The gene encoding phosphodiesterase 4D confers risk of ischemic stroke.

We previously mapped susceptibility to stroke to chromosome 5q12. Here we finely mapped this locus and tested it for association with stroke. We found the strongest association in the gene encoding phosphodiesterase 4D (PDE4D), especially for carotid and cardiogenic stroke, the forms of stroke related to atherosclerosis. Notably, we found that haplotypes can be classified into three distinct groups: wild-type, at-risk and protective. We also observed a substantial disregulation of multiple PDE4D isoforms in affected individuals. We propose that PDE4D is involved in the pathogenesis of stroke, possibly through atherosclerosis, which is the primary pathological process underlying ischemic stroke.

[Acute myocardial infarction among Icelanders forty years old and younger 2005-2009. Comparison with a study carried out 1980-1984].

INTRODUCTION: While acute myocardial infarction  (AMI) mostly is a disease of the elderly it also affects younger individuals, often with serious consequenses. In 1980-1984 a study was carried out on the incidence, risk factors, infarct location and distribution of atherosclerosis among Icelanders forty years and younger with AMI. Here we present the results of a similar study carried out for the five year period 2005-2009. MATERIALS AND METHODS: Medical and autopsy records of all individuals, forty years and younger, diagnosed with AMI (I21 in ICD-10) at Landspitali, National University Hospital 2005-2009, or suffering sudden cardiac death in Iceland during the same period were reviewed. Blood tests, electrocardiograms, echocardiograms, coronary angiograms and autopsy results were reviewed with respect to AMI-criteria. Statistical comparisons of ratios and means were carried out using Chi-square test and T-test, respectively. RESULTS: 38 individuals 40 years and younger, 32 males and 6 females, fulfilled the diagnostic criteria of AMI. Calculated incidence for the population at risk was 10/100.000/year (14/100.000/year in 1980-1984) and the mean age ±S.D. was 36.7±3.9. Three (7.9%) died suddenly before reaching hospital but of the 35 hospitalised patients 30 day mortality was zero, compared to nine (23.7%) pre-hospital deaths and two (6.9%) hospital deaths in 1980-1984. Thus, combined pre-hospital and in-hospital (30 day) mortality was 28.9% and 7.9% in the previous and recent time periods, respectively (p=0.02). In 2005-2009, 77.1% had a smoking history and 31.4% were hypertensive compared to 97% and 6.9% in 1980-85 (p=0.026 and p=0.015, respectively). Body mass index (BMI) was higher in the later period, 28.6±4,8 kg/m2 compared to 26.1±3.6 (mean±S.D.; p=0.04) but s-cholesterol was lower, 5.1±1.4 mmol/L compared to 6.3±1.16 ( mean±S.D.; p<0.01). In both studies single coronary artery disease was the most common angiographic pattern and the left anterior descending artery most often involved. CONCLUSION: Our results show that in two surveys 25 years apart AMI patients 40 years and younger are most often men. Smoking and family history were the most prominent risk factors during both periods but hypertension and high BMI were more common in 2005-2009 than in 1980-1984. Prognosis, as indicated by combined pre-hospital and in-hospital (30 day) mortality has improved. Key words: Myocardial infarction, forty and younger, incidence, risk factors, mortality, time trend Correspondence: Gudmundur Thorgeirsson gudmth@landspitali.is.

Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial.

CONTEXT: Myocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase-activating protein (FLAP) gene are associated with risk of MI. OBJECTIVE: To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk. DESIGN, SETTING, AND PATIENTS: A randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A4 hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004. INTERVENTIONS: Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks. MAIN OUTCOME MEASURES: Changes in levels of biomarkers associated with risk of MI. RESULTS: In response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P = .003) and myeloperoxidase was significantly reduced by 12% (95% CI, 2%-21%; P = .02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16%; 95% CI, -2% to 31%; P = .07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% CI, 5%-40%; P = .02) in C-reactive protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events. CONCLUSION: In patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.

[Pulmonary embolism at Landspítali, the National University Hospital of Iceland 2005-2007 - incidence, clinical manifestations, risk factors and outcome]. / Lungnasegarek a Landspitala 2005-2007 - nygengi, birtingarmynd, ahaettuthaettir og horfur.

INTRODUCTION: Pulmonary embolism is a serious disease and common among hospitalized patients. The incidence of pulmonary embolism in Iceland is largely unknown. The purpose of this study was to evaluate the incidence, clinical presentation, risk factors and outcome among patients diagnosed with pulmonary embolism at Landspítali, The National University Hospital of Iceland. MATERIAL AND METHODS: A retrospective analysis of medical records of patients diagnosed with the ICD-10 diagnosis I26 (Pulmonary embolism) between 2005-2007 was carried out. Data were retrieved on age, clinical manifestations, treatment, risk factors, diagnostic procedures and outcome. RESULTS: The total number of patients was 312 and the in-hospital incidence was 5 per 1.000. Thirty day mortality was 9.9% (95% CI 6.6-13.3). Dyspnea was the most common symptom (81%) and diagnosis was most often established by computed tomography of the pulmonary vasculature (88,8%). Anticoagulation was by far the most common management (96%) but thrombolysis, thrombectomy or use of inferior vena cava filters were very rare. The frequency of atrial fibrillation was significantly higher in patients with pulmonary hypertension by echocardiography than without, 32.4% and 9.7%, respectively (p= 0.026). Thirty day mortality was significantly higher in women than in men (13.2% versus 6.5%, p=0.049), and in patients with no classic symptoms of pulmonary embolism at diagnosis (36.4% versus 8.1%, p=0.012). DISCUSSION: The hospital incidence of pulmonary embolism, 5/1000 patients, at Landspítali The National University Hospital of Iceland is higher than found in similar studies in many other countries. Mortality, while similar, has fallen markedly during the past 40 years.

[Endocarditis in Iceland 2000-2009, a national survey incidence, microbiology and prognosis]. / Hjartathelsbólga á íslandi 2000-2009 - nýgengi, orsakir og afdrif.

INTRODUCTION: The objective of this study was to analyze the incidence, clinical features, microbiology and prognosis of patients with infective endocarditis (IE) in Iceland, and to compare the results with a previous study made in Iceland 1976-85. MATERIAL AND METHODS: A retrospective study including all patients diagnosed with IE in Iceland 2000-2009. Information was obtained from medical records. RESULTS: A total of 88 cases (71% men, mean age 59 years) were diagnosed and the incidence of IE was calculated 2.97/100.000 person-years. The mitral valve was infected in 35 patients (40%), aortic in 27 (31%) and tricuspid in 9 (10%). In 19 cases a prosthetic valve was infected (22%), one early (<<60 days from procedure) and 18 late. Sixteen patients were intravenous drug users. The most common causative organisms were streptococcus (33%), staphylococcus (25%) and enterococcus (16%). Surgical intervention was performed in 16 cases (18%). One and five year survival was 77% and 57% respectively. CONCLUSION: The incidence of IE in Iceland is still low compared to other countries. The clinical profile of the disease has changed since 1976-85, patients with prosthetic heart valves and intravenous drug users were more prominent than before. The microbiological spectrum has not changed much, streptococcus is still the most common pathogen, contrary to what is seen in other industrial countries where S. aureus is more frequent. Death rate is lower than before and one year survival good compared to other reports.

The absolute risk of recurrent myocardial infarction is similar amongst both sexes: MONICA Iceland Study 1981-1999.

BACKGROUND: To do a gender comparison of absolute risk of recurrent myocardial infarction (MI). DESIGN: Registration of all first and second MI amongst Icelandic males and females 1981-1999. METHODS: The whole of Icelandic population, 40-74 years of age. RESULTS: The mean recurrence rate (second attack) for men was 45.7/1000 MI survivors/year and for women 39.0/1000 per year. The male/female (M/F) ratio was 1.17, 95% confidence interval 1.00-1.37, P = 0.05 and did not change significantly with age. The M/F ratio for first MI in comparison was two to seven, lowest in the oldest group. The recurrence rate decreased significantly and similarly in both sexes during the observation period. CONCLUSION: The absolute risk of MI is closely similar amongst both sexes and has decreased similarly suggesting that the same kind of secondary intervention is effective amongst both sexes in a general population.

Declining coronary heart disease mortality in Iceland: contribution by incidence, recurrence and case fatality rate.

OBJECTIVE: To analyse to what extent the recent decline in coronary heart disease mortality in Iceland is due to changes in incidence, recurrence and case fatality rates. DESIGN: A countrywide registration of myocardial infarction (MI) in people aged 25-74 was performed in Iceland during 1981-1999 according to the MONICA protocol. Possible cases were found by review of all hospital discharge records, autopsy records and death certificates. RESULTS: MI death rate declined by 63% in males and 51% in females, most in the youngest age groups in men (86%) and least in the oldest (49%). In women there was not a significant difference in age groups. Overall the age-adjusted reduction in MI death rate was 55.4% in both sexes combined; of this 23.1% was due to incidence reduction, 22.8% to recurrence reduction and 11.6% to case fatality reduction. In the youngest age groups the decline in incidence contributed most to the decline in MI death rate (62% in men and 71% in women), but thereafter the decline in case fatality in men. In the older age groups decline in recurrence rate has greater weight. CONCLUSION: The recent decline in MI mortality under the age of 75 years in Iceland is due to reduction in incidence and recurrence rate by about 40% each and to reduction in case fatality by 20%.

Localization of a susceptibility gene for common forms of stroke to 5q12.

Stroke is one of the most complex diseases, with several subtypes, as well as secondary risk factors, such as hypertension, hyperlipidemia, and diabetes, which, in turn, have genetic and environmental risk factors of their own. Here, we report the results of a genomewide search for susceptibility genes for the common forms of stroke. We cross-matched a population-based list of patients with stroke in Iceland with an extensive computerized genealogy database clustering 476 patients with stroke within 179 extended pedigrees. Linkage to 5q12 was detected, and the LOD score at this locus meets the criteria for genomewide significance (multipoint allele-sharing LOD score of 4.40, P=3.9 x 10(-6)). A 20-cM region on 5q was physically and genetically mapped to obtain accurate marker order and intermarker distances. This locus on 5q12, which we have designated as "STRK1," does not correspond to known susceptibility loci for stroke or for its risk factors and represents the first mapping of a locus for common stroke.