Subha V. Raman

Introduction Type 2 diabetes mellitus (T2D) confers high atherosclerotic cardiovascular disease (ASCVD) risk. The metabolite trimethylamine N-oxide (TMAO) derived via gut flora has been linked to excess ASCVD. Research design and methods We analyzed data, biospecimens, and major adverse cardiovascular events (MACEs) from the prospective multicenter randomized Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to assess its value in 330 high-risk individuals with T2D without evident atherosclerotic disease at enrollment. Results Incident cardiovascular events occurred in 165 cases; 165 controls matched by age, sex, and treatment arm experienced no incident events during follow-up. Cases and controls (mean age 64.5 years) had similar mean glycated hemoglobin (HbA1c) (8.2%) and mean 10-year ASCVD risk (23.5%); groups also had similar use of statins and antihypertensive medications at baseline and follow-up. Baseline plasma TMAO levels did not differ between groups after adjusting for ASCVD risk score, HbA1c, and estimated glomerular filtration rate, nor did TMAO distinguish patients suffering incident MACE from those who remained event-free. Conclusions TMAO’s prognostic value for incident ASCVD events may be blunted when applied to individuals with T2D with poor glycemic control and high baseline ASCVD risk. These results behoove further translational investigations of unique mechanisms of ASCVD risk in T2D.

Background: Duchenne muscular dystrophy incurs nearly universal dilated cardiomyopathy by the third decade of life, preceded by myocardial damage and impaired left ventricular strain by cardiac magnetic resonance. It has been shown that (1) mineralocorticoid receptor antagonist therapy with spironolactone attenuated damage while maintaining function when given early in a mouse model and (2) low‐dose eplerenone stabilized left ventricular strain in boys with Duchenne muscular dystrophy and evident myocardial damage but preserved ejection fraction. We hypothesized that moderate‐dose spironolactone versus eplerenone would provide similar cardioprotection in this first head‐to‐head randomized trial of available mineralocorticoid receptor antagonists, the AIDMD (Aldosterone Inhibition in Duchenne Muscular Dystrophy) trial. Methods and Results: This was a multicenter, double‐blind, randomized, noninferiority trial. Subjects were randomized to eplerenone, 50 mg, or spironolactone, 50 mg, orally once daily for 12 months. The primary outcome was change in left ventricular systolic strain at 12 months. Among 52 enrolled male subjects, aged 14 (interquartile range, 12–18) years, spironolactone was noninferior to eplerenone (∆strain, 0.4 [interquartile range, −0.4 to 0.6] versus 0.2 [interquartile range, −0.2 to 0.7]; P =0.542). Renal and pulmonary function remained stable in both groups, and no subjects experienced serious hyperkalemia. Infrequent adverse events included gynecomastia in one subject in the spironolactone arm and facial rash in one subject in the eplerenone arm. Conclusions: In boys with Duchenne muscular dystrophy and preserved left ventricular ejection fraction, spironolactone added to background therapy is noninferior to eplerenone in preserving contractile function. These findings support early mineralocorticoid receptor antagonist therapy as effective and safe in a genetic disease with high cardiomyopathy risk. Clinical Trial Registration: URL : http://www.clinicaltrials.gov . Unique identifier: NCT 02354352.

Background: T‐wave abnormalities are common during the acute phase of non‐ ST ‐segment elevation acute coronary syndromes, but mechanisms underlying their occurrence are unclear. We hypothesized that T‐wave abnormalities in the presentation of non‐ ST ‐segment elevation acute coronary syndromes correspond to the presence of myocardial edema. Methods and Results: Secondary analysis of a previously enrolled prospective cohort of patients presenting with non‐ ST ‐segment elevation acute coronary syndromes was conducted. Twelve‐lead electrocardiography ( ECG ) and cardiac magnetic resonance with T2‐weighted imaging were acquired before invasive coronary angiography. ECG s were classified dichotomously (ie, ischemic versus normal/nonischemic) and nominally according to patterns of presentation: no ST ‐ or T‐wave abnormalities, isolated T‐wave abnormality, isolated ST depression, ST depression+T‐wave abnormality. Myocardial edema was determined by expert review of T2‐weighted images. Of 86 subjects (65% male, 59.4 years), 36 showed normal/nonischemic ECG , 25 isolated T‐wave abnormalities, 11 isolated ST depression, and 14 ST depression+T‐wave abnormality. Of 30 edema‐negative subjects, 24 (80%) had normal/nonischemic ECG s. Isolated T‐wave abnormality was significantly more prevalent in edema‐positive versus edema‐negative subjects (41.1% versus 6.7%, P =0.001). By multivariate analysis, an ischemic ECG showed a strong association with myocardial edema (odds ratio 12.23, 95% confidence interval 3.65‐40.94, P P <0.0001). Isolated T‐wave abnormality was highly specific (93%) but insensitive (43%) for detecting myocardial edema. Conclusions: T‐wave abnormalities in the setting of non‐ ST ‐segment elevation acute coronary syndromes are related to the presence of myocardial edema. High specificity of this ECG alteration identifies a change in ischemic myocardium associated with worse outcomes that is potentially reversible.