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IMPORTANCEThe efficacy and safety of time-restricted eating have not been explored in large randomized clinical trials.OBJECTIVE To determine the effect of 16:8-hour time-restricted eating on weight loss and metabolic risk markers. INTERVENTIONSParticipants were randomized such that the consistent meal timing (CMT) group was instructed to eat 3 structured meals per day, and the time-restricted eating (TRE) group was instructed to eat ad libitum from 12:00 PM until 8:00 PM and completely abstain from caloric intake from 8:00 PM until 12:00 PM the following day. DESIGN, SETTING, AND PARTICIPANTSThis 12-week randomized clinical trial including men and women aged 18 to 64 years with a body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) of 27 to 43 was conducted on a custom mobile study application. Participants received a Bluetooth scale. Participants lived anywhere in the United States, with a subset of 50 participants living near San Francisco, California, who underwent in-person testing. MAIN OUTCOMES AND MEASURESThe primary outcome was weight loss. Secondary outcomes from the in-person cohort included changes in weight, fat mass, lean mass, fasting insulin, fasting glucose, hemoglobin A 1c levels, estimated energy intake, total energy expenditure, and resting energy expenditure.RESULTS Overall, 116 participants (mean [SD] age, 46.5 [10.5] years; 70 [60.3%] men) were included in the study. There was a significant decrease in weight in the TRE (−0.94 kg; 95% CI, −1.68 to −0.20; P = .01), but no significant change in the CMT group (−0.68 kg; 95% CI, -1.41 to 0.05, P = .07) or between groups (−0.26 kg; 95% CI, −1.30 to 0.78; P = .63). In the in-person cohort (n = 25 TRE, n = 25 CMT), there was a significant within-group decrease in weight in the TRE group (−1.70 kg; 95% CI, −2.56 to −0.83; P < .001). There was also a significant difference in appendicular lean mass index between groups (−0.16 kg/m 2 ; 95% CI, −0.27 to −0.05; P = .005). There were no significant changes in any of the other secondary outcomes within or between groups. There were no differences in estimated energy intake between groups.CONCLUSIONS AND RELEVANCE Time-restricted eating, in the absence of other interventions, is not more effective in weight loss than eating throughout the day.TRIAL REGISTRATION ClinicalTrials.gov Identifiers: NCT03393195 and NCT03637855

Abstract-Studies on patients and large animal models suggest the importance of atrial fibrosis in the development of atrial fibrillation (AF). To investigate whether increased fibrosis is sufficient to produce a substrate for AF, we have studied cardiac electrophysiology (EP) and inducibility of atrial arrhythmias in MHC-TGFcys 33 ser transgenic mice (Tx), which have increased fibrosis in the atrium but not in the ventricles. In anesthetized mice, wild-type (Wt) and Tx did not show significant differences in surface ECG parameters. With transesophageal atrial pacing, no significant differences were observed in EP parameters, except for a significant decrease in corrected sinus node recovery time in Tx mice. Burst pacing induced AF in 14 of 29 Tx mice, whereas AF was not induced in Wt littermates (PϽ0.01). In Langendorff perfused hearts, atrial conduction was studied using a 16-electrode array. Epicardial conduction velocity was significantly decreased in the Tx RA compared with the Wt RA. In the Tx LA, conduction velocity was not significantly different from Wt, but conduction was more heterogeneous. Action potential characteristics recorded with intracellular microelectrodes did not reveal differences between Wt and Tx mice in either atrium. Thus, in this transgenic mouse model, selective atrial fibrosis is sufficient to increase AF inducibility. Key Words: atrial fibrillation Ⅲ fibrosis Ⅲ growth factors A trial fibrillation (AF) is a commonly occurring arrhythmia, present in Ϸ5% of people older than age 65 years. Clinically, increased vulnerability to AF is also associated with underlying heart disease, such as congestive heart failure (CHF) and mitral valve disease. 1 Increased inducibility of AF has been observed in animal models of aging, 2,3 CHF, 4 atrial tachycardia-induced cardiomyopathy, 5,6 and chronic atrial dilatation caused by mitral regurgitation. 7 Theoretical models have implicated atrial interstitial fibrosis as a substrate for AF. 8,9 Atrial interstitial fibrosis increases with age in humans and has been observed in patients with AF 10,11 and in animal models of aging, 2,3 mitral regurgitation, 7 and CHF. 4 With the unknown cause of atrial fibrosis in humans and the presence of compounding factors in animal models, the contribution of atrial fibrosis to AF substrate formation remains unclear. Studies to date have been limited by lack of animal models of selective atrial fibrosis to study the effects of fibrosis without the presence of heart failure or other underlying heart disease.The purpose of this study was to determine the effect of atrial fibrosis on the AF vulnerability. We have studied a transgenic mouse model with cardiac overexpression of a constitutively active form of transforming growth factor (TGF)-␤1, MHC-TGFcys 33 ser. 12 This model has been previously demonstrated to have elevated TGF-␤1 activity in the atria and ventricles. Cardiac development and morphology appear normal, except for increased interstitial fibrosis in the atrial myocardium. Ventricular size and histology is no...

Cardiomyocyte T-tubules are important for regulating ionic flux. Bridging Integrator 1 (BIN1) is a T-tubule protein associated with calcium channel trafficking that is down-regulated in failing hearts. Here we find that cardiac T-tubules normally contain dense protective inner membrane folds that are formed by a cardiac spliced isoform of BIN1. In mice with cardiac Bin1 deletion, T-tubule folding is decreased which does not change overall cardiomyocyte morphology, but frees diffusion of local extracellular calcium and potassium ions, prolonging action potential duration, and increasing susceptibility to ventricular arrhythmias. We also find that T-tubule inner folds are rescued only by the BIN1 isoform BIN1+13+17, which promotes N-WASP dependent actin polymerization to stabilize T-tubule membrane at cardiac Z-discs. In conclusion, BIN1+13+17 recruits actin to fold T-tubule membrane, creating a fuzzy space that protectively restricts ionic flux. When BIN1+13+17 is decreased, as occurs in acquired cardiomyopathy, T-tubule morphology is altered and arrhythmias can result.