Residency · Residency · Internal Medicine
Heart Failure with Reduced vs. Preserved Ejection Fraction
Pathophysiology
HFrEF (EF <= 40%)
Heart failure with reduced ejection fraction is fundamentally a disorder of systolic dysfunction, in which the ventricle loses its ability to contract effectively. The ventricle undergoes eccentric remodeling, dilating with relative wall thinning. This triggers a neurohormonal cascade involving the sympathetic nervous system, the renin-angiotensin-aldosterone system, natriuretic peptides, endothelin, and vasopressin. The most common etiology is ischemic cardiomyopathy, followed by various forms of dilated cardiomyopathy (idiopathic, familial, viral, toxic/alcoholic, peripartum, and tachycardia-mediated) and valvular disease. A maladaptive cycle ensues in which the initial injury drives neurohormonal activation, which in turn causes further myocardial damage.
HFpEF (EF >= 50%)
Heart failure with preserved ejection fraction involves diastolic dysfunction with impaired ventricular relaxation and elevated filling pressures. The ventricle undergoes concentric remodeling, developing increased wall thickness while maintaining or even reducing chamber size. A leading hypothesis is that systemic microvascular inflammation -- driven by comorbidities such as obesity, hypertension, diabetes, and chronic kidney disease -- causes endothelial inflammation that leads to myocardial fibrosis and stiffening. HFpEF is increasingly understood as a heterogeneous syndrome with multiple phenotypes rather than a single disease. HFmrEF (EF 41-49%) occupies an intermediate category and may respond to some HFrEF therapies.
Neurohormonal Cascade
Sympathetic activation increases heart rate, contractility, and vasoconstriction, but chronic stimulation is toxic to the myocardium, causing beta-receptor downregulation and apoptosis. RAAS activation produces angiotensin II (vasoconstriction) and aldosterone (sodium retention and fibrosis). The natriuretic peptide system releases ANP and BNP, which promote vasodilation and natriuresis but are ultimately overwhelmed in heart failure. Arginine vasopressin contributes to water retention and is responsible for the hyponatremia seen in advanced disease.
Clinical Presentation
Symptoms
Left-sided heart failure produces dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, and fatigue. Right-sided failure manifests with peripheral edema, abdominal bloating and early satiety, and right upper quadrant pain from hepatic congestion. The NYHA Functional Classification stratifies severity:
| NYHA Class | Symptom Description | Activity Limitation |
|---|---|---|
| I | No symptoms with ordinary activity | None |
| II | Symptoms with ordinary activity | Slight limitation |
| III | Symptoms with less than ordinary activity | Marked limitation, comfortable only at rest |
| IV | Symptoms at rest | Unable to perform any activity without discomfort |
Physical Examination
Elevated jugular venous pressure is the most specific sign of volume overload. An S3 gallop indicates volume overload and decreased compliance. Pulmonary rales or crackles may be absent in chronic heart failure because lymphatic adaptation occurs over time. Peripheral edema, hepatomegaly, and ascites reflect right-sided congestion. A displaced and diffuse point of maximal impulse suggests a dilated left ventricle. Cool extremities and a narrow pulse pressure point to low cardiac output. Hepatojugular reflux can be elicited at the bedside.
Diagnostic Workup
Biomarkers
A BNP above 100 pg/mL or NT-proBNP above 300 pg/mL supports the diagnosis of acute heart failure. Natriuretic peptides have excellent negative predictive value: BNP below 100 or NT-proBNP below 300 effectively rules out acute heart failure. False negatives can occur in obesity (because adipose tissue clears BNP) and in flash pulmonary edema. Elevated natriuretic peptides are also seen in renal failure, atrial fibrillation, pulmonary embolism, pulmonary hypertension, and advanced age. Serial trending is useful for monitoring but should not be the sole guide to therapy.
Echocardiography
Echocardiography is essential for every new heart failure diagnosis. It assesses ejection fraction, chamber sizes, wall thickness, wall motion abnormalities, valvular function, diastolic parameters, and estimated right ventricular systolic pressure. In HFpEF, key findings include an elevated E/e' ratio (above 14), enlarged left atrium, elevated RVSP, and increased LV wall thickness. Global longitudinal strain (GLS) can detect subclinical systolic dysfunction even when the ejection fraction appears preserved.
Additional Workup
The ECG may reveal arrhythmias (particularly atrial fibrillation), conduction abnormalities (LBBB is relevant for CRT consideration), ischemia, or left ventricular hypertrophy. Baseline labs should include CBC, basic metabolic panel, liver function tests, TSH, iron studies (ferritin and TSAT), lipid panel, and HbA1c. Depending on clinical context, HIV and hepatitis serologies, ANA, serum and urine protein electrophoresis, and genetic testing may be warranted. Cardiac MRI is valuable for assessing myocardial fibrosis (late gadolinium enhancement), infiltrative disease, and iron overload. Right heart catheterization provides definitive hemodynamic assessment, especially before transplant or when the diagnosis is uncertain. Coronary angiography or stress testing evaluates an ischemic etiology. Endomyocardial biopsy is reserved for selected cases such as suspected giant cell myocarditis, amyloidosis, or sarcoidosis. The H2FPEF score and HFA-PEFF algorithm are diagnostic tools for HFpEF when the diagnosis is in question.
Management
HFrEF: The Four Pillars of GDMT
| Pillar | Drug Class | Specific Agents | Target Dose | Key Trial |
|---|---|---|---|---|
| 1 | ARNI / ACEi / ARB | Sacubitril/valsartan | 97/103 mg BID | PARADIGM-HF |
| 2 | Beta-blocker | Carvedilol, metoprolol succinate, bisoprolol | Carvedilol 25 mg BID, metoprolol 200 mg daily, bisoprolol 10 mg daily | MERIT-HF, COPERNICUS |
| 3 | MRA | Spironolactone, eplerenone | Spironolactone 50 mg daily, eplerenone 50 mg daily | RALES, EMPHASIS-HF |
| 4 | SGLT2 inhibitor | Dapagliflozin, empagliflozin | Dapagliflozin 10 mg daily, empagliflozin 10 mg daily | DAPA-HF, EMPEROR-Reduced |
The first pillar is RAAS inhibition with an ACE inhibitor, ARB, or preferably sacubitril/valsartan (ARNI). The PARADIGM-HF trial demonstrated ARNI superiority over enalapril for reducing cardiovascular death and heart failure hospitalization. Clinicians may start with an ACE inhibitor or ARB and switch to ARNI after tolerance is demonstrated (with a 36-hour washout from ACEi), though de novo ARNI initiation is also an option. Potassium and creatinine should be monitored, and a rise in creatinine of up to 30 percent is acceptable.
The second pillar is beta-blockade with one of the three evidence-based agents: carvedilol, metoprolol succinate, or bisoprolol. The dose should start low and be doubled every two weeks as tolerated. Beta-blockers should not be initiated during acute decompensation but should be continued (at a reduced dose if needed) if the patient is already taking one, unless cardiogenic shock is present. Target doses are carvedilol 25 mg twice daily (50 mg twice daily if over 85 kg), metoprolol succinate 200 mg daily, and bisoprolol 10 mg daily.
The third pillar is a mineralocorticoid receptor antagonist -- spironolactone or eplerenone. The RALES and EMPHASIS-HF trials demonstrated mortality reduction in HFrEF. These agents are contraindicated if potassium exceeds 5.0 or eGFR is below 30 (relative contraindication), and potassium should be checked within one week and regularly thereafter.
The fourth pillar is an SGLT2 inhibitor, either dapagliflozin or empagliflozin. The DAPA-HF and EMPEROR-Reduced trials showed reductions in cardiovascular death and heart failure hospitalization regardless of diabetes status. These drugs can be started early, are well tolerated (watch for genital mycotic infections), and are now recommended across the entire ejection fraction spectrum based on the DELIVER trial for HFpEF.
HFrEF: Additional Therapies
Hydralazine combined with isosorbide dinitrate serves as an alternative for patients who cannot tolerate RAAS blockade, or as add-on therapy in Black patients (supported by the A-HeFT trial). Ivabradine is indicated for patients in sinus rhythm with a heart rate of 70 or above despite maximally tolerated beta-blockade (SHIFT trial). Loop diuretics -- furosemide, bumetanide, or torsemide -- are essential for congestion management, though they do not reduce mortality. Digoxin may reduce heart failure hospitalizations (DIG trial) but has a narrow therapeutic window. Intravenous iron (ferric carboxymaltose or iron sucrose) should be given when ferritin is below 100 or ferritin is 100-299 with TSAT below 20 percent, even without anemia (FAIR-HF and AFFIRM-AHF trials). Vericiguat, a soluble guanylate cyclase stimulator, is an option for patients recently hospitalized with worsening heart failure (VICTORIA trial).
Device Therapy
An implantable cardioverter-defibrillator (ICD) is indicated for primary prevention when the ejection fraction remains 35 percent or below despite at least three months of guideline-directed medical therapy, in patients with NYHA Class II-III symptoms and at least one year of life expectancy. Cardiac resynchronization therapy (CRT-D or CRT-P) is indicated when the ejection fraction is 35 percent or below with LBBB and QRS duration of 150 ms or more, in patients with NYHA Class II-IV symptoms on optimal medical therapy. CRT is less beneficial for non-LBBB morphology and QRS 120-149 ms.
HFpEF Management
SGLT2 inhibitors represent the most significant advance, with empagliflozin (EMPEROR-Preserved) and dapagliflozin (DELIVER) both demonstrating benefit. Diuretics manage congestion. Aggressive treatment of underlying comorbidities -- hypertension, obesity, atrial fibrillation, diabetes, sleep apnea, and coronary artery disease -- is central. Exercise training improves functional capacity and quality of life. Spironolactone showed benefit in the Americas subgroup of the TOPCAT trial but not overall, so it is reasonable to consider. ARNI and ACE inhibitors/ARBs have less definitive evidence in HFpEF, though PARAGON-HF showed a trend toward benefit, especially in women and those with lower ejection fractions. GLP-1 receptor agonists are emerging as a treatment for HFpEF with obesity (STEP-HFpEF trial).
Acute Decompensated Heart Failure
Intravenous loop diuretics are the cornerstone, given as bolus or continuous infusion (the DOSE trial showed no clear winner). The initial dose should be equivalent to or greater than the patient's home oral dose. Vasodilators such as nitroglycerin or nitroprusside are used for hypertensive acute heart failure with pulmonary edema. Inotropes (dobutamine, milrinone) are reserved for cardiogenic shock or low-output states; they increase mortality with chronic use. Mechanical circulatory support (IABP, Impella, ECMO) is considered for refractory cardiogenic shock. Ultrafiltration is an option for diuretic resistance, though the CARRESS-HF trial showed no advantage over stepped pharmacologic therapy.
Complications
Cardiorenal syndrome -- worsening renal function in the setting of heart failure -- may require dose adjustment of RAAS blockers, but premature discontinuation should be avoided. Atrial fibrillation is a common comorbidity; rate control with beta-blockers is preferred, and catheter ablation should be considered (CASTLE-AF trial). Ventricular arrhythmias and sudden cardiac death are ongoing risks. Functional mitral regurgitation may improve with guideline-directed therapy; when it persists, MitraClip may be considered (COAPT trial). Pulmonary hypertension (group 2), cardiac cachexia (a poor prognostic marker), and depression (commonly underdiagnosed and associated with worse outcomes) are additional complications to address.
<image> A side-by-side comparison illustration of HFrEF and HFpEF hearts in cross-section. The left panel shows HFrEF with a dilated left ventricle, thin walls, and eccentric hypertrophy. The right panel shows HFpEF with concentric hypertrophy, thickened walls, and a normal or small LV cavity. Include a normal heart in the center for comparison. Label key features: wall thickness, chamber size, myocardial fibrosis pattern (diffuse in HFpEF vs patchy in ischemic HFrEF). Use anatomically accurate coloring with pink-red myocardium and blue/purple fibrosis areas. </image>
<image> An infographic-style diagram showing the "Four Pillars of HFrEF GDMT" as four columns supporting a roof labeled "Improved Survival and Quality of Life." Each pillar should be labeled with the drug class (ARNI/ACEi/ARB, Beta-blocker, MRA, SGLT2i), specific drug names, target doses, and the landmark trial supporting each (PARADIGM-HF, MERIT-HF/COPERNICUS, RALES/EMPHASIS-HF, DAPA-HF/EMPEROR-Reduced). Below the pillars, show additional therapies (hydralazine/nitrate, ivabradine, diuretics, iron) as foundational blocks. Use a clean medical illustration style with blue and white color scheme. </image>
<image> A clinical flowchart for the diagnostic workup of new-onset heart failure. Start with clinical suspicion (symptoms and signs), proceed to BNP/NT-proBNP measurement, then echocardiography branching into HFrEF (EF<=40%), HFmrEF (EF 41-49%), and HFpEF (EF>=50%). For each category, show the key additional workup steps and treatment pathways. Include decision nodes for etiology workup (ischemic evaluation, cardiac MRI, biopsy) and device therapy eligibility (ICD, CRT). Use color coding: red for HFrEF, yellow for HFmrEF, blue for HFpEF. </image>
Clinical Pearls
All four pillars of guideline-directed medical therapy should be initiated simultaneously or in rapid sequence rather than through the traditional approach of titrating one drug at a time -- the current philosophy is "start low, go slow, but start all four." SGLT2 inhibitors can be started regardless of diabetes status and are now recommended across the entire ejection fraction spectrum. A rise in creatinine of up to 30 percent after starting an ACE inhibitor, ARB, or ARNI is expected and acceptable; it should not trigger reflexive discontinuation. Hyponatremia in heart failure reflects neurohormonal activation and poor prognosis, not sodium deficiency -- administering sodium is inappropriate. Beta-blockers should not be initiated during acute decompensation but should be continued (at reduced dose if needed) if the patient is already taking them. Intravenous iron should be administered to symptomatic heart failure patients with iron deficiency even in the absence of anemia, as oral iron is inadequate. HFpEF is likely a heterogeneous syndrome, so clinicians should actively search for specific etiologies (amyloidosis, hypertrophic cardiomyopathy, constrictive pericarditis) that may have targeted treatments. Cardiac amyloidosis should always be considered in patients with HFpEF and LV wall thickness of 14 mm or more, especially in elderly Black men (transthyretin amyloid), because tafamidis is a disease-modifying therapy (ATTR-ACT trial). During acute decompensation, decongestion is the primary goal -- "the only bad diuretic dose is one that is too small."
References
- Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. Circulation. 2022.
- PARADIGM-HF Trial: McMurray JJ, et al. Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure. NEJM. 2014.
- DAPA-HF Trial: McMurray JJ, et al. Dapagliflozin in Heart Failure with Reduced Ejection Fraction. NEJM. 2019.
- EMPEROR-Reduced Trial: Packer M, et al. NEJM. 2020.
- EMPEROR-Preserved Trial: Anker SD, et al. Empagliflozin in Heart Failure with Preserved Ejection Fraction. NEJM. 2021.
- DELIVER Trial: Solomon SD, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. NEJM. 2022.
- RALES Trial: Pitt B, et al. Spironolactone in Severe Heart Failure. NEJM. 1999.
- MERIT-HF: Effect of Metoprolol CR/XL in Chronic Heart Failure. Lancet. 1999.
- ATTR-ACT Trial: Maurer MS, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. NEJM. 2018.
- STEP-HFpEF Trial: Kosiborod MN, et al. Semaglutide in HFpEF and Obesity. NEJM. 2023.
