# Lecture 11: Heart Failure ## Unit 1.7: Cardiovascular System --- ## Learning Objectives By the end of this lecture, students will be able to: 1. Define heart failure and describe its epidemiology 2. Classify heart failure by ejection fraction and stage 3. Explain the pathophysiology of systolic and diastolic dysfunction 4. Describe neurohormonal activation and its consequences 5. Recognize the clinical manifestations of heart failure 6. Describe the principles of heart failure management --- ## Definition and Classification Heart failure is a clinical syndrome resulting from structural or functional cardiac abnormalities that impair the heart's ability to fill with or eject blood. The defining feature is the heart's inability to meet the metabolic demands of the body at normal filling pressures, or the ability to meet those demands only with abnormally elevated filling pressures that cause congestive symptoms. Contemporary classification distinguishes heart failure phenotypes by ejection fraction. Heart failure with reduced ejection fraction (HFrEF) is defined by an ejection fraction of 40% or less and was formerly called systolic heart failure. Heart failure with mildly reduced ejection fraction (HFmrEF) encompasses the borderline range of 41-49%. Heart failure with preserved ejection fraction (HFpEF) is defined by an ejection fraction of 50% or greater and was formerly called diastolic heart failure. These distinctions have therapeutic implications because guideline-directed medical therapy has been proven primarily in HFrEF, though SGLT2 inhibitors have recently shown benefit across the ejection fraction spectrum. The American College of Cardiology/American Heart Association stages describe disease progression and guide prevention and treatment. Stage A identifies patients at risk for heart failure but without structural heart disease or symptoms—for example, patients with hypertension, diabetes, or coronary artery disease. Stage B denotes structural heart disease without heart failure symptoms, such as patients with previous myocardial infarction or left ventricular hypertrophy. Stage C represents structural heart disease with current or prior symptoms of heart failure. Stage D indicates refractory heart failure requiring specialized interventions. This staging system emphasizes that heart failure develops along a continuum and that prevention is possible at early stages. The New York Heart Association functional classification describes symptom severity. Class I patients have no limitation during ordinary physical activity. Class II patients have slight limitation with symptoms occurring during ordinary activity. Class III patients experience marked limitation with symptoms during less than ordinary activity. Class IV patients have symptoms at rest. Unlike the ACC/AHA stages, NYHA class can improve or worsen with treatment or disease progression. Panel A: Three hearts in cross-section representing ejection fraction categories: HFrEF with EF 40% or less showing a dilated thin-walled left ventricle, HFmrEF with EF 41-49% showing intermediate features, and HFpEF with EF 50% or greater showing a thick-walled stiff ventricle. Panel B: ACC/AHA stages as a horizontal progression from Stage A with risk factors through Stage B with structural disease to Stage C with symptomatic heart failure to Stage D with advanced refractory disease. Panel C: NYHA functional classes I through IV with activity tolerance illustrated: Class I walking uphill easily, Class II dyspneic on stairs, Class III dyspneic on level ground, Class IV dyspneic at rest. Panel D: Comparison of classification systems showing that ACC/AHA stages progress unidirectionally while NYHA class can improve or worsen with treatment. --- ## Epidemiology and Etiology Heart failure is a major public health problem affecting approximately 6 million people in the United States, with about 1 million new cases diagnosed annually. The prevalence increases dramatically with age, affecting approximately 10% of people over 70 years. Five-year mortality remains approximately 50% despite therapeutic advances, and heart failure is the leading cause of hospitalization in patients over 65 years. The causes of HFrEF involve conditions that damage or weaken the myocardium. Ischemic heart disease, including coronary artery disease and prior myocardial infarction, is the leading cause in developed countries. Dilated cardiomyopathy may be idiopathic or familial (genetic mutations in cytoskeletal or sarcomeric proteins). Toxic cardiomyopathy results from alcohol abuse or cardiotoxic chemotherapy, particularly anthracyclines. Viral myocarditis can cause acute or chronic left ventricular dysfunction. Inflammatory conditions including autoimmune diseases and sarcoidosis affect the myocardium. Valvular diseases such as aortic regurgitation and mitral regurgitation cause volume overload leading to ventricular dilation and dysfunction. Tachycardia-mediated cardiomyopathy results from prolonged uncontrolled tachyarrhythmias. Peripartum cardiomyopathy is a specific entity occurring in the last month of pregnancy or the first five months postpartum. HFpEF has distinct etiologies centered on conditions that impair ventricular relaxation or increase myocardial stiffness. Hypertension causes left ventricular hypertrophy with diastolic dysfunction. Aging itself increases myocardial stiffness through fibrosis and altered titin phosphorylation. Obesity and metabolic syndrome contribute through multiple mechanisms including systemic inflammation and comorbidities. Infiltrative diseases such as amyloidosis deposit abnormal proteins that stiffen the myocardium. Hypertrophic cardiomyopathy causes severe diastolic dysfunction due to massive hypertrophy. Constrictive pericarditis restricts ventricular filling externally. Panel A: Causes of HFrEF shown as a pie chart with ischemic heart disease as the largest segment, followed by dilated cardiomyopathy showing a dilated thin-walled ventricle. Panel B: Additional HFrEF causes including valvular disease with regurgitant mitral valve, toxic causes from alcohol and chemotherapy, and myocarditis from viral infection. Panel C: Causes of HFpEF including hypertension leading to concentric left ventricular hypertrophy and aging increasing myocardial stiffness. Panel D: Additional HFpEF causes including obesity and metabolic syndrome contributing through systemic inflammation, and infiltrative disease with amyloid fibrils depositing in myocardium. --- ## Pathophysiology of Systolic Dysfunction HFrEF results from impaired myocardial contractility leading to reduced ejection fraction and decreased cardiac output. Understanding the compensatory mechanisms and their eventual failure is essential for rational therapy. The primary defect in HFrEF is diminished contractile function, which reduces stroke volume and ejection fraction. In response, the Frank-Starling mechanism compensates by increasing preload: fluid retention expands intravascular volume, increasing ventricular end-diastolic volume and stretching sarcomeres to enhance contractile force. Initially, this compensatory mechanism maintains stroke volume despite reduced contractility. However, the failing heart operates on a depressed Frank-Starling curve—the same increase in preload produces a smaller increase in stroke volume compared to a normal heart. Eventually, further increases in preload provide no benefit because the heart operates on the flat portion of its curve, while congestion worsens. Pressure-volume loop analysis reveals the hemodynamic abnormalities in HFrEF. The end-systolic pressure-volume relationship (ESPVR), which reflects contractility, is shifted downward and rightward, indicating reduced contractility. End-diastolic volume increases as the heart dilates to maintain stroke volume through the Starling mechanism. End-systolic volume also increases because the weakened ventricle cannot empty completely. The stroke volume (difference between EDV and ESV) decreases, and the ejection fraction (SV/EDV) falls substantially. Chamber remodeling in HFrEF involves eccentric hypertrophy, where sarcomeres are added in series, causing the ventricle to dilate. This dilation increases wall stress according to the Law of LaPlace, further increasing myocardial oxygen demand. As the ventricle becomes more spherical, the mitral valve annulus dilates, causing functional mitral regurgitation that creates additional volume overload and perpetuates deterioration. Panel A: Frank-Starling curves comparing a normal steep curve with a flattened HFrEF curve, showing reduced stroke volume at normal preload and only modest improvement with increased preload. Panel B: Pressure-volume loops comparing normal and HFrEF hearts, with the HFrEF loop shifted rightward showing increased volumes, lower peak pressure, and depressed ESPVR slope indicating decreased contractility. Panel C: Cardiac remodeling progression from a normal elliptical left ventricle to a dilated spherical chamber with sarcomeres added in series and wall thinning. Panel D: Functional mitral regurgitation resulting from ventricular dilation, showing a regurgitant jet through a dilated annulus creating additional volume overload. --- ## Pathophysiology of Diastolic Dysfunction HFpEF results from abnormalities in ventricular relaxation and compliance that elevate filling pressures despite preserved systolic function. While the ejection fraction is normal, this does not mean the heart is normal—patients with HFpEF have significant functional limitation and comparable mortality to HFrEF. The primary defects in HFpEF involve impaired relaxation and increased passive stiffness. Impaired relaxation (reduced lusitropy) occurs when calcium reuptake by SERCA is slowed, prolonging the time required for the ventricle to relax after systole. This is particularly problematic during tachycardia when diastolic filling time is shortened. Increased passive stiffness results from myocardial fibrosis, myocyte hypertrophy, and altered titin isoform expression that make the ventricular wall less compliant. External constraint from pericardial disease can also impair filling. The hemodynamic consequence of reduced compliance is elevated filling pressures. A stiff ventricle requires higher filling pressures to achieve the same end-diastolic volume. The relationship between pressure and volume during diastole (compliance = dV/dP) is reduced, meaning small changes in volume produce large changes in pressure. These elevated left ventricular filling pressures are transmitted backward to the left atrium and pulmonary veins, causing pulmonary congestion despite normal systolic function. Pressure-volume loop analysis in HFpEF shows that the end-diastolic pressure-volume relationship (EDPVR), which reflects passive stiffness, is shifted upward and leftward, indicating reduced compliance. End-diastolic pressure is elevated. End-diastolic volume may be normal or reduced. Stroke volume may be normal or reduced, but because EDV is not increased, the ejection fraction is preserved at 50% or above. The elevated end-diastolic pressure, rather than reduced stroke volume, is the primary hemodynamic abnormality. Chamber remodeling in HFpEF typically involves concentric hypertrophy, where sarcomeres are added in parallel, causing wall thickening with preserved or reduced cavity size. Left atrial enlargement develops chronically due to the elevated filling pressures required to fill the stiff ventricle. Panel A: Mechanisms of diastolic dysfunction showing slow calcium reuptake from impaired SERCA function, increased collagen deposition between myocytes, and stiff titin molecules that resist stretching. Panel B: Pressure-volume loops comparing normal and HFpEF hearts, with the HFpEF loop showing preserved stroke volume and normal ESPVR but a steeply shifted EDPVR indicating elevated filling pressures. Panel C: Cardiac remodeling in HFpEF showing a concentrically hypertrophied left ventricle with thick walls and small cavity. Panel D: Enlarged left atrium resulting from chronic pressure elevation required to fill the stiff ventricle. --- ## Neurohormonal Activation The body responds to decreased cardiac output with activation of neurohormonal systems that initially compensate for reduced perfusion but ultimately become maladaptive and contribute to disease progression. Understanding these pathways is essential because they are the targets of disease-modifying heart failure therapy. The sympathetic nervous system is activated in response to reduced cardiac output and blood pressure detected by arterial baroreceptors. Beta-1 receptor stimulation increases heart rate and contractility, acutely increasing cardiac output. Alpha-1 receptor stimulation causes vasoconstriction, maintaining blood pressure despite reduced output. However, chronic sympathetic activation has deleterious effects. Sustained tachycardia increases myocardial oxygen demand and reduces diastolic filling time. Chronic catecholamine exposure causes myocyte apoptosis and promotes arrhythmias. Beta receptors are downregulated, diminishing the heart's ability to respond to sympathetic stimulation. The renin-angiotensin-aldosterone system (RAAS) is activated by reduced renal perfusion and sympathetic stimulation of juxtaglomerular cells. Angiotensin II causes vasoconstriction, increasing afterload and blood pressure. It promotes sodium and water retention, expanding intravascular volume. Most importantly for long-term outcomes, angiotensin II stimulates cardiac fibrosis and myocyte hypertrophy, promoting adverse remodeling. Aldosterone causes sodium and water retention leading to edema and congestion. It promotes myocardial fibrosis and potassium wasting that predisposes to arrhythmias. Additional neurohormones contribute to the heart failure syndrome. Antidiuretic hormone (vasopressin) is elevated and causes water retention and hyponatremia, a marker of poor prognosis. Endothelin, a potent vasoconstrictor, contributes to increased afterload and promotes remodeling. Natriuretic peptides (ANP and BNP), released in response to myocardial stretch, cause natriuresis and vasodilation in an attempt to counterbalance the vasoconstrictive and volume-retaining effects of the sympathetic and RAAS systems. However, these counterregulatory systems are overwhelmed in advanced heart failure. BNP serves as a valuable biomarker for diagnosis and prognosis. Panel A: Failing heart with reduced cardiac output and sympathetic nervous system response showing acutely beneficial effects including increased heart rate, contractility, and blood pressure, alongside chronically harmful effects including myocyte apoptosis, arrhythmias, and receptor downregulation. Panel B: RAAS pathway showing renin release from the kidney converting to angiotensin II, with acute vasoconstriction and sodium retention contrasted against chronic fibrosis, hypertrophy, and volume overload. Panel C: Aldosterone effects including sodium retention, fibrosis, and hypokalemia, and ADH from the posterior pituitary causing water retention and hyponatremia. Panel D: Natriuretic peptides from the heart attempting to counterbalance through natriuresis and vasodilation, with therapeutic targets including ACE inhibitors, ARBs, beta-blockers, and MRAs indicated at their sites of action. --- ## Cardiac Remodeling Cardiac remodeling refers to changes in the size, shape, structure, and function of the heart in response to injury or hemodynamic stress. While initially compensatory, remodeling ultimately contributes to heart failure progression. Cellular changes in the failing myocardium are profound. Myocyte hypertrophy occurs as individual cells enlarge in response to increased mechanical load. Myocyte death through apoptosis (programmed cell death) and necrosis depletes the functional myocardium. Fibrosis develops as collagen deposition replaces lost myocytes and accumulates in the interstitium, impairing both systolic and diastolic function. Gene expression shifts toward a fetal pattern, with re-expression of fetal isoforms of contractile proteins and downregulation of adult isoforms. Beta-adrenergic receptors are downregulated due to chronic catecholamine exposure, reducing the heart's responsiveness to sympathetic stimulation. Calcium handling becomes abnormal as SERCA (the calcium ATPase that reuptakes calcium into the sarcoplasmic reticulum) is downregulated, impairing both relaxation and contraction. Structural changes include progressive chamber dilation in HFrEF, which increases wall stress according to the Law of LaPlace and further increases oxygen demand. Wall thinning accompanies dilation. The normal elliptical shape of the left ventricle becomes more spherical. Mitral annular dilation causes the mitral valve leaflets to fail to coapt, resulting in functional mitral regurgitation. This mitral regurgitation creates additional volume overload that promotes further dilation—a vicious cycle. Reverse remodeling—improvement in ventricular size, shape, and function—can occur with effective therapy. Beta-blockers, ACE inhibitors, and device therapy (particularly cardiac resynchronization therapy) have been shown to reduce ventricular volumes and improve ejection fraction. Reverse remodeling is associated with improved prognosis and supports the importance of achieving and maintaining guideline-directed medical therapy. Panel A: Normal myocardium with organized myocytes, abundant beta-receptors, and normal calcium handling with SERCA actively reuptaking calcium. Panel B: Failing myocardium showing hypertrophied myocytes, apoptotic cells with fragmented nuclei, increased collagen fibrosis, decreased beta-receptor density, and impaired SERCA function. Panel C: Structural remodeling progression from normal elliptical ventricle through moderate enlargement with wall thinning to severe spherical dilation with functional mitral regurgitation. Panel D: Reverse remodeling with beta-blocker and ACE inhibitor therapy demonstrating reduction in chamber size and restoration of elliptical shape. --- ## Clinical Manifestations Heart failure symptoms result from two mechanisms: congestion (elevated filling pressures causing fluid accumulation) and low cardiac output (inadequate tissue perfusion). Most patients present with a combination of both. Pulmonary congestion from elevated left-sided filling pressures produces the cardinal symptom of dyspnea—difficulty breathing that initially occurs with exertion and progresses to occur at rest in severe disease. Orthopnea is dyspnea when lying flat, caused by redistribution of fluid from the lower extremities to the pulmonary circulation; patients report needing to sleep on multiple pillows. Paroxysmal nocturnal dyspnea (PND) is sudden awakening with severe dyspnea, typically 1-2 hours after falling asleep. Chronic cough, particularly at night, may result from pulmonary congestion. Systemic congestion from elevated right-sided filling pressures causes peripheral edema, typically starting in the dependent areas (feet and ankles in ambulatory patients, sacrum in bedridden patients). Abdominal distension from hepatomegaly and ascites occurs in advanced right heart failure. Rapid weight gain from fluid retention is a sensitive marker of decompensation. Low cardiac output symptoms include fatigue from inadequate skeletal muscle perfusion, exercise intolerance from inability to augment cardiac output with activity, and mental status changes from reduced cerebral perfusion. Cool extremities result from peripheral vasoconstriction aimed at preserving central perfusion. Physical examination reveals characteristic findings. Elevated jugular venous pressure reflects increased right atrial pressure. An S3 gallop (a low-frequency sound in early diastole) indicates rapid ventricular filling and volume overload. An S4 gallop (a sound in late diastole) indicates atrial contraction against a stiff ventricle. Pulmonary rales or crackles indicate alveolar fluid. Peripheral edema is usually pitting and bilateral. Hepatomegaly with hepatojugular reflux indicates hepatic congestion. Ascites occurs in severe right heart failure. The hemodynamic profile framework classifies patients as "warm" (adequate perfusion) or "cold" (hypoperfusion) and "dry" (euvolemic) or "wet" (congested). Warm and dry represents the compensated state. Warm and wet indicates congestion without hypoperfusion, requiring diuresis. Cold and dry suggests hypovolemia rather than heart failure. Cold and wet—congestion with hypoperfusion—represents cardiogenic shock requiring inotropic support. Panel A: Left-sided pulmonary congestion symptoms including dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and cough, with an inset showing fluid-filled alveoli. Panel B: Right-sided systemic congestion symptoms including jugular venous distension, hepatomegaly, ascites, and peripheral pitting edema. Panel C: Low cardiac output symptoms including fatigue, exercise intolerance, cool extremities, and confusion from inadequate tissue perfusion. Panel D: Hemodynamic profiles as a 2x2 grid showing warm-dry as compensated, warm-wet requiring diuresis, cold-dry suggesting hypovolemia, and cold-wet representing cardiogenic shock requiring inotropes. --- ## Diagnosis Heart failure diagnosis requires the combination of clinical symptoms and signs with objective evidence of cardiac dysfunction. Clinical evaluation begins with a thorough history focusing on symptoms of congestion and low output, functional limitation, and potential etiologies. Physical examination assesses volume status and perfusion. Framingham criteria and other clinical scoring systems provide structured approaches to clinical diagnosis. Laboratory testing plays a central role. BNP and NT-proBNP are natriuretic peptides released from ventricular myocytes in response to wall stress. Elevated levels support the diagnosis of heart failure and have prognostic value. Low levels have high negative predictive value for excluding heart failure as a cause of dyspnea. Complete blood count identifies anemia, which can exacerbate heart failure symptoms. Comprehensive metabolic panel assesses renal function (often impaired in heart failure due to reduced cardiac output and venous congestion) and electrolytes (important for medication management). Liver function tests may be elevated from hepatic congestion. Troponin should be measured to exclude acute coronary syndrome as the precipitant. Thyroid function tests identify hyperthyroidism or hypothyroidism as reversible causes of cardiomyopathy. Imaging is essential for characterizing the heart failure phenotype. Echocardiography is the cornerstone of heart failure evaluation, providing measurement of ejection fraction, assessment of chamber sizes and wall motion, evaluation of valvular function, and estimation of filling pressures. Chest radiography may show cardiomegaly, pulmonary vascular congestion, pleural effusions, and Kerley B lines. Cardiac magnetic resonance imaging provides detailed structural assessment and tissue characterization, including detection of fibrosis using late gadolinium enhancement. Additional testing is guided by the clinical situation. Coronary angiography is indicated when ischemic etiology is suspected. Right heart catheterization directly measures hemodynamics and is used in advanced heart failure and transplant evaluation. Cardiopulmonary exercise testing quantifies functional capacity and has prognostic value. Endomyocardial biopsy is reserved for specific situations such as suspected infiltrative disease or unexplained myocarditis. Panel A: Diagnostic flowchart beginning with clinical suspicion and BNP/NT-proBNP testing, with elevated levels supporting diagnosis and low levels making heart failure unlikely. Panel B: Echocardiography determining ejection fraction to classify as HFrEF, HFmrEF, or HFpEF, with sample images showing dilated hypokinetic ventricle versus thick-walled small cavity. Panel C: Laboratory tests including CBC, BMP, LFTs, troponin, and TSH, alongside imaging with chest X-ray findings of cardiomegaly, cephalization, and effusions, and cardiac MRI for tissue characterization. Panel D: Invasive testing including coronary angiography for ischemic etiology, right heart catheterization for hemodynamic assessment, and endomyocardial biopsy for infiltrative disease. --- ## Management of HFrEF Guideline-directed medical therapy (GDMT) for HFrEF has transformed outcomes, and four classes of medications have demonstrated mortality reduction in randomized controlled trials. Renin-angiotensin system inhibitors reduce mortality and hospitalizations by blocking the deleterious effects of angiotensin II. ACE inhibitors (lisinopril, enalapril) were the first class shown to reduce mortality. Angiotensin receptor blockers (losartan, valsartan) provide an alternative for patients intolerant of ACE inhibitors due to cough. Angiotensin receptor-neprilysin inhibitors (ARNI), specifically sacubitril/valsartan, combine ARB therapy with neprilysin inhibition, which prevents degradation of natriuretic peptides. In the PARADIGM-HF trial, ARNI was superior to ACE inhibitor therapy and is now preferred for eligible patients with HFrEF. Beta-blockers were counterintuitive therapy initially, given the role of sympathetic activation in maintaining cardiac output. However, three beta-blockers—carvedilol, metoprolol succinate, and bisoprolol—have demonstrated mortality reduction in HFrEF by reducing maladaptive sympathetic stimulation, promoting reverse remodeling, and reducing arrhythmic death. Beta-blockers should be initiated at low doses and uptitrated gradually. Mineralocorticoid receptor antagonists (spironolactone and eplerenone) block aldosterone's effects on sodium retention and myocardial fibrosis. Mortality reduction has been demonstrated in both moderate and severe heart failure. Monitoring of potassium and renal function is essential. Sodium-glucose cotransporter-2 inhibitors (dapagliflozin, empagliflozin) are the newest addition to GDMT. Originally developed for diabetes, these drugs reduce mortality and heart failure hospitalizations in HFrEF regardless of diabetes status. Proposed mechanisms include diuretic effects, improved myocardial energetics, and effects on sodium-hydrogen exchange. Symptomatic therapy addresses congestion but does not reduce mortality. Loop diuretics (furosemide, bumetanide, torsemide) relieve congestion by promoting sodium and water excretion. Digoxin reduces heart failure hospitalizations without affecting mortality. Hydralazine with isosorbide dinitrate provides an alternative for patients unable to tolerate ACE inhibitors or ARBs and has demonstrated mortality benefit in African American patients. Device therapy is indicated for selected patients. Implantable cardioverter-defibrillators (ICDs) prevent sudden cardiac death in patients with ejection fraction ≤35% who are on optimal medical therapy. Cardiac resynchronization therapy (CRT) improves symptoms, reduces hospitalizations, and reduces mortality in patients with ejection fraction ≤35%, left bundle branch block, and QRS duration ≥150 ms. Left ventricular assist devices (LVADs) provide mechanical circulatory support as a bridge to transplantation or as destination therapy in patients not eligible for transplant. Panel A: Four pillars of guideline-directed medical therapy forming the foundation: ACE-I/ARB/ARNI for renin-angiotensin blockade, beta-blockers for heart rate reduction, MRA for aldosterone blockade, and SGLT2 inhibitors, each with mortality benefit and key trial name. Panel B: Symptomatic therapy tier showing diuretics with loop of Henle sodium excretion and digoxin for symptom relief. Panel C: Device therapy tier showing ICD for preventing VT/VF, CRT with biventricular pacing restoring synchrony, and LVAD as mechanical circulatory support. Panel D: Advanced therapy tier showing heart transplant and palliative care, with arrows indicating treatment escalation based on persistent symptoms. --- ## Management of HFpEF Management of HFpEF has been challenging because until recently, no therapy had demonstrated mortality reduction. The syndrome is heterogeneous, involving multiple pathophysiological processes and comorbidities that vary among patients. SGLT2 inhibitors have emerged as the first class of drugs to improve outcomes in HFpEF. The EMPEROR-Preserved and DELIVER trials demonstrated that empagliflozin and dapagliflozin reduce the composite of cardiovascular death and heart failure hospitalization in patients with ejection fraction greater than 40%. This represents a major advance in HFpEF management. Diuretics remain essential for managing congestion. Loop diuretics relieve symptoms and improve quality of life, though they have not been shown to affect mortality. Careful titration is necessary because HFpEF patients are often sensitive to volume changes—too much diuresis reduces preload and cardiac output, while too little allows congestion to recur. Management of underlying conditions and comorbidities is central to HFpEF therapy. Blood pressure control is essential, as hypertension is both a cause and exacerbating factor. Rate control in atrial fibrillation prevents rapid ventricular rates that shorten filling time. Weight management is critical, as obesity contributes to HFpEF through multiple mechanisms. Treatment of sleep apnea, coronary artery disease, and other comorbidities addresses factors that worsen symptoms and outcomes. Lifestyle modifications are particularly important in HFpEF. Sodium restriction to less than 2 grams daily reduces fluid retention. Fluid restriction may be necessary in patients with hyponatremia. Exercise training, despite seeming counterintuitive, has been shown to improve functional capacity and quality of life. Weight loss in obese patients provides significant symptomatic benefit. Monitoring requires attention to daily weights to detect fluid accumulation early, symptom diaries for self-management, periodic laboratory testing of renal function and electrolytes, and regular clinic follow-up to adjust therapy. Panel A: Central image of HFpEF with thick-walled heart and impaired relaxation, with SGLT2 inhibitors highlighted as the primary disease-modifying therapy referencing EMPEROR-Preserved and DELIVER trials. Panel B: Diuretics for congestion management with a balance scale indicating careful titration, and comorbidity management wheel with spokes for hypertension, atrial fibrillation, obesity, sleep apnea, and coronary artery disease. Panel C: Lifestyle modifications including sodium restriction, fluid restriction when hyponatremic, exercise training, and weight loss. Panel D: Monitoring elements including daily weights, symptom diary, periodic laboratory testing, and regular clinic follow-up. --- ## Summary Heart failure classification distinguishes HFrEF (ejection fraction ≤40%), HFmrEF (41-49%), and HFpEF (≥50%). ACC/AHA stages describe disease progression from risk factors through refractory heart failure, while NYHA classes describe functional limitation. HFrEF results from impaired myocardial contractility leading to reduced ejection fraction and cardiac output. The ventricle dilates (eccentric remodeling) as a compensatory mechanism, but this increases wall stress and leads to progressive dysfunction. Pressure-volume loops show depressed contractility and increased volumes. HFpEF results from impaired ventricular relaxation and reduced compliance, causing elevated filling pressures despite preserved ejection fraction. Concentric hypertrophy is the typical remodeling pattern. Pressure-volume loops show steep end-diastolic pressure-volume relationship. Neurohormonal activation of the sympathetic nervous system and RAAS initially compensates for reduced cardiac output but becomes maladaptive chronically, promoting remodeling, fibrosis, and progression. These systems are the targets of disease-modifying therapy. Clinical manifestations arise from pulmonary congestion (dyspnea, orthopnea, PND), systemic congestion (edema, hepatomegaly), and low output (fatigue, exercise intolerance). BNP is valuable for diagnosis, and echocardiography is essential for determining ejection fraction. HFrEF treatment with guideline-directed medical therapy—ACE inhibitor/ARB/ARNI, beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor—reduces mortality. Device therapy with ICD prevents sudden death; CRT improves outcomes in patients with dyssynchrony. HFpEF treatment now includes SGLT2 inhibitors for outcome improvement. Diuretics manage congestion, and treatment of comorbidities is essential. --- ## Key Terms | Term | Definition | |------|------------| | HFrEF | Heart failure with reduced ejection fraction (≤40%), characterized by impaired contractility and ventricular dilation | | HFpEF | Heart failure with preserved ejection fraction (≥50%), characterized by impaired relaxation and elevated filling pressures | | Neurohormonal activation | Compensatory activation of sympathetic nervous system and RAAS that becomes maladaptive with chronic stimulation | | Cardiac remodeling | Changes in ventricular size, shape, and function in response to injury or hemodynamic stress | | GDMT | Guideline-directed medical therapy: the evidence-based combination of medications proven to reduce mortality in HFrEF | | BNP | B-type natriuretic peptide, a biomarker released from stretched myocardium useful for heart failure diagnosis and prognosis | --- *This content is subject to the [MIT License](https://opensource.org/licenses/MIT). © 2024–2026 Hibbert School of Medicine.*