Benjamin M. Moore

Impact of Perturbed Pancreatic β-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism

Elevated pancreatic β-cell cholesterol levels impair insulin secretion and reduce plasma insulin levels. This study establishes that low plasma insulin levels have a detrimental effect on two major insulin target tissues: adipose tissue and skeletal muscle. Mice with increased β-cell cholesterol levels were generated by conditional deletion of the ATP-binding cassette transporters, ABCA1 and ABCG1, in β-cells (β-DKO mice). Insulin secretion was impaired in these mice under basal and high-glucose conditions, and glucose disposal was shifted from skeletal muscle to adipose tissue. The β-DKO mice also had increased body fat and adipose tissue macrophage content, elevated plasma interleukin-6 and MCP-1 levels, and decreased skeletal muscle mass. They were not, however, insulin resistant. The adipose tissue expansion and reduced skeletal muscle mass, but not the systemic inflammation or increased adipose tissue macrophage content, were reversed when plasma insulin levels were normalized by insulin supplementation. These studies identify a mechanism by which perturbation of β-cell cholesterol homeostasis and impaired insulin secretion increase adiposity, reduce skeletal muscle mass, and cause systemic inflammation. They further identify β-cell dysfunction as a potential therapeutic target in people at increased risk of developing type 2 diabetes.

Incidence and clinical characteristics of sudden cardiac death in adult congenital heart disease

BACKGROUND The life expectancy of adults with congenital heart disease (CHD) has significantly improved in recent decades, with non-cardiovascular causes of death now competing with traditional cardiovascular causes. The risk of sudden cardiac death (SCD), a devastating event, still remains elevated above that of the general population. METHODS We reviewed 2935 patients in our adult CHD database (age≥16years, seen at least once in our centre) and documented all cases of SCD between 2000-2015. Incidence and characteristics of SCD cases by congenital defect and complexity of disease were determined. RESULTS We documented 35 cases of SCD, with an incidence of 0.4 deaths/1000patientyears (py). Incidence in simple, moderate and complex congenital categories was 0.04/1000py, 0.57/1000py and 2.0/1000py respectively. The highest risk category was Eisenmenger syndrome, with an incidence of 4.8 deaths/1000py. Moderate risk lesions included transposition of the great arteries (atrial switch surgery or congenitally corrected) and Fontan circulations. Repaired tetralogy, atrial septal defect and left ventricular outflow tract lesions were all relatively low risk. We observed a high prevalence of atrial arrhythmias (43%) and QRS prolongation (mean 132ms) in our SCD cases. CONCLUSIONS The adult CHD population remains at an elevated risk for SCD, particularly in the setting of complex underlying defects. Moderate to high risk lesions include Eisenmenger syndrome, transposition of the great arteries (atrial switch or congenitally corrected) and Fontan circulations.

Incidence, predictors and outcomes of infective endocarditis in a contemporary adult congenital heart disease population

BACKGROUND The prevalence of congenital heart disease (CHD) in the adult population is steadily increasing. A substrate of prosthetic material and residual lesions, constantly evolving as surgical techniques change over time, predispose these patients to the potentially devastating complication of infective endocarditis (IE). METHODS We retrospectively reviewed 2935 patients in our adult CHD database for all cases of endocarditis between 1991 and 2016. Incidence, clinical course and predictors of outcomes were analysed. RESULTS We document 74 episodes in 62 patients, with an incidence of 0.9 cases/1000 patient years (py). IE was more common in complex CHD (1.4 cases/1000py) and ventricular septal defects (VSDs) (1.9 cases/1000py). Prosthetic material was involved in 47% and left-sided infection predominated (66%). The incidence in bicuspid aortic valves post aortic valve replacement (AVR) was significantly higher than in unoperated valves, being 1.8 and 1.1 cases/1000 patient years respectively. Streptococcus was the most frequently implicated causative organism (37%). Emboli occurred in 34% of cases with a cerebral predilection. 46% of patients required surgery during the admission for IE, most frequently to replace a severely regurgitant bicuspid aortic valve. Early endocarditis-related mortality was 15%, associated with cerebral emboli and acute renal failure. CONCLUSIONS In a contemporary adult CHD cohort, those with complex underlying lesions, VSDs or an AVR were at higher risk for IE. Mortality remains substantial and is more likely in patients with cerebral emboli and/or acute renal failure.

Efficacy and adverse effects of sotalol in adults with congenital heart disease

INTRODUCTION Adults with congenital heart disease (CHD) are predisposed to arrhythmias, which can often be refractory to medical therapy. Sotalol is an attractive alternative antiarrhythmic to amiodarone in this younger patient population, given the latters toxicity profile, but it may have proarrhythmic effects. We therefore aimed to assess the efficacy and safety of sotalol in adults with CHD. METHODS We retrospectively assessed our adult CHD database for all patients ≥16 years old, with moderate to highly complex defects, who were prescribed sotalol between 2000 and 2017. Efficacy in treating the clinical arrhythmia was assessed as complete, partial or failure. Adverse effects, including proarrhythmia, were documented. RESULTS Sotalol was prescribed in 82 of 902 adult CHD patients reviewed (9%). The mean age at sotalol commencement was 31.8 ± 13.1 years, with a median time on sotalol of 2.8 years. The average prescribed dose was 122 ± 51 mg/daily. Sotalol was completely effective in 48% (n = 39), partially effective in 46% (n = 38) and failed to control the clinical arrhythmia in 6% (n = 5). Fifteen patients (18%) discontinued sotalol due to a side effect, most commonly fatigue or dyspnoea. No episodes of torsades de pointes or sudden cardiac death were observed. Significant bradycardia related to sotalol occurred in 13% (n = 11, with permanent pacing implemented in 4), and was associated with Fontan anatomy. CONCLUSIONS In moderate to highly complex adult CHD, sotalol was reasonably effective and safe in low doses. Side effects limiting treatment were typically non-life-threatening, with significant bradycardia related to sotalol more likely in Fontan patients.

Erratum. Impact of Perturbed Pancreatic β-Cell Cholesterol Homeostasis on Adipose Tissue and Skeletal Muscle Metabolism. Diabetes 2016;65:3610-3620.

In the article listed above, a funding source was erroneously omitted. This work was partially …

Transcatheter Mitral Valve Replacement With a Novel Dual Stent Bioprosthesis

There has been great interest in transcatheter mitral valve replacement (TMVR) as a potential therapy for high-risk patients with severe mitral regurgitation, with several distinct device systems undergoing first-in-man clinical studies. The Intrepid TMVR (Medtronic Inc, Redwood City, CA), designed for transapical delivery, comprises 2 interconnected self-expanding nitinol stents: (1) an inner stent that houses a bovine pericardial tissue trileaflet valve and; (2) an outer ring that fixes to the mitral annulus by radial force in a cork-like effect (Figure 1).1 The outer fixation ring is designed to conform to the dynamic anatomy of the mitral valve throughout the cardiac cycle, avoiding distortion of the inner stent and valve. Figure 1. The Intrepid transcatheter mitral valve replacement with en face and side on views showing atrial brim, fixation …