Introduction
Heart failure (HF) is not a single disease but a complex clinical syndrome resulting from impaired cardiac structure or function. It is one of the leading causes of hospitalization and mortality worldwide, particularly among older adults. Traditionally, heart failure was seen as a condition of poor pump function, where the heart could not eject blood efficiently. However, research over the last three decades has revealed a more nuanced reality.
Patients with similar symptoms of fatigue, shortness of breath, and exercise intolerance may have different underlying pathophysiologies, particularly when comparing heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). These two entities not only differ in mechanisms but also in their response to therapy, prognosis, and demographic profiles.
This article explores the pathophysiological differences between HFrEF and HFpEF in depth—covering cellular, molecular, and systemic aspects—while highlighting why these distinctions matter for clinical management.
What is Ejection Fraction?
Ejection fraction (EF) is a measure of the percentage of blood the left ventricle pumps out with each contraction.
- Normal EF: 50–70%
- HFrEF: EF < 40% (reduced)
- HFpEF: EF ≥ 50% (preserved)
- HFmrEF (mid-range): EF 40–49%, representing an intermediate category
Thus, HF is not defined solely by EF, but EF provides a useful framework for categorization.
Epidemiology and Demographics
- HFrEF: More common in men, often due to ischemic heart disease or myocardial infarction.
- HFpEF: More common in elderly women, often associated with hypertension, obesity, diabetes, and atrial fibrillation.
Despite these differences, HFpEF now accounts for over 50% of all HF cases, making it a major public health burden.
Pathophysiology of HFrEF
1. Primary Problem: Systolic Dysfunction
In HFrEF, the main defect lies in the inability of the ventricle to contract effectively, leading to reduced stroke volume and ejection fraction.
2. Myocyte Injury and Death
- Myocardial infarction or chronic ischemia damages cardiomyocytes.
- Loss of viable contractile units reduces overall pump function.
3. Ventricular Remodeling
- The left ventricle dilates to maintain stroke volume (Law of Laplace).
- Remodeling results in spherical geometry, wall thinning, and worsening systolic dysfunction.
4. Molecular and Cellular Mechanisms
- Neurohormonal activation: Chronic activation of RAAS and SNS → fibrosis, apoptosis, hypertrophy.
- Calcium handling abnormalities: Impaired calcium reuptake into sarcoplasmic reticulum → poor contractility.
- Energy deficit: Mitochondrial dysfunction limits ATP supply.
5. Hemodynamic Profile
- Reduced cardiac output, especially during exertion.
- Elevated filling pressures secondary to volume overload.
Pathophysiology of HFpEF
1. Primary Problem: Diastolic Dysfunction
In HFpEF, the ejection fraction is preserved, but the ventricle has impaired relaxation and increased stiffness, leading to elevated filling pressures despite normal contractile function.
2. Myocardial Structural Changes
- Concentric hypertrophy due to chronic pressure overload (e.g., hypertension).
- Increased collagen deposition and fibrosis, reducing compliance.
3. Cellular and Molecular Mechanisms
- Endothelial dysfunction: Reduced nitric oxide bioavailability impairs vasodilation and relaxation.
- Inflammation: Comorbidities (obesity, diabetes) promote systemic inflammation, infiltrating the myocardium.
- Titin modification: Abnormal phosphorylation of titin (a sarcomeric protein) increases stiffness.
- Microvascular rarefaction: Loss of coronary microvessels reduces perfusion reserve.
4. Hemodynamic Profile
- Elevated left ventricular end-diastolic pressure (LVEDP).
- Pulmonary venous congestion despite preserved EF.
- Exercise intolerance due to poor diastolic reserve.
Comparative Pathophysiology: HFrEF vs. HFpEF
| Feature | HFrEF (Reduced EF) | HFpEF (Preserved EF) |
|---|---|---|
| Primary defect | Systolic dysfunction (poor contraction) | Diastolic dysfunction (impaired relaxation, stiffness) |
| Ventricular geometry | Dilated, thin-walled LV | Concentric hypertrophy, thick-walled LV |
| EF | <40% | ≥50% |
| Cardiac output | Reduced at rest and exertion | Often preserved at rest, reduced with exertion |
| Neurohormonal role | Major driver of progression | Less central, but inflammation important |
| Common causes | MI, CAD, myocarditis, dilated cardiomyopathy | Hypertension, obesity, diabetes, aging |
| Molecular abnormalities | Loss of myocytes, abnormal calcium handling, RAAS/SNS overdrive | Endothelial dysfunction, titin stiffness, inflammation |
| Response to therapy | Good response to RAAS and SNS blockade | Limited proven therapies; lifestyle and comorbidity control essential |
Hemodynamic Differences
- HFrEF: Decreased stroke volume → compensatory rise in end-diastolic volume. Frank-Starling mechanism initially helps but eventually fails, leading to pulmonary congestion and systemic hypoperfusion.
- HFpEF: Stiff ventricle → normal stroke volume but elevated LV filling pressure, particularly during exercise → exertional dyspnea is prominent.
Neurohormonal Activation: Similarities and Differences
Both HFrEF and HFpEF involve activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS).
- In HFrEF, neurohormonal activation is a primary driver of progression, leading to fibrosis, apoptosis, and worsening remodeling.
- In HFpEF, neurohormonal activation is present but not the sole driver. Instead, systemic inflammation, endothelial dysfunction, and comorbidity-related stress are more critical.
Systemic Differences
HFrEF
- More related to ischemic injury and loss of functional myocardium.
- Systemic vascular resistance may be reduced due to vasodilation.
HFpEF
- More related to systemic comorbidities: obesity, diabetes, chronic kidney disease.
- Peripheral vascular stiffness and systemic inflammation play larger roles.
Clinical Manifestations
Both types present with:
- Dyspnea, orthopnea, paroxysmal nocturnal dyspnea
- Fatigue, exercise intolerance
- Peripheral edema
However, nuances exist:
- HFrEF: Often history of MI, more overt volume overload, higher BNP levels.
- HFpEF: Frequently elderly hypertensive women, more atrial fibrillation, preserved BNP but still symptomatic.
Diagnostic Tools
Echocardiography
- HFrEF: Dilated LV, reduced EF, global hypokinesis.
- HFpEF: Normal EF, concentric hypertrophy, abnormal diastolic filling patterns (E/e’ ratio ↑).
Biomarkers
- BNP/NT-proBNP elevated in both but relatively lower in HFpEF for similar symptom burden.
Hemodynamic Testing
- HFrEF: Low cardiac index at rest.
- HFpEF: Normal at rest, abnormal rise in filling pressures with exercise.
Therapeutic Differences
HFrEF
- Clear evidence-based therapies:
- ACE inhibitors/ARBs/ARNIs
- Beta-blockers
- Mineralocorticoid receptor antagonists
- SGLT2 inhibitors
- Device therapies (CRT, ICD)
HFpEF
- Limited proven therapies:
- SGLT2 inhibitors recently shown to improve outcomes.
- Diuretics for symptom relief.
- Control of comorbidities (HTN, AF, obesity, DM).
- Lifestyle interventions (exercise, weight loss).
Prognostic Differences
- Both types carry high morbidity and mortality.
- Historically, HFrEF had worse prognosis, but with modern therapies, survival has improved significantly.
- HFpEF remains challenging, with persistent high rates of hospitalization and limited targeted treatments.
Emerging Insights
1. Inflammation and Comorbidities
HFpEF is increasingly viewed as a systemic inflammatory syndrome driven by comorbidities, whereas HFrEF is primarily a cardiac disease.
2. Phenotyping
HFpEF is heterogeneous; some subtypes may respond to therapies differently (e.g., obese HFpEF vs. hypertensive HFpEF).
3. Precision Medicine
Ongoing research is exploring biomarkers and genetic signatures to personalize treatment for both HFrEF and HFpEF.
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