Background-Myocardial dysfunction is a common and important problem in donor hearts. The mechanisms responsible remain unclear. We have studied the cytokines tumor necrosis factor (TNF)-␣ and interleukin-6 (IL-6) in the myocardium and serum from donors with myocardial dysfunction (unused donors) and compared them with donors with good ventricular function (used donors) and patients with advanced heart failure (HF). Methods and Results-Clinical details and ventricular function were assessed in 46 donors (31 used, 15 unused). Real-time reverse transcription-polymerase chain reaction, Western blotting, and immunocytochemistry were performed on myocardium and immunoassays on serum. TNF-␣ mRNA was 1.6-fold higher in unused than in used donors (PϽ0.005) and 1.74-fold higher than in 36 patients with HF. IL-6 mRNA was 2.4-fold higher in unused than in used donors (PϽ0.0001) and 4.67-fold higher than in HF (PϽ0.0001). Western blotting showed higher TNF-␣ in unused (218.3Ϯ6.4, nϭ4 versus 187.3Ϯ5.4, nϭ3 OD units) than used donors (PϽ0.05). TNF-␣ expression was localized to cardiac myocytes. Serum TNF-␣ was higher in unused (8.72Ϯ1.3 pg/mL, nϭ13) than in used (6.12Ϯ0.8 pg/mL, nϭ25, PϽ0.05) donors and HF (4.0Ϯ0.4 pg/mL, nϭ17, PϽ0.005). Serum TNF-␣ receptors did not differ between unused (4.3Ϯ0.8 and 8.6Ϯ1.6 ng/mL, nϭ10) and used (3.5Ϯ0.4 and 6.5Ϯ1.1 ng/mL, nϭ24) donors. There was a trend for higher serum IL-6 in unused (16.5Ϯ2.9 pg/mL, nϭ9) compared with used (13.9Ϯ1.6 pg/mL, nϭ26, PϭNS) donors. Conclusions-This
Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. We here report results from the largest HCM genome-wide association study (GWAS) and multi-trait analysis (MTAG) including 5,900 HCM cases, 68,359 controls, and 36,083 UK Biobank (UKB) participants with cardiac magnetic resonance (CMR) imaging. We identified a total of 70 loci (50 novel) associated with HCM, and 62 loci (32 novel) associated with relevant left ventricular (LV) structural or functional traits. Amongst the common variant HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants cause HCM. Mendelian randomization analyses support a causal role of increased LV contractility in both obstructive and non-obstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, the findings significantly increase our understanding of the genetic basis and molecular mechanisms of HCM, with potential implications for disease management.
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