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Modulation of the inflammatory response is a promising therapeutic strategy in acute myocardial infarction. The novel approach is based on the anti-inflammatory and cytoprotective properties mediated by the engagement of the low-density lipoprotein‒related protein 1 (LRP1) receptor. SERPIN peptide 16 (SP16) is a synthetic, selective LRP1 agonist. We herein present the results of a study with a single subcutaneous administration of SP16 in 10 patients with STEMI, to appraise its safety and tolerability and explore the effects on the acute inflammatory response, infarct size, and cardiac function.Ten patients with ST-segment elevation myocardial infarction (STEMI) were enrolled within 12 hours of symptoms onset and 6 hours of percutaneous coronary intervention in a single-center, single-arm, open-label study of a single subcutaneous administration of SP16 (0.2 mg/kg). Serial clinical biomarkers and echocardiography data were collected up to 12 months. The data are presented separately for the treatment group and compared with historical controls from a placebo-treated arm in a recently completed clinical trial (N = 28) with similar enrollment criteria.All ten patients with STEMI received subcutaneous administration of SP16, 381 [272-478] minutes after percutaneous coronary intervention, without any treatment-related adverse events. The area under the curve for C-reactive protein was 133 [46-528] mg·d/L in the SP16-treated group versus 286 [141-581] mg·d/L in the historical placebo-treated group ( P = 0.161). The area under the curve for creatine kinase-myocardial band was 1432 [675-3089] ng·d/mL in the SP16-treated group versus 2367 [830-4750] ng·d/mL in the historical placebo-treated patients ( P = 0.428). Left ventricular ejection fraction was 46% [39-54] at baseline and 51% [46-58] at 1 year follow-up in SP16-treated patients (interval change 5% [-0.3% to +9%] P = 0.05) and 44% [38%-56%] at baseline and 53% [43%-59%] at 1 year follow-up in historical placebo-treated patients (interval change 3% [-5% to 10%], P = 0.305).A single subcutaneous administration of SP16, a synthetic targeted LRP1 agonist, was safe and well-tolerated in patients with STEMI. A trend toward reduction in the inflammatory response and infarct size with SP16 was noted; however, the sample size for this study was not based on formal statistical criteria. More extensive studies are planned to determine the clinical efficacy of SP16 in STEMI.NCT: NCT04225533.

Aims ST-segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of death and heart failure (HF). In this study, we sought to evaluate the effect of anakinra, a recombinant interleukin-1 receptor antagonist, on the incidence of HF. Methods and results We performed a pooled analysis of three early phase randomized clinical trials. The endpoints included the composite of all-cause death and new-onset HF, and the composite of all-cause death and hospitalization for HF at 1-year follow-up. Safety events, including injection site reaction and serious infections, were also recorded. We analysed 139 patients with STEMI from three separate trials: VCUART (N = 10), VCUART2 (N = 30), and VCUART3 (N = 99). Of these, 84 (60%) patients were randomized to anakinra and 55 (40%) to placebo. Treatment with anakinra significantly reduced the incidence of all-cause death or new-onset HF (7 [8.2%] vs. 16 [29.1%], log-rank P = 0.002) and of all-cause death or HF hospitalization (0 [0] vs. 5 [9.1%], log-rank P = 0.007). Patients treated with anakinra had significantly higher injection site reactions (19 [22.6%] vs. 3 [5.5%], P = 0.016) without a significant difference in the incidence of serious infections (11 [13.1%] vs. 7 [12.7%], P = 0.435). Treatment with anakinra significantly reduced the area under the curve for high-sensitivity C-reactive protein between baseline and 14 days (75.48 [41.7–147.47] vs. 222.82 [117.22–399.28] mg day/L, P Conclusion IL-1 blockade with anakinra for 14 days in patients with STEMI reduces the incidence of new-onset HF or hospitalization for HF at 1 year following STEMI.

Background: Sarcopenia impairs cardiorespiratory fitness (CRF) in patients with heart failure with reduced ejection fraction (HFrEF). Obesity has also been shown to impair CRF; however, the effects of sarcopenia on CRF in patients with obesity and HFrEF are unknown. The aim of this analysis was to examine differences in CRF between patients with sarcopenic obesity (SO) and non-SO (NSO) with HFrEF. We also assessed associations between skeletal muscle mass index (SMMI) and CRF. Methods: Forty patients with HFrEF and obesity underwent cardiopulmonary exercise testing to collect measures of CRF including peak oxygen consumption (VO 2 ), circulatory power, oxygen uptake efficiency slope, O 2 pulse, and exercise time. Body composition was performed in all patients using bioelectrical impedance analysis to quantify fat mass index and divide patients into SO and NSO based on SMMI cutoffs. Results are presented as mean (SD) or median [interquartile range] as appropriate. Results: Nearly half (43% [n=17]) of patients had SO. Patients with SO had a lower SMMI than those with NSO, and no differences in fat mass index were observed between groups. Those with SO achieved a lower absolute peak VO 2 (NSO, 1.62±0.53 L·min -1 versus SO, 1.27±0.44 L·min -1 , P =0.035), oxygen uptake efficiency slope (NSO, 1.92±0.59 versus SO, 1.54±0.48, P =0.036), and exercise time (NSO, 549±198 seconds versus SO, 413±140 seconds, P =0.021) compared to those with NSO. On multivariate analysis, SMMI remained a significant predictor of absolute peak VO 2 when adjusted for age, sex, adiposity, and HF severity. Conclusions: In patients with HFrEF and obesity, sarcopenia, defined as low SMMI, is associated with a clinically significant reduction in CRF, independent of adiposity.

Interleukin-1 (IL-1) blockade is an anti-inflammatory treatment that may affect exercise capacity in heart failure (HF). We evaluated patient-reported perceptions of exertion and dyspnea at submaximal exercise during cardiopulmonary exercise testing (CPET) in a double-blind, placebo-controlled, randomized clinical trial of IL-1 blockade in patients with systolic HF (REDHART [Recently Decompensated Heart Failure Anakinra Response Trial]). Patients underwent maximal CPET at baseline, 2, 4, and 12 weeks and rated their perceived level of exertion (RPE, on a scale from 6 to 20) and dyspnea on exertion (DOE, on a scale from 0 to 10) every 3 minutes throughout exercise. Patients also answered 2 questionnaires to assess HF-related quality of life: the Duke Activity Status Index and the Minnesota Living with Heart Failure Questionnaire. From baseline to the 12-week follow-up, IL-1 blockade significantly reduced RPE and DOE at 3- and 6-minutes during CPET without changing values for heart rate, oxygen consumption, and cardiac workload at 3- and 6-minutes. Linear regression identified 6-minute RPE to be a strong independent predictor of both physical symptoms (Minnesota Living with Heart Failure Questionnaire; β = 0.474, p = 0.002) and perceived exercise capacity (Duke Activity Status Index; β = -0.443, p = 0.008). In conclusion, patient perceptions of exertion and dyspnea at submaximal exercise may be valuable surrogates for quality of life and markers of response to IL-1 blockade in patients with HF.

BACKGROUND: Delayed time of evening meal is associated with favorable cardiorespiratory fitness (CRF) in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. It is unknown, however, if increasing daily non-fasting time or delaying the midpoint of energy intake may also be associated with CRF. OBJECTIVE: Our aim was to examine whether a longer non-fasting time, delayed midpoint of energy intake, or both, are associated with greater CRF in patients with HFpEF and obesity. METHODS: We measured peak oxygen consumption (VO(2)), a measure of CRF, in 32 patients with HFpEF and obesity with cardiopulmonary exercise testing, and dietary intake using a five-pass 24-h dietary recall. Participants were divided into groups by having lesser (

Hypothesis: There is limited understanding on the potential differences in the pathophysiology between de-novo heart failure with reduced ejection fraction (HFrEF) and acute on chronic HFrEF. Objective: the aim of this study was to assess differences in cardiorespiratory fitness (CRF) parameters between de-novo heart failure and acute on chronic HFrEF using cardiopulmonary exercise testing (CPX). Methods: We retrospectively analyzed CPX data measured within 2 weeks of discharge following acute hospitalization for HFrEF. The predicted peak oxygen consumption (VO 2 ) was calculated using the FRIEND formula. Circulatory power, a measure of cardiac reserve, was calculated as the product of peak VO 2 and peak systolic blood pressure. Peak O 2 pulse, a surrogate measure of exercise stroke volume, was calculated by dividing peak VO 2 by the maximum heart rate (HR). Left ventricular ejection fraction (LVEF) was calculated using Simpson method during echocardiography. Data are reported as median and interquartile range or frequency and percentage (%). Results: We included 102 patients: 32 (31%) women, 81 (79%) Black, 57.0 [ 51-64] years of age, BMI of 34 [29-39] Kg/m 2 . Of these, 26 (25%) had de-novo HFrEF and 76 (75%) had acute on chronic HFrEF. When compared with acute on chronic, patients with de-novo HFrEF had a significantly higher peak VO 2 (16.5 [12.2-19.4] vs 12.8 [10.15-15.32] mL·kg -1 ·min -1 , p 2 (58% [51-75] vs 49% [42-59]) p =0.012), peak HR (134 [117-147] vs 117 [104-136] bpm, p =0.004), peak O 2 pulse (12.2 [10.5 -15.5] vs 9.9 [8.0-13.1] mL/beat, p =0.022) and circulatory power (2823 [1973-3299] vs 1902 [1372-2512] mmHg·mL·kg -1 ·min -1 , p=0.002). No significant difference in resting LVEF was found between groups. Conclusion: Patients with de-novo HFrEF patients have better CRF parameters than those with acute on chronic HFrEF. These differences are not explained by resting left ventricular systolic function but may be related to greater preservation in cardiac reserve during exercise in de-novo HFrEF patients.

Background. Leukocytosis is a common finding in patients with ST elevation myocardial infarction (STEMI) and portends a poor prognosis. Interleukin 1-b regulates leukopoiesis and pre-clinical studies suggest that anakinra (recombinant human interleukin-1 [IL-1] receptor antagonist) suppresses leukocytosis in myocardial infarction. However, the effect of IL-1 blockade with anakinra on leukocyte count in patients with STEMI is unknown. Methods. We reviewed the white blood cell (WBC) and differential count of 99 patients enrolled in a clinical trial of anakinra (n=64) versus placebo (n=35) for 14 days after STEMI. A complete blood cell count with differential count were obtained at admission, and after 72 hours, 14 days and 3 months.Results. After 72 hours from treatment, anakinra compared to placebo led to a statistically significant greater percent reduction in total WBC count (-35% [-48 to -24] vs -21% [-34 to -10], P=0.008), absolute neutrophil count (-48% [-60 to -22] vs -27% [-46 to -5], P=0.004) and to an increase in absolute eosinophil count (+50% [0 to +100] vs 0% [-50 to +62], P=0.022). These changes persisted while on treatment at 14 days and were no longer apparent at 3 months after treatment discontinuation. Conclusion. We found that in patients with STEMI IL-1 blockade with anakinra accelerates resolution of leukocytosis and neutrophilia. This modulation may represent one of the mechanisms by which IL-1 blockade improves clinical outcomes.