How do systolic (heart failure with reduced ejection fraction) and diastolic (heart failure with preserved ejection fraction) heart failure differ in pathophysiology and management?

Systolic vs. Diastolic Heart Failure: Key Differences

Systolic heart failure (HFrEF, LVEF ≤40%) and diastolic heart failure (HFpEF, LVEF ≥50%) differ fundamentally in their underlying cardiac mechanics, structural changes, and evidence-based treatments—most critically, only HFrEF has proven mortality-reducing therapies. 1

Pathophysiologic Distinctions

Systolic Heart Failure (HFrEF)

• The primary defect is impaired ventricular contraction, resulting in reduced forward cardiac output and compensatory neurohormonal activation (renin-angiotensin-aldosterone system and sympathetic nervous system). 2

• The left ventricle becomes dilated with large end-diastolic volumes (eccentric remodeling, mass/volume ratio ~0.47), reflecting the chamber's inability to eject blood effectively. 1, 3

• Progressive pump failure and malignant arrhythmias are the most frequent causes of death; thromboembolic events (especially stroke) complicate the clinical course. 1

• Coronary artery disease producing ischemic cardiomyopathy is the most common etiology, though non-ischemic dilated cardiomyopathies (genetic or sporadic) produce identical symptoms and outcomes. 1

Diastolic Heart Failure (HFpEF)

• The core problem is impaired ventricular filling caused by diminished early diastolic relaxation or reduced late diastolic compliance, not contractile failure. 2

• The stiff ventricle elevates filling pressures, causing pulmonary congestion and dyspnea despite preserved systolic function (LVEF ≥50%). 2

• Stroke volume and cardiac output remain normal at rest due to compensatory elevation of filling pressures, but become compromised during exercise when the heart cannot augment output. 2

• The left ventricle shows concentric remodeling (mass/volume ratio ~0.68) with increased wall thickness, normal or mildly enlarged chamber size, and left atrial enlargement reflecting chronic elevated pressures. 1, 3

• HFpEF predominantly affects elderly women with hypertension, representing 50% of all heart failure cases, and is strongly associated with diabetes, obesity, and chronic kidney disease. 2, 4

Clinical Presentation Overlap

• Both phenotypes present with identical symptoms—dyspnea on exertion or at rest, fatigue, ankle edema, orthopnea, and early satiety—making clinical differentiation impossible without imaging. 1, 2

• Echocardiography or radionuclide imaging is mandatory to measure ejection fraction and distinguish systolic from diastolic dysfunction; this single measurement determines all subsequent therapy. 1, 2, 4

• Most patients exhibit both systolic and diastolic abnormalities at rest or during stress; the historic systolic/diastolic dichotomy is artificial and should be abandoned in favor of HFrEF/HFpEF terminology. 2

Diagnostic Criteria

HFrEF (LVEF ≤40%)

• Diagnosis requires only LVEF ≤40% plus symptoms or signs of heart failure; no additional criteria are needed. 1

• Elevated natriuretic peptides (BNP or NT-proBNP) confirm the diagnosis and stratify prognosis. 4

HFpEF (LVEF ≥50%)

• Diagnosis is challenging because it requires excluding non-cardiac causes of dyspnea while demonstrating cardiac dysfunction. 1

• Three mandatory criteria must be met: (1) symptoms/signs of heart failure, (2) LVEF ≥50%, and (3) objective evidence of elevated filling pressures via elevated natriuretic peptides, echocardiographic diastolic parameters (E/e′ ≥15), or invasive hemodynamics. 2, 4

• Structural abnormalities such as left atrial enlargement, increased LV mass, or elevated LV filling pressures support the diagnosis. 4

Management Differences

HFrEF: Evidence-Based Four-Pillar Therapy

Guideline-directed medical therapy (GDMT) for HFrEF has proven mortality benefit and must be initiated immediately in all patients with LVEF ≤40%, even if asymptomatic. 4

• Angiotensin receptor-neprilysin inhibitor (ARNI, sacubitril/valsartan) is first-line RAAS inhibition because it provides superior reductions in cardiovascular mortality and heart failure hospitalization compared to ACE inhibitors or ARBs. 2, 4

• If ARNI is unavailable, substitute an ACE inhibitor (enalapril, lisinopril, ramipril); ARBs are reserved for ACE inhibitor-intolerant patients (cough). 2, 4

• Beta-blockers (carvedilol, metoprolol succinate, or bisoprolol) reduce mortality in all HFrEF patients regardless of symptom status; target resting heart rate 50–60 bpm. 2, 4

• Mineralocorticoid receptor antagonists (spironolactone or eplerenone) are indicated when LVEF ≤35% and NYHA class II–IV symptoms, provided eGFR ≥30 mL/min/1.73 m² and potassium ≤5.0 mmol/L. 4

• SGLT2 inhibitors (dapagliflozin 10 mg or empagliflozin 10 mg daily) lower cardiovascular mortality, all-cause mortality, and heart failure hospitalization in all HFrEF patients regardless of diabetes status. 4, 5, 6

• Loop diuretics relieve congestion but do not reduce mortality; titrate to the lowest dose maintaining euvolemia. 4

• Positive inotropic agents may be beneficial given the impaired contractility in systolic heart failure. 2

HFpEF: Symptom-Focused Management

No therapies have consistently demonstrated mortality reduction in HFpEF; management focuses on symptom control, comorbidity optimization, and SGLT2 inhibitors. 2, 4

• Loop diuretics reduce elevated filling pressures and relieve congestion, but must be started at small doses with careful monitoring to prevent hypotension and reduced cardiac output. 2, 4

• Aggressive blood pressure control (target <130/80 mmHg) using ACE inhibitors, ARBs, beta-blockers, or MRAs addresses the underlying hypertensive etiology. 4

• Beta-blockers or calcium channel blockers improve diastolic filling by reducing heart rate, allowing more time for ventricular filling. 2

• SGLT2 inhibitors reduce cardiovascular death and heart failure hospitalizations in HFpEF patients, representing the only therapy with proven benefit. 4

• Positive inotropic agents are not useful in diastolic heart failure since systolic function is normal or near-normal. 2

• Rate control is essential if atrial fibrillation develops, using agents that suppress AV conduction, because loss of atrial contraction eliminates 15–20% of ventricular filling and can precipitate acute decompensation. 2, 7

Prognostic Differences

• HFrEF carries higher annual mortality (~19%) compared to HFpEF (~8%), though both have substantial morbidity and similar hospitalization rates. 2

• Composite event rates (mortality and heart failure hospitalization) do not differ significantly between HFpEF and HFrEF over long-term follow-up (median 1446 days). 3

• Inflammatory and fibrotic plasma markers are similarly elevated in both phenotypes, but markers of cardiomyocyte stretch/damage (BNP, pro-BNP, NT-proBNP, troponin-I) are significantly higher in HFrEF. 3

Critical Pitfalls to Avoid

• Never rely on symptoms alone to distinguish systolic from diastolic heart failure; echocardiography is mandatory because clinical presentation is identical. 1, 2

• Do not delay GDMT initiation in HFrEF awaiting symptom development; asymptomatic patients with LVEF ≤40% benefit equally from neurohormonal blockade. 4

• Avoid aggressive diuresis in HFpEF without careful blood pressure monitoring; excessive preload reduction can precipitate hypotension and reduced cardiac output. 2

• Do not prescribe positive inotropes in HFpEF; they provide no benefit and may worsen outcomes. 2

• Recognize that most patients have mixed systolic and diastolic dysfunction; the EF-based classification guides therapy but does not fully capture pathophysiology. 2