Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland.

Objective: Familial hypercholesterolemia (FH) is traditionally defined as a monogenic disease characterized by severely elevated LDL-C (low-density lipoprotein cholesterol) levels. In practice, FH is commonly a clinical diagnosis without confirmation of a causative mutation. In this study, we sought to characterize and compare monogenic and clinically defined FH in a large sample of Icelanders. Approach and Results: We whole-genome sequenced 49 962 Icelanders and imputed the identified variants into an overall sample of 166 281 chip-genotyped Icelanders. We identified 20 FH mutations in LDLR, APOB, and PCSK9 with combined prevalence of 1 in 836. Monogenic FH was associated with severely elevated LDL-C levels and increased risk of premature coronary disease, aortic valve stenosis, and high burden of coronary atherosclerosis. We used a modified version of the Dutch Lipid Clinic Network criteria to screen for the clinical FH phenotype among living adult participants (N=79 058). Clinical FH was found in 2.2% of participants, of whom only 5.2% had monogenic FH. Mutation-negative clinical FH has a strong polygenic basis. Both individuals with monogenic FH and individuals with mutation-negative clinical FH were markedly undertreated with cholesterol-lowering medications and only a minority attained an LDL-C target of <2.6 mmol/L (<100 mg/dL; 11.0% and 24.9%, respectively) or <1.8 mmol/L (<70 mg/dL; 0.0% and 5.2%, respectively), as recommended for primary prevention by European Society of Cardiology/European Atherosclerosis Society cholesterol guidelines. Conclusions: Clinically defined FH is a relatively common phenotype that is explained by monogenic FH in only a minority of cases. Both monogenic and clinical FH confer high cardiovascular risk but are markedly undertreated.

Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies.

Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.

Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes.

BACKGROUND: The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA(α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). METHODS AND RESULTS: Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. CONCLUSIONS: Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities.

[Review on coronary artery disease--Part II: medical treatment, percutaneous interventions and myocardial revascularization]. / Yfirlitsgrein um kransæðasjúkdóm--síðari hluti: Lyfjameðferð, kransæðavíkkun og kransæðahjáveituaðgerð.

This article is the second of two review articles on coronary artery disease. The focus is on treatment with coverage of medical treatment, intravascular interventions and surgical therapy. The review is aimed at a wide readership of physicians and other health care providers but also at students of various health sciences. Current literature is reviewed with special focus on recent Icelandic studies.

[Surgical outcome of mitral valve repair in Iceland 2001-2012]. / Árangur míturlokuviðgerða á Íslandi 2001-2012.

OBJECTIVES: To review, for the first time, the outcome of mitral valve repair operations in Iceland. MATERIAL AND METHODS: A retrospective study of all mitral valve repair patients (average age 64 yrs, 74% males) operated in Iceland 2001-2012. All 125 patients had mitral regurgitation; either due to degenerative disease (56%) or functional regurgitation (44%). Survival was estimated using the Kaplan-Meier method. The median follow-up time was 3.9 years RESULTS: The number repair-procedures increased from 39 during the first half of the study period to 86 during the latter period. The mean EuroSCORE was 12.9% and 2/3 of the patients were in NYHA class III/IV. Half of them had severe mitral regurgitation, 12% had a recent myocardial infarction, and 10% a history of previous cardiac surgery. A ring annuloplasty was performed in 98% of cases, a posterior leaflet resection was done in 51 patients (41%), 28 received artificial chordae (Goretex(®)) and 7 an Alfieri-stitch. Concomitant cardiac surgery was performed in 83% of cases, where coronary artery bypass (53%), Maze-procedure (31%) or aortic valve replacement (19%) were most common. Major complications occurred in 56% of the cases and minor complications were noted in 71% of cases. Two patients later required mitral valve replacement. Eight patients died within 30 days (6%) and 5-year overall survival was 79%; or 84% and 74% for the degenerative and functional groups, respectively. CONCLUSIONS: The number of mitral valve repairs in Iceland increased significantly over the study period. Complications are common but operative mortality and long-term survival is similar to that reported in studies from other countries.

[Outcome of mitral valve replacement in Iceland]. / Arangur míturlokuskipta á Islandi.

INTRODUCTION: Mitral valve replacement (MVR) is the second most common valvular replacement procedure after aortic valve replacement (AVR). Studies on the outcome of MVR in Iceland have been missing. We therefore studied short and long-term results following MVR in Iceland, MATERIAL AND METHODS: A retrospective nationwide study on 64 patients (mean age 59 years, 63% males) that underwent 66 MVR procedures in Iceland between 1990-2010. Clinical data was retrieved from patient charts and overall survival estimated. The mean follow-up was 7.4 years. RESULTS: Mitral regurgitation or stenosis was the indication for MVR in 71% and 27% of cases, respectively. Nine patients had endocarditis and 8 a recent myocardial infarction. The mean logEuroSCORE was 14.9% (range 1.5-88.4), 83% of the patients were in NYHA class III/IV preoperatively and 24% had previously undergone cardiac surgery. A biological valve was implanted in six cases and a mechanical valve used in 60 cases. Concomitant CABG was performed in 41% of patients and AVR in 20%. Perioperative myocardial infarction (26%), acute respiratory failure (17%), reoperation for bleeding (15%) and acute renal failure requiring dialysis (9%) were the most common major complications. Three patients required extracorporeal membrane oxygenation (ECMO) and six patients an intra-aortic balloon pump (IABP) postoperatively. Minor complications were noted in 61% of cases. Six patients died within 30 days (9%) and five year survival was 69%. CONCLUSION: The frequency of complication following MVR was high and represents the severity of the underlying heart disease. The operative mortality in the current study was in the lower range compared to other studies.

[Aortic valve replacement for aortic stenosis in Iceland 2002-2006: Long term complications and survival]. / Lokuskipti vegna ósædarlokuthrengsla á Islandi 2002-2006 - langtímafylgikvillar og lifun.

OBJECTIVE: To investigate long-term complications and survival following aortic valve replacement (AVR) in patients with aortic stenosis (AS) in Iceland. MATERIAL AND METHODS: Included were 156 patients (average age 71.7 yrs, 64.7% males) that underwent AVR for AS at Landspitali between 2002 and 2006. A mechanical prosthesis was used in 29 patients (18.6%) and a bioprosthesis in 127. Long-term complications and operation-related admissions were registered from hospital and outpatient records until April 1, 2010. Overall survival was estimated and compared with the Icelandic population of the same age and gender. RESULTS: The mean preop. EuroSCORE(st) was 6.9%, the max. transvalvular pressure gradient 74.1 mmHg and the left ventricular ejection fraction (LVEF) (57.2%). At six months following AVR the maximal pressure gradient was 19.8 mmHg (range; 2.5-38). Echocardiography results were not available for 23.6% of the patients 6 months postoperatively. In the follow-up period one in four patients was admitted due to valve-related problems. Re-admission rate was 6.0/100 patient-years (pt-y); most commonly due to cardiac failure (1.7/100 pt-y), emboli (1.6/100 pt-y), hemorrhage (1.6/100 pt-y), endocarditis (0.7/100 pt-y) and myocardial infarction (0.4/100 pt-y). Survival at 1 and 5 year was 89.7% and 78.2%, respectively, making survival comparable to the estimated survival of Icelanders of the same age and gender. CONCLUSIONS: The rate of long-term complications following AVR in Iceland is in line with other studies. The same applies to long-term survival, which was similar to that of the Icelandic population of the same age and gender. Key words: Aortic valve replacement, aortic stenosis, heart surgery, results, long-term complication, survival.

[Aortic valve replacement for aortic stenosis in Iceland 2002-2006: Indications and short term complications]. / Lokuskipti vegna óædarlokuprengsla á islandi 2002-2006: ábendingar og snemmkomnir fylgikvillar.

OBJECTIVE: Information on surgical outcome of aortic valve replacement (AVR) has not been available in Iceland. We therefore studied the indications, short-term complications and operative mortality in Icelandic patients that underwent AVR with aortic stenosis. MATERIAL AND METHODS: This was a retrospective study including all patients that underwent AVR for aortic stenosis at Landspitali between 2002 and 2006, a total of 156 patients (average age 71.7 years, 64.7% males). Short term complications and operative mortality (≤ 30 days) were registered and risk factors analysed with multivariate analysis. RESULTS: The most common symptoms before AVR were dyspnea (86.9%) and angina pectoris (52.6%). Preop. max aortic valve pressure gradient was on average 74 mmHg, the left ventricular ejection fraction 57.2% and EuroSCORE (st) 6.9%. The average operating time was 282 min and concomitant CABG was performed in 55% of the patients and mitral valve surgery in nine. A bioprothesis was implanted in 127 of the patients (81.4%), of which 102 were stentless valves, and a mechanical valve in 29 (18.6%) cases. The mean prosthesis size was 25.6 mm (range 21-29). Atrial fibrillation (78.0%) and acute renal injury (36.0%) were the most common complications and 20 patients (13.0%) developed multiple-organ failure. Twenty-six patients (17.0%) needed reoperation due to bleeding. Median hospital stay was 13 days and operative mortality was 6.4%. CONCLUSIONS: The rate of short term complications following AVR was relatively high, including reoperations for bleeding and atrial fibrillation. Operative mortality is twice that of CABG, which is in line with other studies.

Cardiac myxoma in Iceland: a case series with an estimation of population incidence.

Cardiac myxoma (CM) is the most common primary benign tumor of the heart, but the true age-standardized incidence rate (ASR) has remained unknown. We therefore used nationwide registries in Iceland to study CM and establish its incidence rate. This was a retrospective study involving all patients diagnosed with CM in Iceland between 1986 and 2010. Cases were identified through three different registries, and hospital charts and histology results reviewed. An ASR was estimated based on a world standard population (w). Nine cases of CM (six women) were identified with a mean age of 62.8 years (range: 37-85), giving an ASR of 0.11 (95% CI: 0.05-0.22) per 100,000. The mean tumor size was 4.4 cm (range: 1.5-8.0) with all the tumors located in the left atrium. Dyspnea (n = 6) and ischemic stroke (n = 2) were the most common symptoms. All patients underwent complete resection of the tumor and there were no postoperative deaths or CM-related deaths at follow-up (mean 85 months). The ASR of CM in Iceland was 0.11 per 100,000. To our knowledge, this is the first study to determine the incidence of CM in an entire population. In Iceland, the presenting symptoms and mode of detection of CM are similar to those in other series.

[Constrictive pericarditis with severe heart failure - a case report and review of the literature]. / Grefjagollurshús - sjúkratilfelli med umraedu.

Constricitve pericarditis is an uncommon condition, often of unknown etiology but can be caused by infections, such as tuberculosis, inflammation of the pericardium, radiation therapy or asbestos exposure. Constrictive pericarditis is characterized by fibrosis and often severe calcifications of the pericardial sac which eventually restricts normal diastolic filling of the heart. This consequently leads to a combination of left and right heart failure, often with prominent jugular venous distentsion, liver enlargement, peripheral edema and lethargy. Diagnosis can be difficult and is often delayed. Surgery, involving partial removal of the pericardial sac, usually leads to relief of symptoms. Here we report a case from Landspitali together with a review of the literature.

[Percutaneous coronary intervention in icelandic diabetic patients.].

INTRODUCTION: Several studies suggest that the primary success of percutaneous coronary intervention (PCI) is less in diabetic patients than others and that complications and restenosis are more frequent. This was therefore assessed in icelandic diabetic patients. METHODS: From 1987 to 2002 a total of 4435 PCI s were performed and of these 377 (8.5%) were in diabetic patients. The clinical background of the patients, primary success after PCI, and in-hospital complications, were retrospectively assessed. RESULTS: The relative frequency of diabetics undergoing PCI increased significantly during the study period from 5.7% to 10.6% (p=0.001). In diabetic compared with non-diabetic patients, the mean age was higher (64 +/- 10 versus 62 +/- 10 years; p=0.002), and women were more frequent. Hypertension and hypercholesterolaemia were more common in the diabetics and a larger proportion of them were current smokers. Further more, diabetics more frequently had a previous history of myocardial infarction, coronary artery bypass surgery, PCI, unstable angina and triple-vessel disease. The overall use of stents was similar in the groups, as was PCI for clinical restenosis (13.3% versus 10.8%; p=0.15). The primary success rate was comparable in diabetics and non-diabetics (93% versus 92%). The need for acute coronary bypass post-PCI was similar in the groups, whereas diabetics more rarely had a three fold increase in creatinine kinase-MB values. Overall, in-hospital mortality was low (0.4%), but higher in diabetic than non-diabetic patients (1.1% versus 0.3%; p=0.04). By multivariate analysis, significant independent predictors of in-hospital mortality were: Primary PCI for acute ST-elevation infarction, number of stenotic coronary vessels, diabetes and age, while the presence of hypercholesterolemia was an inverse predictor. CONCLUSION: The primary success rate for PCI is comparable in icelandic diabetic and non-diabetic patients. Although few patients died in hospital after PCI, the diabetic patients did have a higher in-hospital mortality rate.