HFrEF and HFpEF difference
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"heart failure" AND "HFrEF" AND "HFpEF" AND differences
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Here is a comprehensive comparison of HFrEF vs HFpEF based on Goldman-Cecil Medicine, Braunwald's Heart Disease, and Harrison's Principles of Internal Medicine (22nd ed, 2025):
HFrEF vs HFpEF: Key Differences
1. Definition & EF Cutoffs
| Feature | HFrEF | HFpEF | HFmrEF (borderline) |
|---|---|---|---|
| LVEF | <40% | ≥50% | 41-49% |
| Former name | Systolic HF | Diastolic HF | Borderline / Mid-range EF |
2. Pathophysiology
HFrEF - Goldman-Cecil Medicine, p. 466:
- The core problem is impaired contractility: maladaptive neurohormonal activation (SNS + RAAS) drives prototypical ventricular remodeling - chamber dilation, wall thinning, increased sphericity
- Abnormal calcium cycling: reduced SR calcium content via altered ryanodine receptors + loss of SERCA2a function impairs both contraction and relaxation
- Elevated catecholamines downregulate beta-adrenergic receptors and are directly cardiotoxic
- Replacement fibrosis, TNF-alpha, IL-1beta, IL-6 drive myocyte necrosis and further systolic impairment
- RAAS activation causes vasoconstriction and sodium retention, worsening remodeling over time
HFpEF - Goldman-Cecil Medicine, p. 467:
- The core problem is impaired relaxation (diastole): increased ventricular stiffness from LV hypertrophy + interstitial fibrosis + abnormal calcium cycling
- Most patients have prior/current hypertension - resulting LVH and fibrosis cause rigid chamber walls that cannot fill normally
- Ischemic heart disease contributes via subendocardial fibrosis
- Aging is a major predisposing factor: myocyte apoptosis, shifts to more rigid collagen types, loss of vascular compliance
- Myocardial relaxation is energy-dependent; any process compromising energy metabolism (ischemia) worsens diastolic filling
3. Epidemiology & Demographics
| Feature | HFrEF | HFpEF |
|---|---|---|
| Sex | More common in men | More common in women |
| Age | Younger patients | Older patients |
| Prevalence trend | Declining relative proportion | Increasing - now ~50% of all HF |
| Primary driver | CAD, prior MI | Hypertension, aging, obesity, diabetes |
From Braunwald's Heart Disease, community-based US studies show ~50% of hospitalized HF patients have LVEF >50%, and the proportion with preserved EF increased from 33% (2005) to 39% (2010), with projections to 65% by 2020, making HFpEF the predominant form in aging societies.
4. Common Causes/Etiologies
| HFrEF | HFpEF |
|---|---|
| Coronary artery disease / prior MI (most common in industrialized countries) | Systemic hypertension with LVH |
| Dilated cardiomyopathy (idiopathic, genetic) | Hypertrophic cardiomyopathy |
| Toxic (alcohol, chemotherapy - e.g., trastuzumab) | Infiltrative disease (amyloidosis, sarcoidosis) |
| Myocarditis | Ischemic heart disease (subendocardial fibrosis) |
| Tachycardia-induced cardiomyopathy (potentially reversible) | Restrictive cardiomyopathy |
| Chagas disease (Central/South America) | Aging-related fibrosis |
5. Clinical Features
Both share the same symptoms (dyspnea, orthopnea, PND, fatigue, edema), but differ in some key signs:
- HFrEF: S3 gallop, laterally displaced PMI (dilated ventricle), more prominent jugular venous distension
- HFpEF: S4 gallop (stiff ventricle), normal or small LV cavity on echo, more sensitive to volume loading/depletion - modest volume overload greatly worsens symptoms; diuresis can cause hypotension
HFpEF patients often present with multiple comorbidities: obesity, diabetes, atrial fibrillation, obstructive sleep apnea, CKD.
6. Biomarkers
Both elevate BNP/NT-proBNP, but levels tend to be lower in HFpEF (especially in obese patients, where BNP is suppressed by adipose tissue). Natriuretic peptides counterbalance vasoconstriction/sodium retention in both - Goldman-Cecil Medicine, p. 466.
7. Treatment - The Critical Difference
This is where HFrEF and HFpEF differ most dramatically:
HFrEF: Multiple disease-modifying therapies proven to reduce mortality (Goldman-Cecil Medicine, Braunwald's):
- RAAS blockade: ACE inhibitors or ARBs; or preferably ARNI (sacubitril/valsartan)
- Beta-blockers: carvedilol, metoprolol succinate, bisoprolol
- Mineralocorticoid receptor antagonists (MRA): spironolactone, eplerenone
- SGLT2 inhibitors: dapagliflozin, empagliflozin (also reduce hospitalization + mortality)
- Diuretics: for fluid control (symptom relief but no mortality benefit)
- Digoxin: reduces hospitalizations in sinus rhythm
- Device therapy: ICD (sudden death prevention), CRT (for LBBB/wide QRS)
- Long-chain omega-3 PUFAs: modestly improved outcomes (GISSI-HF trial)
HFpEF: No therapy has conclusively shown mortality benefit (Harrison's 22E, p. 2031):
- Attempts to export HFrEF drugs (ACE inhibitors, ARBs, beta-blockers, digoxin) to HFpEF have generally failed to reduce mortality
- SGLT2 inhibitors (dapagliflozin, empagliflozin 10 mg/day) are the current primary pharmacologic therapy - reduce HF hospitalizations and improve quality of life; also effective in HFmrEF
- MRA (spironolactone): TOPCAT trial showed no improvement in primary composite endpoint but did reduce HF hospitalizations; benefit was principally in those with LVEF closer to 50%
- ARBs (candesartan, irbesartan): CHARM-Preserved showed reduced HF hospitalizations but no mortality benefit; I-PRESERVE showed no benefit
- ARNI (sacubitril/valsartan): possible benefit especially at lower EF ranges (PARAGON-HF)
- GLP-1 agonists: emerging evidence in obese HFpEF patients (e.g., semaglutide - STEP-HFpEF)
- Diuretics: for symptom control
- Treat underlying causes: hypertension, atrial fibrillation (rate/rhythm control), obesity, sleep apnea, diabetes, myocardial ischemia
- Ivabradine and isosorbide mononitrate have no benefit in HFpEF; isosorbide mononitrate actually worsens activity levels
8. Quick Summary Table
| Feature | HFrEF | HFpEF |
|---|---|---|
| EF | <40% | ≥50% |
| Primary dysfunction | Systolic (impaired contraction) | Diastolic (impaired relaxation/filling) |
| Ventricle morphology | Dilated, thin-walled | Concentric hypertrophy, small cavity |
| Dominant sex | Male | Female |
| Main etiology | CAD, dilated CMP | Hypertension, aging, obesity |
| Neurohormonal activation | Prominent RAAS + SNS | Less prominent, more metabolic/inflammatory |
| Mortality-reducing drugs | Multiple (ACEi/ARB/ARNI, BB, MRA, SGLT2i) | None proven; SGLT2i reduce hospitalizations |
| BNP | High (often very high) | Elevated but typically lower |
| Prognosis | Poor; 50% 5-year mortality | Similar or slightly worse long-term due to comorbidities |
Sources: Goldman-Cecil Medicine International Edition (pp. 465-470); Braunwald's Heart Disease, 2-Vol Set (Ch. 51); Harrison's Principles of Internal Medicine 22E (2025), Ch. 28.
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