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The mechanisms underlying the disproportionate effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities, however, remain incompletely understood.1,2 SARS-CoV-2 infects the host using the angiotensin converting enzyme 2 (ACE2) receptor, which is expressed in several organs, including the lung, heart, kidney, and intestine. Intriguingly, SARS-CoV-2 can directly infect engineered human blood vessel organoids in vitro.4 Here we demonstrate endothelial cell involvement across vascular beds of different organs in a series of patients with COVID-19 (further case details are provided in the appendix). The vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homoeostasis.5 Endothelial dysfunction is a principal determinant of microvascular dysfunction by shifting the vascular equilibrium towards more vasoconstriction with subsequent organ ischaemia, inflammation with associated tissue oedema, and a pro-coagulant state.6 Our findings show the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death.

This randomized trial involving patients with osteoarthritis or rheumatoid arthritis who were at increased cardiovascular risk showed the noninferiority of celecoxib to naproxen or ibuprofen with respect to cardiovascular safety. Nonsteroidal antiinflammatory drugs (NSAIDs) were introduced in the 1960s and became the most widely prescribed class of drugs in the world, with more than 100 million prescriptions issued annually in the United States alone. 1 NSAIDs inhibit cyclooxygenase (COX), which reduces pain and inflammation through the inhibition of prostaglandins. However, the COX enzyme is also present in gastric mucosa, where it stimulates gastroprotective prostaglandins. The identification of two isoforms, COX-1 and COX-2, and the recognition that antiinflammatory and analgesic effects are mediated through COX-2 inhibition — whereas the gastrointestinal toxic effects are linked to COX-1 inhibition — resulted in the development . . .

Background Beta-blockers are widely used for many cardiovascular conditions; however, their efficacy in contemporary clinical practice remains uncertain. Methods We performed a prospectively designed, umbrella review of meta-analyses of randomised controlled trials (RCTs) investigating the evidence of beta-blockers in the contemporary management of coronary artery disease (CAD), heart failure (HF), patients undergoing surgery or hypertension (registration: PROSPERO CRD42016038375). We searched MEDLINE, EMBASE and the Cochrane Library from inception until December 2018. Outcomes were analysed as beta-blockers versus control for all-cause mortality, myocardial infarction (MI), incident HF or stroke. Two independent investigators abstracted the data, assessed the quality of the evidence and rated the certainty of evidence. Results We identified 98 meta-analyses, including 284 unique RCTs and 1,617,523 patient-years of follow-up. In CAD, 12 meta-analyses (93 RCTs, 103,481 patients) showed that beta-blockers reduced mortality in analyses before routine reperfusion, but there was a lack of benefit in contemporary studies where ≥ 50% of patients received thrombolytics or intervention. Beta-blockers reduced incident MI at the expense of increased HF. In HF with reduced ejection fraction, 34 meta-analyses (66 RCTs, 35,383 patients) demonstrated a reduction in mortality and HF hospitalisation with beta-blockers in sinus rhythm, but not in atrial fibrillation. In patients undergoing surgery, 23 meta-analyses (89 RCTs, 19,211 patients) showed no effect of beta-blockers on mortality for cardiac surgery, but increased mortality in non-cardiac surgery. In non-cardiac surgery, beta-blockers reduced MI after surgery but increased the risk of stroke. In hypertension, 27 meta-analyses (36 RCTs, 260,549 patients) identified no benefit versus placebo, but beta-blockers were inferior to other agents for preventing mortality and stroke. Conclusions Beta-blockers substantially reduce mortality in HF patients in sinus rhythm, but for other conditions, clinicians need to weigh up both benefit and potential risk.

Heart Failure (HF) is a major health and economic issue worldwide. HF-related expenses are largely driven by hospital admissions and re-admissions, many of which are potentially preventable. Current self-management programs, however, have failed to reduce hospital admissions. This may be explained by their low predictive power for decompensation and high adherence requirements. Slight alterations in the voice profile may allow to detect decompensation in HF patients at an earlier stage and reduce hospitalizations. This pilot study investigates the potential of voice as a digital biomarker to predict health status deterioration in HF patients. In a two-month longitudinal observational study, we collect voice samples and HF-related quality-of-life questionnaires from 35 stable HF patients. Patients use our developed study application installed on a tablet at home during the study period. From the collected data, we use signal processing to extract voice characteristics from the audio samples and associate them with the answers to the questionnaire data. The primary outcome will be the correlation between voice characteristics and HF-related quality-of-life health status. The study was reviewed and approved by the Cantonal Ethics Committee Zurich (BASEC ID:2022-00912). Results will be published in medical and technical peer-reviewed journals.

Background Metabolic cardiomyopathy (MCM), characterized by intramyocardial lipid accumulation, drives the progression to heart failure with preserved ejection fraction (HFpEF). Although evidence suggests that the mammalian silent information regulator 1 (Sirt1) orchestrates myocardial lipid metabolism, it is unknown whether its exogenous administration could avoid MCM onset. We investigated whether chronic treatment with recombinant Sirt1 (rSirt1) could halt MCM progression. Methods db/db mice, an established model of MCM, were supplemented with intraperitoneal rSirt1 or vehicle for 4 weeks and compared with their db/  + heterozygous littermates. At the end of treatment, cardiac function was assessed by cardiac ultrasound and left ventricular samples were collected and processed for molecular analysis. Transcriptional changes were evaluated using a custom PCR array. Lipidomic analysis was performed by mass spectrometry. H9c2 cardiomyocytes exposed to hyperglycaemia and treated with rSirt1 were used as in vitro model of MCM to investigate the ability of rSirt1 to directly target cardiomyocytes and modulate malondialdehyde levels and caspase 3 activity. Myocardial samples from diabetic and nondiabetic patients were analysed to explore Sirt1 expression levels and signaling pathways. Results rSirt1 treatment restored cardiac Sirt1 levels and preserved cardiac performance by improving left ventricular ejection fraction, fractional shortening and diastolic function (E/A ratio). In left ventricular samples from rSirt1-treated db/db mice, rSirt1 modulated the cardiac lipidome: medium and long-chain triacylglycerols, long-chain triacylglycerols, and triacylglycerols containing only saturated fatty acids were reduced, while those containing docosahexaenoic acid were increased. Mechanistically, several genes involved in lipid trafficking, metabolism and inflammation, such as Cd36 , Acox3 , Pparg , Ncoa3 , and Ppara were downregulated by rSirt1 both in vitro and in vivo. In humans, reduced cardiac expression levels of Sirt1 were associated with higher intramyocardial triacylglycerols and PPARG-related genes. Conclusions In the db/db mouse model of MCM, chronic exogenous rSirt1 supplementation rescued cardiac function. This was associated with a modulation of the myocardial lipidome and a downregulation of genes involved in lipid metabolism, trafficking, inflammation, and PPARG signaling. These findings were confirmed in the human diabetic myocardium. Treatments that increase Sirt1 levels may represent a promising strategy to prevent myocardial lipid abnormalities and MCM development. Graphical Abstract

Heart failure (HF) is among the most prevalent health issues worldwide and is associated with high mortality. Adequate decongestion remain the main clinical challenge in HF management. Sodium glucose cotransporter-2 inhibitors (SGLT-2i) have been recently introduced as a new treatment option in patients with HF irrespective of left ventricular ejection fraction. Although the favorable effects of SGLT-2i are profoundly evident, the underlying mechanisms are not yet well understood. The aim of this study is to provide novel insights into the effects of dapagliflozin, a SGLT-2i with proven cardiovascular benefit, on blood volume profile and vascular function in HF patients who had a recent event of acute decompensated heart failure (ADHF). Eighty adult patients with diagnosis of de novo or chronic HF (NYHA class II-IV), clinically stabilized after an ADHF event and with preserved renal function, who were not on treatment with SGLT-2i, are aimed to be included. The patients are randomized with 1:1 allocation to either dapagliflozin 10 mg p.o. once daily or placebo in addition to guideline-directed medical therapy. The primary outcome is the mean change in plasma volume status (PVS) in the dapagliflozin group compared to placebo. PVS is assessed via optimized carbon monoxide rebreathing technique, a reliable and safe method to measure total hemoglobin mass and to estimate blood volume profile, i.e., blood volume, plasma volume and red blood cell volume. Secondary outcomes include differences between the two study groups regarding blood volume profile, micro- and macro-vascular function assessed by retinal vessel analysis and flow-mediated vasodilation, respectively, changes in body water distribution, quality of life, exercise capacity, echocardiographic and laboratory parameters. The study has been approved by the Cantonal Ethics Committee Zurich (BASEC-Nr.:2020-01920, Swissmedic-Nr.:2020DR4175) and has been registered at www.ClinicalTrials.gov‌ (NCT04869124). The results will be published in a peer-reviewed medical journal.

[...]the symptom complex is very similar to ACS, and it cannot be differentiated clinically and by angiography in the acute phase; therefore, TTC has been referred to as a mimic of ACS. 7 Contrary to ACS, however, the coronary arteries are typically open and the area of hypokinesia or akinesia of the left ventricle does not match that of any epicardial coronary artery. Therapeutic management has not yet been established and is rather supportive. [...]the International Takotsubo Registry ( http://www.takotsubo-registry.com ) has been established to provide a better understanding of the natural history of TTC and to improve the management of these patients in daily routine to enhance clinical outcome.

Heart failure with preserved ejection fraction (HFpEF) represents nearly half of all heart failure cases globally. The increased prevalence of cardiometabolic disease, driven by unhealthy lifestyles, has led to a growing population of people developing the so called “cardiometabolic HFpEF (cmHFpEF)” phenotype. This condition represents an end stage cardiometabolic phenotype which results from the clustering of metabolic stress (obesity), hemodynamic stress (hypertension), immune activation, and systemic inflammation. This form of HFpEF is preceded by a “metabolic cardiomyopathy” phenotype, characterized by myocardial metabolic remodeling, rewiring of lipid metabolism, and inflammation eventually fostering left ventricular hypertrophy, diastolic dysfunction and atrial dilatation. Recent work over the last years has unveiled the molecular cues underpinning cmHFpEF pathogenesis thus contributing to the identification of novel therapeutic approaches to treat this complex syndrome. The present review provides an overview of recent advances in cmHFpEF biology and pathophysiology with particular emphasis on the following aspects: (i) metabolic alterations associated with cmHFpEF; (ii) changes of the immune landscape; (iii) microvascular dysfunction; (iv) inflammation; (v) chromatin remodeling. Additionally, we will discuss potential mechanisms-based therapeutic strategies to tackle this growing health concern.

Unlike adult mammals, the hearts of neonatal mice possess the ability to completely regenerate from myocardial infarction (MI). This observation has sparked vast interest in deciphering the potentially lifesaving and morbidity-reducing mechanisms involved in neonatal cardiac regeneration. In mice, the regenerative potential is lost within the first week of life and coincides with a reduction of Insulin-like growth factor 1 receptor ( Igf1r ) expression in the heart. Igf1r is a well-known regulator of cardiomyocyte maturation and proliferation in neonatal mice. To test the role of Igf1r as a pivotal factor in cardiac regeneration, we knocked down (KD) Igf1r specifically in cardiomyocytes using recombinant adeno-associated virus (rAAV) delivery and troponin T promotor driven shRNAmirs. Cardiomyocyte specific Igf1r KD versus control mice were subjected to experimental MI by permanent ligation of the left anterior descending artery (LAD). Cardiac functional and morphological data were analyzed over a 21-day period. Neonatal Igf1r KD mice showed reduced systolic cardiac function and increased fibrotic cardiac remodeling 21 days post injury. This cardiac phenotype was associated with reduced cardiomyocyte nuclei mitosis and decreased AKT and ERK phosphorylation in Igf1r KD, compared to control neonatal mouse hearts. Our in vivo murine data show that Igf1r KD shifts neonatal cardiac regeneration to a more adult-like scarring phenotype, identifying cardiomyocyte-specific Igf1r signaling as a crucial component of neonatal cardiac regeneration.