A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta.

Aims: Coarctation 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 results: We 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. Conclusion: Through 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.

Minimal nocturnal oxygen saturation predicts future subclinical carotid atherosclerosis: the Wisconsin sleep cohort.

Previous data on the associations between nocturnal oxygen saturation parameters and carotid atherosclerosis are conflicting. We examined the prospective associations of nocturnal oxygen saturation (SaO2 ) and cardiovascular disease (CVD) risk factors with carotid intima-media thickness (IMT) and plaques. We used data on 689 Wisconsin sleep cohort participants who had baseline overnight polysomnography followed by carotid ultrasonography a mean (SD) of 7.8 (2.5) years later. Far wall common carotid IMT was measured using B-mode ultrasound. Bilateral common, bifurcation and internal carotid artery segments were evaluated for plaque score. Participants (8) were aged 56 years (55% male); 32% had hypertension and mean body mass index (BMI) was 31 (7) kg m(2). Mean and minimum nocturnal SaO2 were 95% (2) and 86% (7), respectively. Mean percentage sleep time with SaO2 < 90% was 2% (8). Both mean (odds ratio [OR]: 0.60 lower plaque count per 5% higher mean SaO2, 95% confidence interval [CI]: 0.38-0.96, P = 0.033) and minimum SaO2 (OR: 0.88 lower plaque count per 5% higher minimum SaO2, 95% CI: 0.80-0.97, P = 0.013) predicted carotid plaque score after adjusting for age, sex and BMI. Minimum SaO2 predicted future plaque score after adding adjustment for traditional CVD risk factors (OR: 0.90 lower plaque count per 5% higher minimum SaO2, 95% CI: 0.81-0.99, P = 0.038). Mean SaO2 was not associated with carotid IMT after CVD risk factor adjustment. We conclude that minimum nocturnal SaO2 is an independent predictor of future carotid plaque burden. Other nocturnal SaO2 parameters are not associated with future carotid IMT or plaques after adjusting for traditional CVD risk factors.

Obstructive sleep apnea is associated with future subclinical carotid artery disease: thirteen-year follow-up from the Wisconsin sleep cohort.

OBJECTIVE: To determine the longitudinal associations between obstructive sleep apnea, 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 Wisconsin residents who completed a mean of 3.5 (range, 1-6) polysomnograms during the study period. Obstructive sleep apnea was characterized by the apnea-hypopnea index (AHI, events/h). 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 obstructive sleep apnea exposure with subsequent carotid IMT and plaque. At baseline, the mean age of participants was 47.6 (7.7) years (55% men, 97% white). AHI was 4.4 (9.0) events/h (range, 0-97); 7% had AHI >15 events/h. 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 antidiabetic medications, baseline AHI independently predicted future carotid IMT (ß=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 obstructive sleep apnea is independently associated with increased carotid IMT and plaque more than a decade later, indicating increased future cardiovascular disease risk.

Relationship between body composition and glomerular filtration rate estimates in the general population.

BACKGROUND: Differences in body composition may lead to imprecision in estimates of glomerular filtration rate (eGFR) derived from serum creatinine. Our aims were to examine the relationship between eGFR and anthropometric and body composition measures and handgrip strength. METHODS: We analyzed data from a cross-sectional study comprising 1,630 randomly selected community-dwelling adults. The Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations were used to calculate eGFR from IMDS-standardized serum creatinine. Body mass index and body surface area were calculated from measured height and weight. Body composition was determined by dual-energy x-ray absorptiometry, handgrip strength measured by a hand-held dynamometer. Regression analysis was used to examine the association between eGFR and other factors. RESULTS: In women, eGFR determined by the MDRD equation was inversely associated with height (ß = -0.08; p = 0.012), lean mass percentage (ß = -0.06; p = 0.047) and handgrip strength (ß = -0.15; p < 0.001) and eGFR calculated using the CKD-EPI equation was inversely associated with handgrip strength (ß = -0.08; p = 0.001). In men, there was an inverse association between eGFR by the MDRD equation and lean mass percentage (ß = -0.10; p = 0.013) and handgrip strength (ß = -0.12; p = 0.022) and between eGFR by the CKD-EPI equation and lean mass percentage (ß = -0.07; p = 0.018). The R(2) for these variables was <0.02. CONCLUSIONS: The inverse relationship between eGFR and measures of lean mass percentage and handgrip strength suggests that incorporation of these variables might improve eGFR prediction from serum creatinine in the general population. This effect appears to be small however and needs to be examined in studies that include measured GFR.

Heart and kidney transplant: should they be combined or subsequent?

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.

Outcomes of Physician-Staffed Versus Non-Physician-Staffed Helicopter Transport for ST-Elevation Myocardial Infarction.

BACKGROUND: The effect of physician-staffed helicopter emergency medical service (HEMS) on ST-elevation myocardial infarction (STEMI) patient transfer is unknown. The purpose of this study was to evaluate the characteristics and outcomes of physician-staffed HEMS (Physician-HEMS) versus non-physician-staffed (Standard-HEMS) in patients with STEMI. METHODS AND RESULTS: We studied 398 STEMI patients transferred by either Physician-HEMS (n=327) or Standard-HEMS (n=71) for primary or rescue percutaneous coronary intervention at 2 hospitals between 2006 and 2014. Data were collected from electronic medical records and each institution's contribution to the National Cardiovascular Data Registry. Baseline characteristics were similar between groups. Median electrocardiogram-to-balloon time was longer for the Standard-HEMS group than for the Physician-HEMS group (118 vs 107 minutes; P=0.002). The Standard-HEMS group was more likely than the Physician-HEMS group to receive nitroglycerin (37% vs 15%; P<0.001) and opioid analgesics (42.3% vs 21.7%; P<0.001) during transport. In-hospital adverse outcomes, including cardiac arrest, cardiogenic shock, and serious arrhythmias, were more common in the Standard-HEMS group (25.4% vs 11.3%; P=0.002). After adjusting for age, sex, Killip class, and transport time, patients transferred by Standard-HEMS had increased risk of any serious in-hospital adverse event (odds ratio=2.91; 95% CI=1.39-6.06; P=0.004). In-hospital mortality was not statistically different between the 2 groups (9.9% in the Standard-HEMS group vs 4.9% in the Physician-HEMS group; P=0.104). CONCLUSIONS: Patients with STEMI transported by Standard-HEMS had longer transport times, higher rates of nitroglycerin and opioid administration, and higher rates of adjusted in-hospital events. Efforts to better understand optimal transport strategies in STEMI patients are needed.

[Lung volume reduction surgery for severe pulmonary emphysema in Iceland]. / Arangur lungnasmaekkunaradgerda vid langvinnri lungnathembu a Islandi.

INTRODUCTION: Lung volume reduction surgery (LVRS) can benefit patients with severe emphysema. The aim of this study was to evaluate the outcome of LVRS performed in Iceland. MATERIALS AND METHODS: A prospective study of 16 consecutive patients who underwent bilateral LVRS through median sternotomy between January 1996 and December 2008. All patients had disabling dyspnea, lung hyperinflation, and emphysema with upper lobe predominance. Preoperatively all patients underwent pulmonary rehabilitation. Spirometry, lung volumes, arterial blood gases and exercise capacity were measured before and after surgery. Mean follow-up time was 8.7 years. RESULTS: Mean age was 59.2 ± 5.9 years. All patients had a history of heavy smoking. There was no perioperative mortality and survival was 100%, 93%, and 63% at 1, 5, and 10 years, respectively. The forced expiratory volume in 1 second (FEV1) and the forced vital capacity (FVC) improved significantly after surgery by 35% (p<0.001) and 14% (p<0.05), respectively. The total lung capacity, residual volume and partial pressure of CO2 also showed statistically significant improvements but exercise capacity, O2 consumption and diffusing capacity of the lung for CO did not change. Prolonged air leak (≥ 7 days) was the most common complication (n=7). Five patients required reoperation, most commonly for sternal dehiscence (n=4). CONCLUSION: In this small prospective study, FEV1 and FVC increased and lung volumes and PaCO2 improved after LVRS. Long term survival was satisfactory although complications such as reoperations for sternal dehiscence were common and hospital stay therefore often prolonged.

[Surgery for coarctation of the aorta in Iceland 1990-2006]. / Arangur skurdadgerda vid medfaeddri ósaedarthrengingu hjá börnum á Islandi 1990-2006.

BACKGROUND AND AIMS: Coarctation of the aorta (CoA) is a congenital narrowing of the aorta, distal to the origin of the left subclavian artery. Treatment consists of surgical excision but balloon angioplasty is also a treatment option for selected patients. The aim of this study was to evaluate surgical outcome in children operated for CoA in Iceland. MATERIAL AND METHODS: All Icelandic children (<18 yrs.) operated for CoA in Iceland between 1990 and 2006. Patients operated abroad (n=17) or managed conservatively (n=12) were excluded. Mean follow up period was 8.5 +/- 4.3 years. RESULTS: Of 67 children diagnosed with CoA, 38 were operated on in Iceland (mean age 36 +/- 58 months, and 22 male and 16 female patients), 10 required immediate surgery for cardiac failure and eight were diagnosed incidentally. Extended end-to-end anastomosis was the most common procedure (n=31). Subclavian-flap aortoplasty was performed in seven patients. Average operation time was 134 min. and mean aortic closure time was 21 +/- 9 min. Hypertension (58%) and heart failure (11%) were the most common postoperative complications. Recoarctation developed 35 +/- 56 months after surgery in seven patients (18%) and was successfully treated with balloon angioplasty. There were no operative deaths and no patients developed paraplegia. One patient suffered an ischemic injury to the brachial plexus. Today all of the patients are alive, except for one patient that died four months after surgery from heart failure. CONCLUSION: Majority of Icelandic patients with CoA are operated on in Iceland with excellent outcome, both regarding short term complications and long term survival.