Post-cardiac arrest Sedation Promotes Electroencephalographic Slow-wave Activity and Improves Survival in a Mouse Model of Cardiac Arrest.

BACKGROUND: Patients resuscitated from cardiac arrest are routinely sedated during targeted temperature management, while the effects of sedation on cerebral physiology and outcomes after cardiac arrest remain to be determined. The authors hypothesized that sedation would improve survival and neurologic outcomes in mice after cardiac arrest. METHODS: Adult C57BL/6J mice of both sexes were subjected to potassium chloride-induced cardiac arrest and cardiopulmonary resuscitation. Starting at the return of spontaneous circulation or at 60 min after return of spontaneous circulation, mice received intravenous infusion of propofol at 40 mg · kg-1 · h-1, dexmedetomidine at 1 µg · kg-1 · h-1, or normal saline for 2 h. Body temperature was lowered and maintained at 33°C during sedation. Cerebral blood flow was measured for 4 h postresuscitation. Telemetric electroencephalogram (EEG) was recorded in freely moving mice from 3 days before up to 7 days after cardiac arrest. RESULTS: Sedation with propofol or dexmedetomidine starting at return of spontaneous circulation improved survival in hypothermia-treated mice (propofol [13 of 16, 81%] vs. no sedation [4 of 16, 25%], P = 0.008; dexmedetomidine [14 of 16, 88%] vs. no sedation [4 of 16, 25%], P = 0.002). Mice receiving no sedation exhibited cerebral hyperemia immediately after resuscitation and EEG power remained less than 30% of the baseline in the first 6 h postresuscitation. Administration of propofol or dexmedetomidine starting at return of spontaneous circulation attenuated cerebral hyperemia and increased EEG slow oscillation power during and early after sedation (40 to 80% of the baseline). In contrast, delayed sedation failed to improve outcomes, without attenuating cerebral hyperemia and inducing slow-wave activity. CONCLUSIONS: Early administration of sedation with propofol or dexmedetomidine improved survival and neurologic outcomes in mice resuscitated from cardiac arrest and treated with hypothermia. The beneficial effects of sedation were accompanied by attenuation of the cerebral hyperemic response and enhancement of electroencephalographic slow-wave activity.

lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth.

BACKGROUND: The heart grows in response to pathological and physiological stimuli. The former often precedes cardiomyocyte loss and heart failure; the latter paradoxically protects the heart and enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. Although long noncoding RNAs (lncRNAs) are important in cardiac development and disease, less is known about their roles in physiological hypertrophy or cardiomyogenesis. METHODS: RNA sequencing was applied to hearts from mice after 8 weeks of voluntary exercise-induced physiological hypertrophy and cardiomyogenesis or transverse aortic constriction for 2 or 8 weeks to induce pathological hypertrophy or heart failure. The top lncRNA candidate was overexpressed in hearts with adeno-associated virus vectors and inhibited with antisense locked nucleic acid-GapmeRs to examine its function. Downstream effectors were identified through promoter analyses and binding assays. The functional roles of a novel downstream effector, dachsous cadherin-related 2 (DCHS2), were examined through transgenic overexpression in zebrafish and cardiac-specific deletion in Cas9-knockin mice. RESULTS: We identified exercise-regulated cardiac lncRNAs, called lncExACTs. lncExACT1 was evolutionarily conserved and decreased in exercised hearts but increased in human and experimental heart failure. Cardiac lncExACT1 overexpression caused pathological hypertrophy and heart failure; lncExACT1 inhibition induced physiological hypertrophy and cardiomyogenesis, protecting against cardiac fibrosis and dysfunction. lncExACT1 functioned by regulating microRNA-222, calcineurin signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCHS2 overexpression in zebrafish induced pathological hypertrophy and impaired cardiac regeneration, promoting scarring after injury. In contrast, murine DCHS2 deletion induced physiological hypertrophy and promoted cardiomyogenesis. CONCLUSIONS: These studies identify lncExACT1-DCHS2 as a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1-DCHS2 acts as a master switch toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the beneficial effects of exercise.

Effect of Impella 5.5 on Preexisting Functional Mitral Regurgitation in Patients with Heart Failure-Related Cardiogenic Shock.

Background: Heart failure-related cardiogenic shock (HF-CS) is increasingly common. Moderate/severe functional mitral regurgitation (FMR) is commonly seen in patients presenting with decompensated heart failure and is associated with worse outcomes. Percutaneous mechanical circulatory support devices are increasingly used to provide hemodynamic support for ongoing CS. There is no description of the impact of Impella device on hemodynamic response when used in combination with preexisting FMR. Methods: Retrospective review of patients aged ≥18 years, who underwent Impella 5.5 implant for HF-CS, and who had a transthoracic echocardiogram performed pre- and post-Impella. Results: Of 24 patients, 33% had moderate-to-severe/severe FMR, 38% had mild-moderate/moderate FMR, and 29% had trace/mild FMR on pre-Impella transthoracic echocardiogram. Additional right ventricular assist device was simultaneously inserted in 3 patients, of whom 1 had severe, 1 had moderate, and another had mild FMR pre-Impella. Despite maximally tolerated Impella unloading, 6 patients (25%) had persistent moderate-severe/severe FMR, and 9 (37.5%) patients had persistent moderate FMR. Overall, however, there was a decrease in central venous pressure, pulmonary artery diastolic pressure, serum lactate, and vasoactive-inotrope score at 24 â€‹hours post-Impella, and survival was high at 83%. Conclusions: In a retrospective cohort of patients admitted with HF-CS who underwent Impella 5.5 implant for hemodynamic support, Impella did not seem to acutely ameliorate FMR severity. Despite this, there was a significant improvement in hemodynamic response at 24 â€‹hours post-Impella. In carefully selected patients, especially those with isolated left ventricular failure, Impella 5.5 may provide adequate hemodynamic support even in the presence of higher severity FMR.

Mir-30d Regulates Cardiac Remodeling by Intracellular and Paracrine Signaling.

RATIONALE: Previous translational studies implicate plasma extracellular microRNA-30d (miR-30d) as a biomarker in left ventricular remodeling and clinical outcome in heart failure (HF) patients, although precise mechanisms remain obscure. OBJECTIVE: To investigate the mechanism of miR-30d-mediated cardioprotection in HF. METHODS AND RESULTS: In rat and mouse models of ischemic HF, we show that miR-30d gain of function (genetic, lentivirus, or agomiR-mediated) improves cardiac function, decreases myocardial fibrosis, and attenuates cardiomyocyte (CM) apoptosis. Genetic or locked nucleic acid-based knock-down of miR-30d expression potentiates pathological left ventricular remodeling, with increased dysfunction, fibrosis, and cardiomyocyte death. RNA sequencing of in vitro miR-30d gain and loss of function, together with bioinformatic prediction and experimental validation in cardiac myocytes and fibroblasts, were used to identify and validate direct targets of miR-30d. miR-30d expression is selectively enriched in cardiomyocytes, induced by hypoxic stress and is acutely protective, targeting MAP4K4 (mitogen-associate protein kinase 4) to ameliorate apoptosis. Moreover, miR-30d is secreted primarily in extracellular vesicles by cardiomyocytes and inhibits fibroblast proliferation and activation by directly targeting integrin α5 in the acute phase via paracrine signaling to cardiac fibroblasts. In the chronic phase of ischemic remodeling, lower expression of miR-30d in the heart and plasma extracellular vesicles is associated with adverse remodeling in rodent models and human subjects and is linked to whole-blood expression of genes implicated in fibrosis and inflammation, consistent with observations in model systems. CONCLUSIONS: These findings provide the mechanistic underpinning for the cardioprotective association of miR-30d in human HF. More broadly, our findings support an emerging paradigm involving intercellular communication of extracellular vesicle-contained miRNAs (microRNAs) to transregulate distinct signaling pathways across cell types. Functionally validated RNA biomarkers and their signaling networks may warrant further investigation as novel therapeutic targets in HF.

Obesity and the Risk of Intubation or Death in Patients With Coronavirus Disease 2019.

OBJECTIVES: To characterize the impact of obesity on disease severity in patients with coronavirus disease 2019. DESIGN: This was a retrospective cohort study designed to evaluate the association between body mass index and risk of severe disease in patients with coronavirus disease 2019. Data were abstracted from the electronic health record. The primary endpoint was a composite of intubation or death. SETTING: Two hospitals in Massachusetts (one quaternary referral center and one affiliated community hospital). PATIENTS: Consecutive patients hospitalized with confirmed coronavirus disease 2019 admitted between March 13, 2020, and April 3, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 305 patients were included in this study. We stratified patients by body mass index category: < 25 kg/m (54 patients, 18%), ≥ 25 kg/m to < 30 kg/m (124 patients, 41%), ≥ 30 kg/m to < 35 kg/m (58 patients, 19%), and ≥ 35 kg/m (69 patients, 23%). In total, 128 patients (42%) had a primary endpoint (119 patients [39%] were intubated and nine died [3%] without intubation). Sixty-five patients (51%) with body mass index greater than or equal to 30 kg/m were intubated or died. Adjusted Cox models demonstrated that body mass index greater than or equal to 30 kg/m was associated with a 2.3-fold increased risk of intubation or death (95% CI, 1.2-4.3) compared with individuals with body mass index less than 25 kg/m. Diabetes was also independently associated with risk of intubation or death (hazard ratio, 1.8; 95% CI, 1.2-2.7). Fifty-six out of 127 patients (44%) with body mass index greater than or equal to 30 kg/m had diabetes, and the combination of both diabetes and body mass index greater than or equal to 30 kg/m was associated with a 4.5-fold increased risk of intubation or death (95% CI, 2.0-10.2) compared with patients without diabetes and body mass index less than 25 kg/m. CONCLUSIONS: Among consecutive patients hospitalized with coronavirus disease 2019, obesity was an independent risk factor for intubation or death.

Profiling Extracellular Long RNA Transcriptome in Human Plasma and Extracellular Vesicles for Biomarker Discovery.

The recent discovery of extracellular RNAs in blood, including RNAs in extracellular vesicles (EVs), combined with low-input RNA-sequencing advances have enabled scientists to investigate their role in human disease. To date, most studies have been focusing on small RNAs, and methodologies to optimize long RNAs measurement are lacking. We used plasma RNA to assess the performance of six long RNA sequencing methods, at two different sites, and we report their differences in reads (%) mapped to the genome/transcriptome, number of genes detected, long RNA transcript diversity, and reproducibility. Using the best performing method, we further compare the profile of long RNAs in the EV- and no-EV-enriched RNA plasma compartments. These results provide insights on the performance and reproducibility of commercially available kits in assessing the landscape of long RNAs in human plasma and different extracellular RNA carriers that may be exploited for biomarker discovery.

Circulating miRNAs and Risk of Sudden Death in Patients With Coronary Heart Disease.

OBJECTIVES: This study evaluated whether plasma miRNAs were specifically associated with sudden cardiac and/or arrhythmic death (SCD) in a cohort of patients with coronary heart disease (CHD), most of whom were without primary prevention implantable cardioverter-defibrillators. BACKGROUND: Novel biomarkers for sudden death risk stratification are needed in patients with CHD to more precisely target preventive therapies, such as implantable cardioverter-defibrillators. miRNAs have been implicated in regulating inflammation and cardiac fibrosis in cells, and plasma miRNAs have been shown to predict cardiovascular death in patients with CHD. METHODS: We performed a nested case control study within a multicenter cohort of 5,956 patients with CHD followed prospectively for SCD. Plasma levels of 18 candidate miRNAs previously associated with cardiac remodeling were measured in 129 SCD cases and 258 control subjects matched on age, sex, race, and left ventricular ejection fraction. RESULTS: miR-150-5p, miR-29a-3p, and miR-30a-5p were associated with increased SCD risk (odds ratios and 95% confidence intervals: 2.03 [1.12 to 3.67]; p = 0.02; 1.93 [1.07 to 3.50]; p = 0.02; 0.55 [0.31 to 0.97]; p = 0.04, respectively, for third vs. first tertile miRNA level). Unfavorable levels of all 3 miRNAs was associated with a 4.8-fold increased SCD risk (1.59 to 14.51; p = 0.006). A bioinformatics-based approach predicted miR-150-5p, miR-29a-3p, and miR-30a-5p to be involved in apoptosis, fibrosis, and inflammation. CONCLUSIONS: These findings suggest that plasma miRNAs may regulate pathways important for remodeling and may be useful in identifying patients with CHD at increased risk of SCD.

Association Between Triglyceride Lowering and Reduction of Cardiovascular Risk Across Multiple Lipid-Lowering Therapeutic Classes: A Systematic Review and Meta-Regression Analysis of Randomized Controlled Trials.

BACKGROUND: Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events. METHODS: We performed a systematic review and trial-level meta-regression analysis of 3 classes of lipid-lowering therapies that reduce triglycerides to a greater extent than they do low-density lipoprotein cholesterol (LDL-C): fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported major vascular events. We also incorporated data from a previous meta-regression of 25 statin trials. The main outcome measure was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters. RESULTS: A total of 197 270 participants from 24 trials of nonstatin therapy with 25 218 major vascular events and 177 088 participants from 25 trials of statin therapy with 20 962 major vascular events were included, for a total of 374 358 patients and 46 180 major cardiovascular events. Starting with non-high-density lipoprotein cholesterol, a surrogate for very-low-density lipoproteins and low-density lipoproteins, the RR per 1-mmol/L reduction in non-high-density lipoprotein cholesterol was 0.79 (95% CI, 0.76-0.82; P<0.0001; 0.78 per 40 mg/dL). In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for low-density lipoproteins and very-low-density lipoproteins, respectively), the RR was 0.80 (95% CI, 0.76-0.85; P<0.0001) per 1-mmol/L (0.79 per 40 mg/dL) reduction in LDL-C and 0.84 (95% CI, 0.75-0.94; P=0.0026) per 1-mmol/L (0.92 per 40 mg/dL) reduction in triglycerides. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (95% CI, 0.76-0.83; P<0.0001) per 1-mmol/L (0.78 per 40 mg/dL) reduction in LDL-C and 0.91 (95% CI, 0.81-1.006; P=0.06) per 1-mmol/L (0.96 per 40 mg/dL) reduction in triglycerides. In regard to omega-3 dose, each 1 g/d eicosapentaenoic acid administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [95% CI, 0.91-0.95]; P<0.0001), whereas there was no significant association between the dose of docosahexaenoic acid and the relative risk reduction in major vascular events (RR 0.96 [95% CI, 0.89-1.03]). CONCLUSIONS: In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects.

Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus.

BACKGROUND: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. METHODS: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF <45%. Outcomes of interest were the composite of cardiovascular death/HHF, its components, and all-cause mortality. RESULTS: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45-0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76-1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66-1.17]) and those without HF (HR, 0.88 [95% CI, 0.74-1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43-0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62-0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34-0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89-1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40-0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86-1.10]; P for interaction=0.016). CONCLUSIONS: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

Higher cardiorespiratory fitness predicts long-term survival in patients with heart failure and preserved ejection fraction: the Henry Ford Exercise Testing (FIT) Project.

INTRODUCTION: Higher cardiorespiratory fitness (CRF) is associated with improved exercise capacity and quality of life in heart failure with preserved ejection fraction (HFpEF), but there are no large studies evaluating the association of HFpEF, CRF, and long-term survival. We therefore aimed to determine the association between CRF and all-cause mortality, in patients with HFpEF. MATERIAL AND METHODS: In the Henry Ford Exercise Testing (FIT) Project, 167 patients had baseline HFpEF, defined as a clinical diagnosis of heart failure with ejection fraction ≥ 50% on echocardiogram. The CRF was estimated from the peak workload (in METs) from a clinician-referred treadmill stress test and categorized as poor (1-4 METs), intermediate (5-6 METs), and moderate-high (≥ 7 METs). Additional analyses assessing the effect of HFpEF and CRF on mortality were also conducted, matching HFpEF patients to non-HFpEF patients using propensity scores. RESULTS: Mean age was 64 ±13 years, with 55% women, and 46% Black. Over a median follow-up of 9.7 (5.2-18.9) years, there were 103 deaths. In fully adjusted models, moderate-high CRF was associated with 63% lower mortality risk (HR = 0.37, 95% CI: 0.18-0.73) compared to the poor-CRF group. In the propensity-matched cohort, HFpEF was associated with a HR of 2.3 (95% CI: 1.7-3.2) for mortality compared to non-HFpEF patients, which was attenuated to 1.8 (95% CI: 1.3-2.5) after adjusting for CRF. CONCLUSIONS: Moderate-high CRF in patients with HFpEF is associated with improved survival, and differences in CRF partly explain the intrinsic risk of HFpEF. Randomized trials of interventions aimed at improving CRF in HFpEF are needed.

Prognostic role of GDF-15 across the spectrum of clinical risk in patients with NSTE-ACS.

Background Growth differentiation factor (GDF)-15 has been shown to predict cardiovascular (CV) outcomes in acute coronary syndrome (ACS) using non-commercial assays. We evaluated the prognostic performance of GDF-15 measured with the first clinically available assay. Furthermore, we evaluated whether GDF-15 was associated with CV death or heart failure (HF) across the spectrum of risk in non-ST-segment elevation (NSTE)-ACS. Methods We measured baseline GDF-15 (Roche, Elecsys) in 4330 patients with NSTE-ACS enrolled in MERLIN-TIMI 36. Patients were categorized using a priori thresholds of GDF-15 levels (<1200, 1200-1800, ≥1800 ng/L) and stratified according to estimated clinical risk per TIMI risk score (0-2, 3-4, and ≥5). Cox modeling included age, sex, BMI, smoking, HF, diabetes, renal function, NT-proBNP, hsTnT, and hsCRP. Results There were 2286 (53%), 1104 (25%), and 940 (22%) pts with GDF-15 <1200, 1200-1800, and ≥1800 respectively. GDF-15 was significantly associated after multivariable adjustment with CV death/HF modeled either as a categorical (1200-1800 ng/L: Adj hazard ratios [HR] 1.55 [1.09-2.19]; ≥1800 ng/L: Adj HR 1.94 [1.34-2.79]) or continuous variable (Adj HR 1.36 [1.16-1.60] per 1-unit increase in log2-transformed GDF-15). Notably, there was an interaction (Pinteraction=0.003) between TIMI risk score and GDF-15, with GDF-15 identifying the greatest incremental relative risk in those at lowest risk based on the TIMI risk score alone. Conclusions Using a clinically available assay, GDF-15 can be applied using established cut-off points to independently predict risk of CV death/HF in patients with NSTE-ACS. This incremental risk appears to be particularly robust among individuals traditionally identified as low risk.

Comparison of treatment options for depression in heart failure: A network meta-analysis.

BACKGROUND: Depression independently predicts poor outcomes in heart failure (HF) patients, including increased mortality, morbidity and 30-day re-hospitalization. In this network meta-analysis, we compared different interventions designed to treat depression in HF. MATERIALS AND METHODS: Electronic searches were conducted using Ovid MEDLINE, EMBASE, CINAHL, Web of Science, and PsycINFO up to November 2016. Included randomized clinical trials (RCTs) compared interventions (Exercise therapy (ET), cognitive behavioral therapy (CBT) or antidepressant (AD) medications) for depression in heart failure patients. The primary outcome was change in depressive symptoms based on validated measures of depression. Network meta-analysis based on random effects model estimating standardized mean difference (SMD) with 95% confidence interval (CI), compared the effects of the 3 classes of interventions with respect to usual care or placebo control conditions. RESULTS: A total of 21 RCTs (including 4563 HF patients) reporting the effects of treating depression in HF patients were included in the analysis. In comparison to placebo or usual standard of care, ET (SMD -0.38; 95% CI -0.54 to -0.22) and CBT (SMD -0.29; 95% CI -0.58 to -0.01) were associated with reduction in depressive symptoms whereas AD (SMD -0.16; 95% CI -0.44 to 0.11) was less effective. CONCLUSIONS: This meta-analysis is suggestive of therapeutic benefit of ET and CBT in comparison to usual standard of care in treating depression in HF patients. However, comparison among the three interventions was not conclusive. Future randomized clinical trials are warranted to compare the therapeutic effects of ET, CBT and AD in such patients.

Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes.

BACKGROUND: The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined. METHODS: We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 ml per minute per 1.73 m2 of body-surface area, new end-stage renal disease, or death from renal or cardiovascular causes) and death from any cause. RESULTS: We evaluated 17,160 patients, including 10,186 without atherosclerotic cardiovascular disease, who were followed for a median of 4.2 years. In the primary safety outcome analysis, dapagliflozin met the prespecified criterion for noninferiority to placebo with respect to MACE (upper boundary of the 95% confidence interval [CI], <1.3; P<0.001 for noninferiority). In the two primary efficacy analyses, dapagliflozin did not result in a lower rate of MACE (8.8% in the dapagliflozin group and 9.4% in the placebo group; hazard ratio, 0.93; 95% CI, 0.84 to 1.03; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; hazard ratio, 0.83; 95% CI, 0.73 to 0.95; P=0.005), which reflected a lower rate of hospitalization for heart failure (hazard ratio, 0.73; 95% CI, 0.61 to 0.88); there was no between-group difference in cardiovascular death (hazard ratio, 0.98; 95% CI, 0.82 to 1.17). A renal event occurred in 4.3% in the dapagliflozin group and in 5.6% in the placebo group (hazard ratio, 0.76; 95% CI, 0.67 to 0.87), and death from any cause occurred in 6.2% and 6.6%, respectively (hazard ratio, 0.93; 95% CI, 0.82 to 1.04). Diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02), as was the rate of genital infections that led to discontinuation of the regimen or that were considered to be serious adverse events (0.9% vs. 0.1%, P<0.001). CONCLUSIONS: In patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease, treatment with dapagliflozin did not result in a higher or lower rate of MACE than placebo but did result in a lower rate of cardiovascular death or hospitalization for heart failure, a finding that reflects a lower rate of hospitalization for heart failure. (Funded by AstraZeneca; DECLARE-TIMI 58 ClinicalTrials.gov number, NCT01730534 .).

Improvement in Outcomes After Cardiac Arrest and Resuscitation by Inhibition of S-Nitrosoglutathione Reductase.

BACKGROUND: The biological effects of nitric oxide are mediated via protein S-nitrosylation. Levels of S-nitrosylated protein are controlled in part by the denitrosylase, S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine whether GSNOR inhibition improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). METHODS: Adult wild-type C57BL/6 and GSNOR-deleted (GSNOR-/-) mice were subjected to potassium chloride-induced CA and subsequently resuscitated. Fifteen minutes after a return of spontaneous circulation, wild-type mice were randomized to receive the GSNOR inhibitor, SPL-334.1, or normal saline as placebo. Mortality, neurological outcome, GSNOR activity, and levels of S-nitrosylated proteins were evaluated. Plasma GSNOR activity was measured in plasma samples obtained from post-CA patients, preoperative cardiac surgery patients, and healthy volunteers. RESULTS: GSNOR activity was increased in plasma and multiple organs of mice, including brain in particular. Levels of protein S-nitrosylation were decreased in the brain 6 hours after CA/CPR. Administration of SPL-334.1 attenuated the increase in GSNOR activity in brain, heart, liver, spleen, and plasma, and restored S-nitrosylated protein levels in the brain. Inhibition of GSNOR attenuated ischemic brain injury and improved survival in wild-type mice after CA/CPR (81.8% in SPL-334.1 versus 36.4% in placebo; log rank P=0.031). Similarly, GSNOR deletion prevented the reduction in the number of S-nitrosylated proteins in the brain, mitigated brain injury, and improved neurological recovery and survival after CA/CPR. Both GSNOR inhibition and deletion attenuated CA/CPR-induced disruption of blood brain barrier. Post-CA patients had higher plasma GSNOR activity than did preoperative cardiac surgery patients or healthy volunteers ( P<0.0001). Plasma GSNOR activity was positively correlated with initial lactate levels in postarrest patients (Spearman correlation coefficient=0.48; P=0.045). CONCLUSIONS: CA and CPR activated GSNOR and reduced the number of S-nitrosylated proteins in the brain. Pharmacological inhibition or genetic deletion of GSNOR prevented ischemic brain injury and improved survival rates by restoring S-nitrosylated protein levels in the brain after CA/CPR in mice. Our observations suggest that GSNOR is a novel biomarker of postarrest brain injury as well as a molecular target to improve outcomes after CA.

The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial.

BACKGROUND: Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor that reduces blood glucose in patients with type 2 diabetes mellitus (T2DM) by promoting glycosuria via inhibiting urinary glucose reabsorption. In addition to improving blood glucose control, treatment with dapagliflozin results in glucose-induced osmotic diuresis, weight loss, and blood pressure lowering. Previous trials of SGLT-2 inhibitors showed reductions in cardiovascular (CV) events, including CV death and hospitalization for heart failure, and ischemic events in patients with atherosclerotic cardiovascular disease (ASCVD). RESEARCH DESIGN AND METHODS: DECLARE-TIMI 58 (NCT01730534) is a phase 3b randomized, double-blind, placebo-controlled trial designed to evaluate the CV safety and efficacy of dapagliflozin that has completed randomization of 17,160 patients with T2DM and a history of either established ASCVD (n=6,971) or multiple risk factors for ASCVD (n=10,189). Patients were randomized in a 1:1 fashion to dapagliflozin 10 mg or matching placebo. The primary safety outcome is the time to the first event of the composite of CV death, myocardial infarction, or ischemic stroke (major adverse cardiovascular events; MACEs). The co-primary efficacy outcomes are the composite of CV death, myocardial infarction, or ischemic stroke and the composite of CV death or hospitalization for heart failure. This event-driven trial will continue until at least 1,390 subjects have a MACE outcome, thereby providing >99% power to test for the primary outcome of safety of dapagliflozin measured by rejecting the hypothesis that the upper bound of the CI >1.3 for the primary outcome of MACE, as well as 85% power to detect a 15% relative risk reduction in MACE and an estimated 87% power to detect a 20% reduction in the composite of CV death or hospitalization for heart failure at a 1-sided α level of .0231. CONCLUSION: The DECLARE-TIMI 58 trial is testing the hypotheses that dapagliflozin is safe (does not increase) and may reduce the occurrence of major CV events. DECLARE-TIMI 58 is the largest study to address this question with an SGLT-2 inhibitor in patients with T2DM and with established CV disease and without CV disease but with multiple risk factors.

DECLARE-TIMI 58: Participants' baseline characteristics.

AIM: To describe the baseline characteristics of participants randomized in the Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58) trial, the pivotal study conducted to assess cardiovascular (CV) outcomes with dapagliflozin. METHODS: The DECLARE-TIMI 58 trial will analyse 17 160 patients with type 2 diabetes randomized to treatment with dapagliflozin (10 mg/d) or matching placebo. We analysed their baseline characteristics. RESULTS: The participants' mean ± SD age was 63.8 ± 6.8 years, 62.6% were male, and their mean ± SD diabetes duration was 11.8 ± 7.8 years, glycated haemoglobin 8.3% ± 1.2% (67 mmol/mol ± 9.7 mmol/mol) and body mass index 32.1 ± 6.0 kg/m2 . Randomization included 6971 (40.6%) patients with atherosclerotic CV disease (CVD), and 10 189 (59.4%) patients with multiple risk factors (MRF) for CVD (defined as men age ≥ 55 years or women ≥60 years, with at least one of dyslipidaemia, hypertension or smoking). Patients with CVD compared with patients with MRF were younger (62.5 ± 8.1 vs 64.7 ± 5.6 years), more frequently male (72.1% vs 56.1%), less often used metformin (74.6% vs 81.2%), more often used insulin (44.2% vs 36.4%), and more frequently used statins, aspirin, clopidogrel and ß-blockers (82.2%, 71.1%, 24.7% and 66.6% vs 63.7%, 39.1%, 1.5% and 32.3%, respectively). CONCLUSION: The DECLARE-TIMI 58 trial is expected to provide conclusive data on the effect of treatment with dapagliflozin in addition to standard of care, on CV outcomes in a broad patient population with type 2 diabetes and CVD or MRF for CVD.

Usefulness of Coronary Artery Calcium to Predict Heart Failure With Preserved Ejection Fraction in Men Versus Women (from the Multi-Ethnic Study of Atherosclerosis).

We studied the association of coronary artery calcium (CAC) and risk of heart failure with preserved ejection fraction (HFpEF) among men and women in a multiethnic cohort. Coronary artery disease is a risk factor for development of HFpEF and assessment of subclinical atherosclerosis using CAC may allow for the early identification of patients at risk for HFpEF. We used data from the Multi-Ethnic Study of Atherosclerosis. CAC was measured at baseline in all participants. Incident HFpEF was defined as heart failure hospitalization with left ventricular ejection fraction ≥50%. Multivariable-adjusted Cox proportional hazards models were used to calculate HFpEF risk by CAC categories (0, 1 to 100, 101 to 300, and >300) and by CAC (continuous), stratified by gender and race/ethnicity. Of 6809 total participants, 127 incident HFpEF cases (1.8%) were ascertained. Mean age was 62 years (±10 years), and the participants were 53% female, 38% White, and 12% Black. In adjusted analysis, CAC >300 was associated with increased risk of HFpEF (hazard ratio [HR] 1.68, 95% confidence interval [95 CI] 1.00, 1.83); however, this was significant only in women (HR 2.82, 95% CI 1.32, 6.00 vs HR 0.91, 95% CI 0.46, 1.82 for men, interaction p = 0.03). Similarly, CAC modeled as a continuous variable was strongly predictive in women but not in men. In conclusion, measurement of CAC, a marker of coronary atherosclerosis, may stratify risk of HFpEF beyond traditional risk factors for women. Further investigation is needed to better understand potential gender differences in pathophysiology and presentation of HFpEF.