Heart Failure with Supranormal Ejection Fraction: A Female-Predominant Syndrome

Microvascular dysfunction and sympathetic activation

The pathophysiology of HFsnEF involves complex interactions between microvascular dysfunction, sympathetic activation, and gender-specific cardiac adaptations [Figure 2]. A central feature is significant microvascular dysfunction, particularly prevalent in women, characterized by reduced coronary flow reserve and impaired myocardial perfusion despite enhanced systolic function.^[20-22] This dysfunction often occurs in conjunction with sympathetic hyperactivity, which contributes to enhanced contractility but may lead to long-term myocardial dysfunction.^[2,23,24]

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Figure 2:

Pathophysiological mechanisms leading to heart failure with supranormal ejection fraction.

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Gender-specific cardiac adaptations

Women exhibit unique cardiac adaptations that predispose them to developing snLVEF. These include distinct patterns of ventricular remodeling with a tendency toward concentric geometry, enhanced contractile function, and modified calcium handling mechanisms.^[17] Women tend to have smaller end-systolic volume than men.^[17] Small hearts operating in “hyperdynamic mode” (very high EF) require more oxygen to pump sufficient blood which increases oxygen demand.^[17]

Hormonal influences play a crucial role in these adaptations, affecting both cardiac structure and function, especially in post-menopausal women. The loss of estrogen after menopause might contribute to multiple cardiovascular (CV) changes that predispose women to this condition.^[25] Estrogen typically helps regulate blood vessel function and sympathetic nerve activity, and its deficiency leads to increased vascular stiffness and enhanced sympathetic tone.^[25] Human studies have reported that women on Estrogen Replacement Therapy have lower blood pressure,^[26,27] decreased heart rate (HR),^[27] increased baroreceptor sensitivity,^[26,28] and elevated HR variability.^[28] Postmenopausal women experience a 40% increase in sympathetic nervous system activity compared to premenopausal women, contributing to the hyperdynamic cardiac state characteristic of HFsnEF.^[25] In addition, estrogen deficiency is associated with endothelial dysfunction and reduced nitric oxide availability, further compromising microvascular function.^[25]

Body composition plays a significant role in sex differences. After menopause, women tend to develop more central obesity, which is associated with depressed left ventricular (LV) systolic and diastolic function.^[29,30] Interestingly, higher body mass index (BMI) associates with higher LVEF, while higher waist circumference and waist–hip ratio correlate with lower global longitudinal strain.^[30] Central obesity is associated with increased inflammatory markers, insulin resistance, and activation of the renin-angiotensinaldosterone system, all of which contribute to cardiac dysfunction.^[31] In addition, women with HF generally have lower BMI and are more likely to experience frailty and sarcopenia (muscle loss), which can impact their quality of life and clinical outcomes.^[31] Notably, diastolic dysfunction (E/e’ ratio) correlates negatively with psoas muscle mass specifically in women but not men.^[32] The combination of smaller heart volumes, higher baseline sympathetic activity, hormonal changes, and altered body composition in postmenopausal women creates a physiological environment that may contribute to the development of HFsnEF.

Genetic underpinnings

Recent genetic analyses have provided important insights into the hereditary aspects of snLVEF. A genome-wide association study identified 16 independent genetic variants associated with snLVEF, which collectively form a genetic risk score predictive of mortality. This genetic predisposition suggests that snLVEF represents a distinct genetic phenotype rather than simply an extreme of normal variation [Figure 3].^[3] Individuals in the top 10% of genetic risk showed an 11% higher risk of death compared to those in the bottom 10%.^[3] A single-nucleotide polymorphism-based heritability of 30% implicating variants in genes for cardiac hypertrophy has also been demonstrated.^[1,3]

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Figure 3:

Correlation between genetic risk and mortality. (LVEF: Left ventricular ejection fraction.

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Altered cardiac mechanics

The mechanical aspects of cardiac function in HFsnEF patients show important alterations. Studies have revealed increased end-systolic elastance, modified ventricular-arterial coupling, and changes in both longitudinal and circumferential strain patterns.^[33] The relationship between LV stroke volume and incident HF suggests that these mechanical changes play a crucial role in disease progression.^[34] Research from the Strong Heart Study has shown that reduced stroke volume index, even in the presence of preserved EF, strongly predicts HF incidence.^[34]

Comparative outcomes analysis

Comparison with traditional HFpEF and HF with reduced EF (HFrEF) populations reveals distinct prognostic patterns from HFsnEF patients.

JROADHF registry showed similar incidence regarding composite of CV death but lower HF readmission (HR 0.92, confidence interval [CI] : 0.84–1.01, P = 0.081).^[6] CONFIRM registry reported that after 6 years of follow-up, there was no difference in mortality for HFsnEF and HFnEF (7.1% vs. 7%, P = 0.41) while women with HFsnEF showed increased mortality compared to men (8.6% vs. 5.8%, P = 0.031), particularly pronounced in obstructive CAD (16.3% vs. 7.5%, P = 0.003).^[2]

Recent registry data from Israel demonstrated that during 32 months of median follow-up, HFsnEF had the highest mortality at 65.1%, compared to HFpEF at 60.8% and HFmrEF at 58.5% (P = 0.009).^[11] However, after adjusting for baseline characteristics, mortality differences became non-significant. For hospitalizations, HFmrEF had lower all-cause readmission rates (60.7%) versus HFpEF (67.0%) and HFsnEF (66.2%) (P = 0.003). HF-specific readmissions showed no significant differences between groups (39.0% overall, P = 0.106).^[11]

The Swedish HF Registry provided comprehensive outcome data, showing that all-cause mortality was almost similar in HFsnEF (adjusted HR 1.15, 95% CI: 0.85–1.55, P = 0.38) and HFpEF (adjusted HR 1.18, 95% CI: 0.96–1.44, P = 0.12), whereas all cause hospitalization was higher in HFsnEF (adjusted HR 1.14, 95% CI: 0.94–1.37, P = 0.18) than HFpEF (adjusted HR 1.03, 95% CI: 0.91–1.17, P = 0.66); however, these EF differences appeared to have minimal independent prognostic value when other clinical factors were considered.^[7,8]

The LECRA-HF registry reported that HFsnEF patients had higher all-cause mortality as compared to HFpEF patients (65% vs. 55.2%, P = 0.044).^[10]

Electrocardiography

Atrial fibrillation, atrial flutter, as well as ventricular fibrillation have been reported to be the common arrhythmias in these patients.^[1,6,36]

Cardiac imaging techniques

The diagnosis of HFsnEF requires a comprehensive approach incorporating multiple diagnostic modalities. Modern imaging techniques play a crucial role, with echocardiography (ECHO) remaining the primary tool for assessment. Advanced imaging methods such as speckle tracking ECHO and cardiac magnetic resonance (CMR) imaging have revealed subtle abnormalities in cardiac function that may not be apparent with conventional imaging. Speckle tracking ECHO enables detailed strain analysis, while CMR imaging provides superior tissue characterization. Nuclear imaging techniques offer insights into perfusion patterns, and novel 3D imaging approaches allow precise volumetric analysis.^[1,3,20,33]

Biomarker profiles

The biomarker profile in HFsnEF patients shows distinct characteristics compared to other HF phenotypes. These patients can present with higher or lower levels of natriuretic peptides, though they may show evidence of subtle myocardial injury and other markers of CV stress.^[1,3,5,6]

Machine learning applications

Machine learning approaches can be valuable tools in HFsnEF diagnosis and risk stratification. These techniques have proven particularly useful in identifying distinct patient phenotypes, predicting clinical outcomes, and integrating multiple data sources for improved diagnosis in patients with HFpEF.^[41] The application of artificial intelligence has enhanced our ability to recognize patterns and predict outcomes with greater accuracy.

A brief summary of key features of HFsnEF has been shown in Figure 5 and a disease progression timeline has been shown in Figure 6.

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Figure 5:

Key features of heart failure with supranormal ejection fraction. (EF: Ejection Fraction.)

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Figure 6:

Disease progression timeline of heart failure with supranormal ejection fraction. (HTN: Hypertension, LVEF: Left ventricular ejection fraction, LVDD: Left ventricular diastolic dysfunction, EF: Ejection Fraction).

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Pharmacological therapy

The management of HFsnEF requires a tailored approach that considers the unique pathophysiology of the condition. To date, only two drugs have shown some efficacy in patients with HFsnEF: Dapagliflozin and semaglutide, although there is an absence of any concrete evidence.

DELIVER trial demonstrated the effectiveness of dapagliflozin, an SGLT2 inhibitor in reducing the risk of worsening HF or CV death among patients with HF, the benefit of which extended throughout the range of EF.^[42]

A pooled analysis combining data from two clinical trials (STEP-HFpEF and STEP-HFpEF diabetes mellitus) tested semaglutide (2.4 mg weekly subcutaneous injections), a glucagon-like peptide-1 receptor agonist, in treating patients with obesity-related HF with preserved EF (HFpEF), which also included patients with EF >65%. Semaglutide improved HF-related symptoms and physical limitations measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) which showed an improvement by 7.5 points (95% CI : 5.3–9.8, P < 0.0001) compared to placebo and also reduced body weight by 8.4% (−9.2–−7.5, P < 0.0001).^[43] Patients with more severe HF symptoms showed greater improvements in their KCCQ-CSS, even though their weight loss was similar to those with less severe symptoms. In addition, while patients with diabetes lost less weight than those without diabetes, they showed similar improvements in HF symptoms.^[43]

HF medications such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), vasodilators, beta blockers, mineralocorticoid receptor antagonists (MRAs), and empagliflozin (SGLT2 inhibitor) have not proven to be effective in HF with EF >65%.^[44-48] A study analyzed the effectiveness of sacubitril/valsartan across different levels of HF by combining data from two major clinical trials (PARADIGM-HF and PARAGON-HF) and found that sacubitril/valsartan was generally more effective than standard renin-angiotensin-aldosterone system inhibitors in HF with higher EF in women as compared to men, but with minimal benefit in patients with EF >65%.^[49]

Gender-specific considerations

Gender-specific considerations play a crucial role in treatment approaches, given the strong association between HFsnEF and female gender. Women show different drug metabolism patterns, greater prevalence of frailty and comorbidities and may have higher susceptibility to adverse reactions, necessitating careful attention to dosing strategies.^[31]

Lifestyle modifications

A randomized controlled trial investigated whether caloric restriction (Diet) or aerobic exercise training (Exercise) could improve exercise capacity and quality of life in older obese patients with HF with preserved EF (HFpEF).^[50] Patients with EF >65% were also included. The diet intervention involved a carefully monitored reduced-calorie diet (approximately 400 calories/day deficit), while the exercise intervention consisted of supervised walking sessions 3 times/week. The study had two primary outcomes: Peak oxygen consumption (VO₂) and quality of life measured by the Minnesota Living with HF (MLHF) questionnaire. Both diet and exercise significantly improved peak VO₂, with diet showing a main effect of 1.3 mL/kg/min increase and exercise showing a 1.2 mL/kg/min increase. The effects were additive when combined. However, neither intervention significantly improved the MLHF scores. Notably, diet did improve other quality of life measures, including the Kansas City Cardiomyopathy Questionnaire score, which increased by 7 units (beyond the 5-unit threshold for clinical relevance). The diet intervention also led to significant improvements in body composition, with participants losing an average of 7 kg (7%) of body weight, including reductions in both fat mass and lean body mass. The exercise group lost an average of 4 kg (3%) of body weight, primarily from fat mass. The diet group showed additional improvements in various measures, including reduced inflammation markers (C-reactive protein), improved lipid profiles, decreased LV mass and wall thickness, and enhanced muscle quality and better HF symptoms (improved NYHA class). The study found that the improvements in exercise capacity were associated with reduced total fat mass, improved body composition (particularly the ratio of thigh muscle to intermuscular fat), decreased inflammation, and reduced LV mass. The interventions appeared safe, with only minor adverse events reported and no deaths during the study period. These findings are particularly significant because HFpEF is the most common form of HF in older adults, and more than 80% of HFpEF patients are overweight or obese. Previous treatment approaches have had limited success, and this study suggests that lifestyle interventions, particularly caloric restriction and exercise, can improve exercise capacity in patients with HFsnEF.^[50]