Interleukin‐1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D‐HART2)

Abstract

Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of confirmed HF cases in the United States. However, there are no highly effective evidence-based treatments currently available for these patients. Inflammation correlates positively with adverse outcomes in HF patients. Interleukin (IL)-1, a prototypical inflammatory cytokine, has been implicated as a driver of diastolic dysfunction in preclinical animal models and a pilot clinical trial. The Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2) is a phase 2, 2:1 randomized, double-blind, placebo-controlled clinical trial that will test the hypothesis that IL-1 blockade with anakinra (recombinant human IL-1 receptor antagonist) improves (1) cardiorespiratory fitness, (2) objective evidence of diastolic dysfunction, and (3) elevated inflammation in patients with HFpEF (http://www.ClinicalTrials.gov NCT02173548). The co–primary endpoints will be placebo-corrected interval changes in peak oxygen consumption and ventilatory efficiency at week 12. In addition, secondary and exploratory analyses will investigate the effects of IL-1 blockade on cardiac structure and function, systemic inflammation, endothelial function, quality of life, body composition, nutritional status, and clinical outcomes. The D-HART2 clinical trial will add to the growing body of evidence on the role of inflammation in cardiovascular disease, specifically focusing on patients with HFpEF.

IL-1 receptor antagonist, anakinra, prevents myocardial dysfunction in a mouse model of Kawasaki disease vasculitis and myocarditis

“…Blocking tumor necrosis factor (TNF)-α in the LCWE-injected mice significantly decreases vascular inflammation and incidence of coronary arteritis, but had modest effects on preventing myocarditis development [21,48]. This is particularly important, as recent studies have established the beneficial role of IL-1 blockade to treat myocarditis and heart failure [50][51][52], as well as dilated cardiomyopathy [53] and pericarditis secondary to Erdheim-Chester disease [54]. The significance of myocarditis during acute KD for post-inflammatory myocardial fibrosis has not been adequately studied [16].…”

“…Therefore, it was of great interest to observe that IL-1Ra was able to reduce both coronary arterial and myocardial inflammation in the experimental KD vasculitis mouse model. This is particularly important, as recent studies have established the beneficial role of IL-1 blockade to treat myocarditis and heart failure [50][51][52], as well as dilated cardiomyopathy [53] and pericarditis secondary to Erdheim-Chester disease [54].…”

Low NT‐proBNP levels in overweight and obese patients do not rule out a diagnosis of heart failure with preserved ejection fraction

“…We included stable HFpEF outpatients who were enrolled prospectively for a clinical trial (NCT02173548) as described previously. 16 Patients were eligible according to 2007 ESC criteria, 3 which did not mandate an elevated NP level for diagnosis, and were excluded if they had recent (within 1 month prior) hospitalization or were unable to complete cardiopulmonary exercise (CPX) testing.…”

“…None declared. (15)(16)(17)(18) 0.54 Borg dyspnoea score 7 (4-9) 7 (4-9) 7 (3-9) 0.51 DT, deceleration time; E, early diastolic mitral annular inflow velocity; e 0 , early diastolic mitral annular velocity; LAV, left atrial volume; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; IQR, inter-quartile range; OUES, oxygen uptake efficiency slope; RV, right ventricular; s 0 , peak systolic annular velocity; SV, stroke volume; TAPSE, tricuspid annular plane systolic excursion VO 2 , oxygen consumption; VE/VCO 2 slope, minute ventilation-carbon dioxide production slope; VT, ventilatory threshold.…”

Innovative Clinical Trial Designs for Precision Medicine in Heart Failure with Preserved Ejection Fraction

“…Thus, there are several drugs and devices in development for HFpEF, and there are several ongoing HFpEF clinical trials (Table 1), which address various etiologies and pathophysiologies of HFpEF (Figure 1). While some of these trials are targeted to specific etiologies of HFpEF (e.g., transthyrtein cardiac amyloidosis [18], hypertrophic cardiomyopathy [19]) or specific pathophysiologies present in HFpEF (inflammation [20], iron deficiency), for the most part they are non-targeted clinical trials that attempt to treat HFpEF patients using a one-size-fits-all approach.…”