The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young otherwise healthy individuals. We conducted genome-wide association studies (GWAS) and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases), and nine left ventricular (LV) traits in 19,260 UK Biobank participants with structurally normal hearts. We identified 16 loci associated with HCM, 13 with DCM, and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased contractility with HCM risk. A polygenic risk score (PRS) explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that PRS may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

Background: Controversy exists regarding the optimal annular stabilization technique following valve sparing aortic root reconstruction (VSRR) with no comprehensive imaging data to evaluate the natural history of aortic root graft geometry, aortic valve competency and patient prognosis post-reconstruction. Methods: Between 2008-2017, 70 consecutive patients (mean age 56.4±16.4 years, 19.7% females) underwent VSRR. All patients were prospectively evaluated annually with clinical follow-up, echocardiography and CT imaging. Patients were assessed for survival, freedom from reoperation, degree of regurgitation, New York Heart Association (NYHA) status and graft complications and followed up to nine years post-operatively (mean 36±21 months). Results: The largest increase of the aortic annulus diameter observed during the surveillance period was 2.64%±5.4% which occurred between the second and third years of follow-up and the aortic sinuses, sinotubular junction and ascending aorta all remained relatively stable based on annual CT imaging. Echocardiographic data showed far more variability in measurements at each annual post-operative visit with far less precision compared to the CT measurements taken at the same time. Due to the large variability and greater standard deviations, no significant difference was detected between the more precise CT measurements and those from the echocardiogram images. The overall survival rate was 94.3% (66 patients) at one year. Freedom from reoperation was 98.6% (69 patients). Throughout the entire duration of followup, aortic insufficiency was identified as 0 in 46 (65.7%), 1+ in 19 (27.1%), 2+ in 4 (5.7%), 3+ in 0 (0%) and 4+ in 1 (1.4%). Mean NYHA status was 1.1±0.3 at most recent follow-up for all patients. CT evidence showed 97.0% (64 patients) freedom from graft complication including: endocarditis, thrombosis, embolism, aneurysm, pseudoaneurysm, dehiscence, dissection and kinking. Conclusions: The annual imaging data presented here demonstrates stability of the Dacron aortic annuloplasty reconstruction over time, without the need for internal or external annular stabilization. CT imaging proved to be far more reliable than echocardiographic images, however given the stability, annual CT imaging is of little benefit. This is the first prospective study to compare echocardiographic, CT and clinical data following VSRR.

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A 46-year-old man presented with mass on chest x-ray along with a 6-month history of weight loss, dyspnea and cough. He was hypotensive and an echocardiogram showed large extra-cardiac mass compressing the right ventricular outflow tract resulting in features of cardiac tamponade. Chest computed tomography revealed a mediastinal mass invading the pericardium adjacent to right ventricular outflow tract. Biopsy of the mass confirmed primary monophasic synovial sarcoma. Chemotherapy and radiotherapy along with anti-inflammatories were given as surgery was too high risk due to the location of the tumour and pericardial involvement. Patient responded briefly to the treatment with improvement in hemodynamic parameters but over next weeks he became less responsive to treatment with increasing size. He died 2 months after treatment commenced.