Emil L. Sigurdsson

Unrecognized Myocardial Infarction: Epidemiology, Clinical Characteristics, and the Prognostic Role of Angina Pectoris: The Reykjavik Study

The clinical manifestations of coronary heart disease vary considerably. Since it was first described by James B. Herrick in 1912, clinically unrecognized myocardial infarction [1] has been extensively researched and debated. Epidemiologic studies have shown that silent, atypical, or unrecognized myocardial infarctions constitute between 20% and 60% of all myocardial infarctions [2-7]. Unrecognized myocardial infarction is diagnosed objectively using thallium perfusion imaging, radionuclide angiography, or echocardiography; it is most often diagnosed from typical, unequivocal changes on the electro-cardiogram of a patient with symptoms so atypical that neither patient nor physician recognizes the problem as an infarction. Atypical and silent myocardial infarction have traditionally been grouped together as unrecognized myocardial infarction. Patients with silent myocardial infarction seemingly have no symptoms. Half of all patients with unrecognized myocardial infarction recall no symptoms and have therefore had silent myocardial infarctions; the remainder have had atypical myocardial infarctions [8, 9]. Silent myocardial ischemia as an important manifestation in patients with coronary heart disease has been studied in recent decades and clearly affects prognosis unfavorably [10, 11]. Because the prognosis for patients with unrecognized myocardial infarction seems to be as serious as that for patients with recognized myocardial infarction [12, 13], practicing physicians face considerable diagnostic and therapeutic challenges when dealing with the many patients with this condition. Not only is it difficult to choose methods with which to identify these patients, it is also difficult to make decisions about secondary prevention and medical treatment. Detailed knowledge about this disease entity is therefore important and must include a thorough understanding of which patient subgroups are especially vulnerable. We report the results of a long-term study of a population-based cohort participating in the Reykjavik Study. Our purpose was to determine the incidence, prevalence, and prognosis associated with unrecognized myocardial infarction. We evaluated the risk factor profile for patients with unrecognized myocardial infarction compared with that of patients with recognized myocardial infarction, as well as the prognostic role of angina pectoris in persons with unrecognized myocardial infarction. Methods The design of the Reykjavik study has been described previously [6], and only a brief description is included here. The study is a large population-based cohort study that started in 1967. Men living in the Reykjavik area who were born between 1907 and 1934 were invited to participate. The study has been conducted in several stages: 1967-1968, 1970-1971, 1974-1975, 1979-1980, and 1983-1987. The response rate has varied from 64% to 75%. Since 1969, women have also participated in the study, but their results will be the subject of a separate report. Each participant answered a questionnaire that included the Rose chest pain questionnaire used by the London School of Hygiene and Tropical Medicine [14]; was examined by a physician; and had a standardized 12-lead electrocardiogram recorded and evaluated according to the Minnesota Code [15]. A total of 9141 men participated in the study at least once. Since 1981, data on the incidence of myocardial infarction have been collected as part of the World Health Organization MONICA Project [16]. Hospital records for persons who had had myocardial infarctions before 1981 were reviewed and evaluated according to criteria used in the MONICA study. Causes of death were determined from all death certificates from the start of the study until 31 December 1987. All autopsy records were also reviewed (autopsy rate, 55%). Diagnostic categories were defined as follows: 1. Recognized myocardial infarction: Patients who fulfilled the MONICA criteria for definite myocardial infarction [16] were placed in this category. These criteria include electrocardiographic changes (Minnesota codes 1.1.1-1.2.8); typical, atypical, or inadequately described symptoms together with probable electrocardiographic changes and abnormal enzyme levels; and typical symptoms and abnormal enzyme levels with ischemic or noncodable electrocardiographic results. 2. Unrecognized myocardial infarction: Participants in this category had no history or symptoms of heart attack but had electrocardiographic changes that fulfilled the criteria for definite myocardial infarction results (Minnesota codes 1.1.1-1.2.8). 3. Angina pectoris with electrocardiographic manifestations of myocardial ischemia: Participants who fulfilled the Rose questionnaire criteria for angina pectoris and who had either ischemic electrocardiographic results (Minnesota codes 1.3.1-1.3.6, 4.1-4.4, 5.1-5.4) or normal resting electrocardiographic results with a positive exercise stress test result ( 0.2 mV horizontal or down-sloping ST depression) were placed in this category. 4. Angina pectoris with normal resting electrocardiographic results: Participants with normal resting electrocardiographic results who either had normal exercise test results or had had no exercise test were assigned to this category if Rose questionnaire results indicated angina pectoris and if the examining physician could confirm the diagnosis. 5. Angina pectoris by the Rose questionnaire only: Participants fulfilling the Rose questionnaire criteria for angina pectoris, if their electrocardiograms did not indicate ischemia and the investigating physician could not confirm the diagnosis, were placed in this category. 6. No coronary heart disease: Participants in this category had no history or electrocardiographic manifestations of myocardial infarction. Patients were classified as having recognized myocardial infarction (category 1) on the basis of hospital records. Classification into the other diagnostic categories, including that of unrecognized myocardial infarction, was based on data collected at set intervals when patients attended the study clinic. Statistical Methods Three designs were used. In the first, a cross-sectional study, logistic regression was used to compute the prevalence odds of unrecognized myocardial infarction as a function of age and calendar year. It was also used to estimate the dependence of unrecognized and recognized myocardial infarction on simultaneous values of measured variables. In the second design, a prospective study, Poisson regression was used to compute the incidence of unrecognized myocardial infarction as a function of age and calendar year. It was also used to compute the predictive power of the measured variables for future unrecognized and recognized myocardial infarction. In these computations, consecutive visits were paired and each pair was used; pairs of visits were excluded if myocardial infarction had been diagnosed during the former visit. The risk period was the time elapsed between two visits (3 to 6 years), and age was the participants age halfway between the visits. In the third design, a prospective study of survival, Cox regression was used to estimate the simultaneous predictive power for risk for death (cause-specific or from all causes). -coefficients were calculated to investigate the prognostic value of risk factors and to form a composite score for individual persons. The composite risk score was the product sum of -coefficients and values of risk factors. Significance testing was two-sided and based on a 5% probability level. The software package used was EGRET (Epidemiologic Graphics, Estimation and Testing) [17]. Results Prevalence and Incidence The overall prevalence of unrecognized myocardial infarction in the first stage of the study was 0.5% in 1968 and 0.4% in 1971, and it increased in later stages of the study. In 1975 and 1980 it was 1.0% and 1.3%, respectively, and in the last stage, in 1986, it was 2.8%. To adjust for changes in age in the participants during the study period, we used logistic regression in which the prevalence odds were modeled as a function of age and either stage number or calendar year. As shown in Figure 1, prevalence increased steeply after age 60 years; it was 0.5% at age 50 years but exceeded 5% at age 75 years. The odds ratio per year was 1.10 (95% CI, 1.07 to 1.12). There was no significant time trend when the computation of prevalence was limited to the first visit of each participant, thus eliminating the bias introduced by the diagnosis of the previously unrecognized infarction. Figure 1. The prevalence of unrecognized myocardial infarction as a function of age. The incidence rate was obtained from the prospective study using a Poisson regression. The only explanatory variables tried at this stage were age, age squared, and calendar time. The incidence rate did not depend significantly on calendar time. Figure 2 shows that incidence was almost zero before age 40 years and increased steeply from age 40 years to age 60 years, at which it exceeded 300 per year per 100 000 persons. After age 65 years, the incidence rate decreased with age. The odds ratio for age (per year) was 2.06 (CI, 1.23 to 3.46); for age squared it was 0.994 (CI, 0.990 to 0.999). This was a significant (P < 0.05) contribution by age squared to the explanation of the incidence rate and indicated a decrease in the incidence rate of unrecognized myocardial infarction after age 65 years (Figure 2). Figure 2. Incidence of unrecognized myocardial infarction as a function of age. Risk Factor Profile Table 1 compares the mean values of some of the baseline characteristics of the cohort that had unrecognized myocardial infarction with those of the cohort that had recognized myocardial infarction. Although more participants with recognized than with unrecognized myocardial infarction were treated for high blood pressure and diabetes mellitus, the differences were not significant. Age and cholesterol, triglycer

Silent ST-T changes in an epidemiologic cohort study—A marker of hypertension or coronary heart disease, or both: The Reykjavik study

OBJECTIVES We sought to evaluate the prognostic value and clinical characteristics associated with electrocardiographic (ECG) ST-T changes among men without other manifestations of coronary heart disease. BACKGROUND Recent achievements in secondary prevention and treatment of coronary heart disease have highlighted the importance of early diagnosis of both symptomatic and silent forms of the disease. The prognostic and clinical importance of ST-T changes in men with no other manifestations of coronary heart disease is still unclear. Do they reflect silent coronary heart disease or hypertension, or both, and what is their independent contribution to prognosis? METHODS The subjects were 9,139 men born in the years 1907 to 1934 and followed up for 4 to 24 years. On initial visit they were assigned to different categories of coronary heart disease on the basis of Rose chest pain questionnaire, hospital records, 12-lead ECG, history and physical examination. RESULTS The prevalence of silent ST-T changes among men without overt coronary heart disease was strongly influenced by age, increasing from 2% at age 40 years to 30% at age 80 years. Men with such ST-T changes were older and had higher serum triglyceride levels and worse glucose tolerance than men without such changes or other evidence of coronary heart disease. Their blood pressure was higher, and they more often had an enlarged heart or left ventricular hypertrophy and more often took antihypertensive medication, digitalis or diuretic drugs. Serum cholesterol levels were not different between the two groups. After adjustment for other risk factors, these silent ST-T changes had a risk ratio of 2.0 for death from coronary heart disease and 1.6 for subsequent myocardial infarction or angina pectoris. CONCLUSIONS Silent ST-T changes that are ischemic by the Minnesota code are probably both a marker of silent coronary heart disease and high blood pressure. They define a distinct group of patients with highly abnormal risk factor profile. Although not specific for coronary heart disease and often transient, they are associated with the development of every clinical manifestation of coronary heart disease and are independent predictors of reduced survival.

Smoking during pregnancy: Childbirth and Health Study in Primary Care in Iceland

Abstract Objective. To study the prevalence and possible predictors for smoking during pregnancy in Iceland. Design. A cross-sectional study. Setting. Twenty-six primary health care centres in Iceland 2009–2010. Subjects. Women attending antenatal care in the 11th–16th week of pregnancy were invited to participate by convenient consecutive manner, stratified according to residency. A total of 1111 women provided data in this first phase of the cohort study. Main outcome measures. Smoking habits before and during early pregnancy were assessed with a postal questionnaire, which also included questions about socio-demographic background, physical and emotional well-being, and use of medications. Results. The prevalence of smoking prior to pregnancy was 20% (223/1111). During early pregnancy, it was 5% (53/1111). In comparison with women who stopped smoking during early pregnancy, those who continued to smoke had on average a significantly lower level of education, had smoked more cigarettes per day before pregnancy, and were more likely to use nicotine replacement therapy in addition to smoking during pregnancy. A higher number of cigarettes consumed per day before pregnancy and a lower level of education were the strongest predictors for continued smoking during pregnancy. Conclusion. The majority of Icelandic women who smoke stop when they become pregnant, and the prevalence of smoking during pregnancy in Iceland is still about 5%. Our results indicate stronger nicotine dependence in women who do not stop smoking during pregnancy. Awareness of this can help general practitioners (GPs) and others providing antenatal care to approach these women with more insight and empathy, which might theoretically help them to quit.

Primary prevention of cardiovascular diseases

One of the tasks of primary health care is the prevention of disease. Cardiovascular disease is still the leading cause of death, and there are several sets of guidelines dealing with both primary and secondary prevention. The article overviews the risk factors for cardiovascular disease and the strategies for primary prevention.

Prognostic role of cardiovascular risk factors for men with cardiomegaly (The Reykjavik Study)

The Reykjavik Study is a large population-based cohort study, starting in 1967. A total of 9,139 men, born in the years 1907 to 1934, have been followed for 4 to 24 years. Heart size was determined by chest roentgenogram in 2 planes and cardiomegaly, defined as a relative heart size exceeding 550 ml/m2, was detected in 517. Multivariate Cox regression analysis was used to estimate the independent contribution of variables measured at each participants first visit to the risk of both all-cause and coronary artery disease (CAD) mortality. Cardiomegaly was detected in 3.7% of men aged < 40 years and in 21.2% of those > 75 years. One half of these men had hypertension, one third had manifestations of CAD, and 37% had neither. Among men with cardiomegaly, the presence of CAD had marked deleterious effect on prognosis. Serum total cholesterol and systolic blood pressure were significant independent risk factors of CAD mortality with risk ratio of 1.008 per mg/dl serum cholesterol (95% confidence interval 1.00 to 1.01; p = 0.004) and 1.015/mm Hg (95% confidence interval 1.000 to 1.300; p = 0.043), respectively. Smoking > 25 cigarettes/day carried a 2.3-fold risk (95% confidence interval 1.3 to 4.4; p = 0.008) of all-cause mortality. The traditional risk factors for CAD, serum cholesterol, high blood pressure, and smoking maintain their detrimental effect on prognosis among patients with cardiomegaly. These findings have implications for secondary prevention, signifying that in the presence of cardiomegaly, complacency is not justified in controlling major risk factors for CAD.

Medical treatment and secondary prevention of coronary heart disease in general practice in Iceland

Objective - To evaluate the implementation of secondary prevention and treatment of coronary heart disease (CHD) in general practice in Iceland. Settings - Two health care centers adjacent to Reykjavik with a total of 25766 inhabitants. Patients - All patients (533) with CHD living in the study area were sent an invitation letter and a request for informed consent. Those who chose to participate answered a questionnaire about CHD risk factors and their current treatment, and their medical records were reviewed. The patients were divided into four groups on the basis of their history: I. Coronary artery bypass surgery (CABG), II. Percutaneous transluminal coronary angioplasty (PTCA), III. Myocardial infarction (MI), IV. Angina pectoris (AP). If a patient fulfilled the criteria for more than one diagnostic group the CABG group had the highest priority followed by PTCA, MI and finally AP. Main outcome measures - Blood pressure, smoking habits, BMI, exercise profile, cholesterol levels and drug therapy. Results - Of 533 patients with CHD, 402 (75%) participated in the study, 15% were managed exclusively by their family physician and 23% by both cardiologists and family physicians. Obesity was relatively common, with nearly 60% being overweight (BMI > 25). Average cholesterol in the total group was 6.2 mmol/L (95% CI 6.07 to 6.34). Blood pressure had been recorded in 92% of the patients, and mean systolic and diastolic blood pressures were 143 and 82 mmHg, respectively. While 15% were current smokers, 56% were ex-smokers. A total of 113 patients (28%) were being treated with cholesterol-lowering drug therapy at the time of the study. Respective treatment ratios in the four subgroups were 47% in group I, 42% in II, 25% in III and 13% in group IV. Aspirin was taken by 284 patients (71%), beta blockers by 52% and calcium channel blockers by 36%. More than twice as many women than men were treated with nitrates, 57% versus 27%. Conclusions - The results indicate that there are numerous possibilities for improvements in secondary prevention and medical management of coronary heart disease in Iceland. Particular emphasis should be placed on smoking cessation, life-style modification with exercise and diet recommendations to lower BMI and lipid-lowering therapy.

Result of school-based intervention on cardiovascular risk factors

Abstract Objective. To assess the effectiveness of a two-year school-based intervention, consisting of integrated and replicable physical activity and nutritional education on weight, fat percentage, cardiovascular risk factors, and blood pressure. Design and setting. Six elementary schools in Reykjavik were randomly assigned to be either intervention (n = 3) or control (n = 3) schools. Seven-year-old children in the second grade in these schools were invited to participate (n = 321); 268 (83%) underwent some or all of the measurements. These 286 children were followed up for two years. Intervention. Children in intervention schools participated in an integrated and replicable physical activity programme, increasing to approximately 60 minutes of physical activity during school in the second year of intervention. Furthermore, they received special information about nutrition, and parents, teachers, and school food service staff were all involved in the intervention. Subjects. 321seven-year-old schoolchildren. Main outcome measures. Blood pressure, obesity, percentage of body fat, lipid profile, fasting insulin. Results. Children in the intervention group had a 2.3 mmHg increase in systolic blood pressure (SBP) and a 2.9 mmHg increase in diastolic blood pressure (DBP) over the two-year intervention period, while children in the control group increased SBP by 6.7 mmHg and DPB by 8.4 mmHg. These changes were not statistically significant. Furthermore there were no significant changes in percentage body fat, lipid profile, or fasting insulin between the intervention and control schools. Conclusion. A two-year school-based intervention with increased physical activity and healthy diet did not have a significant effect on common cardiovascular risk factors.

Association of BMI and fasting insulin with cardiovascular disease risk factors in seven-year-old Icelandic children

Objective. To look at overweight and common cardiovascular disease (CVD) risk factors, and associations with body mass index (BMI) and fasting insulin in seven-year-old schoolchildren in Reykjavik, Iceland. Study design. Cross-sectional study of seven-year-old schoolchildren. Setting. Six elementary schools in Reykjavik. Subjects. All children attending second grade in these six schools were invited to participate. Main outcome measures. Overweight, fasting serum insulin, CVD risk factors. Results. Some 14% of the participating children were classified as overweight. Overweight children had higher fasting insulin, higher fasting glucose, and higher systolic and diastolic blood pressure. Furthermore, they had significantly lower total cholesterol (TC), lower high-density lipoprotein (HDL), and lower low-density lipoprotein (LDL) but a similar TC/LDL ratio to normal-weight children. The factors that were strongly associated with BMI were serum fasting insulin, systolic blood pressure (SBP), HDL and fasting glucose, while the sum of four skinfolds, triglycerides, glucose, and LDL were highly associated with fasting insulin. Conclusion. Overweight children are likelier to have unfavourable levels of common CVD risk factors included in metabolic syndrome, but surprisingly had lower LDL and TC. Skinfold thickness, higher triglyceride and glucose levels, and being female were associated with increased serum insulin.

Factors associated with bone mineral density and content in 7-year-old children.

OBJECTIVE To evaluate the bone status of 7-year-old school children in Reykjavik, Iceland, and to see if gender, height, lean body mass and fat mass is associated with bone mineral density (BMD) and bone mineral content (BMC) in the lumbar vertebrae and hip. STUDY DESIGN A cross-sectional study of a sample of 7-year-old school children. SETTING Six elementary schools in Reykjavik, Iceland. SUBJECTS All children attending second grade in these six schools were invited to participate. Three hundred twenty-six children were invited and 211 (65%) participated in the study. MAIN OUTCOME MEASURES Lean body mass, bone mineral density, bone mineral content and total fat mass. RESULTS Both BMD and BMC were positively correlated with sex, height and lean body mass. Fat mass was positively correlated to BMC but not BMD in the total body and lumbar vertebrae. When analyzed with multiple linear regression, the bone area and lean body mass (LBM) were positively associated with BMC in the hip and total body, but total fat mass (TFM) was negatively associated with BMC, the model explaining about 88% of the variance (R2) in the total body bone mineral content (TBMC) and 74% of the variance (R2) in the BMC of the hip. LBM was positively associated with total body bone mineral density (TBMD) but TFM negatively associated. Neither height nor gender contributed to total BMC and BMD in our multiple linear regression models. CONCLUSION The study emphasizes that fat mass may play different roles in children and adults and that both LBM and TFM should be taken into consideration when interpreting BMC and BMD for children.

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

Abstract 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.