Safety, Tolerability, and Effects of a Single Subcutaneous Administration of SP16 - a SERPIN-like, Small Peptide Agonist of the Low-Density Lipoprotein-like Receptor 1- on the Acute Inflammatory Response in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

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.

Association of Titin Variations With Late-Onset Dilated Cardiomyopathy.

IMPORTANCE: Dilated cardiomyopathy (DCM) is frequently caused by genetic factors. Studies identifying deleterious rare variants have predominantly focused on early-onset cases, and little is known about the genetic underpinnings of the growing numbers of patients with DCM who are diagnosed when they are older than 60 years (ie, late-onset DCM). OBJECTIVE: To investigate the prevalence, type, and prognostic impact of disease-associated rare variants in patients with late-onset DCM. DESIGN, SETTING, AND PARTICIPANTS: A population of patients with late-onset DCM who had undergone genetic testing in 7 international tertiary referral centers worldwide were enrolled from March 1990 to August 2020. A positive genotype was defined as the presence of pathogenic or likely pathogenic (P/LP) variants. MAIN OUTCOMES AND MEASURES: The study outcome was all-cause mortality. RESULTS: A total of 184 patients older than 60 years (103 female [56%]; mean [SD] age, 67 [6] years; mean [SD] left ventricular ejection fraction, 32% [10%]) were studied. Sixty-six patients (36%) were carriers of a P/LP variant. Titin-truncating variants were the most prevalent (present in 46 [25%] of the total population and accounting for 46 [69%] of all genotype-positive patients). During a median (interquartile range) follow-up of 42 (10-115) months, 23 patients (13%) died; 17 (25%) of these were carriers of P/LP variants, while 6 patients (5.1%) were genotype-negative. CONCLUSIONS AND RELEVANCE: Late-onset DCM might represent a distinct subgroup characterized by and a high genetic variation burden, largely due to titin-truncating variants. Patients with a positive genetic test had higher mortality than genotype-negative patients. These findings support the extended use of genetic testing also in older patients.

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.

Estimated plasma volume and mortality: analysis from NHANES 1999-2014.

BACKGROUND: While estimated plasma volume (ePV) has been studied in some diseases, such as heart failure, the relationship between ePV and all-cause or cause-specific mortality remains unexplored. Therefore, we investigated the association between ePV and all-cause, cardiovascular (CV), and cancer-related mortality among adults in the US. METHOD: We used the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2014 and included participants older than 18 years. Mortality data were obtained from the National Death Index and matched to the NHANES participants. ePV was derived using Strauss formula. Cox proportional hazard models were fit to estimate hazard ratios for all-cause and cause-specific mortality without and with adjustment for potential confounders. RESULTS: Of the 42,705 participants, 5194 died (1121 CV deaths) during mean follow-up of 8.0 (range 0-16.7) years. Mean ± SD age and ePV of the participants were 47.2 ± 19.4 years and 4.2 ± 0.84, respectively. In unadjusted models, 1 unit increase in ePV was associated with 29%, 32%, and 16% increased risk in all-cause (HR 1.29; 95% CI 1.24, 1.35), CV (HR 1.32; 95% CI 1.22, 1.43), and cancer-related (HR 1.16; 95% CI 1.05, 1.27) mortality. Risk remained high in adjusted models (all-cause HR 1.24; 95% CI 1.18, 1.30; CV HR 1.22; 95% CI 1.11, 1.34; cancer-specific HR 1.24; 95% CI 1.10, 1.39). When comparing the highest and lowest ePV quartiles, similar results were noted (adjusted all-cause HR 1.64; 95% CI 1.45, 1.86; CV HR 1.52; 95% CI 1.19, 1.93; cancer HR 1.85; 95% CI 1.38, 2.49). CONCLUSION: An increase in ePV was associated with increased all-cause and cause-specific mortality. Further studies are needed to explore the mechanism of this relationship and translation into a better outcome.

Association between serum vitamin D levels and cardiorespiratory fitness in the adult population of the USA.

AIMS: The small number of studies that have investigated the relationship between serum vitamin D levels and cardiorespiratory fitness (CRF) have reported conflicting results. We investigated the association between vitamin D levels and CRF in a representative sample of the US population using data from the National Health and Nutrition Survey (2001-2004). METHODS: We included participants between the ages of 20 and 49 years and excluded those with vitamin D levels at the 5% extremes of the distribution. We used survey-weighted linear regression without and with adjustment for age, sex, race, body mass index, hypertension, diabetes, smoking, C-reactive protein, hemoglobin, and glomerular filtration rate to examine the relationship between the maximal oxygen consumption (VO2 max) (as a surrogate for CRF) and vitamin D levels. RESULTS: Of the 1995 participants, 45.2% were women, 49.1% were white, 13% had hypertension, and 4% had diabetes. The mean ± SD age was 33 ± 8.6 years, with a mean ± SD vitamin D level of 58 ± 5.3 nmol/L and a mean ± SD VO2 max of 40 ± 9.7 ml/kg/min. Participants in the highest quartile of vitamin D levels had a significantly higher CRF than participants in the lowest quartile (difference 4.3, 95% confidence interval (CI) 3.0-5.5; P < 0.001). After adjustment for potential confounders, the difference between the highest and lowest vitamin D quartiles remained significant (difference 2.9, 95% CI 1.6-4.1; P < 0.001). In unadjusted and adjusted linear regression, each 10 nmol/L increase in vitamin D level was associated with a significant increase in VO2 max (ß = 0.78 ml/kg/min, 95% CI 0.55-1.01; P < 0.001; ß = 0.51 ml/kg/min, 95% CI 0.23-0.79; P = 0.001, respectively). CONCLUSIONS: We found an independent and robust association between serum vitamin D levels and CRF, but our results need to be validated with clinical trials examining the effect of vitamin D supplementation on CRF.