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Publisher's version (útgefin grein)., 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 lphaheavy 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. © 2018. Published by Oxford University Press on behalf of the European Society of Cardiology., deCODE genetics/Amgen, Inc. The study was approved by the Icelandic Data Protection Authority and the National Bioethics Committee of Iceland. Study approval numbers were VSN-15-053, VSN-15-016, VSN-15-056, VSN-15-058, VSN-15-114, VSN-15-057, and 10-009-S1. Written informed consent was obtained from all study participants. The study complies with the declaration of Helsinki.

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.

Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and carries substantial morbidity despite treatment1. We performed a genome-wide association study (GWAS) of CoA among 120 Icelandic cases and 355,166 controls and found association with a rare (frequency = 0.34%) missense mutation p.Arg721Trp inMYH6(odds ratio (OR) = 44.2,P= 5.0x10-22), encoding an essential sarcomere protein. Approximately 20% of CoA cases in Iceland carry p.Arg721Trp. This is the first mutation associated with non-familial or sporadic CoA at a population level. P.Arg721Trp also associates with risk of bicuspid aortic valve (BAV) and other CHDs and has been reported to have a broad effect on cardiac electrical function and to associate strongly with sick sinus syndrome (SSS) and atrial fibrillation (AF)2. These findings suggest that p.Arg721Trp inMYH6causes a cardiac syndrome with highly variable expressivity, and emphasize the major importance of sarcomere integrity for cardiac development and function.

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 P 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.

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 (β=0.027 mm/unit log 10 [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.

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 (β = -0.08; p = 0.012), lean mass percentage (β = -0.06; p = 0.047) and handgrip strength (β = -0.15; p < 0.001) and eGFR calculated using the CKD-EPI equation was inversely associated with handgrip strength (β = -0.08; p = 0.001). In men, there was an inverse association between eGFR by the MDRD equation and lean mass percentage (β = -0.10; p = 0.013) and handgrip strength (β = -0.12; p = 0.022) and between eGFR by the CKD-EPI equation and lean mass percentage (β = -0.07; p = 0.018). The R2 for these variables was 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.

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

Summary Background Obesity is a significant risk factor for psoriasis and body mass index (BMI) correlates with disease severity. Objectives To investigate the relationship between obesity and psoriasis, focusing on the role of adipokines such as leptin and resistin. Patients/methods Patients with psoriasis (n = 30) were recruited and their BMI, waist circumference and disease severity [Psoriasis Area and Severity Index (PASI)] were recorded. Fasting serum samples were obtained on enrolment and after a course of ultraviolet (UV) B treatment. Age-, sex- and BMI-matched healthy controls were also recruited. Results On enrolment, serum leptin and soluble leptin receptor levels were not raised compared with the controls. However, resistin, interleukin (IL)-1β, IL-6, and chemokines CCL2, CXCL8 and CXCL9 were all significantly elevated in the patient group and serum resistin correlated with disease severity (r = 0·372, P = 0·043). Improvement after UVB treatment was accompanied by decreased serum CXCL8. In vitro, both leptin and resistin could induce CXCL8 and tumour necrosis factor-α production by blood monocytes, and leptin could additionally induce IL-1β and IL-1 receptor antagonist production. Leptin also dose dependently increased secretion of the growth factor amphiregulin by ex vivo-cultured lesional psoriasis skin. Conclusions These data support the view that leptin and resistin may be involved in the pathogenesis of psoriasis in overweight individuals, possibly by augmenting the cytokine expression by the inflammatory infiltrate.

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 GPBin 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 FEV1 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 FEV1 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.

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.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.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% (p0.001) and 14% (p0.05), 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).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.

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.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.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.Majority of Icelandic patients with CoA are operated on in Iceland with excellent outcome, both regarding short term complications and long term survival.

Sleep-disordered breathing (SDB) is associated with increased cardiovascular disease (CVD) risk. However, the contributions of traditional CVD risk factors (e.g., hypertension) relative to SDB are unknown. We evaluated longitudinal associations of nocturnal 02 saturation (SaO2) and CVD risk factors