Circulation

BACKGROUND: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without prior cardiovascular disease (primary prevention). METHODS: In CREDENCE, 4401 participants with type 2 diabetes and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. RESULTS: Primary prevention participants (N=2181; 49...

Significant improvements have been achieved in cardiac arrest resuscitation and postarrest resuscitation care, but mortality remains high. Most of the poor outcomes and deaths of cardiac arrest survivors have been attributed to widespread brain injury. This brain injury, commonly manifested as a comatose state, is a marker of poor outcome and a major basis for unfavorable neurological prognostication. Accurate prognostication is important to avoid pursuing futile treatments when poor outcome is inevitable but also to avoid an inappropriate withdrawal of life-sustaining treatment in patients who may otherwise have a chance of achieving meaningful neurological recovery...

BACKGROUND: Fibrosis is a common pathology in many cardiac disorders and is driven by the activation of resident fibroblasts. The global post-transcriptional mechanisms underlying fibroblast-to-myofibroblast conversion in the heart have not been explored. METHODS: Genome-wide changes of RNA transcription and translation during human cardiac fibroblast activation were monitored with RNA sequencing and ribosome profiling. We then used an RNA-binding protein-based analyses to identify translational regulators of fibrogenic genes...

BACKGROUND: The mechanism of adverse limb events associated with peripheral artery disease remains incompletely understood. We investigated whether microvascular disease is associated with amputation in a large cohort of veterans. To determine whether microvascular disease diagnosed in any location increases the risk of amputation alone and in concert with peripheral artery disease. METHODS: Participants in the Veterans Aging Cohort Study from April 1, 2003 through December 31, 2014...

BACKGROUND: Transplantation is the treatment of choice for many patients with end-stage organ disease. Despite advances in immunosuppression, long-term outcomes remain suboptimal, hampered by drug toxicity and immune-mediated injury, the leading cause of late graft loss. The development of therapies that promote regulation while suppressing effector immunity is imperative to improve graft survival and minimize conventional immunosuppression. Notch signaling is a highly conserved pathway pivotal to T cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell-mediated immunity...

BACKGROUND: Surviving cells in the post-infarction border zone are subjected to intense fluctuations of their microenvironment. Recently, border zone cardiomyocytes have been specifically implicated in cardiac regeneration. Here, we defined their unique transcriptional and regulatory properties, and comprehensively validated new molecular markers, including Nppb, encoding B-type natriuretic peptide, after infarction. METHODS: Transgenic reporter mice were used to identify the Nppb-positive border zone after myocardial infarction...

It has been 50 years since Francis Fontan pioneered the operation that today bears his name. Initially designed for patients with tricuspid atresia, this procedure is now offered for a vast array of congenital cardiac lesions when a circulation with 2 ventricles cannot be achieved. As a result of technical advances and improvements in patient selection and perioperative management, survival has steadily increased, and it is estimated that patients operated on today may hope for a 30-year survival of >80%...

BACKGROUND: Hypertriglyceridemia is associated with increased cardiovascular risk and may be caused by impaired lipoprotein clearance. Angiopoietin-like protein 3 (ANGPTL3) inhibits lipoprotein lipase activity, increasing triglycerides and other lipids. Evinacumab, an ANGPTL3 inhibitor, reduced triglycerides in healthy human volunteers and in homozygous familial hypercholesterolemic individuals. Results from 2 Phase 1 studies in hypertriglyceridemic subjects are reported here. METHODS: Subjects with triglycerides >150 but ≤450 mg/dL and LDL-C ≥100 mg/dL (n=83 for single ascending dose study [SAD]; n=56 for multiple ascending dose study [MAD]) were randomized 3:1 to evinacumab:placebo...

Successful resuscitation from cardiac arrest results in a post-cardiac arrest syndrome, which can evolve in the days to weeks after return of sustained circulation. The components of post-cardiac arrest syndrome are brain injury, myocardial dysfunction, systemic ischemia/reperfusion response, and persistent precipitating pathophysiology. Pediatric post-cardiac arrest care focuses on anticipating, identifying, and treating this complex physiology to improve survival and neurological outcomes. This scientific statement on post-cardiac arrest care is the result of a consensus process that included pediatric and adult emergency medicine, critical care, cardiac critical care, cardiology, neurology, and nursing specialists who analyzed the past 20 years of pediatric cardiac arrest, adult cardiac arrest, and pediatric critical illness peer-reviewed published literature...

BACKGROUND: Acute limb ischemia (ALI) is an important clinical event and an emerging cardiovascular clinical trial outcome. Risk factors for and outcomes after ALI have not been fully evaluated. METHODS: EUCLID randomized patients with peripheral artery disease (PAD) to ticagrelor versus clopidogrel. Enrollment criteria included an ankle-brachial index (ABI) ≤0.80 or prior lower extremity revascularization. Patients were grouped according to the primary outcome, post-randomization ALI hospitalization...

BACKGROUND: In patients with acute minor ischemic stroke or high-risk transient ischemic attack enrolled in the POINT trial, the combination of clopidogrel and aspirin for 90 days reduced major ischemic events but increased major hemorrhage compared to aspirin alone. METHODS: In a secondary analysis of POINT (N=4,881), we assessed the time course for benefit and risk from the combination of clopidogrel and aspirin. The primary efficacy outcome was a composite of ischemic stroke, myocardial infarction, or ischemic vascular death...

BACKGROUND: Drug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are among the most commonly used medications worldwide. METHODS: Genetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure at genome-wide significance...

BACKGROUND: Myocardial ischemia-reperfusion (MI/R) injury is a significant clinical problem without effective therapy. Unbiased-omics approaches may reveal key MI/R mediators to initiate MI/R injury. METHODS: We utilized a dynamic transcriptome analysis of mouse heart exposed to various MI/R periods to identify S100a8/a9 as an early mediator. Using loss/gain of function approaches to understand the role of S100a8/a9 in MI/R injury. We explored the mechanisms through transcriptome and functional experiment...

BACKGROUND: Polycystin-1 (PC1) is a transmembrane protein originally identified in autosomal dominant polycystic kidney disease (ADPKD) where it regulates the calcium-permeant cation channel polycystin-2. ADPKD patients develop renal failure, hypertension, left ventricular hypertrophy, atrial fibrillation, among other cardiovascular disorders. These individuals harbor PC1 loss-of-function mutations in their cardiac myocytes, but the functional consequences are unknown. PC1 is ubiquitously expressed, and its experimental ablation in cardiomyocyte-specific knockout mice reduces contractile function...

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BACKGROUND: Total cholesterol and HDL-C measurements are central to CVD risk assessment, but there is continuing debate around the utility of other lipids for risk prediction. METHODS: Participants from UK Biobank without baseline CVD and not taking statins, with relevant lipid measurements (n=346,686), were included in the primary analysis. An incident fatal or non-fatal CVD event occurred in 6,216 participants (1,656 fatal) over a median of 8.9 years. Associations of non-fasting lipid measurements (total cholesterol, HDL-C, non-HDL-C, direct and calculated LDL-C, ApoA1 and ApoB) with CVD were compared using Cox models adjusting for classical risk factors, and predictive utility was determined by the C-index and net reclassification index...

BACKGROUND: Novel, effective, and safe drugs are warranted for treatment of ischemic stroke. Circulating protein biomarkers with causal genetic evidence represent promising drug targets but no systematic screen of the proteome has been performed. METHODS: First, using Mendelian Randomization (MR) analyses, we assessed 653 circulating proteins as possible causal mediators for three different subtypes of ischemic stroke: large artery atherosclerosis, cardioembolic stroke, and small artery occlusion...

BACKGROUND: Bridge to transplant (BTT) with left ventricular assist devices (LVAD) is a mainstay of therapy for heart failure in patients awaiting heart transplantation (HT). Criteria for HT listing does not differ between patients medically managed versus mechanically bridged to HT. The objectives of the current study were to evaluate the impact of BTT with LVAD on posttransplant survival, to describe differences in causes of 1-year mortality in medically and mechanically bridged patients, and to evaluate differences in risk factors for 1-year mortality between those with and without LVAD at the time of HT...

BACKGROUND: World-wide, diabetes and heart failure represent frequent comorbidities with high socioeconomic impact and steadily growing incidence, calling for a better understanding of how diabetic metabolism promotes cardiac dysfunction. Paradoxically, some glucose-lowering drugs have been shown to worsen heart failure, raising the question of how glucose mediates protective versus detrimental cardiac signaling. Here, we identified a histone deacetylase 4 (HDAC4) subdomain as a molecular checkpoint of adaptive and maladaptive signaling in the diabetic heart...

BACKGROUND: Abnormal calcium (Ca2+ ) release from the sarcoplasmic reticulum (SR) contributes to the pathogenesis of atrial fibrillation (AF). Increased phosphorylation of two proteins essential for normal SR-Ca2+ cycling, the type-2 ryanodine receptor (RyR2) and phospholamban (PLN), enhances the susceptibility to AF, but the underlying mechanisms remain unclear. Protein phosphatase 1 (PP1) limits steady-state phosphorylation of both RyR2 and PLN. Proteomic analysis uncovered a novel PP1-regulatory subunit (PPP1R3A) in the RyR2 macromolecular channel complex which has been previously shown to mediate PP1 targeting to PLN...