Heart failure (HF) is a complex clinical syndrome characterized by exercise intolerance due to shortness of breath and fatigue. Approximately half of HF patients have reduced cardiac contractility (HF with reduced ejection fraction [HFrEF]), whereas the remaining half has preserved contractility but impaired relaxation of the heart (HF with preserved ejection fraction [HFpEF] or diastolic heart failure). There are currently no established therapies for HFpEF and many of the treatments with demonstrated effectiveness in HFrEF provide no benefit in HFpEF. There is therefore an urgent need to develop novel treatments to alleviate symptoms, slow disease progression, and prevent hospitalizations in patients with HFpEF. A significant correlation exists between physical impairment and increasing levels of inflammatory cytokines in patients with HF. Among these cytokines, Interleukin-1 (IL-1) is a key mediator of systemic inflammation that becomes elevated in both HFrEF and HFpEF and may contribute to impaired cardiac function and exercise intolerance. In a recent proof-of-concept study, 2 weeks treatment with recombinant human IL-1 receptor antagonist (anakinra) produced a significant improvement in aerobic exercise performance as measured by peak oxygen consumption (VO2) and ventilatory efficiency (VE/VCO2 slope) in patients with HFrEF. We propose that enhanced inflammation (IL-1) also contributes to the severity of illness in patients with HFpEF and propose to measure the effect of IL-1 blockade with anakinra on exercise performance and to estimate the potential benefit of IL-1 blockade on hospital admission rates in a randomized, double-blind, pilot study (n=60) of patients with HFpEF. Eligible patients will be randomized (2:1) to 12 weeks treatment with anakinra (n=40) or placebo treatment (n=20). Patients will undergo cardiopulmonary exercise test to measure aerobic exercise performance and stress echocardiography to measure filling patterns, diastolic function, and contractility at rest and during stress. Biomarkers will be analyzed in correlation with the clinical variables. Results from this pilot study will be used to optimize the treatment strategy and design a subsequent phase III clinical trial to evaluate the potential long-term morbidity and mortality with IL-1 blockade in patients with HFpEF.

Public Health Relevance

Heart failure is a leading cause of morbidity and mortality in the US. While numerous studies have identified treatments that are effective in those patients who have heart failure with reduced ejection fraction, no effective therapies are available for patients who have preserved ejection fraction-who represent approximately half of all heart failure patients. This application will evaluate the use of a targeted anti-inflammatory approach (to block Interleukin-1) to improve aerobic exercise performance in patients with heart failure and preserved ejection fraction.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Planning Grant (R34)
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Clinical Trials Review Committee (CLTR)
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Hasan, Ahmed AK
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Virginia Commonwealth University
Internal Medicine/Medicine
Schools of Medicine
United States
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Carbone, Salvatore; Canada, Justin M; Buckley, Leo F et al. (2017) Dietary Fat, Sugar Consumption, and Cardiorespiratory Fitness in Patients With Heart Failure With Preserved Ejection Fraction. JACC Basic Transl Sci 2:513-525
Van Tassell, Benjamin W; Buckley, Leo F; Carbone, Salvatore et al. (2017) Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2). Clin Cardiol 40:626-632
Trankle, Cory; Canada, Justin M; Buckley, Leo et al. (2017) Impaired myocardial relaxation with exercise determines peak aerobic exercise capacity in heart failure with preserved ejection fraction. ESC Heart Fail 4:351-355
Carbone, Salvatore; Canada, Justin M; Buckley, Leo F et al. (2016) Obesity Contributes to Exercise Intolerance in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol 68:2487-2488
Abbate, Antonio; Arena, Ross; Abouzaki, Nayef et al. (2015) Heart failure with preserved ejection fraction: refocusing on diastole. Int J Cardiol 179:430-40