Amr Marawan

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.

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. Graphical abstract

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 (β = 0.78 ml/kg/min, 95% CI 0.55–1.01; P < 0.001; β = 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.