Heart failure, also known as congestive heart failure, is a chronic clinical syndrome in which the heart muscle is unable to pump blood efficiently enough to meet the body's needs for oxygen and nutrients, often resulting in fluid buildup in the lungs, legs, and other tissues.[1][2][3] This condition affects approximately 56 million people worldwide as of 2021, with prevalence continuing to rise due to aging populations and increasing risk factors, and is a leading cause of hospitalization in older adults, with rates increasing with age and higher observed in men and Black individuals.[4][3] While there is no cure, heart failure can often be managed effectively through medications, lifestyle modifications, and in advanced cases, surgical interventions, allowing many patients to achieve symptom relief and improved quality of life.[1][3]Heart failure is classified into several types based on the affected side of the heart and the underlying dysfunction. Left-sided heart failure, the most common form, impairs the left ventricle's ability to pump blood to the body, leading to pulmonary congestion and symptoms like shortness of breath.[5][2]Right-sided heart failure typically results from left-sided issues or lung conditions and causes fluid accumulation in the veins, leading to swelling in the legs, ankles, and abdomen.[5] It can also be categorized as systolic (reduced ejection fraction, where the heart cannot contract forcefully) or diastolic (preserved ejection fraction, where the heart cannot relax and fill properly).[3]Congestive heart failure refers to cases involving significant fluid retention, exacerbating symptoms across types.[5]The primary causes of heart failure stem from conditions that damage or overwork the heart muscle, with coronary artery disease and high blood pressure accounting for the majority of cases.[6][3] Other key etiologies include heart attacks, heart valve disease, cardiomyopathies, diabetes, arrhythmias, and congenital defects, while risk factors such as obesity, smoking, excessive alcohol use, and sleep apnea further elevate susceptibility.[2][6] Pathophysiologically, the heart initially compensates through mechanisms like chamber enlargement and activation of the renin-angiotensin-aldosterone system, but these adaptations eventually lead to worsening function and congestion.[3]Common symptoms of heart failure include shortness of breath during activity or at rest, persistent fatigue, rapid or irregular heartbeat, swelling (edema) in the extremities, coughing with frothy sputum, and reduced ability to exercise.[7][2] These arise from inadequate cardiac output and fluid overload, and acute exacerbations may present with sudden weight gain or chest pain.[3] Diagnosis typically involves clinical evaluation, blood tests (e.g., B-type natriuretic peptide levels), echocardiography to assess ejection fraction, and electrocardiography.[3]Treatment follows a staged approach per guidelines from the American College of Cardiology and American Heart Association (updated as of 2022), emphasizing prevention in early stages and comprehensive management in advanced disease.[3] Foundational therapies include diuretics to reduce fluid, angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers, and SGLT2 inhibitors to improve heart function and prognosis, alongside lifestyle changes like sodium restriction, exercise, and smoking cessation.[8][3] For severe cases, options extend to implantable devices (e.g., pacemakers), ventricular assist devices, or heart transplantation.[3] Complications such as kidney failure, arrhythmias, and sudden cardiac death underscore the importance of ongoing monitoring and multidisciplinary care.[2]
Overview
Definition
Heart failure is a clinical syndrome arising from structural or functional impairments in the heart that result in reduced cardiac output and/or elevated intracardiac pressures at rest or during stress, thereby compromising the heart's ability to meet the body's metabolic demands.[9]The Universal Definition of Heart Failure, established in 2021 by the Heart Failure Society of America, the Heart Failure Association of the European Society of Cardiology, and other international bodies, describes it as a syndrome characterized by typical symptoms such as dyspnea and fatigue, and/or signs such as elevated jugular venous pressure and pulmonary crackles, caused by a structural and/or functional cardiac abnormality, with confirmation provided by objective evidence of cardiogenic pulmonary or systemic congestion.[10][11] This definition emphasizes the need for corroborative evidence, such as elevated natriuretic peptide levels, to distinguish heart failure from other conditions mimicking its presentation.Heart failure manifests in acute or chronic forms, with the acute form involving sudden onset or worsening of symptoms requiring urgent intervention, while the chronic form develops gradually over time.[9] It is subclassified based on left ventricular ejection fraction (LVEF) into heart failure with reduced ejection fraction (HFrEF, LVEF ≤40%), heart failure with mid-range ejection fraction (HFmrEF, LVEF 41–49%), and heart failure with preserved ejection fraction (HFpEF, LVEF ≥50%), reflecting differences in underlying ventricular mechanics.Central to understanding heart failure are the concepts of forward and backward failure: forward failure refers to inadequate systemic perfusion due to diminished cardiac output, leading to symptoms of hypoperfusion, whereas backward failure involves upstream congestion from elevated filling pressures, resulting in fluid retention and pulmonary or systemic edema.[12] Similarly, systolic dysfunction, characterized by impaired myocardial contractility and reduced ejection fraction, contrasts with diastolic dysfunction, where ventricular relaxation and filling are compromised despite preserved ejection fraction, contributing to elevated pressures.[3]
Epidemiology
Heart failure affects approximately 64 million people worldwide, representing a significant global health burden that has more than doubled since 1990 due to aging populations and rising risk factors.[13] In the United States, an estimated 6.7 million adults aged 20 years and older live with heart failure, accounting for about 2.5% of the adult population as of 2025, with projections indicating growth to 8.7 million by 2030 and 11.4 million by 2050.[14] The lifetime risk of developing heart failure has risen to 24% in the US, meaning one in four individuals may be affected over their lifetime.[15]Incidence rates of heart failure remain stable when age-adjusted, but absolute numbers are increasing due to population aging, with approximately 960,000 new cases diagnosed annually in the US.[16] Mortality associated with heart failure is substantial; it served as the underlying cause in 85,855 US deaths in 2020, a figure trending upward, and contributed to 425,147 deaths in 2022, representing 45% of all cardiovascular deaths.[17][18] The age-adjusted mortality rate has increased since 2012, underscoring the growing lethality despite advances in treatment.[18]Regional variations highlight differing etiologies: prevalence is higher in developing countries, where rheumatic heart disease remains a leading cause, contrasting with high-income nations like the US and UK, where ischemic heart disease predominates.[19] In the US, the projected economic burden of heart failure is expected to reach $858 billion by 2050, driven by direct medical costs and lost productivity.[14] Demographically, heart failure is rising among younger adults under 65, with incidence higher in men but prevalence greater in women due to longer survival post-diagnosis; ethnic disparities are pronounced, as Black Americans experience higher rates of both incidence and prevalence compared to other groups.[20][21][21]
Etiology and pathophysiology
Causes
Heart failure results from structural or functional cardiac disorders that impair ventricular filling or ejection of blood, leading to diverse etiologies that can be categorized by mechanism. Ischemic heart disease is the leading cause globally and accounts for the majority of cases in developed countries.[4][22]Ischemic causes primarily involve coronary artery disease and myocardial infarction, which damage myocardial tissue and reduce left ventricular ejection fraction, often necessitating revascularization such as coronary artery bypass grafting in patients with ejection fraction ≤35%.[22] These conditions are the most common precipitants in Western populations, with post-infarction remodeling contributing to systolic dysfunction.[23]Non-ischemic causes include hypertension, which induces left ventricular hypertrophy and diastolic dysfunction through chronic pressure overload, representing a primary etiology especially in some developing regions.[24] Valvular heart disease, such as aortic stenosis or mitral regurgitation, imposes volume or pressure overload on the ventricles, straining cardiac output over time. Rheumatic heart disease, prevalent in low- and middle-income countries, leads to valvular damage and heart failure through chronic inflammation and scarring.[23][19] Cardiomyopathies—encompassing dilated, hypertrophic, and restrictive forms—arise from genetic mutations, infiltrative processes like amyloidosis, or idiopathic mechanisms, leading to impaired contractility or stiffness.[22] Congenital heart defects, including septal defects or anomalous pulmonary venous return, contribute when uncorrected or associated with long-term hemodynamic stress.[6]High-output heart failure occurs when systemic demands exceed cardiac capacity, as seen in severe anemia, which reduces oxygen-carrying capacity and increases cardiac workload; thyrotoxicosis, elevating metabolic rate and tachycardia; arteriovenous fistulas, causing shunting and volume overload; and beriberi from thiamine deficiency, impairing myocardial energy metabolism.[23]Acute precipitants often decompensate chronic heart failure and include infections such as pneumonia or sepsis, which increase metabolic demands and induce inflammation; arrhythmias like atrial fibrillation, disrupting atrial contribution to ventricular filling; non-compliance with medications, leading to fluid retention; and excessive salt intake, exacerbating volume overload.[22][6]Iatrogenic causes stem from cardiotoxic agents, including anthracyclines used in chemotherapy, which cause dose-dependent myocyte damage, and HER2 inhibitors like trastuzumab, which disrupt cardioprotective signaling pathways.[24] Supplements such as ephedra have been linked to sympathetic overstimulation and arrhythmias precipitating failure.[23]Social factors contributing to heart failure include alcohol abuse, which leads to dilated cardiomyopathy through toxic metabolites and nutritional deficiencies, and illicit drugs like cocaine and amphetamines, which induce vasospasm, hypertension, and direct myocardial toxicity.[22][6]
Pathophysiology
Heart failure involves complex hemodynamic alterations that impair cardiac output and elevate filling pressures. In the failing heart, reduced stroke volume results from diminished myocardial contractility, leading to inadequate ejection of blood during systole. This is compounded by elevated left ventricular end-diastolic pressure due to impaired ventricular relaxation or increased stiffness, which limits preload optimization. The Frank-Starling mechanism, which normally enhances stroke volume through myocyte stretch-induced contraction, fails in heart failure as the curve flattens, preventing compensatory increases in output despite higher end-diastolic volumes.[25]Compensatory mechanisms initially mitigate these hemodynamic deficits but eventually contribute to decompensation. Ventricular dilation occurs as a response to volume overload, attempting to maintain stroke volume via the Laplace law by increasing chamber radius; however, excessive dilation leads to wall stress escalation and further systolic dysfunction. Cardiac hypertrophy, both concentric and eccentric, develops to normalize wall tension and preserve ejection, but chronic activation promotes maladaptive remodeling, transitioning from compensation to failure.[26]Neurohormonal activation exacerbates progression through systemic responses to perceived low perfusion. The renin-angiotensin-aldosterone system (RAAS) overdrive, triggered by reduced renal perfusion, promotes vasoconstriction, sodium retention, and myocardial fibrosis via angiotensin II and aldosterone. Sympathetic nervous system hyperactivity increases catecholamine release, initially boosting heart rate and contractility but chronically causing β-receptor downregulation, arrhythmias, and myocyte damage. Natriuretic peptides, such as BNP, are released to counterbalance these effects through vasodilation and diuresis, though resistance develops in advanced stages.[27]At the cellular level, remodeling involves structural and molecular changes that perpetuate dysfunction. Myocyte hypertrophy arises from mechanical stress and neurohormonal signals, reactivating fetal gene programs and increasing cell size without proliferation, which stiffens the myocardium over time. Apoptosis contributes to progressive myocyte loss, particularly post-injury, reducing contractile mass and amplifying workload on surviving cells. Fibrosis, driven by fibroblast activation and excessive extracellular matrix deposition (e.g., collagen types I and III), replaces viable tissue and impairs relaxation, fostering arrhythmias and diastolic dysfunction. These alterations disrupt calcium handling and energy metabolism, accelerating disease.[28]Pathophysiology differs markedly between subtypes. In heart failure with reduced ejection fraction (HFrEF), systolic dysfunction predominates, characterized by eccentric remodeling with ventricular dilation and thinning walls due to myocyte loss and slippage, leading to reduced contractility. Conversely, heart failure with preserved ejection fraction (HFpEF) features diastolic dysfunction and concentric hypertrophy, where thickened walls and increased fibrosis from comorbidities like hypertension impair relaxation and elevate filling pressures without significant dilation. These distinctions influence compensatory responses and therapeutic targets.[29]Multi-organ effects amplify heart failure severity, notably through cardiorenal syndrome. Reduced cardiac output causes renal hypoperfusion, activating RAAS and sympathetic pathways that worsen sodium retention and glomerular filtration decline, creating a vicious cycle of fluid overload. Pulmonary congestion arises from backward failure, with elevated left atrial pressure transmitting to pulmonary veins, causing edema and impaired gas exchange. These interactions extend to hepatic and systemic vascular dysfunction, underscoring heart failure as a multisystem disorder.[30]
Clinical presentation
Signs and symptoms
Heart failure manifests through a variety of symptoms and signs primarily resulting from impaired cardiac output and fluid retention, often affecting multiple organ systems. The cardinal symptoms include dyspnea, which can present as exertional shortness of breath during physical activity, orthopnea requiring elevation of the head to sleep, and paroxysmal nocturnal dyspnea that awakens patients at night.[22][31] Fatigue and reduced exercise tolerance are also hallmark features, stemming from inadequate perfusion to skeletal muscles and overall diminished cardiac performance.[22][31]Systemic signs of fluid retention are prominent, including peripheral edema in the legs and ankles, ascites in the abdomen, and sudden weight gain due to sodium and fluid overload.[22][31] Jugular venous distension reflects elevated central venous pressure and right-sided congestion.[22][31]Pulmonary manifestations arise from left-sided backup of blood into the lungs, leading to crackles or rales on auscultation, pleural effusions, and a persistent cough that may produce frothy, pink-tinged sputum in severe cases.[22][31]Cardiac examination may reveal an S3 gallop sound indicative of ventricular filling abnormalities, a displaced apex beat due to cardiomegaly, and tachycardia as a compensatory mechanism for low output.[22][31]Additional symptoms include nocturia from redistribution of fluid when recumbent and cachexia with muscle wasting in advanced stages. Hepatic congestion can cause hepatomegaly and right upper quadrant discomfort.[22][31]In acute heart failure, symptoms often worsen suddenly, such as with flash pulmonary edema presenting as rapid-onset severe dyspnea and hypotension, contrasting with the more gradual progression of chronic heart failure where symptoms like fatigue and edema build over time.[22][31]
Classification
Heart failure is classified using multiple systems that categorize the condition based on anatomical involvement, ventricular function, symptom severity, and temporal or hemodynamic characteristics. These frameworks guide clinical assessment, treatment selection, and prognosis evaluation.[22]
Anatomical Classification
Heart failure can be anatomically classified according to the affected side of the heart, which influences the predominant congestion pattern. Left-sided heart failure primarily involves dysfunction of the left ventricle, leading to backup of blood into the pulmonary circulation and resulting in pulmonary congestion, such as dyspnea and orthopnea.[32] Right-sided heart failure affects the right ventricle, causing systemic venous congestion with manifestations like peripheral edema, jugular venous distension, and hepatomegaly.[33] Biventricular heart failure, also known as congestive heart failure, combines features of both, with simultaneous pulmonary and systemic congestion, often seen in advanced disease.[34]
Functional Classification
Functional classification delineates heart failure subtypes based on left ventricular ejection fraction (LVEF), reflecting underlying systolic or diastolic dysfunction. Heart failure with reduced ejection fraction (HFrEF) is defined by LVEF ≤40%, typically involving systolic impairment and reduced cardiac output.[22] Heart failure with mildly reduced ejection fraction (HFmrEF) encompasses LVEF 41%–49%, representing an intermediate phenotype with partial systolic dysfunction and elevated filling pressures.[22] Heart failure with preserved ejection fraction (HFpEF) is characterized by LVEF ≥50%, often due to diastolic dysfunction and stiff ventricles, accounting for approximately half of heart failure cases.[22] Heart failure with improved ejection fraction (HFimpEF) refers to patients with prior HFrEF (LVEF ≤40%) whose LVEF has improved to >40% with treatment, recognized as a distinct phenotype with ongoing management needs.[22]
Severity Classification
Severity is assessed through symptom-based and stage-based systems to quantify functional limitations and disease progression. The New York Heart Association (NYHA) functional classification stratifies patients into four classes based on physical activity tolerance:
NYHA Class
Description
I
No limitation of physical activity; ordinary activities do not cause symptoms.
II
Slight limitation; comfortable at rest, but ordinary physical activity causes fatigue, palpitation, or dyspnea.
III
Marked limitation; comfortable at rest, but less than ordinary activity causes symptoms.
IV
Unable to carry on any physical activity without discomfort; symptoms present even at rest; any activity worsens symptoms.
The American College of Cardiology/American Heart Association (ACC/AHA) stages outline disease progression from risk to advanced failure:
Stage
Description
A
At high risk for heart failure but without structural heart disease or symptoms (e.g., hypertension, diabetes).
B
Structural heart disease present but no signs or symptoms of heart failure (e.g., reduced LVEF without symptoms).
C
Structural heart disease with prior or current symptoms of heart failure.
Heart failure is further categorized temporally as acute or chronic. Acute heart failure involves sudden or rapid onset of symptoms, often requiring hospitalization, and may result from decompensation of chronic disease or new insults like myocardial infarction.[35] Chronic heart failure represents a progressive, long-term condition with persistent structural and functional abnormalities.[35] Hemodynamically, it is distinguished as forward or backward failure; forward failure impairs systemic perfusion and organ oxygenation due to low cardiac output, while backward failure emphasizes upstream congestion from impaired ventricular filling or ejection.[35]
Diagnosis
Diagnostic criteria
The diagnosis of heart failure (HF) relies on a combination of clinical symptoms, physical signs, and objective evidence of cardiac dysfunction, with established criteria guiding the process to ensure accuracy and exclude alternative causes.[22]The Framingham criteria, developed from the longitudinal Framingham Heart Study, provide a foundational clinical framework for diagnosing congestive HF. These criteria categorize findings into major and minor groups; a definite diagnosis requires two major criteria or one major criterion plus two minor criteria present concurrently, while probable HF is indicated by one major and one minor criterion. Major criteria include paroxysmal nocturnal dyspnea, jugular venous distention, pulmonary rales, radiographic cardiomegaly, acute pulmonary edema, third heart sound (S3 gallop), central venous pressure greater than 16 cm H2O, and circulation time exceeding 25 seconds. Minor criteria encompass ankle edema, dyspnea on exertion, hepatomegaly, pleural effusion, reduced vital capacity by one-third from maximum, and tachycardia (rate ≥120 beats per minute). These criteria demonstrate high sensitivity (97%) and specificity (79%) for definite HF in population studies.[36]Contemporary guidelines, such as the 2021 European Society of Cardiology (ESC) recommendations (with 2023 focused updates), emphasize a broader, evidence-based approach requiring typical HF symptoms (e.g., breathlessness or fatigue) and/or signs (e.g., elevated jugular venous pressure, pulmonary crackles, or peripheral edema), plus objective evidence of underlying cardiac abnormality. This objective evidence includes elevated natriuretic peptide levels—such as B-type natriuretic peptide (BNP) greater than 35 pg/mL or N-terminal pro-B-type natriuretic peptide (NT-proBNP) greater than 125 pg/mL in non-acute settings—or structural/functional heart disease identified via imaging, like echocardiography showing reduced ejection fraction or diastolic dysfunction. Recent ESC Heart Failure Association recommendations propose age-adjusted NT-proBNP thresholds to improve accuracy in older patients, such as 125 pg/mL for those under 50 years, increasing to 300 pg/mL for those over 75 years in non-acute settings.[37] In acute settings, higher thresholds apply (e.g., NT-proBNP >300 pg/mL or BNP >100 pg/mL) to account for age and comorbidities, with levels below these effectively ruling out HF in low-risk patients due to high negative predictive value (up to 99%). Natriuretic peptides like NT-proBNP play a pivotal role in initial triage, particularly for ruling out HF in dyspneic patients without obvious cardiac etiology, thereby guiding further testing.[31][38]Diagnostic algorithms adopt a stepwise approach to confirm HF efficiently. Initial evaluation begins with a thorough history and physical examination to identify suggestive symptoms and signs, followed by natriuretic peptide measurement to stratify risk—if elevated, proceed to imaging for confirmation of cardiac involvement; if normal in low-probability cases, HF is unlikely, prompting consideration of alternatives. This sequence minimizes unnecessary testing while ensuring high diagnostic yield, as endorsed by both ESC and American Heart Association guidelines.[22][9]Differential diagnosis is integral to the process, focusing on excluding non-cardiac causes of similar presentations, such as chronic obstructive pulmonary disease (COPD), renal failure, anemia, or pulmonary embolism, which can mimic HF symptoms like dyspnea and edema. Natriuretic peptide levels aid this distinction, as low values (<125 pg/mL NT-proBNP in stable patients) strongly favor non-cardiac etiologies, whereas elevated levels support pursuing cardiac-specific evaluation.[3]
Laboratory and imaging tests
Laboratory tests play a crucial role in the diagnosis of heart failure by assessing biomarkers of cardiac stress, myocardial injury, and comorbidities that influence cardiac function. B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels are key biomarkers, with elevated concentrations indicating increased ventricular wall stress and aiding in the confirmation of heart failure diagnosis, particularly in distinguishing it from non-cardiac causes of dyspnea.[22] High-sensitivity troponin assays detect subclinical myocardial injury, which is common in heart failure and supports risk stratification, with recommendations for their inclusion in initial evaluations (Class of Recommendation [COR] 1, Level of Evidence [LOE] B-NR).[22] Assessments of renal and hepatic function, electrolytes, and anemia screening are essential to identify organ dysfunction and electrolyte imbalances that exacerbate heart failure or result from reduced cardiac output, guiding therapy adjustments and monitoring during treatment initiation (COR 1, LOE C-LD).[22]Echocardiography serves as the cornerstone imaging modality for evaluating heart failure, providing noninvasive assessment of cardiac structure and function. It measures left ventricular ejection fraction (LVEF) to classify heart failure types—HFrEF (LVEF ≤40%), HFmrEF (LVEF 41-49%), and HFpEF (LVEF ≥50%)—and evaluates diastolic function through parameters like tissue Doppler imaging to detect impaired relaxation and elevated filling pressures (COR 1, LOE B-NR).[22] Valvular assessments identify regurgitation or stenosis contributing to heart failure etiology, while Doppler echocardiography estimates pulmonary artery systolic pressure and intracardiac filling pressures, informing prognosis and management (COR 1, LOE B-R).[22] Repeat echocardiography is recommended when there is a significant change in clinical status to monitor progression or response to therapy (COR 1, LOE C-LD).[22]Chest X-ray is a readily available initial imaging tool that reveals signs of heart failure such as cardiomegaly, reflecting chamber enlargement, and pulmonary vascular congestion or edema indicative of elevated left-sided filling pressures.[22] It also detects pleural effusions, often bilateral in heart failure, supporting the assessment of congestion severity (COR 1, LOE C-LD).[22]Advanced imaging modalities offer detailed characterization when echocardiography is inconclusive. Cardiac magnetic resonance imaging (MRI) quantifies myocardial fibrosis using late gadolinium enhancement, aiding in the diagnosis of non-ischemic cardiomyopathies and risk stratification (COR 2a, LOE B-NR).[22] Computed tomography (CT) angiography evaluates coronary arteries to identify ischemic etiology, particularly in patients with suspected acute coronary syndrome (COR 2a, LOE B-NR).[22]Invasive procedures are reserved for cases requiring precise hemodynamic data or tissue analysis. Cardiac catheterization directly measures intracardiac and pulmonary pressures, confirming elevated filling pressures diagnostic of heart failure when noninvasive methods are equivocal (COR 2b, LOE C-LD).[22] Endomyocardial biopsy is indicated for suspected specific cardiomyopathies, such as amyloidosis or myocarditis, providing histopathological confirmation (COR 2a, LOE C-LD).[22]Electrophysiological evaluations detect arrhythmias that may precipitate or worsen heart failure. A 12-lead electrocardiogram (ECG) is performed at initial presentation to identify rhythm abnormalities, conduction delays, or signs of ischemia (COR 1, LOE C-LD).[22] Ambulatory Holter monitoring assesses for intermittent arrhythmias, such as atrial fibrillation, which contribute to heart failure progression, and guides decisions on anticoagulation or device therapy (COR 2a, LOE B-R).[22]
Staging systems
Staging systems for heart failure provide structured frameworks to assess disease progression, stratify risk, and inform therapeutic strategies, distinct from classifications based on ejection fraction or anatomical features. The American College of Cardiology (ACC) and American Heart Association (AHA) staging system, updated in guidelines, categorizes heart failure into four progressive stages: Stage A represents individuals at high risk for developing heart failure but without structural heart disease or symptoms, such as those with hypertension, diabetes, or coronary artery disease; Stage B denotes pre-heart failure with structural heart disease (e.g., left ventricular hypertrophy or reduced ejection fraction) or elevated biomarkers but no current or prior symptoms; Stage C indicates symptomatic heart failure with structural heart disease and current or previous symptoms; and Stage D signifies advanced, refractory heart failure with severe symptoms despite optimal medical therapy, often requiring specialized interventions.[22][39]The New York Heart Association (NYHA) functional classification complements the ACC/AHA stages by evaluating symptom severity and functional limitations, primarily applied to Stages C and D. It divides patients into four classes: Class I, no limitation of physical activity with no symptoms from ordinary activities; Class II, slight limitation with symptoms during ordinary activity; Class III, marked limitation with symptoms during less than ordinary activity; and Class IV, inability to carry on any physical activity without discomfort, with symptoms present even at rest.[40][39] This integration allows for a combined assessment, where, for example, a patient in ACC/AHA Stage C might be NYHA Class II, guiding tailored management.The Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score offers a validated tool for predicting mortality in heart failure patients, incorporating 13 predictors including age, sex, body mass index, ejection fraction (assessed via echocardiography), NYHA class, serum creatinine, and use of medications such as angiotensin-converting enzyme inhibitors or beta-blockers.[41] Developed from a meta-analysis of over 39,000 patients, it estimates 1- and 3-year mortality risk to support prognostic discussions and therapy optimization.[41]The 2022 AHA/ACC/HFSA guidelines reinforce these staging systems with greater emphasis on early identification and intervention in Stages A and B to prevent progression, particularly for heart failure with preserved ejection fraction (HFpEF), through aggressive risk factor management like blood pressure control and sodium-glucose cotransporter-2 inhibitors in high-risk individuals.[39][22]Overall, these staging systems guide escalation of management—from preventive lifestyle modifications in early stages to advanced therapies in later ones—and aid in estimating prognosis to facilitate patient-centered care planning.[22][41]
Management
Acute management
Acute management of heart failure focuses on rapid stabilization of patients with decompensated symptoms, particularly those presenting with acute pulmonary edema, severe congestion, or low-output states, to alleviate symptoms, improve hemodynamics, and prevent further deterioration. Initial assessment involves evaluating vital signs, oxygenation, perfusion, and volume status to identify reversible precipitants such as ischemia or arrhythmias, followed by prompt triage to appropriate care settings. Multidisciplinary monitoring is essential to guide therapy and optimize outcomes.[22][42]Oxygen therapy is administered to hypoxemic patients to maintain peripheral oxygen saturation (SpO2) above 90% or partial arterial oxygen pressure (PaO2) greater than 60 mmHg, typically via nasal cannula or face mask, while avoiding hyperoxia which may worsen outcomes. For patients with respiratory distress, progressive failure, or acidosis (pH <7.35), non-invasive ventilation such as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) is recommended to reduce the need for intubation and improve respiratory mechanics. These interventions are particularly beneficial in acute pulmonary edema with respiratory rates exceeding 25 breaths per minute and SpO2 below 90%.[42][22]Intravenous loop diuretics, such as furosemide at an initial dose of 20-40 mg or 1-2 times the prior oral dose, serve as first-line therapy for congestion relief in volume-overloaded patients, aiming to achieve euvolemia with the lowest effective dose to minimize renal impairment. Doses may be escalated by doubling or combined with thiazide diuretics if response is inadequate, with monitoring to resolve congestion before discharge.[42][22]In hypertensive crises with systolic blood pressure (SBP) above 110 mmHg and adequate perfusion, vasodilators like intravenous nitroglycerin are considered to reduce preload and relieve dyspnea, though they provide symptomatic rather than prognostic benefits and require caution to avoid hypotension. For low-output states with SBP below 90 mmHg and signs of hypoperfusion, short-term inotropes such as dobutamine or milrinone are used to augment cardiac output, with selection based on blood pressure and arrhythmia risk, while monitoring for tachyphylaxis and adverse events.[42][22]For diuretic-resistant fluid overload with refractory congestion, ultrafiltration is an option to remove excess volume, particularly in advanced cases, though it is associated with procedural risks like catheter complications. As of 2025, early initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors during hospitalization for acute decompensated heart failure is considered safe based on the DAPA ACT HF-TIMI 68 trial, which showed no significant reduction in short-term cardiovascular death or worsening heart failure but confirmed tolerability and potential benefits in meta-analyses for reducing readmissions and acute kidney injury, aligning with updated guidelines for integration into acute care pathways.[22][43][44][45]Hospitalization criteria are guided by ESC risk stratification tools, such as the Multiple Estimation of risk based on the Epidemiology of acute heart failure in the Emergency Department (MEESSI) score, incorporating clinical assessment, biomarkers like NT-proBNP, and imaging to identify high-risk patients with severe symptoms (New York Heart Association class III-IV), hemodynamic instability, or recurrent decompensations requiring intravenous therapies. Early post-discharge follow-up within 1-2 weeks is recommended to reassess and optimize management.[42][46]
Chronic management
Chronic management of heart failure focuses on guideline-directed medical therapy (GDMT) to improve symptoms, reduce hospitalizations, and prolong survival, particularly in patients with heart failure with reduced ejection fraction (HFrEF).[22] For HFrEF, GDMT includes four foundational classes: renin-angiotensin-aldosterone system inhibitors such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), with preference for angiotensin receptor-neprilysin inhibitors (ARNIs) like sacubitril/valsartan; evidence-based beta-blockers such as carvedilol; mineralocorticoid receptor antagonists (MRAs) like spironolactone; and sodium-glucose cotransporter 2 (SGLT2) inhibitors such as dapagliflozin.[22] These therapies are recommended to be initiated at low doses and titrated to target levels as tolerated, with regular monitoring for side effects like hypotension or hyperkalemia.[22]Recent advances as of 2025 have expanded options for specific heart failure phenotypes. Finerenone, a nonsteroidal MRA, received FDA approval in July 2025 for adults with heart failure with preserved ejection fraction (HFpEF) or mildly reduced ejection fraction (HFmrEF), defined as left ventricular ejection fraction ≥40%, to reduce the risk of cardiovascular death, heart failure hospitalization, and urgent heart failure visits.[47] Vericiguat, a soluble guanylate cyclase stimulator, is indicated for high-risk HFrEF patients (ejection fraction <45%) who have recently worsened despite GDMT, to lower the risk of cardiovascular death and heart failure hospitalization.[48]Symptom relief in chronic heart failure often requires adjunctive therapies. Loop diuretics, such as furosemide, are used to manage fluid overload and alleviate congestion, with dosing adjusted based on daily weight and symptoms.[8] Ivabradine is recommended for HFrEF patients in sinus rhythm with persistent heart rate >70 beats per minute despite maximum-tolerated beta-blocker therapy, to further reduce heart rate and improve outcomes.[22]Ongoing monitoring is essential to detect early decompensation and optimize therapy. Daily self-monitoring of weight, with patients instructed to report gains of 2-3 pounds in 24 hours or 5 pounds in a week, helps guide diuretic adjustments and prevent hospitalizations.[49] Telemonitoring systems transmit vital signs like blood pressure and heart rate remotely, while implantable devices such as CardioMEMS enable pulmonary artery pressure (PAP) monitoring to proactively manage volume status and reduce heart failure events.[50]Advance care planning integrates into chronic management to align treatments with patient values, including discussions on goals of care and potential deactivation of implantable cardioverter-defibrillators (ICDs) when therapies no longer provide benefit, such as in advanced stages.[51]Lifestyle modifications support pharmacological strategies by addressing fluid and sodium balance. Sodium restriction to less than 2 grams per day is advised to minimize fluid retention, while fluid intake is typically limited to 1.5-2 liters daily in symptomatic patients to prevent overload.[22]
Device and surgical interventions
Device and surgical interventions are considered for patients with advanced heart failure, typically those in New York Heart Association (NYHA) functional class III or IV who remain symptomatic despite optimal guideline-directed medical therapy (GDMT).[22] These therapies aim to improve symptoms, prevent sudden cardiac death, restore synchrony, or support circulation in refractory cases, with selection based on ejection fraction (EF), QRS duration, etiology, and comorbidities.[38]Implantable cardioverter-defibrillators (ICDs) are recommended for primary prevention of sudden cardiac death in patients with heart failure and reduced EF (HFrEF) ≤35% who are on GDMT and have a reasonable life expectancy.[22] These devices detect and terminate life-threatening ventricular arrhythmias via shocks or antitachycardia pacing, reducing mortality by approximately 20-30% in eligible patients.[22] Cardiac resynchronization therapy (CRT) is indicated for HFrEF patients with EF ≤35%, sinus rhythm, left bundle branch block morphology, and QRS duration ≥150 ms, as it improves ventricular synchrony, enhances EF, and reduces heart failure hospitalizations by synchronizing left and right ventricular contraction.[38] In 2025, advances in conduction system pacing, including His-bundle pacing and left bundle branch area pacing, have emerged as alternatives to traditional biventricular CRT, offering narrower QRS durations and better hemodynamic outcomes in select patients with dyssynchrony, particularly those with non-left bundle branch block patterns.[52]Ventricular assist devices (VADs), such as left ventricular assist devices (LVADs), provide mechanical circulatory support for end-stage heart failure patients ineligible for or awaiting transplant.[53] LVADs are used as a bridge to transplant in acutely decompensated patients or as destination therapy for those with contraindications to transplantation, improving survival to 80% at 1 year and quality of life by unloading the failing ventricle and maintaining organ perfusion.[53] Extracorporeal membrane oxygenation (ECMO) serves as a short-term bridge for acute cardiogenic shock refractory to other supports, stabilizing patients for LVAD implantation or recovery, with 2025 data showing improved bridging success rates when initiated early in specialized centers.[22]Surgical interventions target underlying structural issues contributing to heart failure. Coronary artery bypass grafting (CABG) or revascularization is performed in ischemic cardiomyopathy to restore myocardial perfusion, improving outcomes in patients with viable myocardium and left ventricular dysfunction, with evidence of reduced mortality when combined with medical therapy.[54] Valve repair or replacement addresses mitral or tricuspid regurgitation exacerbating heart failure, using techniques like annuloplasty or prosthetic valves to reduce volume overload and improve forward flow, particularly in functional mitral regurgitation with EF <50%.[55] For hypertrophic cardiomyopathy causing obstructive physiology, septal myectomy surgically reduces the hypertrophied septum to relieve left ventricular outflow tract obstruction, alleviating symptoms in 90-95% of patients and preventing heart failure progression.[56]Heart transplantation remains the definitive therapy for select end-stage heart failure patients refractory to other interventions. Candidates typically have NYHA IV symptoms, EF <20%, peak VO2 <10-12 mL/kg/min, and no active malignancy, irreversible end-organ damage, or severe pulmonary hypertension, with age generally under 70 years.[57] Waitlist management involves status prioritization based on acuity (e.g., United Network for Organ Sharing levels 1-6), mechanical support optimization, and nutritional support, with mid-2025 data indicating median wait times of 3-6 months and 1-year post-transplant survival exceeding 90% in high-volume centers.[58] Donor selection emphasizes hemodynamic stability and low ischemic time, with expanded criteria in 2025 allowing use of donation after circulatory death hearts to address organ shortages.[59]
Palliative care
Palliative care in heart failure (HF) emphasizes symptom relief, psychosocial support, and quality-of-life improvement for patients with advanced disease, integrating alongside guideline-directed medical therapy (GDMT) to address refractory symptoms such as dyspnea and fatigue.[60] This approach is recommended for patients in advanced stages, where curative options are limited, and focuses on holistic care rather than disease modification.[61]Symptom management often involves low-dose opioids, such as morphine at 2.5–5 mg orally every 4 hours or oxycodone at 1–2.5 mg, to alleviate refractory dyspnea without significant respiratory depression, as supported by European Society of Cardiology (ESC) and American Heart Association (AHA) guidelines.[62] Anxiolytics like low-dose benzodiazepines (e.g., lorazepam 0.5 mg) may be used concurrently for anxiety exacerbating breathlessness, particularly in patients not responding to non-pharmacologic interventions such as oxygen or positioning.[63] These therapies are titrated carefully to minimize side effects while enhancing comfort.[64]Hospice eligibility typically applies to patients classified as New York Heart Association (NYHA) class IV, experiencing significant symptoms at rest despite optimal therapy, with frequent hospitalizations (e.g., three or more in the past year) and a prognosis of less than six months.[65] Advanced HF staging, such as frequent decompensations, further informs this transition.[66]A multidisciplinary team, including palliative specialists, cardiologists, nurses, social workers, and chaplains, coordinates care to manage pain through multimodal strategies, provide spiritual support to address existential distress, and alleviate caregiver burden via respite services and counseling.[67] Caregivers often face high emotional and physical strain, with interventions like support groups reducing their psychological distress.[68]As of 2025, AHA and Heart Failure Society of America (HFSA) guidelines strongly advocate early palliative care integration—ideally upon diagnosis of advanced HF—to improve quality of life, reduce hospitalizations, and enhance patient and family satisfaction, based on evidence from randomized trials showing better symptom control.[60][69]In end-stage HF, withdrawal of therapy may include deactivation of implantable cardioverter-defibrillators (ICDs) or left ventricular assist devices (LVADs) to prevent distressing shocks or mechanical burdens, a process guided by shared decision-making and palliative expertise to align with patient goals.[70] This occurs in 30–40% of terminal cases, emphasizing ethical discussions to avoid prolonging suffering.[71]
Prevention
Risk factor modification
Modifying modifiable risk factors plays a crucial role in preventing the development of heart failure, as these interventions target underlying contributors such as hypertension, smoking, diabetes, dyslipidemia, obesity, and excessive alcohol intake. Lifestyle changes, including diet, exercise, and behavioral adjustments, combined with pharmacological therapies where appropriate, can significantly lower the incidence of heart failure by addressing these factors at the individual level. Evidence from major cardiovascular guidelines emphasizes proactive management to mitigate progression to symptomatic disease.Controlling hypertension is a cornerstone of heart failure prevention, with guidelines recommending a target blood pressure of less than 130/80 mm Hg for adults at risk. This goal is achieved through lifestyle modifications, such as adopting a low-sodium diet, regular physical activity, and weight management, alongside antihypertensive medications like ACE inhibitors, ARBs, or beta-blockers when necessary. Achieving this target reduces the risk of left ventricular hypertrophy and diastolic dysfunction, key precursors to heart failure.[72][22]Smoking cessation substantially decreases the risk of ischemic heart disease, a major pathway to heart failure, with evidence showing a reduction of approximately 50% in cardiovascular event risk within the first year of quitting. Quitting eliminates exposure to nicotine and other toxins that promote endothelial dysfunction and atherosclerosis, leading to long-term benefits in coronary perfusion and myocardial health. Supportive interventions, including counseling, nicotine replacement therapy, and pharmacotherapies like varenicline, facilitate sustained abstinence and amplify these preventive effects.[73][74]Effective diabetes management, particularly glycemic control to maintain HbA1c below 7% in most patients, helps prevent microvascular and macrovascular complications that predispose to heart failure. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as empagliflozin or dapagliflozin, offer dual benefits by improving glycemic control while independently reducing heart failure risk through mechanisms like natriuresis, reduced cardiac preload, and anti-inflammatory effects, even in patients without established cardiovascular disease. These agents are recommended as first-line therapy in type 2 diabetes with high cardiovascular risk.[75][76]Lipid management with statin therapy is essential for preventing atherosclerosis, which can lead to ischemic cardiomyopathy and heart failure. High-intensity statins, such as atorvastatin or rosuvastatin, are advised to reduce LDL cholesterol by at least 50% in individuals with elevated risk, thereby stabilizing plaques and improving endothelial function. This approach is particularly beneficial in primary prevention for those with diabetes, hypertension, or other cardiovascular risk factors.[77][78]Addressing obesity through intentional weight loss of 5-10% of body weight via calorie-restricted diets, increased physical activity, and behavioral support can improve cardiovascular risk profiles and lower the likelihood of developing heart failure. Such modest reductions enhance insulin sensitivity, reduce blood pressure, and alleviate cardiac strain from excess adiposity, with evidence indicating decreased incidence of heart failure in obese individuals achieving these goals. Pharmacological options like GLP-1 receptor agonists may augment these efforts in appropriate candidates.[79][80]Limiting alcohol consumption to less than 14 units per week, spread across several days, helps prevent alcoholic cardiomyopathy and related hypertensive effects that contribute to heart failure. This threshold, aligned with low-risk drinking guidelines, minimizes direct myocardial toxicity and indirect risks like arrhythmias, with complete abstinence recommended for those with a history of heavy use. Monitoring intake through self-assessment tools supports adherence to these limits.[81][82]
Primary prevention strategies
Primary prevention of heart failure focuses on strategies to avert the development of the condition in at-risk populations, particularly through the American College of Cardiology/American Heart Association (ACC/AHA) staging system, where Stage A encompasses individuals with risk factors but no structural heart disease, and Stage B includes those with asymptomatic structural changes such as left ventricular hypertrophy or reduced ejection fraction.[22] In Stage A, interventions target modifiable risk factors like hypertension and diabetes to prevent progression, while Stage B emphasizes treatments such as angiotensin-converting enzyme inhibitors or beta-blockers in patients with asymptomatic left ventricular dysfunction to reduce the incidence of symptomatic heart failure.[22] These approaches are supported by evidence showing that early intervention in pre-heart failure states can lower the lifetime risk by up to 20-30% in high-risk groups.[83]Routine screening for cardiovascular risk factors plays a central role in primary prevention, with guidelines recommending blood pressure measurements at least every 3-5 years for adults aged 18 and older, and more frequently (annually) for those over 40 or with additional risks like family history.[84] Cholesterol screening, including lipid panels to assess low-density lipoprotein and high-density lipoprotein levels, is advised starting at age 20, with fasting profiles every 4-6 years for low-risk individuals and more often for those over 40 or at elevated risk, enabling early detection and management to mitigate heart failure onset.[84] Such screenings in at-risk groups, including those with obesity or metabolic syndrome, have been shown to identify up to 25% more preventable cases through timely interventions.[83]Vaccinations against infections that can precipitate or exacerbate cardiac stress are a key preventive measure, with annual influenza vaccination recommended for all adults to reduce the risk of acute myocardial infarction and subsequent heart failure in vulnerable populations.[85] Pneumococcal vaccination, particularly the PCV20 or PPSV23 series, is advised for adults over 65 or those with chronic conditions, as it lowers the incidence of pneumonia-related cardiovascular events, including heart failure hospitalizations.[85] These immunizations are especially critical in primary prevention for at-risk groups, as infections like influenza can trigger acute decompensation in preclinical heart disease.[22]Public health initiatives emphasize broad population-level interventions, such as policies promoting salt reduction, which can lower average sodium intake and decrease blood pressure by 2-5 mmHg population-wide.[86] Anti-smoking campaigns, including tobacco taxes and cessation programs, have contributed to a more than 70% decline in smoking prevalence since 1965, correlating with a 20-30% reduction in cardiovascular disease burden, including heart failure precursors like coronary artery disease.[83][87] These strategies, implemented through national guidelines, prioritize environmental changes over individual actions to achieve sustainable risk reduction.[83]As of 2025, updated frameworks incorporate community-based programs addressing social determinants of health, such as expanded access to care in underserved areas through initiatives like mobile screening units and subsidized risk assessments, which improve early detection rates among low-income populations.[88] These efforts, including partnerships to tackle housing instability and food insecurity, aim to mitigate disparities in heart failure risk, with evidence showing that high social disadvantage indices significantly increase incidence in affected communities.[89] Such programs align with a risk-based approach to primary prevention, emphasizing equitable resource allocation.[88]
Prognosis
Survival rates
Heart failure is associated with substantial mortality, with approximately 50-60% of patients surviving five years following diagnosis as of recent data.[90][91] One-year mortality rates range from 20% to 30% among those hospitalized for acute decompensation.[92]Survival outcomes vary by ejection fraction subtype. In heart failure with reduced ejection fraction (HFrEF), guideline-directed medical therapy (GDMT) has achieved roughly a 50% reduction in mortality compared to historical controls without such treatments. In contrast, heart failure with preserved ejection fraction (HFpEF) carries an annual mortality rate of approximately 15%, with one-year mortality often reaching 20-29% in hospitalized patients.[93][94]Mortality trends have shown improvement since 2000, driven by advances in pharmacotherapy and device therapies, with five-year survival rising from about 41% to 48% in population-based cohorts.[95] However, age-adjusted mortality rates have stabilized or increased since 2012, and absolute heart failure-related deaths continue to rise, contributing to 425,147 fatalities in the United States in 2022, representing 45% of all cardiovascular deaths.[15] Recent projections incorporating lifetime risk—estimated at 24% for individuals aged 45—underscore the growing burden, with millions more expected to develop heart failure by 2050 amid aging populations.[96]Hospital readmission remains a key indicator of poor outcomes, occurring in 20-25% of patients within 30 days of discharge for heart failure exacerbation.[92]
Prognostic factors
Several comorbidities significantly worsen the prognosis in heart failure (HF) patients. Diabetes mellitus is associated with increased mortality risk, with hazard ratios (HR) ranging from 1.2 to 1.4 in large cohort studies and meta-analyses, due to accelerated myocardial remodeling and endothelial dysfunction.[97] Similarly, chronic kidney disease (CKD), defined by an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m², independently elevates the risk of cardiovascular death and HF hospitalization, with HRs of 1.6 to 2.2 observed across meta-analyses, reflecting shared pathophysiology of fluid overload and uremic toxins.[98]Biomarkers provide valuable prognostic insights in HF. Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels exceeding 1000 pg/mL at diagnosis or follow-up are strongly predictive of adverse events, including mortality and rehospitalization, as demonstrated in trials like PARADIGM-HF, where such levels correlated with a 50-60% higher event rate over 2 years.[99] Cardiac troponin elevations, particularly high-sensitivity troponin T or I above 14-17 ng/L, indicate ongoing myocardial ischemia or injury and are linked to doubled mortality risk in chronic HF, independent of ejection fraction.[100][101]Functional parameters remain central to risk stratification. A left ventricular ejection fraction (LVEF) below 30% in HF with reduced ejection fraction (HFrEF) is associated with substantially higher all-cause mortality compared to preserved EF, particularly in severe cases.[102] Advanced New York Heart Association (NYHA) class IV symptoms, characterized by symptoms at rest, portend a grim short-term outlook, with 6-month mortality approaching 40-50% in ambulatory and hospitalized cohorts.[103][104]Socioeconomic determinants profoundly influence HF outcomes. Limited access to care, often tied to low income or rural residence, correlates with higher readmission rates and mortality, with disadvantaged patients facing 20-30% increased risk due to delayed guideline-directed medical therapy (GDMT) initiation.[89] Ethnic disparities exacerbate this, as racial minorities such as Black and Hispanic individuals experience 1.5-2.0 times higher HF mortality, attributable to systemic barriers and higher comorbidity burdens.[21][105]As of 2025, emerging clinical considerations highlight hypotension as a barrier to GDMT optimization, with systolic blood pressure below 100 mmHg increasing intolerance to agents like ARNI and SGLT2 inhibitors, potentially worsening prognosis by limiting dose escalation.[106] Additionally, inflammation markers such as high-sensitivity C-reactive protein (hsCRP >3 mg/L) and interleukin-6 have gained recognition as predictors of progression, with elevated levels associating with 1.5-2.0 fold higher event rates in recent meta-analyses.[107][108]
Society and culture
Historical development
The understanding of heart failure traces back to ancient times, when it was primarily recognized through symptoms like edema, known as "dropsy." Around 400 BCE, Hippocrates described dropsy as a condition involving fluid accumulation and thirst, attributing it to imbalances in bodily humors, marking one of the earliest documented recognitions of what is now associated with cardiac dysfunction.[109] This classical view persisted for centuries, focusing on symptomatic relief rather than underlying mechanisms.In the 17th century, William Harvey's seminal work revolutionized cardiovascular knowledge by demonstrating the circulatory system in his 1628 publication De Motu Cordis, establishing that blood flows in a closed loop driven by the heart, which laid the groundwork for linking dropsy to cardiac impairment.[110] By the late 18th century, therapeutic advances emerged with William Withering's 1785 report on digitalis (foxglove extract), which he used to treat dropsy in 158 patients, noting relief in 101 cases of congestive symptoms through its diuretic and cardiac effects, though toxicity risks were also identified.[111]The 20th century brought formalized classifications and diagnostic tools. In 1928, the New York Heart Association (NYHA) introduced a functional classification system for heart disease, categorizing patients by symptom severity and activity limitation, which was later refined in 1994 to better assess heart failure progression.[112] The concept of ejection fraction, measuring the heart's pumping efficiency, gained prominence in the 1950s as physiologists quantified systolic function to differentiate heart failure subtypes.[113]Therapeutic milestones shifted paradigms from symptom management to targeting underlying pathophysiology. In the 1980s, the CONSENSUS trial (1987) demonstrated that enalapril, an ACE inhibitor, reduced mortality by 40% in severe heart failure when added to conventional therapy, establishing neurohormonal blockade as a core strategy.[114] The 1990s saw beta-blockers integrated into care, with the MERIT-HF trial (1999) showing metoprolol CR/XL lowered all-cause mortality by 34% in chronic heart failure patients.[115] This era marked a broader transition to the neurohormonal paradigm, recognizing excessive activation of systems like the renin-angiotensin-aldosterone as drivers of disease progression rather than mere consequences.[116]By the early 21st century, this approach evolved further with the 2014 PARADIGM-HF trial, which established sacubitril/valsartan (an ARNI) as superior to enalapril, reducing cardiovascular death and heart failure hospitalization by 20% in patients with reduced ejection fraction, reinforcing combined neprilysin and angiotensin receptor inhibition.[117] Subsequent advancements expanded the neurohormonal framework with sodium-glucose cotransporter-2 (SGLT2) inhibitors, initially developed for diabetes but proven beneficial in heart failure regardless of diabetes status. Landmark trials such as DAPA-HF (2019) and EMPEROR-Reduced (2020) demonstrated that dapagliflozin and empagliflozin, respectively, reduced the risk of worsening heart failure and cardiovascular death by approximately 25% in patients with heart failure with reduced ejection fraction (HFrEF).[118][119] For heart failure with preserved ejection fraction (HFpEF), the EMPEROR-Preserved trial (2021) showed empagliflozin reduced composite outcomes of hospitalization and cardiovascular death.[120] In 2025, finerenone, a non-steroidal mineralocorticoid receptor antagonist, received FDA approval for heart failure with mildly reduced or preserved ejection fraction (LVEF ≥40%), further advancing options for this previously undertreated population based on the FINEARTS-HF trial results.[121] These pre-2025 and 2025 developments transformed heart failure from a terminal diagnosis to a manageable condition through multifaceted evidence-based therapies.
Economic impact
Heart failure imposes a substantial economic burden on healthcare systems and societies worldwide, driven by high rates of hospitalization, ongoing medical management, and indirect costs from lost productivity. In the United States, direct medical costs for heart failure reached an estimated $32 billion in 2020, with indirect costs adding another $14 billion, primarily from morbidity and premature mortality.[14] These figures are projected to escalate significantly, with total annual costs for heart failure expected to exceed $70 billion by 2030 due to rising prevalence and aging populations.[122] Globally, the economic impact was estimated at $284 billion in 2021, split nearly evenly between direct costs ($137 billion) and indirect costs ($147 billion).[123] In Europe, cardiovascular diseases, including heart failure, accounted for €282 billion in total costs in 2021, with heart failure contributing a notable portion through recurrent care needs.[124]The primary components of these costs include hospitalizations, which constitute approximately 60-70% of direct expenditures in the US, often exceeding $12,000 per inpatient stay due to acute decompensations.[125][126] Medications and outpatient care account for the remainder of direct costs, while lost productivity from work absenteeism and caregiving further amplifies the societal toll, particularly among working-age patients.[127] Economic disparities exacerbate this burden, as ethnic minorities such as Black Americans face higher overall costs linked to delayed care, lower access to guideline-directed therapies, and increased hospitalization rates, leading to 1.5-2 times greater per-patient expenditures compared to White individuals.[14][128]Emerging therapies offer potential for cost mitigation; for instance, finerenone, approved in 2025 for heart failure with preserved or mildly reduced ejection fraction, has demonstrated cost-effectiveness by reducing cardiovascular events and hospitalizations, yielding lifetime savings of approximately €2,700 per patient when added to standard care in comorbid chronic kidney disease populations.[129][130] Such interventions could lower projections for 2030 by curbing acute care utilization, though broader adoption depends on addressing access inequities.[131]
Research directions
Emerging therapies
In 2025, the U.S. Food and Drug Administration approved finerenone, a nonsteroidal mineralocorticoid receptor antagonist, for the treatment of heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF, LVEF ≥40%), based on the FINEARTS-HF trial demonstrating a reduction in the composite risk of cardiovascular death and heart failure events.[47] This approval expands its role beyond chronic kidney disease, addressing unmet needs in HFpEF where guideline-directed medical therapy options remain limited. Similarly, the DIGIT-HF phase III trial reported in 2025 that digitoxin, a cardiac glycoside, reduced the composite endpoint of all-cause death or hospitalization for worsening heart failure by 18% (hazard ratio 0.82, 95% CI 0.69-0.98) in patients with advanced HFrEF when added to standard therapy, prompting discussions on its potential regulatory pathway despite historical concerns with digoxin-like agents.[132]Antifibrotic therapies targeting myocardial fibrosis, a key driver of heart failure progression, are advancing in clinical development. Pirfenidone, an oral antifibrotic agent approved for idiopathic pulmonary fibrosis, showed in the phase II PIROUETTE trial that 52 weeks of treatment reduced myocardial extracellular volume by 1.21% (95% CI -2.12 to -0.31; as measured by cardiac magnetic resonance imaging) in patients with HFpEF, alongside improvements in diastolic function, though larger trials are needed to confirm clinical outcomes.[133] Pamrevlumab, a monoclonal antibody inhibiting connective tissue growth factor (CTGF), has demonstrated preclinical antifibrotic effects in models of cardiac pressure overload and remodeling, with early-phase data suggesting potential to attenuate fibrosis in heart failure contexts, building on its investigational use in other fibrotic diseases.[134]Gene and cell therapies represent frontier approaches for heart failure, particularly in regenerative and genetic subtypes. CRISPR-Cas9-based genome editing has shown promise in preclinical models of hypertrophic cardiomyopathy (HCM), a common genetic cause of heart failure, by correcting mutations in genes like MYH7 to prevent sarcomere dysfunction and hypertrophy, with early human applications emerging in 2024-2025 clinical explorations.[135] Stem cell therapies aim to regenerate damaged myocardium; a 2025 Mayo Clinic study introduced a minimally invasive patch using reprogrammed adult stem cells to deliver lab-grown heart tissue, improving ejection fraction and quality of life in phase I/II trials for ischemic heart failure, while ongoing multicenter trials continue to evaluate safety and long-term engraftment.[136]Intravenous iron supplementation with ferric carboxymaltose has gained traction for iron-deficient heart failure patients, irrespective of anemia. The phase III HEART-FID trial showed a non-significant trend toward fewer heart failure hospitalizations (13.3% vs. 14.8%) and improved 6-minute walk distance by 18 m compared to placebo in patients with HFrEF and iron deficiency, though the primary composite outcome was neutral, supporting its integration into management for this prevalent comorbidity affecting up to 50% of cases.[137]Omecamtiv mecarbil, a selective cardiac myosin activator, targets contractile dysfunction in HFrEF. The phase III GALACTIC-HF trial involving over 8,000 patients reported a 9% relative risk reduction in the primary composite of heart failure events or cardiovascular death, with greater benefits in those with lower ejection fractions (<28%), despite FDA declining approval in 2023 due to modest efficacy, development continues with the ongoing phase 3 COMET-HF trial initiated in 2024.[138][139]
Ongoing clinical trials
As of 2025, several pivotal clinical trials are investigating novel therapeutic approaches to improve outcomes in heart failure (HF), focusing on pharmacological, genetic, and device-based interventions tailored to specific HF phenotypes. These efforts aim to address unmet needs in preserved ejection fraction (HFpEF), reduced ejection fraction (HFrEF), acute decompensation, and specialized etiologies like amyloidosis and arrhythmia-induced cardiomyopathy (AIC). Ongoing studies emphasize long-term efficacy, safety in high-risk populations, and strategies to mitigate disparities in trial participation and treatment access, including updated ACC/AHA guidelines from mid-2025 promoting diverse enrollment.[93]Post-hoc analyses of the EMPEROR-Preserved trial in 2025 have shown greater benefits of empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), in HFpEF patients with echocardiographic features of diastolic impairment. These analyses, building on the original trial's demonstration of reduced cardiovascular death and HF hospitalizations, explore impacts on diastolic dysfunction and resistant hypertension. They support broader SGLT2i integration while ongoing substudies assess real-world applicability in diverse cohorts.[140][141]In high-risk HFrEF, the VICTOR trial serves as a key follow-up to the original VICTORIA study, assessing vericiguat's role in ambulatory patients without recent decompensation. This phase 3, double-blind, placebo-controlled study, completed in early 2025, examined vericiguat's effect on the composite of cardiovascular death or HF hospitalization, showing a neutral primary outcome but a significant reduction in cardiovascular mortality. Pooled analyses with VICTORIA data reinforce vericiguat's potential in guideline-directed therapy optimization, particularly for patients with elevated natriuretic peptides.[142][143]For acute HF, the SOLOIST-WHF trial's extended evaluations of sotagliflozin, a dual SGLT1/2 inhibitor, continue to inform initiation strategies in hospitalized patients with type 2 diabetes and worsening HF. Post-hoc analyses from 2025 highlight improvements in health status, early mortality risk, and total cardiovascular events, with sotagliflozin reducing HF-related readmissions when started in-hospital. These findings support its use in acute settings, though ongoing monitoring addresses concerns like volume depletion in vulnerable populations.[144][44]Gene therapy trials targeting transthyretin amyloidosis, a cause of infiltrative HF, feature NTLA-2001 (nexiguran ziclumeran), an in vivo CRISPR-based therapy in phase 1/2 studies. This single-dose treatment inactivates the TTR gene to halt amyloid production, with 2025 interim data from 24 patients showing sustained TTR reduction (up to 89% at 24 months) and stabilization of cardiac biomarkers in those with HF symptoms. Early safety profiles were favorable, and it received FDA Regenerative Medicine Advanced Therapy (RMAT) designation earlier in 2025, positioning it as a potential one-time curative option for ATTR-CM. However, as of November 2025, the phase 3 MAGNITUDE trial is on temporary clinical hold following a patient death on November 9, 2025, pending further safety review.[145][146][147][148]Device-based trials are advancing next-generation cardiac resynchronization therapy (CRT) and wireless hemodynamic monitoring. The Heart Rhythm 2025 late-breaking trials demonstrated left bundle branch area pacing's superiority in improving ejection fraction and reducing HF events compared to traditional biventricular CRT, with ongoing multicenter studies evaluating multipoint pacing in non-responders. Concurrently, trials like VECTOR-HF (completed 2023) and evolutions of CardioMEMS assess wireless left atrial or pulmonary artery pressure sensors for congestion-guided management; 2025 meta-analyses confirm reduced hospitalizations through remote adjustments, with next-gen iterations focusing on implantation safety and integration with wearable tech.[149][150][151]In 2025, trial designs increasingly prioritize disparity reduction and AIC. Initiatives like expanded enrollment in global HF studies aim to boost representation of underrepresented racial/ethnic groups, addressing historical underinclusion (e.g., <20% in prior SGLT2i trials) through targeted recruitment and equity-focused protocols, potentially improving generalizability of findings, as emphasized in mid-2025 ACC/AHA guidelines. For AIC, the Genetic Characterization of Patients With Arrhythmia-Induced Cardiomyopathy (NCT06896266) is an ongoing observational study profiling genetic variants and prognosis in tachycardia-mediated HF, while related efforts explore ablation timing to reverse remodeling. These trials underscore a shift toward inclusive, etiology-specific research to enhance equitable HF management.[152][153][154]