Mandibuloacral Dysplasia With Type a Lipodystrophy

BMS-986141 is a novel, oral, protease-activated, receptor 4 (PAR4)-antagonist that exhibited robust antithrombotic activity and low bleeding risk in preclinical studies. The pharmacokinetic, pharmacodynamic, and tolerability profiles of BMS-986141 in healthy participants were assessed in a randomized, double-blind, placebo-controlled, single-ascending-dose (SAD; N = 60) study; a multiple-ascending-dose (MAD; N = 32) study; and a Japanese MAD (JMAD; N = 32) study. Exposure was dose-proportional for BMS-986141 2.5 mg and 150 mg; maximum concentrations were 17.6 ng/mL and 958 ng/mL; and areas under the curve (AUC) to infinity were 183 h* × ng/mL and 9207 h* × ng/mL, respectively. Mean half-life ranged from 33.7 to 44.7 hours across dose panels. The accumulation index following once-daily administration for 7 days suggested a 1.3- to 2-fold AUC increase at steady state. In the SAD study, BMS-986141 75 and 150 mg produced ≥80% inhibition of 25-100 µM PAR4 agonist peptide (AP)-induced platelet aggregation, without affecting PAR1-AP-induced platelet aggregation, through ≥24 hours postdose. In the MAD and JMAD studies, BMS-986141 doses ≥10 mg completely inhibited 12.5 μM and 25 μM PAR4-AP-induced platelet aggregation through 24 hours. This study found BMS-986141 was safe and well tolerated, with dose-proportional pharmacokinetics and concentration-dependent pharmacodynamics in healthy participants over a wide dose range. ClinicalTrials.gov ID: NCT02341638.

Mitral valve prolapse (MVP) is the most frequent valve condition but remains a conundrum in many aspects, particularly in regard to the existence and frequency of an arrhythmic form (AMVP) and its link to sudden cardiac death. Furthermore, the presence, frequency, and significance of the anatomic functional feature called mitral annular disjunction (MAD) have remained widely disputed. Recent case series and cohorts have shattered the concept that MVP is most generally benign and have emphasized the various phenotypes associated with clinically significant ventricular arrhythmias, including AMVP. The definition, evaluation, follow-up, and management of AMVP represent the focus of the present review, strengthened by recent coherent studies defining an arrhythmic MVP phenotypic that would affect a small subset of patients with MVP at concentrated high risk. The role of MAD in this context is of particular importance, and this review highlights the characteristics of AMVP phenotypes and MAD, their clinical, multimodality imaging, and rhythmic evaluation. These seminal facts lead to proposing a risk stratification clinical pathway with consideration of medical, rhythmologic, and surgical management and have been objects of recent expert consensus statements and of proposals for new research directions.

Mitral annular disjunction (MAD) is the atrial displacement of the mitral valve (MV) hinge point, especially along the posterior mitral leaflet, which leads to inhomogeneous blood flow into the left ventricle, causing chronic fibrotic changes, malignant arrhythmias, and even sudden cardiac arrest. Some studies suggest that MAD is a part of normal heart morphology; however, the origin is still controversial. MAD commonly occurs with MV prolapse and myxomatous degenerative MV disease. In almost 20% of cases, MAD can occur independently as well. The prevalence of MAD in normal hearts varies from 8.6% to 96%, depending on the imaging modality and the cutoff used to define MAD. Transthoracic echocardiography is often the initial screening test, but the low sensitivity of transthoracic echocardiography to identify MAD makes it easy to miss the diagnosis altogether. More advanced imaging, especially cardiac MRI, is the gold standard for diagnosing MAD and risk stratification. MAD is an independent predictor of malignant arrhythmia. Among patients with MAD, risk stratification is based on the age at diagnosis, previous syncopal attacks, premature ventricular contractions, papillary muscle fibrosis, and longitudinal disjunction distance. Most asymptomatic patients are managed conservatively; however, radiofrequency ablation should be considered in patients with high-risk or symptomatic MAD due to the risk of ventricular arrhythmias and sudden cardiac death.