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Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study).

ABSTRACT: Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome of exercise intolerance due to impaired myocardial relaxation and/or increased stiffness. Patients with HFpEF often show signs of chronic systemic inflammation, and experimental studies have shown that interleukin-1 (IL-1), a key proinflammatory cytokine, impairs myocardial relaxation. The aim of the present study was to determine the effects of IL-1 blockade with anakinra on aerobic exercise capacity in patients with HFpEF and plasma C-reactive protein (CRP) >2 mg/L (reflecting increased IL-1 activity). A total of 12 patients were enrolled in a double-blind, randomized, placebo-controlled, crossover trial and assigned 1:1 to receive 1 of the 2 treatments (anakinra 100 mg or placebo) for 14 days and an additional 14 days of the alternate treatment (placebo or anakinra). The cardiopulmonary exercise test was performed at baseline, after the first 14 days, and after the second 14 days of treatment. The placebo-corrected interval change in peak oxygen consumption was chosen as the primary end point. All 12 patients enrolled in the present study and receiving treatment completed both phases and experienced no major adverse events. Anakinra led to a statistically significant improvement in peak oxygen consumption (+1.2 ml/kg/min, p = 0.009) and a significant reduction in plasma CRP levels (-74%, p = 0.006). The reduction in CRP levels correlated with the improvement in peak oxygen consumption (R = -0.60, p = 0.002). Three patients (25%) had mild and self-limiting injection site reactions. In conclusion, IL-1 blockade with anakinra for 14 days significantly reduced the systemic inflammatory response and improved the aerobic exercise capacity of patients with HFpEF and elevated plasma CRP levels.

SUBMITTER: Van Tassell BW

PROVIDER: S-EPMC4899612 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study).

Van Tassell Benjamin Wallace BW Arena Ross R Biondi-Zoccai Giuseppe G Canada Justin McNair JM Oddi Claudia C Abouzaki Nayef Antar NA Jahangiri Arehzo A Falcao Raquel Appa RA Kontos Michael Christopher MC Shah Keyur Bharat KB Voelkel Norbert Felix NF Dinarello Charles Anthony CA Abbate Antonio A

The American journal of cardiology 20131004 2

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome of exercise intolerance due to impaired myocardial relaxation and/or increased stiffness. Patients with HFpEF often show signs of chronic systemic inflammation, and experimental studies have shown that interleukin-1 (IL-1), a key proinflammatory cytokine, impairs myocardial relaxation. The aim of the present study was to determine the effects of IL-1 blockade with anakinra on aerobic exercise capacity in patients with ...[more]

PMID: 24262762

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Project description:BackgroundInorganic nitrate (NO3(-)), abundant in certain vegetables, is converted to nitrite by bacteria in the oral cavity. Nitrite can be converted to nitric oxide in the setting of hypoxia. We tested the hypothesis that NO3(-) supplementation improves exercise capacity in heart failure with preserved ejection fraction via specific adaptations to exercise.Methods and resultsSeventeen subjects participated in this randomized, double-blind, crossover study comparing a single dose of NO3-rich beetroot juice (NO3(-), 12.9 mmol) with an identical nitrate-depleted placebo. Subjects performed supine-cycle maximal-effort cardiopulmonary exercise tests, with measurements of cardiac output and skeletal muscle oxygenation. We also assessed skeletal muscle oxidative function. Study end points included exercise efficiency (total work/total oxygen consumed), peak VO2, total work performed, vasodilatory reserve, forearm mitochondrial oxidative function, and augmentation index (a marker of arterial wave reflections, measured via radial arterial tonometry). Supplementation increased plasma nitric oxide metabolites (median, 326 versus 10 μmol/L; P=0.0003), peak VO2 (12.6±3.7 versus 11.6±3.1 mL O2·min(-1)·kg(-1); P=0.005), and total work performed (55.6±35.3 versus 49.2±28.9 kJ; P=0.04). However, efficiency was unchanged. NO3(-) led to greater reductions in systemic vascular resistance (-42.4±16.6% versus -31.8±20.3%; P=0.03) and increases in cardiac output (121.2±59.9% versus 88.7±53.3%; P=0.006) with exercise. NO3(-) reduced aortic augmentation index (132.2±16.7% versus 141.4±21.9%; P=0.03) and tended to improve mitochondrial oxidative function.ConclusionsNO3(-) increased exercise capacity in heart failure with preserved ejection fraction by targeting peripheral abnormalities. Efficiency did not change as a result of parallel increases in total work and VO2. NO3(-) increased exercise vasodilatory and cardiac output reserves. NO3(-) also reduced arterial wave reflections, which are linked to left ventricular diastolic dysfunction and remodeling.Clinical trial registration urlwww.clinicaltrials.gov. Unique identifier: NCT01919177.

Project description:AimsThis study aimed to assess plasma fibroblast growth factor 23 (FGF23) in patients with heart failure with preserved ejection fraction (HFpEF) and its relation to inflammation, renal function, clinical and imaging characteristics, exercise capacity, and prognosis.Methods and resultsWe performed a prospective, observational study of 172 age-matched and sex-matched subjects (HFpEF n = 130; controls n = 42, age 73 ± 9, female 50%) who underwent plasma biomarker sampling, echocardiography, cardiac magnetic resonance imaging, and 6 min walk testing (6MWT). The primary endpoint was the composite of all-cause death or HF hospitalization. FGF23 was higher in HFpEF compared with controls (62 [42-105] vs. 34 [22-41] pg/mL, P < 0.0001). In HFpEF, FGF23 correlated with greater symptom burden (New York Heart Association class: r = 0.308), poorer exercise capacity (6MWT distance: r = -0.345), and plasma biomarkers reflecting inflammation (highly sensitive C-reactive protein: r = 0.207, myeloperoxidase: r = 0.311), bone metabolism (osteoprotegerin: r = 0.446), renal dysfunction (urea: r = 0.267, creatinine: r = 0.351, estimated glomerular filtration rate: r = -0.367), and echocardiographic E/e' (r = 0.298); P < 0.05. Following multivariable linear regression modelling, FGF23 remained independently associated with shorter 6MWT distance (P = 0.012) in addition to age, body mass index, and lower haemoglobin. During follow-up (median 1428 days), there were 61 composite events (21 deaths, 40 HF hospitalizations) in patients with HFpEF. In multivariable Cox regression analysis, FGF23 [adjusted hazard ratio (HR) 1.665; 95% confidence interval (CI) (1.284-2.160; P < 0.0001)], B-type natriuretic peptide (HR 1.433; CI 1.053-1.951; P = 0.022), and prior HF hospitalization (HR 2.058; CI 1.074-3.942; P = 0.030) were independent predictors of the composite endpoint.ConclusionsPlasma FGF23 is higher in HFpEF compared with age-matched and sex-matched controls and is strongly associated with exercise incapacity and prognosis. FGF23 correlates with plasma markers of inflammation and renal impairment.

Project description:AimsExercise intolerance is the leading manifestation of heart failure with preserved or mid-range ejection fraction (HFpEF or HFmrEF), and left atrial (LA) function might contribute to modulating left ventricular filling and pulmonary venous pressures. We aim to assess the association between LA function and maximal exercise capacity in patients with HFpEF or HFmrEF.Methods and resultsSixty-five patients, prospectively enrolled in the German HFpEF Registry, were analysed. Inclusion criteria were New York Heart Association functional class ? II, left ventricular ejection fraction > 40%, structural heart disease or diastolic dysfunction, and elevated levels of N terminal pro brain natriuretic peptide (NT-proBNP). LA function was evaluated through speckle-tracking echocardiography by central reading in the Charité Academic Echocardiography core lab. All patients underwent maximal cardiopulmonary exercise test and were classified according to a peak VO2 cut-off of prognostic value (14 mL/kg/min). NT-pro-BNP was measured. Twenty-nine patients (45%) reached a peak VO2 < 14 mL/kg/min (mean value 12.4 ± 1.5) and 36 patients (55%) peak VO2 ? 14 mL/kg/min (mean value 19.4 ± 3.9). There was no significant difference in left ventricular ejection fraction (60 ± 9 vs. 59 ± 8%), left ventricular mass (109 ± 23 vs. 112 ± 32 g/m2 ), LA volume index (45 ± 17 vs. 47 ± 22 mL/m2 ), or E/e´ (13.1 ± 4.7 vs. 13.0 ± 6.0) between these groups. In contrast, all LA strain measures were impaired in patients with lower peak VO2 (reservoir strain 14 ± 5 vs. 21 ± 9%, P = 0.002; conduit strain 9 ± 2 vs. 13 ± 4%, P = 0.001; contractile strain 7 ± 4 vs. 11 ± 6%, P = 0.02; reported lower limits of normality for LA reservoir, conduit and contractile strains: 26.1%, 12.0%, and 7.7%). In linear regression analysis, lower values of LA reservoir strain were associated with impaired peak VO2 after adjustment for age, sex, body mass index, heart rhythm (sinus/AFib), and log-NTproBNP [? 0.29, 95% confidence interval (CI) 0.02-0.30, P = 0.02], with an odds ratio 1.22 (95% CI 1.05-1.42, P = 0.01) for peak VO2 < 14 mL/kg/min for LA reservoir strain decrease after adjustment for these five covariates. Adding left ventricular ejection fraction, it did not influence the results. On the other hand, the addition of LA strain to the adjustment parameters alone described above provided a significant increase of the predictive value for lower peak VO2 values (R2 0.50 vs. 0.45, P = 0.02). With receiver operating characteristic curve analysis, we identified LA reservoir strain < 22% to have 93% sensitivity and 49% specificity in predicting peak VO2 < 14 mL/kg/min. Using this cut-off, LA reservoir strain < 22% was associated with peak VO2 < 14 mL/kg/min in logistic regression analysis after comprehensive adjustment for age, sex, body mass index, heart rhythm, and log-NTproBNP [odds ratio 95% CI 10.4 (1.4-74), P = 0.02].ConclusionsIn this HFpEF and HFmrEF cohort, a reduction in LA reservoir strain was a sensible marker of decreased peak exercise capacity. Therefore, LA reservoir strain might be of clinical value in predicting exercise capacity in patients with HFpEF or HFmrEF.

Project description:ImportanceSex differences in heart failure with preserved ejection fraction (HFpEF) have been established, but insights into the mechanistic drivers of these differences are limited.ObjectiveTo examine sex differences in cardiometabolic profiles and exercise hemodynamic profiles among individuals with HFpEF.Design, setting, and participantsThis cross-sectional study was conducted at a single-center tertiary care referral hospital from December 2006 to June 2017 and included 295 participants who met hemodynamic criteria for HFpEF based on invasive cardiopulmonary exercise testing results. We examined sex differences in distinct components of oxygen transport and utilization during exercise using linear and logistic regression models. The data were analyzed from June 2018 to May 2019.Main outcomes and measuresResting and exercise gas exchange and hemodynamic parameters obtained during cardiopulmonary exercise testing.ResultsOf 295 participants, 121 (41.0%) were men (mean [SD] age, 64 [12] years) and 174 (59.0%) were women (mean [SD] age, 61 [13] years). Compared with men, women with HFpEF in this tertiary referral cohort had fewer comorbidities, including diabetes, insulin resistance, and hypertension, and a more favorable adipokine profile. Exercise capacity was similar in men and women (percent predicted peak oxygen [O2] consumption: 66% in women vs 68% in men; P = .38), but women had distinct deficits in components of the O2 pathway, including worse biventricular systolic reserve (multivariable-adjusted analyses: ΔLVEF β = -1.70; SE, 0.86; P < .05; ΔRVEF β = -2.39, SE=0.80; P = .003), diastolic reserve (PCWP/CO: β = 0.63; SE, 0.31; P = .04), and peripheral O2 extraction (C(a-v)O2 β=-0.90, SE=0.22; P < .001)).Conclusions and relevanceDespite a lower burden of cardiometabolic disease and a similar percent predicted exercise capacity, women with HFpEF demonstrated greater cardiac and extracardiac deficits, including systolic reserve, diastolic reserve, and peripheral O2 extraction. These sex differences in cardiac and skeletal muscle responses to exercise may illuminate the pathophysiology underlying the development of HFpEF and should be investigated further.

Dataset Information

Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study).

Publications

Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study).

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