Hospital Management Based on Digital Health Intervention on Cardiac Function in Patients With Heart Failure: a Prospective, Multicenter, Randomized Controlled Study
  • Neural Cardiac Therapy for Heart Failure Study
  • A Phase 2/3 Randomized, Placebo-Controlled, Double-blind, Clinical Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Vericiguat in Pediatric Participants With Heart Failure Due to Systemic Left Ventricular Systolic Dysfunction (VALOR)
  • REdo tranScatheter Aortic Valve Replacement for Transcatheter aOrtic Valve failuRE
  • Effects of Steep Trendelenburg and Pneumoperitoneum on Cardiac Performance During Robotic-assisted Surgery in Patients With Normal and Low Ejection Fraction.
  • Direct HIS/LBB Pacing as an Alternative to Biventricular Pacing in Patients With Symptomatic Heart Failure Despite Optimal Medical Treatment and an ECG With a Typical Left Bundle Branch Block Pattern.
  • Implementing Spiritual Care in Inpatient Palliative Care
  • The Study of a tHerApeutic and monitoRing Device iMplanted at the Atrial Septum prOvides Heart Failure maNagement in sYmptomatic Patients (HARMONY Trial)
  • A Randomized Controlled Clinical Study on the Effect of Dapagliflozin on Myocardial Strain in Patients With Acute Heart Failure
  • Adherence Assesment for Diuretics in Patients Suffering From Precapillary Pulmonary Hypertension
  • A Stylet-Driven ICD Lead Intended for Conduction System Pacing IDE Study
  • Evaluation and Support Care Process Within the Care Pathway of Heart Failure Patients
  • Impact of Multidisciplinary Transitions of Care Clinic on Readmission Rates for Patients With Heart Failure With Preserved Ejection Fraction at a University Medical Center
  • Efficacy and Safety With Early Treatment of Finerenone in Hospitalized Patients With Heart Failure
  • Screening for Heart Failure in General Medicine Consultations (FIL-EAS ic Depistage)
  • Endovascular Ablation Of The Right Greater Splanchnic Nerve In Subjects Having Heart Failure With Reduced Ejection Fraction: Randomized Controlled Feasibility Trial
  • Corticotrophin Releasing Factor 2 for the Treatment of Worsening Heart Failure (WHF) - The CRAFT-WHF Study
  • Prospective Evaluation of Artificial Intelligence-enabled Screening for Transthyretin Amyloid Cardiomyopathy (ATTR-CM): TRACE-AI Prospective Study
  • Pulsed Field or Cryoballoon Pulmonary Vein Isolation for Atrial Fibrillation in Heart Failure (a Propensity Score Matched Comparison)
  • Real-World Experience -- Barostim™ Advancing the Level of Clinical Evidence (REBALANCE Registry) A Post-Market Registry With the Barostim™ System
  • Epicardial Injection of Allogeneic Human Pluripotent Stem Cell-derived Cardiomyocytes to Treat Severe Chronic Ischemic Heart Failure
  • Optimizing the Management of Patients With Heart Failure With Reduced Ejection Fraction Using BaroStim and CardioMems
  • Comparative Effectiveness of Oral Semaglutide vs Sitagliptin Among Individuals With Heart Failure With Preserved Ejection Fraction (STEP-HFpEF DM ORAL)
  • Heart Failure With Preserved Ejection Fraction in Patients With Сhronic Obstructive Pulmonary Disease: Clinical Course and Prognosis
  • Effects of Ziltivekimab Versus Placebo on Morbidity and Mortality in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction and Systemic Inflammation
  • Effects of Ziltivekimab Versus Placebo on Heart Failure Symptoms and Physical Function in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction and Systemic Inflammation
  • Implementation of an Augmented Reality System to Complement Discharge Information in Hospitalized Cardiology Patients

Therapeutic area: Cardiovascular