Justin M. Canada

Enhanced Interleukin-1 Activity Contributes to Exercise Intolerance in Patients with Systolic Heart Failure

Background Heart failure (HF) is a complex clinical syndrome characterized by impaired cardiac function and poor exercise tolerance. Enhanced inflammation is associated with worsening outcomes in HF patients and may play a direct role in disease progression. Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects. Methods and Results We developed a model of IL-1β-induced left ventricular (LV) dysfunction in healthy mice that exhibited a 32% reduction in LV fractional shortening (P<0.001) and a 76% reduction in isoproterenol response (P<0.01) at 4 hours following a single dose of IL-1β 3 mcg/kg. This phenotype was reproducible in mice injected with plasma from HF patients and fully preventable by pretreatment with IL-1 receptor antagonist (anakinra). This led to the design and conduct of a pilot clinical to test the effect of anakinra on cardiopulmonary exercise performance in patients with HF and evidence of elevated inflammatory signaling (n = 7). The median peak oxygen consumption (VO2) improved from 12.3 [10.0, 15.2] to 15.1 [13.7, 19.3] mL·kg–1·min–1 (P = 0.016 vs. baseline) and median ventilator efficiency (VE/VCO2 slope) improved from 28.1 [22.8, 31.7] to 24.9 [22.9, 28.3] (P = 0.031 vs. baseline). Conclusions These findings suggest that IL-1β activity contributes to poor exercise tolerance in patients with systolic HF and identifies IL-1β blockade as a novel strategy for pharmacologic intervention. Trial Registration ClinicalTrials.gov NCT01300650

Heart failure with preserved ejection fraction: Refocusing on diastole

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of exercise intolerance and/or congestion, in the presence of a left ventricular (LV) ejection fraction within the normal limits (i.e. LVEF>50%). Determining the presence of impaired LV relaxation and/or filling (diastolic dysfunction) in HFpEF is needed to pragmatically to distinguish it from other cardiac and non-cardiac conditions where symptoms are not due to HF. There are multiple mechanisms for diastolic dysfunction ranging from structural abnormalities to functional derangements in HFpEF yet tailored therapies are lacking. Treatments proven effective in HF with systolic dysfunction have failed to show significant benefit in patients with HFpEF, which prognosis remains poor. This review will discuss the challenges inherent to the use of diagnostic criteria for HFpEF, differential diagnosis, prognostic evaluation, and treatment, highlighting the need for more research in this field.

Exercise blood pressure response during assisted circulatory support: Comparison of the total artifical heart with a left ventricular assist device during rehabilitation

BACKGROUND The total artificial heart (TAH) consists of two implantable pneumatic pumps that replace the heart and operate at a fixed ejection rate and ejection pressure. We evaluated the blood pressure (BP) response to exercise and exercise performance in patients with a TAH compared to those with a with a continuous-flow left ventricular assist device (LVAD). METHODS We conducted a single-center, retrospective study of 37 patients who received a TAH and 12 patients implanted with an LVAD. We measured the BP response during exercise, exercise duration and change in tolerated exercise workload over an 8-week period. RESULTS In patients with a TAH, baseline BP was 120/69 ± 13/13, exercise BP was 118/72 ± 15/10 and post-exercise BP was 120/72 ± 14/12. Mean arterial BP did not change with exercise in patients with a TAH (88 ± 10 vs 88 ± 11; p = 0.8), but increased in those with an LVAD (87 ± 8 vs 95 ± 13; p < 0.001). Although the mean arterial BP (MAP) was negatively correlated with metabolic equivalents (METs) achieved during exercise, the association was not statistically significant (β = -0.1, p = 0.4). MAP correlated positively with METs achieved in patients with LVADs (MAP: β = 0.26, p = 0.04). Despite the abnormal response to exercise, patients with a TAH participated in physical therapy (median: 5 days; interquartile range [IQR] 4 to 7 days) and treadmill exercise (19 days; IQR: 13 to 35 days) early after device implantation, with increased exercise intensity and duration over time. CONCLUSIONS During circulatory support with a TAH, the BP response to exercise was blunted. However, aerobic exercise training early after device implantation was found to be safe and feasible in a supervised setting.

Dietary Fat, Sugar Consumption, and Cardiorespiratory Fitness in Patients With Heart Failure With Preserved Ejection Fraction

Visual Abstract

Obesity Contributes to Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome of exertional breathlessness and/or fatigue caused by impaired cardiac function, preserved left ventricular ejection fraction, and impaired diastolic function [(1)][1]. The incidence and prevalence of HFpEF in the United

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

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.

Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure: Results From REDHART (Recently Decompensated Heart Failure Anakinra Response Trial)

Background An enhanced inflammatory response predicts worse outcomes in heart failure (HF). We hypothesized that administration of IL-1 (interleukin-1) receptor antagonist (anakinra) could inhibit the inflammatory response and improve peak aerobic exercise capacity in patients with recently decompensated systolic HF. Methods and Results We randomly assigned 60 patients with reduced left ventricular ejection fraction (<50%) and elevated C-reactive protein levels (>2 mg/L), within 14 days of hospital discharge, to daily subcutaneous injections with anakinra 100 mg for 2 weeks, 12 weeks, or placebo. Patients underwent measurement of peak oxygen consumption (VO2 [mL/kg per minute]) and ventilatory efficiency (the VE/VCO2 slope). Treatment with anakinra did not affect peak VO2 or VE/VCO2 slope at 2 weeks. At 12 weeks, patients continued on anakinra showed an improvement in peak VO2 from 14.5 (10.5–16.6) mL/kg per minute to 16.1 (13.2–18.6) mL/kg per minute (P=0.009 for within-group changes), whereas no significant changes occurred within the anakinra 2-week or placebo groups. The between-groups differences, however, were not statistically significant. The incidence of death or rehospitalization for HF at 24 weeks was 6%, 31%, and 30%, in the anakinra 12-week, anakinra 2-week, and placebo groups, respectively (log-rank test P=0.10). Conclusions No change in peak VO2 occurred at 2 weeks in patients with recently decompensated systolic HF treated with anakinra, whereas an improvement was seen in those patients in whom anakinra was continued for 12 weeks. Additional larger studies are needed to validate the effects of prolonged anakinra on peak VO2 and rehospitalization for HF. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936909.

Interleukin-1 blockade in rheumatoid arthritis and heart failure: a missed opportunity?

a VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, United States b Department of Physical Therapy, Virginia Commonwealth University, Richmond, VA, United States c Department of Pharmacotherapy and Outcome Sciences, Virginia Commonwealth University, Richmond, VA, United States d Division of Rheumatology, Virginia Commonwealth University, Richmond, VA, United States e Department of Medicine, University of Colorado, Aurora, CO, United States

Clinical predictors of response to anakinra in patients with heart failure

Letter to the Editor Systemic inflammation is often present in patients with heart failure (HF)1. Interleukin-1 (IL-1) a key pro-inflammatory cytokine regulates cardiac function in acute and chronic inflammatory illnesses2. Recent data from two pilot studies showed that treatment with an interleukin-1 blocker, anakinra, improved cardiopulmonary exercise testing (CPX) performance in patients with heart failure - reduced ejection fraction (HFrEF)3 as well as in patients with heart failure - preserved ejection fraction (HFpEF)4. HFrEF and HFpEF share a similar burden of symptoms, such as exercise intolerance, but different mechanisms of disease5. The aim of this analysis was to pool data from the 2 pilot studies to explore whether baseline characteristics could serve as predictors of improved CPX performance with anakinra. The analysis included 19 patients, 7 with HFrEF 3 and 12 with HFpEF 4. Inclusion criteria included symptoms of HF (New York Heart Association [NYHA] class II-III) on stable medical therapy without any changes in medications in the prior 3 months, hospital admissions in the prior 12 months, and evidence of impaired left ventricular systolic function (left ventricular ejection fraction [LVEF] 2 mg/l. All patients underwent a baseline transthoracic Doppler echocardiographic study according to the American Society of Echocardiography recommendations 6: LVEF was measured using volumetric analysis for two perpendicular apical views, diastolic function was measured as ratio of transmitral early diastolic velocity (E) to the mitral annulus early diastolic velocity at tissue Doppler (E’) obtained from an average of the septal and lateral wall measurements, right ventricular function was measured as tricuspidal annulus plane systolic excursion (TAPSE). A CPX was completed according to the American Heart Association recommendations as previously described.7 Patients were then treated with anakinra (Kineret™, Swedish Orphan Biovitrum, Stockholm, Sweden); 100 mg subcutaneously daily for 14 days and repeated determination of CRP levels and CPX.3–4 Patients with HFrEF received open-label treatment, whereas patients with HFpEF had blinded treatment. 3–4 Peak VO2 and the minute ventilation/carbon dioxide production (VE/VCO2) slope were pre-specified primary end-points, reflecting 2 important and complementary prognostic indicators in HF.8–9 Additional endpoints included the oxygen uptake efficiency slope (OUES),10 the Duke activity status index (DASI)11, plasma CRP levels and B-type natriuretic peptide levels. Data are reported as median and interquartile range for continuous variables to account for potential deviation from a Gaussian distribution. Discrete variables are reported as a number (%). Paired changes in each variable were analyzed using the Wilcoxon test and correlations between variables were measured with the Spearman correlation test (SPSS 21, IBM, NY, USA). The characteristics of the 19 patients as a whole are reported in Table 1, whereas characteristics of the subgroups are available in the original publications3,4 Table 1 Clinical characteristics. Treatment with anakinra led to a significant improvement in peak VO2 (from 14.1 [11.4–16.7] to 15.9 [13.7–17.5] ml•kg−1•min−1, P=0.002), the VE/VCO2 slope (from 25.6 [22.8–31.1] to 24.9 [22.8–28.2], P=0.002), OUES (from 2.1 [1.7–2.4] to 2.2 [1.8–2.5], P=0.003), and the DASI (24 [15–31] to 27 [24–37], P=0.016). Anakinra also led to a significant reduction in CRP levels (6.6 [3.6–15.2] to 1.3 [0.5–3.1] mg/l, P<0.001), and no significant change in B-type natriuretic peptide (25 [15–112] to 37 [10–57] pg/ml, P=0.48). Anakinra had no significant effects on blood pressure, heart rate or body weight (data not shown). Baseline LVEF was linearly correlated with peak VO2 (R=+0.52, P=0.024) but not with the VE/VCO2 slope or OUES (both P>0.2). Reduced LVEF predicted greater improvement peak VO2 with treatment (R=-0.47, P=0.044), but not in the VE/VCO2 slope or OUES. Values of E/E’ ratio or TAPSE did not correlate with baseline CPX variables or changes following anakinra treatment. On the other hand, the greater baseline impairment in peak VO2 (i.e. lower value), the VE/VCO2 slope (i.e. higher value), and OUES (i.e. lower value), the greater the improvement seen with anakinra treatment in each of these variables (Figure 1). Baseline CRP or BNP levels failed to predict changes in peak VO2, the VE/VCO2 slope or OUES. Figure 1 Baseline cardiopulmonary exercise test (CPX) variables such as peak oxygen consumption (peak VO2) and ventilatory efficiency (VE/VCO2 slope and OUES) predict improvement with anakinra. In summary, the data pooled from two pilot studies confirm the improvement in CPX performance with anakinra across the spectrum of HFrEF and HFpEF, with improvements in peak VO2, (+1.8 ml•kg−1•min−1), the VE/VCO2 slope (−0.7) and the OUES (+0.1) that are considered clinically relevant,8–10 and an associated improvement in perceived functional capacity (DASI questionnaire +3).11 Inflammatory biomarkers, such as CRP, predict cardiac dysfunction and risk.12–14 The current study shows a significant reduction in CRP levels with anakinra. In this pooled analysis, we explored whether baseline characteristics, such as CRP, could serve as predictors of improved performance. We set forth 4 hypotheses. First, we proposed that inflammation (CRP levels) would predict improvement. However, in this analysis of all patients with CRP>2.0 mg/l, this was not the case. Second, we hypothesized that the degree of LV systolic or diastolic dysfunction or RV systolic dysfunction would identify a group of subjects with greater improvement with treatment. While this was in part true for LVEF, the strength of the relationship and statistical significance were marginal and limited to peak VO2. Third, we analyzed whether the effects of anakinra were most evident in those subjects with more severe baseline impairment.15 In our data, peak VO2, the VE/VCO2 slope and OUES prior to treatment strongly predicted the improvement in each of the 3 variables, with greater improvement seen with anakinra in patients with worse baseline CPX performance. The superior prognostic value of exercise parameters should not come as a surprise considering that majority of symptoms in HF are provoked by exertion and are absent at rest, and these parameters are equally valuable in HFrEF and HFpEF.16 Fourth, we explored whether baseline BNP levels, used to stratify patients with HF,17 would predict improvement, but found no association between BNP levels and changes in CPX variables.

Low NT-proBNP levels in overweight and obese patients do not rule out a diagnosis of heart failure with preserved ejection fraction: HFpEF and very low NT-proBNP levels

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome that presents clinicians with a diagnostic challenge. The use of natriuretic peptides to exclude a diagnosis of HFpEF has been proposed. We sought to compare HFpEF patients with N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) level above and below the proposed cut‐off.