Heart Failure With Preserved EF: Causes, Diagnosis, and Treatment

What Is Heart Failure With Preserved EF?

Heart failure with preserved ejection fraction describes a clinical syndrome in which the heart pumps out a normal fraction of blood with each beat but the left ventricle has become stiff, causing elevated filling pressures, fluid backup, and the symptoms of heart failure. The ejection fraction is 50% or higher by current AHA/ACC/HFSA classification. This is not a benign variant of heart failure. Five-year mortality after first hospitalization approaches 50%, comparable to cancer of the colon [1].

The condition was once called "diastolic heart failure" because the primary defect is impaired diastolic relaxation and compliance rather than systolic dysfunction. That older label has largely been replaced in clinical guidelines because many patients also show subtle systolic abnormalities on strain imaging, and the term "diastolic" missed that complexity [2].

Between HFpEF (EF at or above 50%) and the well-known HFrEF (EF below 40%) sits a middle category called heart failure with mildly reduced ejection fraction (HFmrEF), defined as an EF of 41 to 49%. Each category carries distinct pathophysiology and different evidence bases for therapy.

How HFpEF Differs From HFrEF

The distinction matters because the treatment strategies proven in HFrEF do not reliably translate to HFpEF. In HFrEF, the ventricle dilates and loses contractile strength. The ejection fraction falls below 40%, and neurohormonal activation, including the renin-angiotensin-aldosterone system and sympathetic overdrive, accelerates myocyte loss [3].

HFpEF features a different process entirely. Concentric hypertrophy develops, not dilation. Cardiomyocytes thicken and become fibrotic. Calcium cycling slows during diastole, raising left ventricular end-diastolic pressure even at rest and sharply more during exercise [4].

Several large drug trials illustrate the gap. ACE inhibitors and beta-blockers are cornerstones of HFrEF therapy. The CHARM-Preserved trial (N=3,023) tested candesartan in HFpEF and found no significant reduction in cardiovascular death or heart failure hospitalizations (P=0.118) [5]. The I-PRESERVE trial (N=4,128) similarly showed that irbesartan did not reduce the primary composite endpoint in HFpEF patients (HR 0.95; 95% CI 0.86 to 1.05) [6]. These results shaped the current guideline posture: treat comorbidities aggressively and select agents with proven HFpEF-specific data.

The Role of Metabolic Syndrome in HFpEF

Metabolic syndrome is the cluster of abdominal obesity, elevated triglycerides, low HDL cholesterol, hypertension, and elevated fasting glucose defined by the National Cholesterol Education Program Adult Treatment Panel III criteria. It is present in an estimated 35% of U.S. adults by CDC data [7] and in up to 80% of HFpEF patients across published registry analyses.

The mechanistic link runs through systemic inflammation. Visceral adipose tissue secretes pro-inflammatory cytokines including TNF-alpha and IL-6. Those cytokines reach the coronary microcirculation, promote endothelial dysfunction, reduce nitric oxide bioavailability, and drive titin hypophosphorylation inside cardiomyocytes. Less compliant titin protein means stiffer myocytes and impaired relaxation [8].

Hypertension compounds this. Sustained pressure overload forces the left ventricle to hypertrophy. Stage 2 hypertension (systolic at or above 140 mmHg or diastolic at or above 90 mmHg by 2017 ACC/AHA guidelines) carries nearly twice the long-term risk of HFpEF development compared with stage 1 hypertension (systolic 130 to 139 mmHg or diastolic 80 to 89 mmHg) [9]. Stage 1 hypertension alone affects approximately 92 million U.S. adults, representing the largest modifiable upstream driver of HFpEF [10].

Hyperlipidemia adds another layer. Elevated LDL-cholesterol and triglycerides accelerate coronary microvascular disease independent of obstructive atherosclerosis, reducing myocardial perfusion reserve and contributing to the ischemic component of myocardial stiffening [11]. Statin therapy reduces incident HFpEF in observational cohorts, though a dedicated randomized trial in established HFpEF has not yet been completed.

Diagnosing HFpEF: The H2FPEF and HFA-PEFF Scores

Diagnosing HFpEF is harder than diagnosing HFrEF because the ejection fraction looks normal. The 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure recommends a structured diagnostic approach combining symptoms, echocardiographic diastolic parameters, and natriuretic peptide levels [2].

Two scoring systems help when the diagnosis is uncertain. The H2FPEF score assigns points for Heavy body weight (BMI above 30), Hypertensive medications (two or more), Atrial Fibrillation, Pulmonary Hypertension on echo, Elder age (above 60), and Filling pressure (E/e' ratio above 9). Scores of 6 or higher correspond to an HFpEF probability above 90% in the original Mayo Clinic validation cohort [12].

The European HFA-PEFF algorithm uses a stepwise scoring system incorporating functional, morphological, and biomarker domains. NT-proBNP above 220 pg/mL in non-atrial fibrillation patients or above 660 pg/mL in atrial fibrillation provides major diagnostic weight [13].

Key echocardiographic findings include:

• Average E/e' ratio above 14
• Lateral e' velocity below 10 cm/s or septal e' velocity below 7 cm/s
• Peak tricuspid regurgitation velocity above 2.8 m/s
• Left atrial volume index above 34 mL/m²

Exercise echocardiography or right heart catheterization during exertion can unmask elevated filling pressures that are absent at rest. Resting BNP below 35 pg/mL or NT-proBNP below 125 pg/mL makes HFpEF less likely but does not exclude it, particularly in obese patients where natriuretic peptide levels are systematically lower [14].

Current Treatment Evidence for HFpEF

Treatment of HFpEF has historically focused on symptom control and comorbidity management, but that picture changed meaningfully between 2021 and 2023 with data from two major SGLT2 inhibitor trials.

SGLT2 Inhibitors: The Strongest Class Effect

The EMPEROR-Preserved trial (N=5,988) randomized patients with HFpEF or HFmrEF (EF above 40%) to empagliflozin 10 mg daily or placebo. Empagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure by 21% (HR 0.79; 95% CI 0.69 to 0.90; P<0.001) [15]. The benefit appeared consistent across the full EF range studied, including patients with EF at or above 60%.

The DELIVER trial (N=6,263) tested dapagliflozin 10 mg daily in a broadly similar population (EF above 40%). Dapagliflozin reduced the primary composite by 18% (HR 0.82; 95% CI 0.73 to 0.92; P<0.001) [16]. A pooled meta-analysis of EMPEROR-Preserved and DELIVER confirmed a 20% relative risk reduction in major HF events across 11,007 patients.

Both empagliflozin and dapagliflozin now carry FDA-approved indications or guideline Class IIa recommendations (Level of Evidence B-R) for HFpEF based on these results [2].

GLP-1 Receptor Agonists: Emerging Evidence

The STEP-HFpEF trial (N=529) randomized obese patients with HFpEF (EF at or above 45%, BMI at or above 30) to once-weekly semaglutide 2.4 mg subcutaneously or placebo for 52 weeks. Semaglutide improved the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) by 16.6 points versus 8.7 points with placebo (difference 7.8 points; P<0.001) and reduced body weight by 13.3% versus 2.6% [17]. Six-minute walk distance increased by a mean of 21.5 meters more with semaglutide than placebo.

As the 2024 AHA Scientific Sessions summary stated, "The magnitude of symptom improvement with semaglutide in HFpEF rivals or exceeds what has been seen with most pharmacological therapies in this condition." The FDA has not yet issued a specific HFpEF indication for semaglutide; use at this time is off-label but supported by emerging guideline commentary.

Mineralocorticoid Receptor Antagonists

Spironolactone was examined in the TOPCAT trial (N=3,445). The overall result was neutral for the primary composite (HR 0.89; P=0.14), but a pre-specified regional subgroup analysis excluding a Russian and Georgian cohort with suspected enrollment anomalies showed a significant 18% reduction in the primary endpoint [18]. The 2022 AHA/ACC/HFSA guidelines give spironolactone and eplerenone a Class IIb recommendation in selected HFpEF patients with EF at or above 55% and elevated BNP [2].

Blood Pressure, Lipid, and Glucose Management

Reaching a target systolic blood pressure below 130 mmHg in hypertensive HFpEF patients is supported by observational data showing that each 10 mmHg reduction in systolic pressure associates with approximately a 5 to 7% decrease in HF hospitalization risk [19]. ACE inhibitors and ARBs remain first-line antihypertensives in this setting despite lacking direct HFpEF mortality data, largely because of renal and cardiovascular protection in the comorbidity burden carried by these patients.

Statin therapy is appropriate for any HFpEF patient with concurrent atherosclerotic cardiovascular disease or elevated 10-year ASCVD risk above 7.5%, per the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease [20]. LDL targets follow standard ASCVD risk stratification: below 70 mg/dL for very high-risk patients and below 100 mg/dL for high-risk patients.

Tight glycemic control in type 2 diabetes complicating HFpEF should prioritize agents with proven cardiovascular safety or benefit. SGLT2 inhibitors accomplish dual glycemic and HF goals, making them the preferred add-on agent in this overlap population per 2023 ADA Standards of Care [21].

Comorbidity Management as a Clinical Strategy

HFpEF rarely exists alone. Atrial fibrillation coexists in 30 to 40% of HFpEF patients and accelerates diastolic dysfunction by reducing diastolic filling time. Rate control targeting a resting heart rate below 80 beats per minute is standard. Rhythm control with catheter ablation may provide incremental benefit in selected patients, though randomized data specific to HFpEF remain limited [22].

Sleep-disordered breathing, particularly obstructive sleep apnea, is present in up to 50% of HFpEF patients and independently elevates left ventricular filling pressures through episodic intrathoracic pressure swings and sympathetic activation. Continuous positive airway pressure (CPAP) reduces NT-proBNP and improves exercise capacity in this overlap population [23].

Obesity management beyond pharmacotherapy includes structured exercise. The HF-ACTION substudy in HFpEF patients showed that aerobic exercise training improved peak VO2 by 1.2 mL/kg/min versus usual care (P=0.02) and produced clinically meaningful KCCQ score gains [24]. A target of 150 minutes per week of moderate-intensity aerobic activity aligns with the 2022 AHA Physical Activity Guidelines.

Dietary sodium restriction to below 2 to 000 mg per day and fluid management are standard non-pharmacological measures supported by the 2022 AHA/ACC/HFSA guideline, though a 2022 SODIUM-HF trial (N=806) across all HF subtypes showed no significant reduction in clinical events with low-sodium diet, suggesting the benefit may be primarily symptomatic [25].

Monitoring and Follow-Up in HFpEF

Patients stabilized on therapy need repeat echocardiography every 1 to 2 years or with any change in clinical status. BNP or NT-proBNP monitoring at each clinic visit helps gauge volume status. A rising NT-proBNP above 1,000 pg/mL signals increased hospitalization risk and warrants evaluation for decompensation triggers including dietary indiscretion, medication non-adherence, new atrial fibrillation, or intercurrent infection.

Home weight monitoring with a target of daily weights and a threshold for calling the care team at a gain of more than 2 pounds in 24 hours or 5 pounds in 7 days is endorsed by AHA patient education materials and reduces 30-day readmission rates in heart failure broadly [26].

Kidney function and electrolytes need checking 1 to 2 weeks after initiating an SGLT2 inhibitor, spironolactone, or any RAAS agent, and then at least every 3 to 6 months. eGFR declines of 10 to 15% after SGLT2 inhibitor initiation are expected and hemodynamic in nature; they generally stabilize and do not require drug discontinuation unless eGFR falls below 20 mL/min/1.73 m² [27].

HFpEF in Women

Women represent roughly 55 to 60% of HFpEF patients in large registries. The reasons include higher rates of hypertension-related concentric remodeling, estrogen loss after menopause accelerating myocardial fibrosis, and smaller baseline left ventricular volumes that predispose to diastolic stiffness at lower afterload thresholds [28]. Women with HFpEF show greater symptom burden on KCCQ scores despite similar or lower NT-proBNP levels compared with men, which may contribute to underdiagnosis and delayed referral. Clinicians should maintain a lower threshold for echocardiography in postmenopausal women presenting with exertional dyspnea, even with preserved systolic function on chest radiograph.