Comparison of Safety and Biological Efficacy of Anakinra (Kineret) Dispensed in Polycarbonate Plastic versus Borosilicate Glass Syringes: A Patient-Level Analysis of VCUART2 and VCUART3 Clinical Trials.

Anakinra is a recombinant human interleukin-1 receptor antagonist approved for the treatment of inflammatory diseases. Kineret is available as a solution prepared in a borosilicate glass syringe. For implementing a placebo-controlled double-blind randomized clinical trial, anakinra is commonly transferred into plastic syringes. However, there is limited data on anakinra's stability in polycarbonate syringes. We described the results of our previous studies on the use of anakinra in glass (VCUART3) versus plastic syringes (VCUART2) compared with placebo. These studies were conducted in patients with ST-segment elevation myocardial infarction (STEMI), and we assessed the anti-inflammatory effects of anakinra versus placebo by comparing the area under the curve for high-sensitivity cardiac reactive protein (AUC-CRP) levels during the first 14 days of STEMI, its clinical effects on heart failure (HF) hospitalization, cardiovascular death, or new diagnosis of HF as well as adverse events profile between groups. The levels of AUC-CRP were 75 (50-255 mg·day/l) for anakinra in plastic syringes versus 255 (116-592 mg·day/l) in placebo and 60 (24-139 mg·day/l) and 86 (43-123 mg·day/l) for anakinra once and twice daily in glass syringes, respectively, compared with placebo 214 (131-394 mg·day/l). The rate of adverse events was also comparable between groups. There were no differences in the rate of HF hospitalization or cardiovascular death in patients who received anakinra in plastic or glass syringes. Fewer cases of new-onset heart failure occurred in patients receiving anakinra in plastic or glass syringes compared with placebo. Anakinra stored in plastic (polycarbonate) syringes provides comparable biologic and clinical effect to glass (borosilicate) syringes. SIGNIFICANCE STATEMENT: Anakinra (Kineret) 100 mg administered subcutaneously in patients with ST-segment elevation myocardial infarction (STEMI) for a duration of up to 14 days appears to have comparable safety and biological efficacy signals when delivered in prefilled glass or transferred into plastic polycarbonate syringes. This may have important implications for the feasibility of designing clinical trials in STEMI and other clinical conditions.

Interleukin-1 Inhibition for the Prevention and Treatment of Heart Failure.

ABSTRACT: Heart failure (HF) is a complex syndrome that remains a leading cause of morbidity and mortality worldwide. Abundant evidence suggests inflammation plays a key role in the development and perpetuation of HF, but there are currently no anti-inflammatory treatments approved for use in HF. Interleukin-1 (IL-1), the prototypical pro-inflammatory cytokine, has been implicated in adverse cardiac remodeling and left ventricular dysfunction. Multiple early phase clinical trials using IL-1 blockade in patients at risk for or diagnosed with HF have suggested favorable safety and efficacy in reducing inflammatory biomarkers, as well as positive signals in surrogate and clinical endpoints. Additional large scale clinical trials are urgently needed to confirm the safety and efficacy of this therapeutic approach specifically in HF. In this narrative review, we discuss current evidence regarding IL-1 blockade in the prevention and treatment of HF.

Rationale and design of interleukin-1 blockade in recently decompensated heart failure (REDHART2): a randomized, double blind, placebo controlled, single center, phase 2 study.

BACKGROUND: Heart failure (HF) is a global leading cause of mortality despite implementation of guideline directed therapy which warrants a need for novel treatment strategies. Proof-of-concept clinical trials of anakinra, a recombinant human Interleukin-1 (IL-1) receptor antagonist, have shown promising results in patients with HF. METHOD: We designed a single center, randomized, placebo controlled, double-blind phase II randomized clinical trial. One hundred and two adult patients hospitalized within 2 weeks of discharge due to acute decompensated HF with reduced ejection fraction (HFrEF) and systemic inflammation (high sensitivity of C-reactive protein > 2 mg/L) will be randomized in 2:1 ratio to receive anakinra or placebo for 24 weeks. The primary objective is to determine the effect of anakinra on peak oxygen consumption (VO2) measured at cardiopulmonary exercise testing (CPX) after 24 weeks of treatment, with placebo-corrected changes in peak VO2 at CPX after 24 weeks (or longest available follow up). Secondary exploratory endpoints will assess the effects of anakinra on additional CPX parameters, structural and functional echocardiographic data, noninvasive hemodynamic, quality of life questionnaires, biomarkers, and HF outcomes. DISCUSSION: The current trial will assess the effects of IL-1 blockade with anakinra for 24 weeks on cardiorespiratory fitness in patients with recent hospitalization due to acute decompensated HFrEF. TRIAL REGISTRATION: The trial was registered prospectively with ClinicalTrials.gov on Jan 8, 2019, identifier NCT03797001.

Exercise Cardiovascular Magnetic Resonance: A Review.

While pharmacologic stress cardiovascular magnetic resonance imaging (MRI) is a robust noninvasive tool in the diagnosis and prognostication of epicardial coronary artery disease, clinical guidelines recommend exercise-based testing in those patients who can exercise. This review describes the development of exercise cardiovascular MRI protocols, summarizes the insights across various patient populations, and highlights future research initiatives. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 2.

Effect of Canagliflozin Compared With Sitagliptin on Serum Lipids in Patients with Type 2 Diabetes Mellitus and Heart Failure with Reduced Ejection Fraction: A Post-Hoc Analysis of the CANA-HF Study.

ABSTRACT: The sodium glucose co-transporter 2 inhibitors have demonstrated favorable effects on cardiovascular and renal disease; however, they may also increase low-density lipoprotein cholesterol (LDL-C). There are limited data directly comparing the effects of sodium glucose co-transporter 2inhibitors on serum lipids to other antihyperglycemic therapies. In this post-hoc analysis of the CANA-HF trial, we sought to compare the effects of canagliflozin to sitagliptin in patients with type 2 diabetes mellitus (T2DM) and heart failure and reduced ejection fraction (HFrEF). The CANA-HF trial was a prospective, randomized controlled study that compared the effects of canagliflozin 100 mg daily to sitagliptin 100 mg daily on cardiorespiratory fitness in patients with HFrEF and T2DM. Of the 36 patients enrolled in CANA-HF, 35 patients had both baseline and 12-weeks serum lipids obtained via venipuncture. The change in LDL-C from baseline to 12 weeks was 5 (-12.5 to 19.5) mg/dL versus -8 (-19 to -1) mg/dL (P = 0.82) and triglyceride levels was -4 (-26 to 9) mg/dL and -10.5 (-50 to 29.3) mg/dL (P = 0.52) for canagliflozin and sitagliptin, respectively. No significant differences were found between canagliflozin and sitagliptin for total cholesterol, high-density lipoprotein cholesterol or non-HDL-C (P > 0.5 for all). These data suggest that compared with sitagliptin, canagliflozin may not increase LDL-C in patients with T2DM and HFrEF.

Time of eating and cardiorespiratory fitness in patients with heart failure with preserved ejection fraction and obesity.

BACKGROUND AND AIMS: Our objective was to examine the impact of caloric intake before or after the mean time of evening meal on cardiorespiratory fitness (CRF) in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. METHODS AND RESULTS: Twelve patients with HFpEF and obesity completed a cardiorespiratory exercise test to measure CRF, defined as peak oxygen consumption (VO2). Three five-pass 24-h dietary recalls were performed for each participant and mean evening meal time was determined for each participant individually as well as the group. Participants were divided into those who ate before (Group I) and after (Group II) the mean time of evening meal, 7:25 PM. Peak VO2 and exercise time were significantly greater in Group II compared to Group I, moreover, delaying time of evening meal was associated with greater peak VO2. CONCLUSION: Caloric intake after the mean time of evening meal was associated with better CRF in patients with HFpEF and concomitant obesity. Later nutrient intake may help prevent fasting related stress associated with cardiac metabolic disturbances present in HFpEF. Based on these findings, prospective trials aimed at examining the effects of later evening meal times in patients with HFpEF and obesity are warranted.

Diastolic Dysfunction Contributes to Impaired Cardiorespiratory Fitness in Patients with Lung Cancer and Reduced Lung Function Following Chest Radiation.

Cardiorespiratory fitness (CRF) is a robust and independent predictor of cardiovascular health and overall mortality. Patients with lung cancer often have chronic lung disease, contributing to impaired CRF. Radiation to the heart during lung cancer treatment may further reduce CRF. The determinants of CRF in this population are not well understood. We prospectively evaluated 12 patients with lung cancer without known cardiovascular disease with reduced lung function receiving curative intent thoracic radiotherapy to determine whether cardiac diastolic function, as assessed by Doppler echocardiography and N-terminal pro-brain natriuretic peptide (NTproBNP) levels, correlate with CRF measured by peak oxygen consumption (VO2). Doppler-derived measures of diastolic function and serum NTproBNP levels inversely correlated with peak VO2. In a multivariate regression model, NTproBNP was the strongest independent variable associated with peak VO2. These results suggest that diastolic dysfunction further contributes to reduced CRF in patients with lung cancer who have received radiotherapy.

The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA-HF study.

BACKGROUND: Canagliflozin reduces hospitalizations for heart failure (HF) in type 2 diabetes mellitus (T2DM). Its effect on cardiorespiratory fitness and cardiac function in patients with established HF with reduced ejection fraction (HFrEF) is unknown. METHODS: We conducted a double-blind randomized controlled trial of canagliflozin 100 mg or sitagliptin 100 mg daily for 12 weeks in 88 patients, and measured peak oxygen consumption (VO2 ) and minute ventilation/carbon dioxide production (VE/VCO2 ) slope (co-primary endpoints for repeated measure ANOVA time_x_group interaction), lean peak VO2 , ventilatory anaerobic threshold (VAT), cardiac function and quality of life (ie, Minnesota Living with Heart Failure Questionnaire [MLHFQ]), at baseline and 12-week follow-up. RESULTS: The study was terminated early due to the new guidelines recommending canagliflozin over sitagliptin in HF: 17 patients were assigned to canagliflozin and 19 to sitagliptin, total of 36 patients. There were no significant changes in peak VO2 and VE/VCO2 slope between the two groups (P = .083 and P = .98, respectively). Canagliflozin improved lean peak VO2 (+2.4 mL kgLM-1 min-1 , P = .036), VAT (+1.5 mL kg-1 min-1 , P = .012) and VO2 matched for respiratory exchange ratio (+2.4 mL Kg-1 min-1 , P = .002) compared to sitagliptin. Canagliflozin also reduced MLHFQ score (-12.1, P = .018). CONCLUSIONS: In this small and short-term study of patients with T2DM and HFrEF, interrupted early after only 36 patients, canagliflozin did not improve the primary endpoints of peak VO2 or VE/VCO2 slope compared to sitagliptin, while showing favourable trends observed on several additional surrogate endpoints such as lean peak VO2 , VAT and quality of life.

Phase 1B, Randomized, Double-Blinded, Dose Escalation, Single-Center, Repeat Dose Safety and Pharmacodynamics Study of the Oral NLRP3 Inhibitor Dapansutrile in Subjects With NYHA II-III Systolic Heart Failure.

ABSTRACT: The NLRP3 inflammasome has been implicated in the development and progression of heart failure. The aim of this study was to determine the safety of an oral inhibitor of the NLRP3 inflammasome, dapansutrile (OLT1177), in patients with heart failure and reduced ejection fraction (HFrEF). This was a phase 1B, randomized, double-blind, dose escalation, single-center, repeat dose safety and pharmacodynamics study of dapansutrile in stable patients with HFrEF (New York Heart Association Class II-III). Subjects were randomized to treatment with dapansutrile for up to 14 days at a ratio of 4:1 into 1 of 3 sequential ascending dose cohorts (500, 1000, or 2000 mg) each including 10 patients. Subjects underwent clinical assessment, biomarker determination, transthoracic echocardiogram, and maximal cardiopulmonary exercise testing at baseline, day 14, and day 28 to ascertain changes in clinical status. Placebo cases (N = 2 per cohort) were used as a decoy to reduce bias and not for statistical comparisons. Thirty participants (20 men) were treated for 13 (12-14) days. No serious adverse events during the study were recorded. All clinical or laboratory parameters at day 14 compared with baseline suggested clinical stability without significant within-group differences in the dapansutrile-pooled group or the 3 dapansutrile cohorts. Improvements in left ventricular EF [from 31.5% (27.5-39) to 36.5% (27.5-45), P = 0.039] and in exercise time [from 570 (399.5-627) to 616 (446.5-688) seconds, P = 0.039] were seen in the dapansutrile 2000 mg cohort. Treatment with dapansutrile for 14 days was safe and well tolerated in patients with stable HFrEF.

Effects of empagliflozin on cardiorespiratory fitness and significant interaction of loop diuretics.

The effects of empagliflozin on cardiorespiratory fitness in patients with type 2 diabetes mellitus (T2DM) and heart failure with reduced ejection fraction (HFrEF) are unknown. In this pilot study we determined the effects of empagliflozin 10 mg/d for 4 weeks on peak oxygen consumption (VO2 ) in 15 patients with T2DM and HFrEF. As an exploratory analysis, we assessed whether there was an interaction of the effects of empagliflozin on peak VO2 of loop diuretics. Empagliflozin reduced body weight (-1.7 kg; P = .031), but did not change peak VO2 (from 14.5 mL kg-1 min-1 [12.6-17.8] to 15.8 [12.5-17.4] mL kg-1 min-1 ; P = .95). However, patients using loop diuretics (N = 9) demonstrated an improvement, whereas those without loop diuretics (N = 6) experienced a decrease in peak VO2 (+0.9 [0.1-1.4] vs -0.9 [-2.1 to -0.3] mL kg-1 min-1 ; P = .001), and peak VO2 changes correlated with the baseline daily dose of diuretics (R = +0.83; P < .001). Empagliflozin did not improve peak VO2 in patients with T2DM and HFrEF. However, as a result of exploratory analysis, patients concomitantly treated with loop diuretics experienced a significant improvement in peak VO2 .

Effect of Interleukin-1 Blockade on Left Ventricular Systolic Performance and Work: A Post Hoc Pooled Analysis of 2 Clinical Trials.

BACKGROUND: Interleukin-1 (IL-1) blockade seems to improve anaerobic exercise in patients with systolic heart failure through improved left ventricular (LV) systolic performance. However, it is unclear whether IL-1 blockade affects LV systolic performance. METHODS: We pooled data from 2 clinical trials of patients with systolic heart failure who were randomized to IL-1 blockade or placebo. We estimated changes in LV systolic performance (LV ejection fraction [LVEF] and end-systolic elastance [LVEes]) and pressure-volume area (PVA), a surrogate of oxygen consumption, after 14 days of treatment. RESULTS: LVEF increased from 30% (24%-38%) to 36% (29%-43%) between baseline and day 14 only in anakinra-treated patients (P = 0.03 for within-group change and P = 0.02 for between-group change compared with placebo). LVEes increased from 1.0 mm Hg/mL (0.7-1.5) to 1.3 mm Hg/mL (0.8-1.6) in anakinra-treated patients between baseline and day 14 but not in placebo-treated patients (P = 0.03 for within-group change and P = 0.08 for between-group change). A change in PVA between baseline and 14 days was not detected in either anakinra or placebo patients. CONCLUSIONS: In this post hoc analysis, LVEes and LVEF increased significantly in patients treated with an IL-1 blocker but not in placebo-treated patients. An effect of IL-1 blockade on calculated PVA was not detected.

Pharmacologic and surgical interventions to improve functional capacity in heart failure.

Heart failure (HF) is a clinical syndrome of breathlessness, lower extremity swelling, fatigue, and exercise intolerance affecting a large portion of the population worldwide, and associated with premature death. Despite improvement in the management of HF, many patients remain unable to complete activities of daily living without experiencing exertional symptoms. Although prevention of death in patients with HF is imperative, treatment of symptoms and improving functional capacity are equally important goals. This article discusses treatments (medical and surgical) associated with improved functional capacity in HF.

Early reduction in cardiorespiratory fitness and diastolic reserve following radiation therapy for lung cancer.

BACKGROUND: Contemporary radiotherapy for the treatment of lung cancer is effective in targeting tumor tissue while limiting heart exposure, yet cardiac toxicity still occurs, often becoming clinically apparent years later. Cardiorespiratory fitness (CRF) is an independent predictor of cardiovascular, cancer-related, and overall mortality and may serve as a sensitive measure of subclinical cardiac toxicity following anti-cancer treatments. Prior work has demonstrated a significant relationship between reduced CRF and impaired left-ventricular (LV) diastolic reserve in cancer survivors following thoracic radiotherapy. The purpose of this study was to assess early longitudinal changes in CRF and cardiac function in patients with lung cancer following radiotherapy. METHODS: Ten patients (69 [61-76] years, 70% female) with lung cancer without known cardiovascular disease scheduled to receive radiotherapy involving a clinically-relevant heart dose (≥ 5 Gy to > 10% of heart volume) were evaluated prior to and following treatment. Changes in CRF (peak oxygen consumption [VO2peak], oxygen uptake efficiency slope [OUES]), cardiac function (LV ejection fraction [LVEF], rest and exercise diastolic function [diastolic functional reserve index (DFRI)]), cardiac biomarkers (N-terminal pro-brain natriuretic peptide [NT-proBNP], high-sensitivity C-reactive protein [hsCRP]), and health-related quality of life (HRQOL; Functional Assessment of Cancer Therapy-General-7 [FACT-G7]) were measured. RESULTS: The VO2peak was reduced at baseline (1.245 [0.882-1.605] L·min- 1; 70 [62-86] %-predicted) and significantly declined (1.095 [0.810-1.448] L·min- 1, P = 0.047; 62 [56-76] %-predicted, P = 0.005) at 6.0 [3.0-6.0] months post-radiotherapy. Similarly, a significant decline in the OUES was observed (1.63 [1.27-1.88] to 1.57 [1.12-1.75], P = 0.032). Systolic cardiac function was normal at baseline and did not change following radiotherapy (LVEF; 62 [56-65]% to 66 [57-68]%, P = 0.475). The DFRI significantly declined following radiotherapy (34.9 [22.7-41.6] vs. 12.8 [3.1-35.9]). The hsCRP increased significantly from 4.4 [1.4-5.8] to 6.1 [3.7-20.7] g/L, P = 0.047 with a trend towards higher levels of NT-proBNP (65 [49-125] to 121 [88-191] pg/mL, P = 0.110). Health-related quality of life significantly decreased (FACT-G7; 21.5 [18.8-25] to 15.5 [11.5-20]; P = 0.021) post-radiotherapy. CONCLUSIONS: Patients with lung cancer receiving radiotherapy with a clinically-significant heart dose experience reductions in CRF (VO2peak, OUES) as early as six months following treatment with concurrent reductions in diastolic reserve (DFRI), HRQOL, and increases in cardiac biomarkers (NT-proBNP, hsCRP).

Response to interleukin-1 blockade with anakinra in women and men with ST-segment elevation myocardial infarction.

BACKGROUND: Interleukin-1 blockade with anakinra reduces high-sensitivity C-reactive protein (hsCRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). Sex-based differences in STEMI patients have been reported, but no data are available regarding response to anakinra. METHODS: We analyzed the systemic inflammation and composite end-point of new-onset HF or death in women and men with STEMI treated with anakinra from three different Virginia Commonwealth University Anakinra Response Trial (VCUART) randomized clinical trials. RESULTS: We analyzed 139 patients, 29 (21%) were women while 110 (79%) were men. Baseline hsCRP was higher in women compared to men (8.9 [5.2-13.5] vs. 4.2 [2.1-7.7] mg/L, P<0.001). Eighty-four patients were treated with anakinra (22 [75%] women and 62 [56%] men). The area under the curve of hsCRP (hsCRP-AUC) after 14 days was numerically lower in patients receiving anakinra versus placebo both in men (86 [37-130] vs. 223 [119-374] mg day/L) and in women (73 [46-313] vs. 242 [102-988] mg day/L) (P<0.001 for multiple groups, P for interaction 0.22). The incidence of the composite endpoint was also numerically lower in the anakinra group compared to placebo, both in men (4 [6.4%] vs. 14 [29.1%]) and in women (3 [13.6%] vs. 2 [28.5%]) (P=0.019 for multiple groups, P for interaction 0.44). There were no statistically significant differences between women and men in hsCRP-AUC and death or HF events when comparing separately the anakinra and placebo groups (all P>0.05). CONCLUSIONS: Women were underrepresented in the VCUART trials, they appeared to have higher hsCRP levels at time of presentation, yet to benefit similar to men by treatment with anakinra in STEMI.

Right Ventricular Contractile Reserve: A Key Metric to Identifying When Cardiorespiratory Fitness Will Improve With Pulmonary Vasodilators.

Cardiorespiratory fitness (CRF) has been proposed as a vital sign for the past several years, supported by a wealth of evidence demonstrating its significance as a predictor of health trajectory, exercise/functional capacity, and the quality of life. According to the Fick equation, oxygen consumption (VO2) is the product of cardiac output (CO) and arterial-venous oxygen difference, with the former being a primary driver of one's aerobic capacity. In terms of the dependence of aerobic capacity on a robust augmentation of CO from rest to maximal exercise, left ventricular (LV) CO has been the historic focal point. Patients with pulmonary arterial hypertension (PAH) or secondary pulmonary hypertension (PH) present with a significantly compromised CRF; as pathophysiology worsens, so too does CRF. Interventions to improve pulmonary hemodynamics continue to emerge and are now a standard of clinical care in several patient populations with increased pulmonary pressures; new pharmacologic options continue to be explored. Improvement in CRF/aerobic capacity has been and continues to be a primary or leading secondary endpoint in clinical trials examining the effectiveness of pulmonary vasodilators. A central premise for including CRF/aerobic capacity as an endpoint is that pulmonary vasodilation will lead to a significant downstream increase in LV CO and therefore peak VO2. However, the importance of right ventricular (RV) CO to the peak VO2 response continues to be overlooked. The current review provides an overview of relevant principles of exercise physiology, approaches to assessing RV contractile reserve and proposals for clinical trial design and subject phenotyping.

Simultaneous exercise stress cardiac magnetic resonance and cardiopulmonary exercise testing to elucidate the Fick components of aerobic exercise capacity: a feasibility and reproducibility study and pilot study in hematologic cancer survivors.

BACKGROUND: Patients treated for hematologic malignancy often experience reduced exercise capacity and increased fatigue; however whether this reduction is related to cardiac dysfunction or impairment of skeletal muscle oxygen extraction during activity is unknown. Cardiopulmonary exercise testing (CPET) coupled with stress cardiac magnetic resonance (ExeCMR), may provide a noninvasive method to identify the abnormalities of cardiac function or skeletal muscle oxygen extraction. This study was performed to determine the feasibility and reproducibility of a ExeCMR + CPET technique to measure the Fick components of peak oxygen consumption (VO2) and pilot its discriminatory potential in hematologic cancer patients experiencing fatigue. METHODS: We studied 16 individuals undergoing ExeCMR to determine exercise cardiac reserve with simultaneous measures of VO2. The arteriovenous oxygen content difference (a-vO2diff) was calculated as the quotient of VO2/cardiac index (CI). Repeatability in measurements of peak VO2, CI, and a-vO2diff was assessed in seven healthy controls. Finally, we measured the Fick determinants of peak VO2 in hematologic cancer survivors with fatigue (n = 6) and compared them to age/gender-matched healthy controls (n = 6). RESULTS: Study procedures were successfully completed without any adverse events in all subjects (N = 16, 100%). The protocol demonstrated good-excellent test-retest reproducibility for peak VO2 (intraclass correlation coefficient [ICC] = 0.992 [95%CI:0.955-0.999]; P < 0.001), peak CI (ICC = 0.970 [95%CI:0.838-0.995]; P < 0.001), and a-vO2diff (ICC = 0.953 [95%CI:0.744-0.992]; P < 0.001). Hematologic cancer survivors with fatigue demonstrated a significantly lower peak VO2 (17.1 [13.5-23.5] vs. 26.0 [19.7-29.5] mL·kg-1·min-1, P = 0.026) and lower peak CI (5.0 [4.7-6.3] vs. 7.4 [7.0-8.8] L·min-1/m2, P = 0.004) without a significant difference in a-vO2diff (14.4 [11.8-16.9] vs. 13.6 [10.9-15.4] mLO2/dL, P = 0.589). CONCLUSIONS: Noninvasive measurement of peak VO2 Fick determinants is feasible and reliable with an ExeCMR + CPET protocol in those treated for a hematologic malignancy and may offer insight into the mechanisms of exercise intolerance in those experiencing fatigue.

Interleukin-1 blockade in heart failure: an on-treatment and off-treatment cardiorespiratory fitness analysis.

AIMS: Interleukin-1 (IL-1) blockade may improve exercise capacity in patients with heart failure (HF) patients. The extent of the improvement and its persistence beyond discontinuation of IL-1 blockade is unknown. METHODS AND RESULTS: The primary objective was to determine changes in cardiorespiratory fitness and cardiac function on-treatment with IL-1 blocker, anakinra, and off-treatment, after treatment cessation. We performed cardiopulmonary exercise testing, Doppler echocardiography, and biomarkers in 73 patients with HF, 37 (51%) females, 52 (71%) Black-African-American, before and after treatment with anakinra 100 mg daily. In a subset of 46 patients, testing was also repeated after treatment cessation. Quality of life was assessed in each patient using standardized questionnaires. Data are presented as median and interquartile range. Treatment with anakinra for 4 [2-12] weeks was associated with a significant improvement in high-sensitivity C-reactive protein (from 6.2 [3.3-15.4] to 1.4 [0.8-3.4] mg/L, P < 0.001), peak oxygen consumption (VO2peak , from 13.9 [11.6-16.6] to 15.2 [12.9-17.4] mL/kg/min, P < 0.001). Ventilatory efficiency, exercise time, Doppler-derived signs and biomarkers of elevated intracardiac pressures, and quality-of-life measures also improved with anakinra. In the 46 patients in whom off-treatment data were available 12 [4-12] weeks later, many of the favourable changes seen with anakinra were largely reversed (from 1.5 [1.0-3.4] to 5.9 [1.8-13.1], P = 0.001 for C-reactive protein, and from 16.2 [14.0-18.4] to 14.9 [11.5-17.8] mL/kg/min, P = 0.017, for VO2peak ). CONCLUSIONS: These data validate IL-1 as an active and dynamic modulator of cardiac function and cardiorespiratory fitness in HF.

Contribution of hemoglobin concentration to cardiorespiratory fitness in black African American patients with recently decompensated heart failure and reduced ejection fraction.

BACKGROUND: Previous studies have shown that patients with heart failure with reduced ejection fraction (HFrEF) and anemia have reduced peak oxygen consumption (VO2). Black or African American (B-AA) patients have a higher prevalence of anemia and are underrepresented in clinical studies of HFrEF. The aim of this study was to determine the contribution of hemoglobin to peak VO2 in B-AA patients recently hospitalized for acute decompensated HFrEF. METHODS: We analyzed cardiopulmonary exercise testing (CPX) data measured within two weeks of discharge for acute decompensated HF in B-AA patients with HFrEF (left ventricular ejection fraction [LVEF] ≤40%) without severe anemia (Hb<8 g/dL). Blood samples were collected prior to CPX. Data are reported as median [interquartile range] and compared between groups with the Mann-Whitney, Chi-Square, and Spearman's rank tests. RESULTS: We included 81 patients; 27 (33%) women, 57 [27-79] years of age, Body Mass Index of 33 [15-55] kg/m2 and LVEF of 30 [23-36] %. Hemoglobin ranged between 9.1 to 18.1 g/dL (median= 13.3 [11.9-14.5] g/dL); 26 (32%) were considered to have anemia based on a Hb concentration of males <13 g/dL and females <12 g/dL. Peak VO2 was lower in patients with anemia (11.8 [10.0-14.2] vs. 14.1 [10.6-17.0] mL·kg-1·min-1; P=0.010) with a significant correlation between peak VO2 and hemoglobin concentration (R=+0.455; P<0.001). CONCLUSIONS: Anemia is prevalent among B-AA patients with recently decompensated HFrEF and appears to be a significant contributor to reductions in peak VO2.