Evolution of HF-PEF Management: Insights from Clinical Trials

In this episode, CardioNerds Dr. Anna Radakrishnan and Dr. Apoorva Gangavelli are joined by prevention expert Dr. Martha Gulati and heart failure expert Dr. Anu Lala to discuss heart failure with preserved ejection fraction (HFpEF), a multifactorial, evolving challenge, particularly in women. In this episode, we delve into the distinctive clinical presentation and pathophysiology of HFpEF among women, exploring both traditional and gender-specific risk factors, from metabolic and inflammatory processes to the impact of obesity, sleep apnea, and gender-specific conditions. We also discussed the latest evidence on prevention strategies and emerging therapies that not only target HFpEF symptoms but also address underlying risk factors. This conversation highlights the importance of multidisciplinary, holistic care to advance diagnosis, management, and ultimately, patient outcomes for women with HFpEF. Audio editing by CardioNerds academy intern, Christiana Dangas. 

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Pearls – HFpEF in Women

1. HFpEF Is a Multisystem Syndrome:
   HFpEF in women involves more than just diastolic dysfunction—it represents a convergence of metabolic, inflammatory, and hormonal factors that make its diagnosis and management uniquely challenging.
2. Visceral Adiposity Drives Risk:
   Obesity isn’t just excess weight; central or visceral adiposity actively promotes inflammation, insulin resistance, and microvascular dysfunction, which are crucial in triggering HFpEF in women.
3. Early Identification Is Key:
   Recognizing—and treating—subtle risk factors such as sleep-disordered breathing, hypertension, and subtle metabolic dysfunction early, especially in women who may underreport symptoms, can prevent progression to HFpEF.
4. Holistic, Lifespan Approach Matters:
   Effective HFpEF care involves managing the whole cardiometabolic profile with tailored lifestyle interventions, advanced medications (e.g., SGLT2 inhibitors, GLP-1 agonists), and even cardiac rehabilitation, which remain critical at every stage, even after diagnosis.
5. Tailoring Prevention to Unique Risks in Women:
   Gender-specific factors such as postmenopausal hormonal changes, pregnancy-related complications, and autoimmune conditions demand a customized prevention strategy, reminding us that prevention isn’t one-size-fits-all.

Show notes – HFpEF in Women

Notes drafted by Dr. Apoorva Gangavelli

1. What are the gender-based differences in HFpEF presentation?

• HFpEF in women often presents with more subtle symptoms such as exertional dyspnea and fatigue, which may be mistakenly attributed to aging or obesity.
• Women tend to have a higher prevalence of preserved ejection fraction despite a similar heart failure symptom burden to men.
• The diagnostic challenge is compounded by lower natriuretic peptide levels influenced by hormonal factors, particularly postmenopausal estrogen deficiency, leading to false negatives and underdiagnosis.

2. How do traditional and gender-specific risk factors contribute to the development of HFpEF in women?

• Traditional risk factors include obesity, hypertension, diabetes, and metabolic syndrome.
• Gender-specific risk factors encompass pregnancy-related complications, menopause, and autoimmune diseases, which may uniquely affect cardiovascular structure and function in women.
• The interaction between visceral adiposity and systemic inflammation is central in predisposing women to HFpEF.

3. What underlying pathophysiological mechanisms make women more susceptible to HFpEF?

• Chronic inflammation and endothelial dysfunction contribute to myocardial stiffness and diastolic dysfunction.
• Insulin resistance results in impaired myocardial metabolism and lipotoxicity.
• Microvascular dysfunction, with reduced nitric oxide bioavailability, is more pronounced in women, exacerbating cardiac remodeling and fibrosis.

4. What prevention strategies can be tailored across different life stages to reduce HFpEF risk in women?

• Early detection and aggressive management of traditional risk factors (e.g., blood pressure control, weight management) during perimenopause and early adulthood.
• Incorporating lifestyle modifications such as structured exercise programs, improved dietary habits, and sleep optimization.
• Preventive interventions might also include screening for gender-specific risk factors like pregnancy complications and autoimmune conditions early in life.

5. What current and emerging therapeutic approaches are used in the management of HFpEF in women?

• Use of mineralocorticoid receptor antagonists and nonsteroidal alternatives shows promise, particularly in reducing hospitalizations.
• Novel pharmacologic agents such as SGLT2 inhibitors and GLP-1 receptor agonists address both heart failure symptoms and metabolic dysfunction.
• Cardiac rehabilitation is advocated to improve functional capacity and quality of life despite challenges with insurance coverage.

References – HFpEF in Women

1. Borlaug BA, Sharma K, Shah SJ, Ho J. Heart Failure With Preserved Ejection Fraction. Journal of the American College of Cardiology. 2023;81(18). doi:https://doi.org/10.1016/j.jacc.2023.01.049
2. ‌Kittleson MM, Gurusher Panjrath, Kaushik Amancherla, et al. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction. Journal of the American College of Cardiology. 2023;81(18). doi:https://doi.org/10.1016/j.jacc.2023.03.393
3. Radakrishnan A, Agrawal S, Singh N, et al. Underpinnings of Heart Failure With Preserved Ejection Fraction in Women – From Prevention to Improving Function. A Co-publication With the American Journal of Preventive Cardiology and the Journal of Cardiac Failure. Journal of Cardiac Failure. Published online February 2025. doi:https://doi.org/10.1016/j.cardfail.2025.01.008