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The purpose of this study was to investigate the effect of empagliflozin on diastolic function in a nondiabetic heart failure with reduced ejection fraction (HFrEF) scenario and on the pathways causing diastolic dysfunction. This group demonstrated that empagliflozin ameliorates adverse cardiac remodeling, enhances myocardial energetics, and improves left ventricular systolic function in a nondiabetic porcine model of HF. Whether empagliflozin also improves diastolic function remains unknown. Hypothetically, empagliflozin would improve diastolic function in HF mediated both by a reduction in interstitial myocardial fibrosis and an improvement in cardiomyocyte stiffness (titin phosphorylation). HF was induced in nondiabetic pigs by 2-h balloon occlusion of proximal left anterior descending artery. Animals were randomized to empagliflozin or placebo for 2 months. Cardiac function was evaluated with cardiac magnetic resonance (CMR), 3-dimensional echocardiography, and invasive hemodynamics. In vitro relaxation of cardiomyocytes was studied in primary culture. Myocardial samples were obtained for histological and molecular evaluation. Myocardial metabolite consumption was analyzed by simultaneous blood sampling from coronary artery and coronary sinus. Despite similar initial ischemic myocardial injury, the empagliflozin group showed significantly improved diastolic function at 2 months, assessed by conventional echocardiography (higher e′ and color M-mode propagation velocity, lower E/e′ ratio, myocardial performance Tei index, isovolumic relaxation time, and left atrial size), echocardiography-derived strain imaging (strain imaging diastolic index, strain rate at isovolumic relaxation time and during early diastole, and untwisting), and CMR (higher peak filling rate, larger first filling volume). Invasive hemodynamics confirmed improved diastolic function with empagliflozin (better peak LV pressure rate of decay (–dP/dt), shorter Tau, lower end-diastolic pressure-volume relationship (EDPVR), and reduced filling pressures). Empagliflozin reduced interstitial myocardial fibrosis at the imaging, histological and molecular level. Empagliflozin improved nitric oxide signaling (endothelial nitric oxide synthetase [eNOS] activity, nitric oxide [NO] availability, cyclic guanosine monophosphate (cGMP) content, protein kinase G [PKG] signaling) and enhanced titin phosphorylation (which is responsible for cardiomyocyte stiffness). Indeed, isolated cardiomyocytes exhibited better relaxation in empagliflozin-treated animals. Myocardial consumption of glucose and ketone bodies negatively and positively correlated with diastolic function, respectively. Empagliflozin ameliorates diastolic function in a nondiabetic HF porcine model, mitigates histological and molecular remodeling, and reduces both left ventricle and cardiomyocyte stiffness. [ABSTRACT FROM AUTHOR]

Background: The Fontan operation has provided life-saving palliation and adult survival for individuals born with single ventricle physiology. Many now seek advice about safe pregnancy. Little data are, however, available, consisting mainly of anecdotal experience and small series. This article seeks to review the published literature and identify lessons learnt from this collective experience.Methods and Results: We conducted a systematic review to evaluate maternal and fetal outcomes of pregnancy in women with a Fontan circulation. Among 1150 studies that were screened, 6 studies had sufficient longitudinal data points to qualify for meaningful inclusion, yielding 255 pregnancies in 133 women after Fontan procedure resulting in 115 live births (45%; including reports from 1986 to 2015). There was a total of 137 pregnancy losses (69%), with 115 miscarriages (45%), 19 elective terminations of pregnancy (7%), 2 stillbirths (1%), and 1 ectopic pregnancy (1%).The most common cardiovascular adverse events were supraventricular arrhythmia affecting 8.4% (range, 3%-37%) and heart failure affecting 3.9% (range, 3%-11%) of pregnancies. These complications were successfully managed with conventional approaches. No maternal deaths were reported. Postpartum hemorrhage was the predominant obstetric complication affecting 14% of the patients. Most patients were on antiplatelet agents (27%) or anticoagulants (50%) whereas only a minority (11%) were on neither. Among the 115 live births, 68 were premature (59%), 17 were small for gestational age (20%), and neonatal death occurred in 6 patients (5%).Conclusions: The most commonly reported cardiovascular complications in patients with Fontan physiology-associated pregnancy were arrhythmia and heart failure. Miscarriages were highly prevalent as was prematurity and intrauterine growth restriction. Postpartum hemorrhage seems to be the most common obstetric complication. Large-scale data sets are needed to confirm these early observations and address the late sequelae of pregnancy in women with a Fontan circulation. [ABSTRACT FROM AUTHOR]