Hfref , hfpef , hpmpef according to Harrison
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Block 27 is neurology content, not cardiology. I already have the key content from block28. I have enough comprehensive information from Harrison's 22E to provide a detailed answer. Let me now compile the complete response.
HFrEF, HFpEF, and HFmrEF - According to Harrison's Principles of Internal Medicine 22E (2025)
Definitions and LVEF Cutoffs
Harrison's 22E classifies symptomatic chronic HF (ACC/AHA Stage C) based on LVEF measurement:
| Type | Full Name | LVEF |
|---|---|---|
| HFrEF | Heart Failure with Reduced Ejection Fraction | ≤40% |
| HFmrEF | Heart Failure with Mildly Reduced Ejection Fraction | 41-49% |
| HFpEF | Heart Failure with Preserved Ejection Fraction | ≥50% |
HFrEF (LVEF ≤40%)
Evidence Base
HFrEF has the richest evidence from prospective randomized clinical outcome trials. The "Fantastic Four" pillars of therapy are:
- RAAS antagonists - ACEi / ARB / MRA (mineralocorticoid receptor antagonists)
- Neprilysin inhibitors - combined as ARNI (sacubitril-valsartan)
- Beta-adrenergic receptor antagonists (beta-blockers)
- SGLT-2 inhibitors (e.g., dapagliflozin, empagliflozin)
Device Therapy
- Cardiac Resynchronization Therapy (CRT)
- Implantable Cardioverter-Defibrillator (ICD)
HFmrEF (LVEF 41-49%)
Harrison's treats HFmrEF as an intermediate group with evolving evidence:
- Because benefits of RAAS antagonists, ARNIs, and other HFrEF therapies are principally confined to those with LVEF below the normal range (<60%), many guidelines now recommend treating HFmrEF patients with the same therapies as HFrEF.
- The PARAGLIDE-HF trial (sacubitril-valsartan in EF >40%) showed clinical benefits confined to those with EF ≤60%, suggesting ARNI may be most effective in HFmrEF.
- SGLT-2 inhibitors are supported for use in HFmrEF to reduce cardiovascular mortality and HF hospitalizations.
- Harrison's specifically notes: "This has led many to recommend that patients with HFmrEF should be treated with the same therapies as those with HFrEF."
HFpEF (LVEF ≥50%)
General Principles (Harrison's 22E)
HFpEF is a therapeutic challenge. No therapy has conclusively demonstrated a mortality reduction. Management has historically been symptom-focused.
Clinical Trials - What Has Failed in HFpEF
| Drug Class | Trial | Result |
|---|---|---|
| ARB (candesartan) | CHARM-Preserved | Reduced HF hospitalizations, no mortality benefit |
| ARB (irbesartan) | I-PRESERVE | No difference in CV death or HF hospitalization |
| ACEi (perindopril) | PEP-CHF | Early benefit attenuated over longer follow-up |
| Digoxin | DIG Ancillary | No mortality benefit; modest reduction in HF hospitalizations |
| Beta-blockers | SENIORS (nebivolol subgroup) | No significant reduction in mortality |
| MRA (spironolactone) | TOPCAT | No improvement in primary composite endpoint; reduced HF hospitalizations; significant regional variability in results |
| PDE-5 inhibitor (sildenafil) | - | Ineffective |
What Works / Emerging Therapy in HFpEF
SGLT-2 Inhibitors - now the cornerstone of HFpEF-specific pharmacotherapy:
- Supported by clinical trials to reduce cardiovascular mortality and HF hospitalizations in both HFmrEF and HFpEF
ARNI (sacubitril-valsartan):
- PARAGON-HF trial: missed primary endpoint (p = .06), but directional benefit in QOL, NYHA class, renal function
- Benefits principally in women and those with lower (mildly reduced) EF
- Now FDA-approved for the full spectrum of EF, acknowledging greatest benefit at LVEF below normal
GLP-1 agonists (e.g., semaglutide):
- Improve quality of life in obese HFpEF patients, irrespective of diabetes status
Aldosterone antagonists (MRA):
- Variable benefit; may be considered, especially in those with EF <60%
General Therapeutic Principles for HFpEF
Harrison's lists these guiding principles for HFpEF management:
- Reduce the congestive state - use diuretics but avoid excessive preload reduction (can cause azotemia, hypotension, syncope); implantable hemodynamic monitors may guide therapy
- Control blood pressure - aggressive BP control to guideline targets; central aortic BP may be particularly relevant
- Maintain atrial contraction / prevent tachycardia - maintain sinus rhythm in AF; AF ablation may reduce morbidity and mortality
- Treat and prevent myocardial ischemia - ischemia can mimic HF as an "angina equivalent"; evaluate for and treat CAD
- Detect and treat sleep apnea - common comorbidity driving hypertension and pulmonary hypertension (note: adaptive servo-ventilation is ineffective)
- Lifestyle modification - diet, exercise, weight reduction
Comorbidities to Actively Manage in HFpEF
Harrison's emphasizes comprehensive comorbidity management:
- Obesity (GLP-1 agonists)
- Obstructive sleep apnea
- Diabetes / insulin resistance
- Atrial fibrillation
- Anemia / iron deficiency
- Chronic kidney disease
- Obstructive lung disease
Diagnostic Caution
Harrison's stresses that HF with normal/near-normal LVEF is heterogeneous - always rule out:
- Infiltrative disease: amyloidosis, hemochromatosis, sarcoidosis
- Storage disease: Fabry's, Gaucher's
- Hypertrophic cardiomyopathy
- Pericardial disease
- Pulmonary arterial hypertension
- Valvular heart disease
- Primary right ventricular failure
Summary Comparison Table
| Feature | HFrEF | HFmrEF | HFpEF |
|---|---|---|---|
| LVEF | ≤40% | 41-49% | ≥50% |
| Evidence base | Extensive RCTs | Emerging | Limited |
| 4 pillars | ACEi/ARB, MRA, BB, SGLT-2i | Same as HFrEF (recommended) | SGLT-2i (main); ARNI in select |
| Mortality-reducing drugs | Multiple proven | Same as HFrEF | None conclusively proven |
| SGLT-2i | Yes (reduce mortality + hospitalization) | Yes | Yes (hospitalization reduction) |
| ARNI | Sacubitril-valsartan (first-line) | Benefit in EF ≤60% | Modest/uncertain; FDA approved |
| GLP-1 agonists | Not established | Not established | Yes (obese HFpEF patients) |
| Device therapy | CRT, ICD | Limited evidence | Not routinely indicated |
- Harrison's Principles of Internal Medicine 22E (2025), Chapter 265: Heart Failure: Management
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