Heart failure with preserved EF and reduced EF note
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I now have comprehensive information from multiple authoritative textbooks. Let me compile the complete clinical note.
Heart Failure: HFpEF vs. HFrEF - Clinical Reference Note
1. Definitions & Classification
| Parameter | HFrEF | HFmrEF | HFpEF |
|---|---|---|---|
| LVEF | ≤40% | 41-49% | ≥50% |
| Also called | Systolic HF | Mid-range EF | Diastolic HF |
| ACC/AHA Stage | C or D | C | C |
The older terms "systolic" and "diastolic" heart failure are now discouraged. Most patients have both systolic and diastolic components; EF-based classification is preferred. - Goldman-Cecil Medicine, p. 472
2. Epidemiology
- HFpEF accounts for >50% of all HF cases in older adults, with a substantially higher prevalence in women.
- HFrEF is more prevalent in men and is often caused by ischemic cardiomyopathy.
- Prognosis: HFpEF has somewhat better mortality than HFrEF, but symptoms, quality of life (QOL), and hospitalization rates are similar between the two. - Braunwald's Heart Disease, p. 1035
- A 2026 systematic review and meta-analysis (PMID: 41711724) confirmed that HFpEF carries lower mortality risk than HFrEF but comparable HF hospitalization burden.
3. Pathophysiology
HFrEF
- Myocardial dysfunction limits cardiac output or requires elevated filling pressures to maintain it.
- Neurohormonal activation is central: the sympathetic nervous system and RAAS are activated early, initially compensatory but causing maladaptive remodeling over time.
- Chronically elevated norepinephrine downregulates beta-adrenergic receptors and is directly cardiotoxic.
- RAAS activation causes vasoconstriction and sodium retention via renal hypoperfusion, beta-adrenergic stimulation, and hyponatremia.
- Natriuretic peptides (BNP/NT-proBNP) counterbalance by causing vasodilation, natriuresis, and diuresis - their elevation marks disease severity.
- Endothelin causes prolonged vasoconstriction and pulmonary arteriolar constriction.
- Arginine vasopressin causes vasoconstriction (V1) and reduces free water clearance (V2).
- Cardiorenal interactions: passive venous congestion and reduced forward flow impair renal function, perpetuating sodium and water retention.
- Prototypical ventricular remodeling: dilation, sphericalization, increased wall stress, interstitial fibrosis.
- Goldman-Cecil Medicine, p. 471
HFpEF
The pathophysiology is multifactorial and now understood as a systemic inflammatory illness rather than isolated diastolic dysfunction:
- Diastolic dysfunction - increased ventricular stiffness from LVH and interstitial fibrosis; abnormal calcium cycling impairing myocardial relaxation (energy-dependent process).
- Elevated filling pressures - raised pulmonary capillary wedge pressure causing dyspnea; disproportionately worse with tachycardia and exercise.
- Microvascular endothelial inflammation - comorbidities (hypertension, diabetes, obesity) drive systemic inflammation impairing nitric oxide (NO) signaling, leading to myocardial stiffening via reduced protein kinase G (PKG) activity.
- Narrow fluid window - modest volume overload dramatically worsens symptoms; over-diuresis risks hypotension from ventricular underfilling.
- Atrial fibrillation is especially damaging: atrial contraction contributes disproportionately to filling in a noncompliant ventricle.
- Additional contributors: abnormal sodium handling, autonomic dysfunction, arterial stiffness, pulmonary hypertension, sarcopenia, obesity, deconditioning.
- Goldman-Cecil Medicine, p. 472; Harrison's 22E, p. 2031
Key difference: HFrEF = pump failure (systolic) with neurohormonal activation as target. HFpEF = stiffness/relaxation failure with multimorbidity/inflammation as target.
4. Risk Factors & Common Etiologies
| Feature | HFrEF | HFpEF |
|---|---|---|
| Primary drivers | CAD/MI, dilated CMP, viral myocarditis, tachycardia-mediated | Hypertension (60-80%), aging, obesity |
| Demographics | More common in men | More common in older women |
| Comorbidities | AF, CKD, CAD | HTN, DM, AF, CKD, OSA, obesity |
| Genetic causes | Familial cardiomyopathy (cytoskeletal/nuclear mutations) | TTR amyloidosis (esp. elderly men) |
Special note - Cardiac Amyloidosis in HFpEF: Transthyretin amyloid cardiomyopathy (ATTR) is an increasingly recognized cause. Wild-type ATTR (ATTRwt) causes 10-15% of HFpEF in older adults (>80% male). Hereditary ATTR has the Val122Ile variant in ~3-4% of African Americans. Clues: peripheral neuropathy, carpal tunnel syndrome, lumbar spinal stenosis, low QRS voltage on ECG. - Braunwald's Heart Disease, p. 1035
5. Clinical Features
Both share the classic triad:
- Dyspnea (exertional, orthopnea, PND)
- Fatigue and exercise intolerance
- Fluid retention (edema, weight gain, elevated JVP, S3 gallop in HFrEF)
Distinguishing clues on exam:
- HFrEF: displaced PMI, S3 gallop, cardiomegaly on CXR, dilated LV on echo.
- HFpEF: normal or near-normal LV size on echo, often LVH, normal or hyperdynamic EF, Doppler evidence of diastolic dysfunction.
6. Diagnosis
| Test | HFrEF findings | HFpEF findings |
|---|---|---|
| Echo | LVEF ≤40%, dilated LV | LVEF ≥50%, LVH, abnormal E/e' ratio (diastolic dysfunction) |
| BNP/NT-proBNP | Elevated | Elevated (may be lower than in HFrEF; obesity blunts levels) |
| ECG | May show prior MI, LBBB | LVH pattern, AF; low voltage if amyloid |
| CXR | Cardiomegaly, pulmonary edema | May show pulmonary congestion with normal cardiac size |
| LV strain (echo) | Reduced | May be abnormal even in HFpEF (more sensitive than EF) |
HFpEF diagnosis: based on echocardiographic criteria - normal LVEF + impaired diastolic relaxation + elevated filling pressures (elevated E/e', dilated left atrium, elevated PASP). - Washington Manual, p. 195
7. Treatment
7A. HFrEF - The "Fantastic Four" (Guideline-Directed Medical Therapy)
All four drug classes reduce mortality and morbidity. They should be initiated and up-titrated as early as tolerated:
| Drug Class | Key Agents | Mechanism | Key Evidence |
|---|---|---|---|
| ARNI (preferred over ACEi) | Sacubitril-valsartan (Entresto) | Blocks RAAS + neprilysin (raises natriuretic peptides) | PARADIGM-HF: reduced CV mortality and HF hospitalization vs. enalapril |
| ACEi / ARB (if ARNI not tolerated) | Enalapril, ramipril / Losartan, valsartan | RAAS blockade | Foundational mortality benefit |
| Beta-blocker | Carvedilol, metoprolol succinate, bisoprolol | Blunts adrenergic toxicity, reverse remodeling | Reduces all-cause mortality |
| MRA (mineralocorticoid receptor antagonist) | Spironolactone, eplerenone | Blocks aldosterone; reduces fibrosis | RALES, EMPHASIS-HF |
| SGLT-2 inhibitor | Dapagliflozin 10 mg, empagliflozin 10 mg (once daily) | Natriuresis/osmotic diuresis, pleiotropic cardiac effects | DAPA-HF, EMPEROR-REDUCED: reduced CV death + HF hospitalization regardless of diabetes |
SGLT-2 inhibitors: reduce LV size, improve EF, reduce symptoms, hospitalizations, and prolong survival in both diabetic and non-diabetic patients with HFrEF. They also mitigate MRA-induced hyperkalemia. Only contraindications: T1DM, history of DKA, eGFR <20 mL/min/1.73m². No dose titration required. - Goldman-Cecil Medicine, p. 483
Diuretics (loop > thiazide): not disease-modifying but essential for symptom control and decongestion. Furosemide is first-line. Loop + thiazide combination (e.g., furosemide + metolazone) for diuretic resistance in stage D. Monitor electrolytes.
Second-line / selected patients:
- Ivabradine: for sinus rhythm with HR ≥70 bpm despite max beta-blocker (reduces hospitalizations)
- Hydralazine + isosorbide dinitrate: for patients who cannot tolerate RAAS inhibitors (especially Black patients in whom this combination showed added benefit in A-HeFT)
- Digoxin: rate control in AF; modest reduction in HF hospitalizations
- Vericiguat (soluble guanylate cyclase stimulator): for worsening HF despite GDMT
Device therapy:
- ICD: LVEF ≤35%, NYHA II-III, on optimal GDMT ≥3 months, expected survival >1 year
- CRT (cardiac resynchronization therapy): LVEF ≤35% + LBBB + QRS ≥150 ms
7B. HFpEF - Management
No pharmacologic therapy has been shown to reduce mortality in HFpEF. Treatments reducing the combined endpoint of CV death + HF hospitalization: ARNI, MRA, and SGLT-2 inhibitors. - Washington Manual, p. 195
| Treatment | Evidence | Notes |
|---|---|---|
| SGLT-2 inhibitors (dapagliflozin, empagliflozin 10 mg daily) | DELIVER (dapagliflozin) and EMPEROR-PRESERVED (empagliflozin): both reduced CV death/HF hospitalization in LVEF >40%. Now foundational therapy regardless of EF. | First class with consistent benefit; also improve symptoms and QOL |
| Blood pressure control | Essential | Target guideline-recommended BP; treats underlying HTN-driven LVH/fibrosis |
| Diuretics | Symptom control only | Judicious use - avoid overdiuresis (narrow fluid window) |
| MRA (spironolactone) | TOPCAT trial: no significant reduction in primary composite endpoint; did reduce HF hospitalizations by 17%. Americas subgroup showed 18% primary outcome reduction (concerns about Russian/Georgian site conduct). Weak guideline recommendation. | FINEARTS-HF (finerenone) results pending |
| ARNI (sacubitril-valsartan) | PARAGON-HF (n=4822): 13% reduction in CV death + HF hospitalizations - narrowly non-significant (P=0.06). Benefit concentrated in women and LVEF <57% (below-median subgroup). | Consider in HFmrEF and low-normal EF HFpEF |
| Heart rate control / AF management | Sinus rhythm or rate control with beta-blocker or rate-limiting CCB | Restoration of sinus rhythm improves filling; avoid excessive rate control |
| Exercise / cardiac rehab | Small studies show improved functional capacity and QOL | Aerobic exercise improves exercise tolerance in older adults |
| Weight loss | Caloric restriction + STEP-HFpEF trial (semaglutide): improved exercise capacity, symptoms, and QOL in obese HFpEF | GLP-1 agonists (semaglutide) emerging as therapy for obese HFpEF |
| Ischemia treatment | Treat underlying CAD |
What does NOT work in HFpEF:
- Sildenafil (RELAX trial): no benefit
- Isosorbide mononitrate (NEAT-HFpEF): worsened activity levels
- Inorganic nitrate (INDIE-HFpEF): no benefit
- Ivabradine: no benefit on exercise capacity
- Adaptive servo-ventilation: increases mortality in HF + central sleep apnea
7C. HFmrEF (EF 41-49%)
Treat like HFrEF. SGLT-2 inhibitors are foundational. Retrospective analyses suggest ARNI, ACEi/ARB, beta-blocker, and MRA also benefit this group. - Goldman-Cecil Medicine, p. 483
8. Drugs to Avoid in Heart Failure
- Antiarrhythmics: most (except amiodarone and dofetilide)
- Calcium channel blockers: most (amlodipine may be cautiously used, but may increase pulmonary edema risk)
- NSAIDs / COX-2 inhibitors: sodium retention, worsen renal function
- Thiazolidinediones (e.g., pioglitazone): fluid retention
- Saxagliptin: increased HF hospitalizations
- Corticosteroids: sodium/fluid retention
- Dronedarone: increased mortality in severe HF
- Pramipexole: may increase HF risk
- Alpha-blockers (e.g., tamsulosin): hypotension and fluid retention
- Goldman-Cecil Medicine, p. 484
9. Side-by-Side Summary
| Feature | HFrEF (EF ≤40%) | HFpEF (EF ≥50%) |
|---|---|---|
| Pathophysiology | Systolic dysfunction, neurohormonal activation, remodeling | Diastolic dysfunction, stiffness, microvascular inflammation |
| Primary etiology | CAD, dilated CMP | Hypertension, aging, obesity |
| Demographics | More in men | More in older women |
| BNP | Markedly elevated | Elevated (may be blunted in obesity) |
| Echo hallmark | Dilated, hypokinetic LV, EF ≤40% | Concentric LVH, normal/small LV cavity, abnormal E/e' |
| Mortality-reducing Rx | ARNI/ACEi/ARB + BB + MRA + SGLT2i + ICD/CRT | None proven; SGLT2i reduce CV death/HF hospitalization |
| Key drug class | "Fantastic Four" (ARNI, BB, MRA, SGLT2i) | SGLT-2 inhibitors + BP/AF control + diuretics |
| SGLT2i evidence | DAPA-HF, EMPEROR-REDUCED | DELIVER, EMPEROR-PRESERVED |
| Avoid | NSAIDs, most CCBs, dronedarone | Same; also avoid over-diuresis |
Sources: Braunwald's Heart Disease (p. 1035), Goldman-Cecil Medicine (pp. 471-492), Harrison's Principles of Internal Medicine 22E (pp. 2031-2032), Washington Manual of Medical Therapeutics (p. 195), Goodman & Gilman's Pharmacological Basis of Therapeutics. Recent literature: PMID 41711724 (2026 meta-analysis on HFpEF vs HFrEF outcomes); PMID 39232490 (2024 Lancet meta-analysis on MRA in HF).
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