Long-read sequencing of 3,622 Icelanders provides insight into the role of structural variants in human diseases and other traits.

Long-read sequencing (LRS) promises to improve the characterization of structural variants (SVs). We generated LRS data from 3,622 Icelanders and identified a median of 22,636 SVs per individual (a median of 13,353 insertions and 9,474 deletions). We discovered a set of 133,886 reliably genotyped SV alleles and imputed them into 166,281 individuals to explore their effects on diseases and other traits. We discovered an association of a rare deletion in PCSK9 with lower low-density lipoprotein (LDL) cholesterol levels, compared to the population average. We also discovered an association of a multiallelic SV in ACAN with height; we found 11 alleles that differed in the number of a 57-bp-motif repeat and observed a linear relationship between the number of repeats carried and height. These results show that SVs can be accurately characterized at the population scale using LRS data in a genome-wide non-targeted approach and demonstrate how SVs impact phenotypes.

Genetic insight into sick sinus syndrome.

AIMS: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. METHODS AND RESULTS: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). CONCLUSION: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.

Genetic insight into sick sinus syndrome.

AIMS: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. METHODS AND RESULTS: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). CONCLUSION: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.

Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation.

Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in RPL3L, the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in RPL3L results in exon skipping. We also observe an association with a missense variant in MYZAP (OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.

Congenital aortic stenosis due to unicuspid unicommissural aortic valve: a case report.

BACKGROUND: Unicuspid unicommissural aortic valve is an extremely rare congenital anomaly that usually presents in adulthood but can rarely present in infancy. We report a 17-year-old patient with congenital aortic stenosis secondary to unicuspid unicommissural aortic valve that was successfully treated with aortic valve replacement. CASE PRESENTATION: The patient was diagnosed with aortic stenosis after a murmur was heard in the newborn nursery and subsequently underwent aortic balloon valvuloplasty 6 weeks after birth. He had been regularly followed up since and underwent numerous cardiac catheterizations, including another aortic balloon valvuloplasty at age 13. During follow-up at age 17, the patient presented with symptomatic severe aortic stenosis and mild left ventricular hypertrophy. Aortic valve replacement was planned since the patient was nearly adult-sized and to reduce the risk of cardiac decompensation. During the operation an unicuspid unicommissural aortic valve was revealed. The patient recovered well post-operatively. He was discharged 5 days after the surgery in good condition and was completely symptom-free at follow-up 6 weeks later. CONCLUSIONS: Unicuspid aortic valve is a rare congenital anomaly that can cause congenital aortic stenosis. It is seldom diagnosed pre-operatively but should be suspected in infants presenting with aortic stenosis.

Do high levels of n-3 polyunsaturated fatty acids in cell membranes increase the risk of postoperative atrial fibrillation?

OBJECTIVES: Postoperative atrial fibrillation (POAF) has been associated with an inflammatory response to the surgical procedure. n-3 long-chain polyunsaturated fatty acids (LC-PUFA) have been proposed for the prevention of POAF. We investigated the relationship between the plasma concentration of inflammatory mediators, levels of n-3 LC-PUFA in red blood cell (RBC) membrane lipids, and the risk of POAF after coronary artery bypass grafting (CABG). METHODS: A total of 125 patients who underwent CABG were studied. Inflammatory mediators in plasma and the content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in RBC membranes were assessed. RESULTS: Sixty-two patients (49.6%) developed POAF. The POAF group had higher RBC levels of total n-3 LC-PUFA and DHA than did patients remaining in sinus rhythm (p < 0.05). Of the inflammatory mediators, only postoperative interleukin-6 levels differed, being higher in the POAF group (p < 0.05). Inflammatory mediators were not independent predictors of POAF by multivariable logistic regression analysis. Higher levels of DHA and total n-3 LC-PUFA in RBC membranes, measured immediately prior to CABG and on postoperative day 3, were linearly associated with an increased risk of POAF (p < 0.05). CONCLUSIONS: Our findings suggest that inflammatory mediators are not associated with the occurrence of POAF. Interestingly, high n-3 LC-PUFA levels in RBC membranes appear to increase the risk of POAF.

[Cervicofascial subcutaneous emphysema and pneumomediastinum following routine restorative dentistry--two case reports]. / Skyndilegur broti í andliti og þyngslaverkur yfir brjóstkassa eftir tannvidgerd--tvö sjúkratilfelli.

Although a well-known complication of dental treatment, cervicofacial subcutaneous emphysema is uncommon, especially with co-existing pneumomediastinum. This complication is usually attributed to high-speed air-driven handpieces or air-water syringes. Pneumomediastinum is usually self-limiting but potentially life threatening. We present two cases where both patients suffered from cervicofacial subcutaneous emphysema, one additionally having pneumomediastinum following routine restorative dentistry.

Plasma n-3 and n-6 fatty acids and the incidence of atrial fibrillation following coronary artery bypass graft surgery.

BACKGROUND: The anti-inflammatory or anti-arrhythmic effects of n-3 long-chain polyunsaturated fatty acids (LC-PUFA) may decrease the risk of postoperative atrial fibrillation (POAF), but interventional studies have yielded conflicting results. We examined the association between n-3 LC-PUFA and n-6 LC-PUFA in plasma phospholipids (PL) and POAF in patients undergoing coronary artery bypass grafting (CABG). METHODS: A total of 125 patients undergoing CABG were enrolled in the study. The levels of fatty acids in PL were measured preoperatively and on the third postoperative day. The endpoint was defined as POAF lasting ≥5 min. The incidence of POAF was compared between quartiles of the level of each fatty acid in plasma PL by univariate and multivariable analysis. RESULTS: The incidence of POAF was 49·6%. By univariate analysis, the incidence of POAF increased significantly with each higher quartile of pre- and postoperative docosahexaenoic acid (DHA) and diminished significantly with each higher quartile of pre- and postoperative arachidonic acid (AA). For postoperative total n-3 LC-PUFA, there was a significant U-curve relationship where the second quartile had the lowest incidence of POAF or 25·8%. In multivariable analysis, this U-curve relationship between n-3 LC-PUFA levels and POAF risk was not significant, whereas the association between POAF and DHA or AA remained statistically significant. CONCLUSIONS: This study suggests that n-3 LC-PUFA supplements might prevent POAF in CABG patients with low baseline levels of these fatty acids in plasma PL, but may be harmful in those with high levels. AA may play an important role in electrophysiological processes.

[Pulmonary embolism in a teenage girl]. / Blóðsegarek til lungna hjá unglingsstúlku - sjúkratilfelli.

Pulmonary embolism is an uncommon but potentially life threatening disease in children and adolescents. The clinical findings can be similar to other more common conditions such as pneumonia. Therefore high level of suspicion is required for early and accurate diagnosis. Most children have at least one underlying risk factor, either inherited or acquired. Computed tomography is the most widely used method in diagnosing pulmonary embolism. Anticoagulation is the mainstay of therapy for pulmonary embolism, however, acute surgery may be required for removal of the embolism. We report a case of pulmonary embolism in a teenage girl with serious circulatory failure where emergency surgery was needed.

Does treatment with n-3 polyunsaturated fatty acids prevent atrial fibrillation after open heart surgery?

AIMS: To examine the effect of n-3 polyunsaturated fatty acid (PUFA) treatment on the incidence of post-operative atrial fibrillation (POAF). METHODS AND RESULTS: A prospective, randomized, double-blinded, placebo-controlled trial was conducted in patients admitted for coronary artery bypass grafting and/or valvular repair surgery. The patients received either n-3 PUFA capsules, containing a daily dose of 1240 mg eicosapentaenoic acid and 1000 mg docosahexaenoic acid, or olive oil capsules for 5-7 days prior to surgery and post-operatively until hospital discharge. The endpoint was POAF, defined as an episode detected by continuous electrocardiographic monitoring, lasting >5 min. A total of 170 patients were enrolled in the study, and 168 patients underwent surgery. Their median age was 67 (range 43-82) years, and 79.2% were males. There was no difference in baseline characteristics between the n-3 PUFA group (n = 83) and the placebo group (n = 85), and the incidence of POAF was 54.2 and 54.1% (P = 0.99), respectively. Factors associated with POAF included advanced age, peak post-operative C-reactive protein level, valvular surgery, lower body mass index, and non-smoking, but n-3 PUFA concentration in plasma lipids was not associated with POAF. CONCLUSION: There is no evidence for a beneficial effect of treatment with n-3 PUFA on the occurrence of POAF in patients undergoing open heart surgery.

[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.

Bilateral extralobar pulmonary sequestration communicating with the upper gastrointestinal system in a newborn with duodenal atresia.

We report a rare form of bilateral pulmonary sequestration (PS) that was directly connected to the gastroesophageal junction with a well-formed aberrant bronchus-like structure. An upper gastrointestinal contrast series was performed directly after birth, and a unique PS bronchogram was identified, along with duodenal atresia. The PS was successfully resected and the duodenal atresia was corrected.

[Comparison of video-assisted thoracoscopic surgery and limited axillary thoracotomy for spontaneous pneumothorax]. / Samanburdur á opinni adgerd og adgerd med brjóstholssjá vid sjálfkrafa loftbrjósti.

INTRODUCTION: Historically, surgery for SP has been performed with open thoracotomy. Today video-assisted thoracoscopic surgery (VATS) has replaced open surgery for SP in most centers. Long-term results (i.e. recurrent pneumothorax) following VATS have been debated. In Iceland surgery for SP has been performed with both VATS and limited axillary thoracotomy (LAT). The aim of this study was to compare these two approaches, especially reoperations for prolonged airleakage and late recurrences. MATERIAL AND METHODS: This is a retrospective non-randomized study on all patients operated first time for SP at our institution between 1991-2005. Out of 210 patients that underwent 234 procedures (160 males, mean age 29 yrs.), 200 had primary SP (95%) and 10 secondary SP. The cases were divided into two groups; 134 VATS procedures and 100 thoracotomies (LAT). Three surgeons performed a LAT and four performed VATS. RESULTS: Wedge resection was performed in all cases and mechanical pleurodesis was added in 25% of the VATS and 67% of the LAT cases. Median operation time was 20 minutes longer for VATS (p=0.006). Reoperations for late recurrent pneumothorax were 10 vs. 3 in the VATS and LAT group, and reoperations for persistent airleakage 3 vs. 0, respectively (p=0.03). Operative mortality within 30 days from surgery was 0%. Median hospital stay was one day longer after LAT. CONCLUSION: Reoperations following VATS for SP are more common compared to open thoracotomy, explained by a higher rate of both late recurrent pneumothoraces and prolonged early postoperative airleakage. Both approaches are safe and major complications are infrequent. Hospital stay is shorter after VATS, however, VATS takes longer and the higher reoperation rate is a shortcoming and is of concern.

[Spontaneous pneumothorax: a review article]. / Sjálfkrafa loftbrjóst--Yfirlitsgrein.

Spontaneous pneumothorax is a relatively common disease primarily affecting young and otherwise healthy individuals. Chest pain and dyspnea are the most common presenting symptoms and in majority of cases only a chest X-ray is needed to confirm the diagnosis. The initial treatment usually consist of a chest tube drainage, however, persistent airleakage and recurrent pneumothorax are frequent, these patients often requiring surgery. Open thoracotomy was the most common surgical approach with wedge resection of the leaking part of the lung. Today, video-assisted thoracoscopic surgery has in most centers replaced open surgery for spontaneous pneumothorax. In this article the presentation, diagnosis and treatment of spontaneous pneumothorax, including different surgical strategies, are reviewed in an evidence-based approach.

[Desmoid tumor of chest wall--an important differential diagnosis to malignancies]. / Desmoid-aexli í brjóstvegg--mikilvaeg mismunagreining vieth illkynja mein.

Desmoid tumors are rare solid tumors that arise from musculoaponeurotic tissues. They are classified as benign as they do not metastasize. Desmoid tumors can, however, exhibit rapid local growth and clinically they can mimic sarcomas. Their histological appearance can also resemble some malignant neoplasms such as low grade sarcomas, rendering the differential diagnosis difficult. The present report describes a 60-year-old woman with a history of left mastectomy, performed for a lymph node negative adenocarcinoma. At follow-up 4 years later, a solid nodule was palpated below the right breast. The tumor increased in size over several weeks and caused local radiating chest pain. Clinically a breast cancer metastasis was suspected. Open biopsy revealed a desmoid tumor. The tumor was resected together with a part of the anterior hemithorax, and the defect in the chest wall covered with a Goretex-patch. Six months postoperatively, the patient is doing well with no signs of locally recurrent disease.

Changes in muscle compartment pressure after cardiopulmonary bypass.

PURPOSE: Hemodilution and inflammation lead to edema and increased muscle compartment pressure after cardiac surgery. The aim of this study was to find whether muscle compartment pressure was affected by the addition of albumin and mannitol to the pump prime, heparin coating or leukocyte depletion. Additionally, we studied the relationship between intraocular pressure and lower leg muscle compartment pressure. Edema during and following cardiac surgery is due to hemodynamic, osmotic and inflammatory changes, according to Starling's Law. We attempted to influence the osmotic balance and reduce the inflammatory response in order to reduce the edema. METHODS: Thirty-six patients who underwent cardiac surgery were randomly allocated into four groups. Group A received albumin and mannitol into the pump prime. Group B had an, heparin-coated perfusion system, Group C had a leukocyte-depletion arterial line filter and Group D was the control group, where intraocular pressure was also measured. RESULTS: Lower leg muscle compartment pressure increased significantly during and after cardiac surgery in all groups, but this increase was significantly less in Group A than in the control group 24 h after surgery. No correlation was found between muscular compartment pressure and intraocular pressure. The intraocular pressure profile is different from the muscular compartment pressure and recovers much faster. CONCLUSION: Lower leg muscle compartment pressure and intraocular pressure behave differently during and after cardiac surgery. Albumin and mannitol added to the pump prime decreases muscle compartment pressure after cardiac surgery.

The use of implantable cardioverter defibrillators in Iceland: a retrospective population based study.

BACKGROUND: Indications for implantable cardioverter defibrillator (ICD) implantation have expanded considerably in recent years, resulting in steadily growing numbers of ICD recipients worldwide. The aim of this study was to review the overall experience with ICDs in Iceland. METHODS: This was a retrospective single centre study set at the University Hospital in Iceland. Data on all ICD implantations in Iceland from the first implantation in 1992 till the end of 2002 was reviewed. RESULTS: Sixty-two patients (71% male) received an ICD during this period. There was an increase in the number of implants by year and the number of new implants in 2001 and 2002 amounted to 56 and 38 per million, respectively. The mean age at implantation was 58 (+/-14) years. Forty patients (65%) had coronary artery disease. The most common indications for ICD implantation were cardiac arrest, 32 (52%) and another 26 (42%) had experienced ventricular tachycardia without cardiac arrest. The most common adverse event was inappropriate shocks. Twenty-eight patients (45%) received therapy from their ICDs, with the majority receiving appropriate therapy. Of the thirteen patients deceased before or during the study period, no case of sudden arrhythmic death was observed. CONCLUSION: This study shows that the experience with ICDs in Iceland is in most respects similar to other Western countries.

Health-related quality of life of patients with implantable cardioverter defibrillators compared with that of pacemaker recipients.

AIMS: Studies indicate a poorer quality of life (QoL) for implantable cardioverter defibrillator (ICD) patients than for the general population. However, studies comparing the QoL of ICD patients with that of patients with other implantable cardiac devices are scarce. We hypothesized that ICD patients had a poorer QoL than pacemaker patients. METHODS AND RESULTS: All ICD patients living in Iceland at the beginning of 2002 (44 subjects), and a comparison group of 81 randomly selected patients with pacemakers were invited to participate. The Icelandic Quality of Life Questionnaire (IQL), the General Health Questionnaire (GHQ), the Beck Anxiety Inventory (BAI), and the Beck Depression Inventory (BDI) were submitted to measure QoL, psychiatric distress, and symptoms of anxiety and depression. The ICD and pacemaker groups did not differ on IQL, BAI, BDI, or GHQ scores. ICD patients were as a group more fearful of death (P = 0.056) and showed more concerns about returning to work (P = 0.072), although these items fell just short of statistical significance. CONCLUSION: Contrary to our expectations, ICD patients had a comparable QoL with pacemaker recipients and were not more likely to suffer from anxiety, depression, or general psychiatric distress. These findings are encouraging in view of expanding ICD indications.

Respiratory movements are altered three months and one year following cardiac surgery.

OBJECTIVE: Pulmonary complications following cardiac surgery through sternotomy are well known, but little is known about the proposed alterations of the chest wall mechanism. The purpose of this study was to examine changes in chest wall motion and pulmonary function after cardiac surgery. DESIGN: The subjects were 20 cardiac surgery patients, 13 men and 7 women, mean age 65 years. MEASUREMENTS: Bilateral respiratory movements were measured using the Respiratory Movement Measuring Instrument before, 3 and 12 months after the operation. Vital capacity (VC), forced vital capacity (FVC) and forced expiratory volume (FEV1) were measured with the Pulminet III (Gold Godart Ltd Vitalograph Alpha Ltd. Maids Morton, Buckingham, England) preoperatively, 3 and 12 months postoperatively, and radiographs were taken at the same points in time. ANALYSIS: Descriptive statistics, paired sample t-tests, Mann-Whitney and Wilcoxon Signed Rank tests were used for analyses, p < or = 0.05. RESULTS: Average abdominal movements 3 months postoperatively were significantly decreased and the difference between right and left side in upper thoracic and abdominal movements was significant. All pulmonary function measurements except the FEV1/FVC showed a significant decrease and a restrictive pattern compared with preoperative values. Twelve months after the operation the upper thoracic movements were significantly increased. Five patients had an abnormal chest x-ray before the operation, eight 3 months and three 12 months after the operation. CONCLUSION: The motor system of the respiratory organs suffers considerable injury from cardiac surgery, which in part at least can explain the restrictive breathing 3 months postoperatively.

Short-term changes in pulmonary function and respiratory movements after cardiac surgery via median sternotomy.

OBJECTIVE: To study the changes in bilateral respiratory motion and pulmonary function following sternotomy and the relationships between the changes in respiratory movements, spirometry, radiographic analyses, and several intra-operative surgical characteristics. DESIGN: Respiratory motion during deep breathing and lung volumes were measured in 20 patients (mean age 65 years, SD 16) before and after median sternotomy. Chest x-rays were analyzed pre- and postoperatively and a variety of perioperative variables were measured. RESULTS: Average abdominal motion decreased to 57% of preoperative values bilaterally 1 week postoperatively, the average lower thoracic motion decreased to 72%, and the average upper thoracic motion decreased to 87%, whereas the right upper thoracic motion increased 3% compared with preoperative values. Lung volumes decreased to around 60% of preoperative values (p<0.05). Significant correlations were found between the decrease in pulmonary function and the mean respiratory movements. Abnormal chest radiographs were found in all patients. CONCLUSION: The breathing pattern before sternotomy is predominantly abdominal but moves to a thoracic and upper thoracic pattern postoperatively and is associated with reduced pulmonary function. Therapeutic interventions aimed at correcting the less effective upper thoracic breathing pattern should likely be implemented.