What are the clinical presentation and pathophysiology of Heart Failure with Reduced Ejection Fraction (HFrEF)?

Heart Failure with Reduced Ejection Fraction: Clinical Presentation and Pathophysiology

Definition and Classification

HFrEF is defined as a clinical syndrome with symptoms and/or signs caused by structural and/or functional cardiac abnormality with a left ventricular ejection fraction (LVEF) ≤40%. 1

• The 2022 AHA/ACC/HFSA guidelines classify HF into four categories based on LVEF: HFrEF (LVEF ≤40%), HFmrEF (LVEF 41-49%), HFpEF (LVEF ≥50%), and HFimpEF (previous LVEF ≤40% with follow-up measurement >40%) 1
• HFrEF represents approximately half of the total HF population, with over 64 million people affected by HF globally 1

Clinical Presentation

Cardinal Symptoms

Patients with HFrEF present primarily with dyspnea and functional impairment due to impaired myocardial function of the left ventricle. 1, 2

• Dyspnea occurs at rest or with exertion, reflecting elevated left ventricular filling pressures and pulmonary congestion 1
• Fatigue and exercise intolerance result from inadequate cardiac output to meet metabolic demands 2
• Orthopnea and paroxysmal nocturnal dyspnea indicate advanced volume overload 1
• Peripheral edema develops from systemic venous congestion 2

Physical Examination Findings

Look specifically for elevated jugular venous pressure, pulmonary rales, S3 gallop, displaced apical impulse, and peripheral edema. 1

• Cardiomegaly on chest radiography with pulmonary vascular congestion patterns 1
• Signs of low cardiac output including cool extremities, narrow pulse pressure, and altered mental status in advanced cases 3

Diagnostic Confirmation

Diagnosis requires elevated natriuretic peptides (BNP/NT-proBNP) AND objective evidence of cardiac dysfunction on imaging, typically echocardiography showing LVEF ≤40%. 1

• Echocardiography demonstrates reduced LVEF, ventricular dilation, and often regional wall motion abnormalities 1
• Chest radiography shows cardiomegaly, pulmonary venous hypertension, and interstitial or alveolar edema 1
• Cardiac MRI provides detailed assessment of ventricular function, myocardial fibrosis, and tissue characterization 1

Pathophysiology

Primary Mechanisms

HFrEF pathophysiology centers on an initial myocardial insult leading to reduced cardiac output, triggering maladaptive neurohormonal activation and progressive ventricular remodeling. 3

Initial Cardiac Injury

• Ischemic cardiomyopathy from coronary artery disease represents the most common etiology in clinical practice 1
• Nonischemic dilated cardiomyopathy encompasses heterogeneous myocardial disorders including idiopathic, viral, toxic (alcohol, chemotherapy), genetic, and inflammatory causes 1, 3
• The initial insult causes myocyte loss, contractile dysfunction, and triggers compensatory mechanisms 3

Neurohormonal Activation

Reduced cardiac output activates the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, initially compensatory but ultimately maladaptive. 4, 3

• RAAS activation increases angiotensin II and aldosterone, causing vasoconstriction, sodium retention, and myocardial fibrosis 4, 3
• Sympathetic activation increases heart rate, contractility, and peripheral vasoconstriction, but chronically leads to myocyte toxicity and arrhythmias 4
• Natriuretic peptide system is upregulated as a counter-regulatory mechanism but becomes insufficient 4

Ventricular Remodeling

Pathological left ventricular remodeling with progressive chamber dilation and wall thinning is the hallmark of HFrEF progression. 4, 3

• Myocyte changes include hypertrophy, apoptosis, and altered calcium handling 3
• Extracellular matrix remodeling with increased collagen deposition and fibrosis reduces ventricular compliance 5, 3
• Chamber geometry changes with spherical remodeling increase wall stress and reduce contractile efficiency 3
• Even with EF improvement, microscopic abnormalities including cardiomyocyte morphological changes and pathological gene expression persist 5

Hemodynamic Consequences

Reduced contractility leads to decreased stroke volume and cardiac output, elevated filling pressures, and systemic and pulmonary congestion. 1, 3

• Elevated left ventricular end-diastolic pressure transmits backward to pulmonary circulation 1
• Reduced forward flow causes end-organ hypoperfusion, particularly affecting kidneys and skeletal muscle 3
• Increased wall stress perpetuates neurohormonal activation in a vicious cycle 3

Systemic Effects

Peripheral vascular dysfunction with endothelial impairment, skeletal muscle abnormalities, and renal dysfunction contribute to symptom burden beyond cardiac dysfunction alone. 3

• Endothelial dysfunction impairs vasodilation and contributes to exercise intolerance 3
• Skeletal muscle atrophy and metabolic changes reduce functional capacity 3
• Cardiorenal syndrome with progressive kidney dysfunction worsens volume overload 3

Prognostic Considerations

HFrEF carries high morbidity and mortality, worse than many common cancers, with frequent hospitalizations and progressive functional decline. 1

• Low blood pressure in HFrEF indicates worse prognosis, though guideline-directed medical therapy attenuates this association 1
• Progressive reduction in LVEF over time is a poor prognostic factor 1
• The total cost of HF in the US was $30.7 billion in 2012, projected to reach $69.7 billion by 2030 1

Clinical Pitfall

Do not withhold or reduce guideline-directed medical therapy based solely on asymptomatic or mildly symptomatic low blood pressure, as these medications provide mortality benefit even in patients with low BP. 1, 6

• Treatment with GDMT weakens the association between low BP and poor outcomes 1
• Relative benefits of pharmacological therapy remain consistent across baseline BP categories 1