Physical model for the gating mechanism of ionic channels

We propose a physical model for the gating mechanism of ionic channels. First, we investigate the fluctuation-mediated interactions between two proteins imbedded in a cellular membrane and find that the interaction depends on their orientational configuration as well as the distance between them. The orientational dependence of interactions arises from the fact that the noncircular cross-sectional shapes of individual proteins constrain fluctuations of the membrane differently according to their orientational configuration. Then, we apply these interactions to ionic channels composed of four, five, and six proteins. As the gating stimulus creates the changes in the structural shape of proteins composing ionic channels, the orientational configuration of the ionic channels changes due to the free energy minimization, and ionic channels are open or closed according to the conformation thereof.open3

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

Long-Term Survivors Following Pediatric Heart Transplantation: A PHTS Database Analysis

Short-term outcomes following pediatric heart transplantation have improved over time with 1-year survival of over 90%, but comparable improvements in longer-term survival continues to have important barriers. We sought to investigate long-term outcomes following pediatric heart transplantation and to identify favorable factors associated with long-term survival. The Pediatric Heart Transplant Society (PHTS) database was queried for pediatric heart transplant recipients from 1993-2010. Patients with graft survival ≥10 years were compared to the general cohort and to patients with follow up ≥3 but <10 years. Kaplan-Meier analysis was used to evaluate overall survival and 3-year conditional survival. Factors associated with graft loss after 3-year conditional survival were identified using Cox proportional hazard modeling. 3,436 patients were transplanted between 1993-2010, of whom 1355 (39.4%) had ≥10 years of follow up (median 13.7 years (range 10.0-27.5)). Of those surviving to 10 years post-transplant, 84.4% and 74.3% survived to 15 and 20 years, respectively. Of the complete PHTS cohort, overall survival at 15 years was 53.3%. Patients <1 year at transplant who survived to 10 years had improved survival compared to other age groups (Figure). In 10-year survivors, the leading cause of subsequent mortality was cardiac allograft vasculopathy (CAV). Risk factors for graft loss after 3 years post-transplant were age, female gender, African American race, use of steroids at 2 years, rejection (particularly with hemodynamic compromise) and CAV (p-value for all <0.05). Use of mTORi was not associated with long-term survival. Heart transplantation remains an effective therapy in pediatric patients with a growing number of long-term survivors. Of modifiable risk factors, cessation of steroids may provide long-term survival benefit. Additional studies on social determinants of health are warranted to address increased mortality among African Americans