AimsCoarctation of the aorta (CoA) accounts for 4–8% of congenital heart defects (CHDs) and confers substantial morbidity despite treatment. It is increasingly recognized as a highly heritable condition. The aim of the study was to search for sequence variants that affect the risk of CoA.Methods and resultsWe performed a genome-wide association study of CoA among Icelanders (120 cases and 355 166 controls) based on imputed variants identified through whole-genome sequencing. We found association with a rare (frequency = 0.34%) missense mutation p.Arg721Trp in MYH6 (odds ratio = 44.2, P = 5.0 × 10−22), encoding the alpha-heavy chain subunit of cardiac myosin, an essential sarcomere protein. Approximately 20% of individuals with CoA in Iceland carry this mutation. We show that p.Arg721Trp also associates with other CHDs, in particular bicuspid aortic valve. We have previously reported broad effects of p.Arg721Trp on cardiac electrical function and strong association with sick sinus syndrome and atrial fibrillation.ConclusionThrough a population approach, we found that a rare missense mutation p.Arg721Trp in the sarcomere gene MYH6 has a strong effect on the risk of CoA and explains a substantial fraction of the Icelanders with CoA. This is the first mutation associated with non-familial or sporadic form of CoA at a population level. The p.Arg721Trp in MYH6 causes a cardiac syndrome with highly variable expressivity and emphasizes the importance of sarcomere integrity for cardiac development and function.

Objective To determine the longitudinal associations between obstructive sleep apnea (OSA), carotid artery intima-media thickness (IMT), and plaque. Approach and Results This is a population-based, prospective cohort study conducted from July, 1989 to November, 2012 on 790 randomly selected employed Wisconsin residents who completed a mean of 3.5 (range 1–6) polysomnograms during the study period. OSA was characterized by the apnea-hypopnea index (AHI, events/hour). Common carotid artery IMT and plaque were assessed by B-mode ultrasound. The mean (SD) time from the first polysomnograms to carotid ultrasound was 13.5 (3.6) years. Multivariable regression models were created to estimate the independent associations of baseline and cumulative OSA exposure with subsequent carotid IMT and plaque. At baseline, participants were mean 47.6 (7.7) years old (55% male, 97% white). AHI was 4.4 (9.0) events/hour (range, 0–97); 7% had AHI>15 events/hour. Carotid IMT was 0.755 (0.161) mm; 63% had plaque. Adjusting for age, sex, body-mass index, systolic blood pressure, smoking, and use of lipid-lowering, antihypertensive, and diabetes medications, baseline AHI independently predicted future carotid IMT (β=0.027 mm/unit log10[AHI+1], p=0.049), plaque presence (odds ratio 1.55 [95% confidence intervals 1.02–2.35], p=0.041) and plaque score (odds ratio 1.30 [1.05–1.61], p=0.018). In cumulative risk factor-adjusted models, AHI independently predicted future carotid plaque presence (p=0.012) and score (p=0.039), but not IMT (p=0.608). Conclusions Prevalent OSA is independently associated with increased carotid IMT and plaque over a decade later, indicating increased future cardiovascular disease risk.

Aims End-stage heart failure patients often present with severe kidney failure and have limited treatment options. We compared the clinical characteristics and outcomes among end-stage heart and kidney failure patients who underwent combined heart and kidney transplant (HKTx) with those who underwent kidney transplant after heart transplant (KAH). Methods and results All patients from 2007-2016 who underwent combined HKTx (n = 715) and those who underwent KAH (n = 130) using the United Network for Organ Sharing database were included. Kaplan Meier curves and Cox models compared survivals and identified predictors of death. Number of combined HKTx performed annually in United States increased from 59 in 2007 to 146 in 2016 whereas KAH decreased from 34 in 2007 to 6 in 2016. Among KAH patients, average wait time for kidney transplant was 3.0 years, time to dialysis or to kidney transplant after heart transplant did not differ with varying severity of kidney disease at baseline (P for both >0.05). Upon follow-up (mean 3.5 ± 2.7 years), 151 patients died. In multivariable models, patients who underwent combined HKTx had 4.7-fold greater risk of death [95% confidence interval (CI) 2.4-9.4) than KAH patients upon follow up. A secondary analysis using calculation of survival only after kidney transplant for KAH patients still conferred higher risk for combined HKTx patients [hazard ratio (HR) 2.6 95% CI 1.33-5.15]. In subgroup analyses after excluding patients on dialysis (HR 3.99 95% CI 1.98-8.04) and analysis after propensity matching for age, gender, and glomerular filtration rate (HR 3.01 95% CI 1.40-6.43) showed similar and significantly higher risk for combined HKTx patients compared with KAH patients. Lastly, these results also remained unchanged after excluding transplant centres who performed only one type of procedure preferentially, i.e. HKTx or KAH (HR 4.70 95% CI 2.35-9.42). Conclusions National registry data show continual increase in combined HKTx performed annually in the United States but inferior survival compared with KAH patients. Differences in patient characteristics or level of kidney dysfunction at baseline do not explain these poor outcomes among HKTx patients compared with KAH patients. Consensus guidelines are greatly needed to identify patients who may benefit more from dual organ transplants.

Background: giant pulmonary bullae (gpb) are rare and there is little information on incidence, long-term prognosis, and outcome of treatment.Objectives: to assess the incidence of gpb in the Icelandic population and to evaluate the outcome of surgical treatment.Methods: twelve consecutive patients (11 males; mean age 60 ± 15.7 years) underwent resection for gpb in Iceland between 1992 and 2009. all were heavy smokers and had bullae occupying > 30% of the involved lung. there were 8 bilateral and 3 unilateral bullectomies and one lobectomy. pulmonary function tests were performed preoperatively, and at one month and 5.4 years postoperatively. age-standardized incidence rate (asr) was calculated, complications and operative mortality were registered, and overall survival was estimated. mean follow-up time was 8.2 years.Results: the asr for gpb was 0.40 and 0.03 per 100,000 per year for men and women, respectively. there was no operative mortality, but prolonged air leakage (75%) and pneumonia (17%) were the most common postoperative complications. one month postoperatively, mean feV 1 increased from 1.0 ± 0.48 l (33% predicted) to 1.75 ± 0.75 l (57.5% predicted) (p < 0.01), but fVc remained unchanged. rV decreased from 3.9 ± 0.8 l (177% predicted) to 3.0 ± 1.0 l (128% predicted) (p < 0.05), but tlc and dlco did not change after operation. at long-term follow-up the feV 1 and fVc had declined to near-baseline values. five-year and 10-year survival were 100% and 60%, respectively.Conclusions: the asr of gpb in Iceland was 0.21 per 100,000 per year. In this small series, bullectomy was found to be a safe procedure that significantly improved pulmonary function. the functional improvement then declined over time. prolonged air leakage was a common postoperative complication that prolonged hospital stay.