No abstract

No abstract

Objectives Heart failure (HF) is characterized by perturbations in energy homeostasis and metabolism. The reversibility and prognostic value of circulating markers reporting on these changes remain unclear. We sought to describe the metabolomic profiles of patients along the spectrum of systolic HF, determine their association with adverse outcomes in a clinical trial of HF, and evaluate whether identified metabolites change with treatment for end-stage systolic HF. Methods To assess association of metabolites with clinical outcomes, a population of 453 chronic systolic HF patients who participated in the HF-ACTION trial, which randomized ambulatory, stable patients to exercise training versus usual care, were included. To assess change in metabolites with mechanical circulatory support, 41 patients with end-stage HF who underwent left ventricular assist device (LVAD) placement were studied. Targeted, quantitative profiling of 60 metabolites using tandem flow injection mass spectrometry was performed on frozen plasma samples obtained prior to randomization in the HF-ACTION group, as well as, prior to and ≥90 days post placement in the LVAD group. Principal components analysis (PCA) was used for data reduction; linear regression and Cox-proportional hazards regression modeling were used to assess the relation between the PCA-derived metabolite factor levels and clinical outcomes among patients from the HF-ACTION study. Differences between metabolite factors associated with outcomes in the HF-ACTION and LVAD groups were assessed using Wilcoxon rank sum tests. Results Five PCA-derived factors were significantly associated with peak VO2 levels at baseline in fully adjusted models. Of these, Factor 5 (composed of long-chain acylcarnitines) was associated with increased risk of all 3 pre-specified HF-ACTION clinical outcomes: all-cause mortality/all-cause hospitalization (HR: 1.24; 95% CI 1.09–1.42), all cause-hospitalization (HR: 1.42; 95% CI 1.16–1.74), and cardiovascular death or cardiovascular hospitalization (HR: 1.22; CI 1.06–1.39). Individual components of Factor 5 (C16, C18:1, and C18:2 acylcarnitine metabolites) were significantly higher in patients with end-stage HF prior to LVAD placement and decreased significantly after LVAD therapy. Conclusions In chronic HF patients, circulating long chain acylcarnitine metabolite levels were independently associated with clinical outcomes and decreased after long-term mechanical circulatory support. These metabolites, which report on mitochondrial fatty acid β-oxidation, highlight pathways that may serve as potential targets for new diagnostics or therapeutic interventions.

We report two cases of myocarditis, in two young and previously healthy individuals, temporally related to the second dose of the mRNA-COVID-19 vaccine. Both patients developed acute chest pain, changes on electrocardiogram (ECG), and elevated serum troponin within two days of receiving their second dose. Cardiac magnetic resonance (CMR) findings were consistent with acute myocarditis.

Toll-like receptors (TLRs), a large group of proteins which recognize various pathogen-associated molecular patterns, are critical for the normal function of the innate immune system. Following their discovery many single nucleotide polymorphisms within TLRs and components of their signaling machinery have been discovered and subsequently implicated in a wide range of human diseases including atherosclerosis, sepsis, asthma, and immunodeficiency. This review discusses the effect of genetic variation on TLR function and how they may precipitate disease.

Wnt signaling has recently emerged as an important regulator of cardiac progenitor cell proliferation and differentiation, but the exact mechanisms by which Wnt signaling modulates these effects are not known. Understanding these mechanisms is essential for advancing our knowledge of cardiac progenitor cell biology and applying this knowledge to enhance cardiac therapy. Here, we explored the effects of Sfrp2, a canonical Wnt inhibitor, in adult cardiac progenitor cell (CPC) differentiation and investigated the molecular mechanisms involved. Our data show that Sfrp2 treatment can promote differentiation of CPCs after ischemia-reperfusion injury. Treatment of CPCs with Sfrp2 inhibited CPC proliferation and primed them for cardiac differentiation. Sfrp2 binding to Wnt6 and inhibition of Wnt6 canonical pathway was essential for the inhibition of CPC proliferation. This inhibition of Wnt6 canonical signaling by Sfrp2 was important for activation of the non-canonical Wnt/Planar Cell Polarity (PCP) pathway through JNK, which in turn induced expression of cardiac transcription factors and CPC differentiation. Taken together, these results demonstrate a novel role of Sfrp2 and Wnt6 in regulating the dynamic process of CPC proliferation and differentiation, as well as providing new insights into the mechanisms of Wnt signaling in cardiac differentiation.

No abstract

Background Heart rate and systolic blood pressure (SBP) are prognostic markers in heart failure (HF) with reduced ejection fraction (HFrEF). Their combination in rate pressure product (RPP) as well as their role in heart failure with preserved ejection fraction (HFpEF) remains unclear. Hypothesis RPP and its components are associated with HFpEF outcomes. Methods We performed an analysis of Acute Study of Clinical Effectiveness of Nesiritide in Subjects With Decompensated Heart Failure (ASCEND‐HF; http://www.clinicaltrials.gov NCT00475852), which studied 7141 patients with acute HF. HFpEF was defined as left ventricular ejection fraction ≥40%. Outcomes were assessed by baseline heart rate, SBP, and RPP, as well as the change of these variables using adjusted Cox models. Results After multivariable adjustment, in‐hospital change but not baseline heart rate, SBP, and RPP were associated with 30‐day mortality/HF hospitalization (hazard ratio [HR]: 1.17 per 5‐bpm heart rate, HR: 1.20 per 10‐mm Hg SBP, and HR: 1.02 per 100 bpm × mm Hg RPP; all P < 0.05). Baseline SBP was associated with 180‐day mortality (HR: 0.88 per 10‐mm Hg, P = 0.028). Though change in RPP was associated with 30‐day mortality/HF hospitalization, the RPP baseline variable did not provide additional associative information with regard to outcomes when compared with assessment of baseline heart rate and SBP variables alone. Conclusions An increase in heart rate and SBP from baseline to discharge was associated with increased 30‐day mortality/HF hospitalization in HFpEF patients with acute exacerbation. These findings suggest value in monitoring the trend of vital signs during HFpEF hospitalization.