Toxicity from the immunosuppressant mycophenolate mofetil is prevented by eliminating gut bacteria expressing β-glucuronidase.

Current methods for the maturation of induced pluripotent stem cell-derived cardiomyocytes

Background: Coronary artery aneurysms (CAAs) may occur after Kawasaki disease (KD) and lead to important morbidity and mortality. As CAA in patients with KD are rare and heterogeneous lesions, prognostication and risk stratification are difficult. We sought to derive the cumulative risk and associated factors for cardiovascular complications in patients with CAAs after KD. Methods and Results: A 34‐institution international registry of 1651 patients with KD who had CAAs (maximum CAA Z score ≥2.5) was used. Time‐to‐event analyses were performed using the Kaplan–Meier method and Cox proportional hazard models for risk factor analysis. In patients with CAA Z scores ≥10, the cumulative incidence of luminal narrowing (>50% of lumen diameter), coronary artery thrombosis, and composite major adverse cardiovascular complications at 10 years was 20±3%, 18±2%, and 14±2%, respectively. No complications were observed in patients with a CAA Z score <10. Higher CAA Z score and a greater number of coronary artery branches affected were associated with increased risk of all types of complications. At 10 years, normalization of luminal diameter was noted in 99±4% of patients with small (2.5≤ Z <5.0), 92±1% with medium (5.0≤ Z <10), and 57±3% with large CAAs ( Z ≥10). CAAs in the left anterior descending and circumflex coronary artery branches were more likely to normalize. Risk factor analysis of coronary artery branch level outcomes was performed with a total of 893 affected branches with Z score ≥10 in 440 patients. In multivariable regression models, hazards of luminal narrowing and thrombosis were higher for patients with CAAs of the right coronary artery and left anterior descending branches, those with CAAs that had complex architecture (other than isolated aneurysms), and those with CAAs with Z scores ≥20. Conclusions: For patients with CAA after KD, medium‐term risk of complications is confined to those with maximum CAA Z scores ≥10. Further risk stratification and close follow‐up, including advanced imaging, in patients with large CAAs is warranted.

Human mitochondrial disorders impact tissues with high energetic demands and can be associated with cardiac muscle disease (cardiomyopathy) and early mortality. However, the mechanistic link between mitochondrial disease and the development of cardiomyopathy is frequently unclear. In addition, there is often marked phenotypic heterogeneity between patients, even between those with the same genetic variant, which is also not well understood. Several of the mitochondrial cardiomyopathies are related to defects in the maintenance of mitochondrial protein homeostasis, or proteostasis. This essential process involves the importing, sorting, folding and degradation of preproteins into fully functional mature structures inside mitochondria. Disrupted mitochondrial proteostasis interferes with mitochondrial energetics and ATP production, which can directly impact cardiac function. An inability to maintain proteostasis can result in mitochondrial dysfunction and subsequent mitophagy or even apoptosis. We review the known mitochondrial diseases that have been associated with cardiomyopathy and which arise from mutations in genes that are important for mitochondrial proteostasis. Genes discussed include DnaJ heat shock protein family member C19 (DNAJC19), mitochondrial import inner membrane translocase subunit TIM16 (MAGMAS), translocase of the inner mitochondrial membrane 50 (TIMM50), mitochondrial intermediate peptidase (MIPEP), X-prolyl-aminopeptidase 3 (XPNPEP3), HtraA serine peptidase 2 (HTRA2), caseinolytic mitochondrial peptidase chaperone subunit B (CLPB) and heat shock 60-kD protein 1 (HSPD1). The identification and description of disorders with a shared mechanism of disease may provide further insights into the disease process and assist with the identification of potential therapeutics.