Aims Pre-existing cardiovascular disease in general and related risk factors have been associated with poor coronavirus disease-2019 (COVID-19) outcomes. However, data on outcomes of COVID-19 among people with pre-existing diagnosis of heart failure (HF) have not been studied in sufficient detail. We aimed to perform detailed characterization of the association of pre-existing HF with COVID-19 outcomes. Methods and results A retrospective cohort study based on Veterans Health Administration (VHA) data comparing 30 day mortality and hospital admission rates after COVID-19 diagnosis among Veterans with and without pre-existing diagnosis of HF. Cox-regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) with adjustment for covariates. Among 31 051 veterans (97% male) with COVID-19, 6148 had pre-existing diagnosis of HF. The mean (SD) age of patients with HF was 70 (13) whereas the mean (SD) age of patients without HF was 57 (17). Within the HF group with available data on left ventricular ejection fraction (EF), 1844 patients (63.4%) had an EF of >45%, and 1063 patients (36.6%) had an EF of ≤45%. Patients in the HF cohort had higher 30 day mortality (5.4% vs. 1.5%) and admission (18.5% vs. 8.4%) rates after diagnosis of COVID-19. After adjustment for age, sex, and race, HRs (95% CIs) for 30 day mortality and for 30 day hospital admissions were 1.87 (1.61-2.17) and 1.79 (1.66-1.93), respectively. After additional adjustment for medical comorbidities, HRs for 30 day mortality and for 30 day hospital admissions were 1.37 (1.15-1.64) and 1.27 (1.16-1.38), respectively. The findings were similar among HF patients with preserved vs. reduced EF, among those taking vs. not taking angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or angiotensin receptor neprilysin inhibitors, and among those taking vs. not taking anticoagulants. Conclusions Patients with COVID-19 and pre-existing diagnosis of HF had a higher risk of 30 day mortality and hospital admissions compared to those without history of HF. The findings were similar by EF categories and by angiotensin-converting enzyme inhibitors/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitors or anticoagulant use.

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Mice with targeted disruption of both IA-2 and IA-2␤ (double-knockout, or DKO mice) have numerous endocrine and physiological disruptions, including disruption of circadian and diurnal rhythms. In the present study, we have assessed the impact of disruption of IA-2 and IA-2␤ on molecular rhythms in the brain and peripheral oscillators. We used in situ hybridization to assess molecular rhythms in the hypothalamic suprachiasmatic nuclei (SCN) of wild-type (WT) and DKO mice. The results indicate significant disruption of molecular rhythmicity in the SCN, which serves as the central pacemaker regulating circadian behavior. We also used quantitative PCR to assess gene expression rhythms in peripheral tissues of DKO, single-knockout, and WT mice. The results indicate significant attenuation of gene expression rhythms in several peripheral tissues of DKO mice but not in either single knockout. To distinguish whether this reduction in rhythmicity reflects defective oscillatory function in peripheral tissues or lack of entrainment of peripheral tissues, animals were injected with dexamethasone daily for 15 days, and then molecular rhythms were assessed throughout the day after discontinuation of injections. Dexamethasone injections improved gene expression rhythms in liver and heart of DKO mice. These results are consistent with the hypothesis that peripheral tissues of DKO mice have a functioning circadian clockwork, but rhythmicity is greatly reduced in the absence of robust, rhythmic physiological signals originating from the SCN. Thus, IA-2 and IA-2␤ play an important role in the regulation of circadian rhythms, likely through their participation in neurochemical communication among SCN neurons. circadian; suprachiasmatic nucleus; vasoactive intestinal peptide; Prprn; Ptprn2 INSULINOMA-ASSOCIATED PROTEIN 2 (IA-2; also called islet antigen 2, ICA 512, and Prprn) and IA-2␤ (also called phogrin and Ptprn2) are transmembrane proteins with homology to protein tyrosine phosphatase but which lack phosphatase activity (29,35,36; for review, see Ref. 51). IA-2 and IA-2␤ are components of dense core vesicle membranes and play important roles in vesicle loading and release (11,14,17,29,44,49). Targeted disruption of these genes in mice leads to impaired secretion of hormones and neurotransmitters, which are more severe in mice lacking functional alleles of both genes (16, 22, 24 -26, 42, 48). These proteins are also of interest at the clinical level, since the majority of newly diagnosed diabetic patients have antibodies against these proteins, and antibodies appear years before disease development, identifying them as major autoantigens predictive of type 1 diabetes (30,36,49).A recent study to assess the cardiovascular impact of targeted disruption of IA-2 and IA-2␤ revealed that mice lacking these proteins did not have daily rhythms in blood pressure, heart rate, core body temperature, or spontaneous locomotor activity (21). Electrophysiological studies on the suprachiasmatic nuclei (SCN), the site of the brain's master cir...

Myocardial depression is a common yet reversible phenomenon that occurs in patients in septic shock. Initially, it was unclear whether this provided an adaptive survival benefit, as early studies showed decreased mortality in septic patients with myocardial depression. However, subsequent larger studies have debunked this myth. Given that no benefit exists, cardiac dysfunction in septic patients may be monitored via echocardiography and may be treated with inotropic agents. Beta-blockers provide a novel avenue of treatment as they aid in reducing adrenergic overstimulation and cytokine production, which may drive the pathogenesis of septic shock. This review chronicles how the understanding of myocardial depression in sepsis has evolved and how it should be clinically managed.