We conducted blinded psychiatric assessments of 26 Amish subjects (52 ± 11 years) from four families with prevalent bipolar spectrum disorder, identified 10 potentially pathogenic alleles by exome sequencing, tested association of these alleles with clinical diagnoses in the larger Amish Study of Major Affective Disorder (ASMAD) cohort, and studied mutant potassium channels in neurons. Fourteen of 26 Amish had bipolar spectrum disorder. The only candidate allele shared among them was rs78247304, a non-synonymous variant of KCNH7 (c.1181G>A, p.Arg394His). KCNH7 c.1181G>A and nine other potentially pathogenic variants were subsequently tested within the ASMAD cohort, which consisted of 340 subjects grouped into controls subjects and affected subjects from overlapping clinical categories (bipolar 1 disorder, bipolar spectrum disorder and any major affective disorder). KCNH7 c.1181G>A had the highest enrichment among individuals with bipolar spectrum disorder (χ² = 7.3) and the strongest family-based association with bipolar 1 (P = 0.021), bipolar spectrum (P = 0.031) and any major affective disorder (P = 0.016). In vitro, the p.Arg394His substitution allowed normal expression, trafficking, assembly and localization of HERG3/Kv11.3 channels, but altered the steady-state voltage dependence and kinetics of activation in neuronal cells. Although our genome-wide statistical results do not alone prove association, cumulative evidence from multiple independent sources (parallel genome-wide study cohorts, pharmacological studies of HERG-type potassium channels, electrophysiological data) implicates neuronal HERG3/Kv11.3 potassium channels in the pathophysiology of bipolar spectrum disorder. Such a finding, if corroborated by future studies, has implications for mental health services among the Amish, as well as development of drugs that specifically target HERG3/Kv11.3.

The number of advanced heart failure patients who can receive a heart transplant is limited by a shortage of suitable organ donors. In efforts to expand the donor pool, alternative donation and procurement methods have been developed, including heart transplantation following donation after circulatory death (DCD HT). While short-term survival following DCD HT is non-inferior to heart transplantation with brain-dead donors, there may be an increased rate of primary graft dysfunction (PGD) associated with DCD HT allografts. The underlying etiology of PGD is multifactorial and incompletely understood. For DCD HT allografts, the period of warm ischemic injury during DCD procurement is a potential risk factor for PGD to which brain death allografts are not exposed. The functional warm ischemic time thus may be an important driver of PGD in DCD HT. However, the mechanisms underlying PGD in this clinical scenario are poorly understood at the molecular level. The work presented herein aims to describe the development and validation of a high-fidelity non-survival porcine model of DCD orthotopic heart transplantation. We hypothesize that the use of this translational large animal model is critical to elucidate molecular mechanisms contributing to PGD, as well as to investigate interventions designed to optimize allograft preservation and early performance. This model replicates the perioperative and surgical approach used in DCD HT clinically, with modifications to account for porcine anatomy and physiology. The development of this large animal surgical model will not only provide mechanistic insights into the development of PGD but also can be modified to enhance translational research efforts aimed at improving organ recovery following DCD HT.

Coronary artery bypass graft (CABG) uses the patient's internal mammary artery and saphenous vein; however, unavailable or poor quality autologous vessels limit revascularization. This study addresses the critical need for alternative CABG conduits by evaluating a small diameter acellular tissue-engineered vessel ([sdATEV], 3.5 mm) in a primate model. Adult baboons (n = 5) underwent CABG to the right coronary artery (RCA) with an sdATEV. Patency, diameter, and cardiac function were longitudinally assessed by computed tomography angiography. All sdATEVs remained patent throughout the 6-month study. Computed tomography angiography demonstrated that the distal sdATEV diameter gradually remodeled to approximate the smaller baboon RCA. Histology and spatial transcriptomics revealed that sdATEVs recellularized with host endothelial and smooth muscle cells including a quiescent neomedia layer with gene expression patterns similar to the RCA, indicating that host cell ingrowth from the bypassed coronary artery regulates sdATEV diameter. These results suggest that the sdATEV is a durable alternative CABG conduit.