Jari A. Laukkanen

Mercury, Fish Oils, and Risk of Acute Coronary Events and Cardiovascular Disease, Coronary Heart Disease, and All-Cause Mortality in Men in Eastern Finland

Objective— Mercury has been suggested to have negative effects on cardiovascular health. We investigated the effects of high mercury content in hair on the risk of acute coronary events and cardiovascular and all-cause mortality in men from eastern Finland. Methods and Results— The population-based prospective Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) cohort of 1871 Finnish men aged 42 to 60 years and free of previous coronary heart disease (CHD) or stroke at baseline was used. During an average follow-up time of 13.9 years, 282 acute coronary events and 132 cardiovascular disease (CVD), 91 CHD, and 525 all-cause deaths occurred. Men in the highest third of hair mercury content (>2.03 &mgr;g/g) had an adjusted 1.60-fold (95% CI, 1.24 to 2.06) risk of acute coronary event, 1.68-fold (95% CI, 1.15 to 2.44) risk of CVD, 1.56-fold (95% CI, 0.99 to 2.46) risk of CHD, and 1.38-fold (95% CI, 1.15 to 1.66) risk of any death compared with men in the lower two thirds. High mercury content in hair also attenuated the protective effects of high-serum docosahexaenoic acid plus docosapentaenoic acid concentration. Conclusions— High content of mercury in hair may be a risk factor for acute coronary events and CVD, CHD, and all-cause mortality in middle-aged eastern Finnish men. Mercury may also attenuate the protective effects of fish on cardiovascular health.

Metabolic Syndrome and the Risk of Stroke in Middle-Aged Men

Background and Purpose— The metabolic syndrome, a clustering of disturbed glucose and insulin metabolism, obesity and abdominal fat distribution, dyslipidemia, and hypertension is associated with cardiovascular diseases. The aim of this study was to examine the relationship of metabolic syndrome, as defined by National Cholesterol Education Program (NCEP) and World Health Organization (WHO) criteria, with the risk for stroke. Methods— Population-based cohort study with an average follow-up of 14.3 years from eastern Finland. A total of 1131 men with no history of cardiovascular disease and diabetes at baseline participated. Sixty-five strokes occurred, of which 47 were ischemic strokes. Results— Men with the metabolic syndrome as defined by the NCEP criteria had a 2.05-fold (95% CI, 1.03 to 4.11; P=0.042) risk for all strokes and 2.41-fold (95% CI, 1.12 to 5.32; P=0.025) risk for ischemic stroke, after adjusting for socioeconomic status, smoking, alcohol, and family history of coronary heart disease. Additional adjustment for ischemic changes during exercise test, serum low-density lipoprotein cholesterol, plasma fibrinogen, energy intake for saturated fats, energy expenditure of leisure time physical activity, and white blood cell count, the results remained significant. The risk ratios among men with metabolic syndrome as defined by the WHO criteria were 1.82 (95% CI, 1.01 to 3.26; P=0.046) for all strokes and 2.16 (95% CI, 1.11 to 4.19; P=0.022) for ischemic stroke. After further adjustment, the respective risks were 2.08 (95% CI, 1.12 to 3.87; P=0.020) and 2.47 (95% CI, 1.21 to 5.07; P=0.013). Conclusion— The risk of any stroke is increased in men with metabolic syndrome, in the absence of stroke, diabetes and cardiovascular disease at baseline. Prevention of the metabolic syndrome presents a great challenge for clinicians with respect to stroke.

Cardiorespiratory fitness and the progression of carotid atherosclerosis in middle-aged men

Accumulating epidemiologic and clinical evidence indicates that physical inactivity and poor cardiorespiratory fitness are major risk factors for atherosclerotic vascular diseases. The increased risk is similar to that seen for conventional modifiable risk factors, including hypercholesterolemia, cigarette smoking, and hypertension (1). Physical inactivity, which causes an estimated 12% of all deaths in the United States, is currently considered one of the most important public health problems (1). In prospective population studies, regular physical activity (2-6) and good cardiorespiratory fitness (6-9), as well as increased physical activity (10) and improved cardiorespiratory fitness (11), have been associated with reduced risk for clinical events of atherosclerotic vascular diseases. Clinical trials have provided additional evidence for the antiatherogenic effect of regular physical activity and good cardiorespiratory fitness. Physical activity alone (12), physical activity combined with a low-fat diet (13, 14) or comprehensive lifestyle modification (15-17), together with concomitant improvement in cardiorespiratory fitness, slows the progression of angiographically quantified coronary atherosclerosis in patients with coronary heart disease. Atherosclerosis in the human arteries develops from an asymptomatic phase to a manifest disease over decades. The occurrence of clinically significant atherosclerotic lesions and consequent symptomatic atherosclerotic vascular diseases increases progressively in middle age. Ultrasonography of the arteries allows noninvasive investigation of preclinical stages of atherosclerosis in unselected human populations (18, 19). When assessed by ultrasonography, carotid intimamedia thickeningwhich is related to an atherogenic risk factor profile, increased prevalence of coronary and peripheral atherosclerosis, and increased incidence of coronary heart disease and stroke (18-21)is regarded as a valid indicator of generalized atherosclerosis. In some cross-sectional population-based studies, regular physical activity (22, 23) and good cardiorespiratory fitness (24) have been associated with reduced prevalence of early atherosclerosis, as indicated by ultrasonographically assessed carotid intimamedia thickening. However, no prospective evidence from population-based studies shows that physical activity or good cardiorespiratory fitness is related to slower progression of early atherosclerosis. We therefore investigated the associations of cardiorespiratory fitness and physical activity with the progression of carotid atherosclerosis in a population-based sample of middle-aged men. Cardiorespiratory fitness was evaluated by directly measuring maximal oxygen uptake (Vo 2 max), and physical activity was assessed by using a detailed quantitative questionnaire. Atherosclerosis in the common carotid arteries was assessed over a 4-year period by using high-resolution B-mode ultrasonography to evaluate maximal intimamedia thickness (IMT), plaque height, surface roughness, and mean IMT. Methods Participants We studied participants in the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), an ongoing population study designed to investigate risk factors for atherosclerotic vascular diseases and related outcomes. The study involves men from eastern Finland (25), an area known for its high prevalence and incidence of atherosclerotic vascular diseases (26). The study group is a representative sample of men who lived in the town of Kuopio or neighboring rural communities and were 42, 48, 54, or 60 years of age at baseline examinations between March 1984 and December 1989. Of 3235 eligible men, 2682 (82.9%) participated. The KIHD was approved by the Research Ethics Committee of the University of Kuopio, Kuopio, Finland. Each participant gave written informed consent. A total of 1229 men who had undergone ultrasonographic examination of the common carotid arteries in the KIHD baseline study between February 1987 and December 1989 were invited to participate in the KIHD 4-year follow-up study. Of the invited men, 1038 (84.5%) participated; 107 declined; 52 could not participate because of death, severe illness, or relocation; and 32 could not be contacted. Of the 1038 participants, 184 had missing baseline data on some of the study variables. Our study is based on the remaining 854 men who had complete data on all study variables. Of these 854 men, 73 were in the pravastatin treatment group in the Kuopio Atherosclerosis Prevention Study (KAPS) between 1990 and 1993 (27). Assessment of Cardiorespiratory Fitness Cardiorespiratory fitness was assessed in the baseline study between August 1986 and December 1989 by use of a maximal but symptom-limited exercise test on an electrically braked 400 L-cycle ergometer (Medical Fitness, Mearn, the Netherlands), as explained in detail elsewhere (6). For safety reasons, and to obtain reliable information about exercise test variables, the tests were supervised by an experienced physician with the assistance of an experienced nurse. The exercise tests were performed between 8:00 a.m. and 10:00 a.m. by using a standardized testing protocol, which called for a linear increase in the workload by 20 W/min. Oxygen consumption was measured by using the breath-by-breath method of respiratory gas exchange (Medical Graphics, St. Paul, Minnesota). The Vo 2 max was defined as the highest value for or the plateau in oxygen uptake and was indexed by body weight (mL/kg per minute). Assessment of Physical Activity Physical activity was assessed in the baseline study between August 1986 and December 1989 by using the KIHD 12-Month Leisure-Time Physical Activity History, as explained elsewhere (6, 28). This detailed quantitative questionnaire deals with the most common physical activities of middle-aged Finnish men and enables the assessment of all components of physical activity, including energy expenditure, duration, frequency, and mean intensity [28]. Physical activity was categorized according to type: 1) conditioning physical activity [walking; jogging; cross-country skiing; bicycling; swimming; rowing; ball games; and gymnastics, dancing, or weightlifting], 2) nonconditioning physical activity [crafts, repairs, or building; yard work, gardening, farming, or shoveling snow; hunting, picking berries, or gathering mushrooms; fishing; and forest work] and 3) walking or bicycling to work. Assessment of Carotid Atherosclerosis The extent and severity of carotid atherosclerosis were assessed in the baseline study between February 1987 and December 1989 and in the 4-year follow-up study between March 1991 and December 1993. High-resolution B-mode ultrasonography was used to examine a 1.0- to 1.5-cm section at the distal end of the left and right common carotid artery proximal to the carotid bulb, as explained in detail elsewhere (18). Time from the baseline exercise test to baseline carotid ultrasonography was less than 1 month (range, 0 to 812 days) for 94% of the men. The ultrasonographers and the exercise testers were blinded with regard to each others findings. Average time from baseline to follow-up carotid ultrasonography was 4.2 years (range, 3.8 to 5.2 years). Four indicators of carotid atherosclerosis were used in our study: 1) the maximal IMT [the average of the maximal IMT values from the right and left common carotid arteries, an indicator of how deep the intimamedia layer protruded into the lumen], 2) plaque height [the average of the differences between the maximal and minimal IMT of the right and left common carotid arteries, an indicator of how steeply atherosclerotic lesions protruded into the lumen], 3) surface roughness (the standard deviation of the approximately 100 IMT measurements from the right and left common carotid arteries, an indicator of variability in IMT [for example, roughness of the surface of the artery wall]], and 4) the mean IMT (the mean of the approximately 100 IMT values from the right and left common carotid arteries, an overall indicator of atherosclerosis). The baseline IMT recordings were classified into four categories according to their severity: 1) no atherosclerotic lesion, 2) intimamedia thickening [a distance of>1.0 mm between the lumenintima and the mediaadventitia interfaces], 3) a nonstenotic plaque [a distinct area of mineralization or focal protrusion into the lumen], and 4) a large stenotic plaque (obstruction of>20% of the lumen diameter). A participant was considered to have advanced atherosclerosis if he had a nonstenotic plaque (category 3) or a large stenotic plaque (category 4). Assessment of Other Variables The examination protocol (25) and the assessment of medical history, medications, cigarette smoking, dietary intake of nutrients (29), blood pressure, body mass index, waist-to-hip ratio (30), and adult socioeconomic status (29) have been described in detail elsewhere. Collection of blood specimens and the measurement of levels of serum lipids and lipoproteins (29), blood glucose, serum insulin (30), and plasma fibrinogen (29) have been presented in detail elsewhere. All of these variables were assessed in the baseline and 4-year follow-up studies. Statistical Analysis The heterogeneity of the means of baseline variables between the quartiles of Vo 2 max was tested by using analysis of variance. Baseline risk factors for a 4-year increase in indicators of carotid atherosclerosis were selected by using multiple linear regression analyses. First, each potential risk factor was forced one at a time into a linear regression model with age and technical covariates (examination years, follow-up time, baseline zooming depth given separately for right and left side, baseline indicator of carotid atherosclerosis, baseline sonographer, and pravastatin treatment in KAPS). Second, all baseline risk factors that were statistically significantly associated with a 4-year increase in any of the indicators of carotid atherosc

Serum Antibody Levels to Actinobacillus actinomycetemcomitans Predict the Risk for Coronary Heart Disease

Objective—The association between serum antibody levels to major periodontal pathogens and coronary heart disease (CHD) was analyzed in a prospective population-based study. Methods and Results—The population comprised 1023 men (aged 46 to 64 years) in the Kuopio Ischemic Heart Disease Study. The subjects with CHD at baseline (n=113) were more often seropositive for Porphyromonas gingivalis IgA (38.9% versus 28.5%, P=0.021) and IgG (60.2% versus 46.7%, P=0.007) than those without CHD. During the 10-year follow-up, 109 men free from CHD at baseline experienced an acute myocardial infarction or CHD death. The men with an end point were more often seropositive for Actinobacillus actinomycetemcomitans IgA (15.5% versus 10.2%, P=0.019) than those who remained healthy. In the highest tertile of A. actinomycetemcomitans IgA-antibodies compared with the lowest one, the relative risk (RR) for an end point adjusted for CHD risk factors was 2.0 (95% confidence interval [CI], 1.2 to 3.3). In the Porphyromonas gingivalis IgA-antibody tertiles, the highest RR of 2.1 (1.3 to 3.4) was observed in the second tertile. All antibody levels correlated positively with the carotid artery intima-media thickness. Conclusions—High-serum antibody levels to major periodontal pathogens are associated with subclinical, prevalent, and future incidence of CHD. Periodontal pathogens or host response against them may contribute to the pathogenesis of CHD.

Exercise-induced silent myocardial ischemia and coronary morbidity and mortality in Middle-aged men

OBJECTIVES We investigated the prognostic significance of exercise-induced silent myocardial ischemia in both high and low risk men with no prior coronary heart disease (CHD). BACKGROUND Silent ischemia predicts future coronary events in patients with CHD, but there is little evidence of its prognostic significance in subjects free of CHD. METHODS We investigated the association of silent ischemia, as defined by ST depression during and after maximal symptom-limited exercise test, with coronary risk in a population-based sample of men with no prior CHD followed for 10 years on average. RESULTS Silent ischemia during exercise was associated with a 5.9-fold (95% CI 2.3 to 11.8) CHD mortality in smokers, 3.8-fold (95% CI 1.9 to 7.9) in hypercholesterolemic men and 4.7-fold (95% CI 2.4 to 9.1) in hypertensive men adjusting for other risk factors. The respective relative risks (RRs) of any acute coronary event were 3.0 (95% CI 1.7 to 5.1), 1.9 (95% CI 1.2 to 3.1) and 2.2 (95% CI 1.4 to 3.5). These associations were weaker in men without these risk factors. Furthermore, silent ischemia after exercise was a stronger predictor for the risk of acute coronary events and CHD death in smokers and in hypercholesterolemic and hypertensive men than in men without risk factors. CONCLUSIONS Exercise-induced silent myocardial ischemia was a strong predictor of CHD in men with any conventional risk factor, emphasizing the importance of exercise testing to identify asymptomatic high risk men who could benefit from risk reduction and preventive measures.

Cardiorespiratory Fitness Is Related to the Risk of Sudden Cardiac Death : A Population-Based Follow-Up Study

OBJECTIVES Our aim was to examine the relation of cardiorespiratory fitness with sudden cardiac death (SCD) in a population-based sample of men. BACKGROUND Very limited information is available about the role of cardiorespiratory fitness in the prediction of SCD. METHODS This population study was based on 2,368 men 42 to 60 years of age. Cardiorespiratory fitness was defined by using respiratory gas exchange analyzer and maximal workload during cycle ergometer exercise test. RESULTS During the 17-year follow-up, there were 146 SCDs. As a continuous variable, 1 metabolic equivalent (MET) increment in cardiorespiratory fitness was related to a decrease of 22% in the risk of SCD (relative risk: 0.78, 95% confidence interval: 0.71 to 0.84, p<0.001). In addition to cardiorespiratory fitness, ischemic ST-segment depression during exercise testing, smoking, systolic blood pressure, prevalent coronary heart disease, family history of coronary heart disease, and type 2 diabetes mellitus were related to the risk of SCD. The Harrell C-index for the total model discrimination was 0.767, while cardiorespiratory fitness provides modest improvement (from 0.760 to 0.767) in the risk prediction when added with all other risk factors. The integrated discrimination improvement was 0.0087 (p=0.018, relative integrated discrimination improvement 0.11) when cardiorespiratory fitness was added in the model. However, the net reclassification index (-0.018) was not statistically significantly improved (p=0.703). CONCLUSIONS Cardiorespiratory fitness is a predictor of SCD in addition to that predicted by conventional risk factors. There was a slight improvement in the level of discrimination, although the net reclassification index did not change while using cardiorespiratory fitness with conventional risk factors.

Plasma Vitamin C Modifies the Association Between Hypertension and Risk of Stroke

Background and Purpose— There are no prospective studies to determine whether plasma vitamin C modifies the risk of stroke among hypertensive and overweight individuals. We sought to examine whether plasma vitamin C modifies the association between overweight and hypertension and the risk of stroke in middle-aged men from eastern Finland. Methods— We conducted a 10.4-year prospective population-based cohort study of 2419 randomly selected middle-aged men (42 to 60 years) with no history of stroke at baseline examination. A total of 120 men developed a stroke, of which 96 were ischemic and 24 hemorrhagic strokes. Results— Men with the lowest levels of plasma vitamin C (<28.4 &mgr;mol/L, lowest quarter) had a 2.4-fold (95% CI, 1.4 to 4.3;P =0.002) risk of any stroke compared with men with highest levels of plasma vitamin C (>64.96 &mgr;mol/L, highest quarter) after adjustment for age and examination months. An additional adjustment for body mass index, systolic blood pressure, smoking, alcohol consumption, serum total cholesterol, diabetes, and exercise-induced myocardial ischemia attenuated the association marginally (relative risk, 2.1; 95% CI, 1.2 to 3.8;P =0.01). Adjustment for prevalent coronary heart disease and atrial fibrillation did not attenuate the association any further. Furthermore, hypertensive men with the lowest vitamin C levels (<28.4 &mgr;mol/L) had a 2.6-fold risk (95% CI, 1.52 to 4.48;P <0.001), and overweight men (≥25 kg/m2) with low plasma vitamin C had a 2.7-fold risk (95% CI, 1.48 to 4.90;P =0.001) for any stroke after adjustment for age, examination months, and other risk factors. Conclusions— Low plasma vitamin C was associated with increased risk of stroke, especially among hypertensive and overweight men.

Systolic Blood Pressure During Recovery From Exercise and the Risk of Acute Myocardial Infarction in Middle-Aged Men

We prospectively assessed the association of systolic blood pressure (SBP) after exercise with the risk of an acute myocardial infarction. Limited information exists currently on the role of SBP during recovery period with the risk of acute myocardial infarction. SBP was measured every 2 minutes during and after a progressive cycle ergometer exercise test in a representative sample of 2336 men (aged 42 to 61 years). During an average follow-up period of 13.1 years, 358 acute myocardial infarctions occurred. An incremental rise of 10 mm Hg per minute in SBP at 2 minutes after exercise (relative risk, 1.07-fold; 95% confidence interval [CI], 1.03 to 1.12; P=0.001) was associated with the risk of acute myocardial infarction after adjustment for age, alcohol consumption, smoking, serum lipids, diabetes mellitus, body mass index, resting SBP, regular use of antihypertensive medications, physical fitness, heart rate, and ischemic ECG findings during exercise. Men with elevated SBP of >195 mm Hg after exercise had a 1.69-fold (95% CI, 1.24 to 2.30; P=0.001) risk for an acute myocardial infarction compared with those with SBP <170 mm Hg after adjustment for age, other risk factors, and resting SBP. SBP after exercise provides an incremental predictive value for acute myocardial infarction beyond that of resting SBP. This emphasizes the importance of SBP measurements after the exercise test because it provides additional valuable prognostic measure with regard to acute myocardial infarction.

Coronary angioplasty in drug eluting stent era for the treatment of unprotected left main stenosis compared to coronary artery bypass grafting

Background. Improved outcomes of percutaneous coronary interventions (PCI) with drug-eluting stents (DES) have resulted in their expanded use for left main coronary artery (LMCA) stenosis. Aim. We compared outcomes of patients undergoing PCI for unprotected LMCA stenosis and patients treated by coronary artery bypass grafting (CABG). Method. Between January 2005 and January 2007, 6705 patients were studied with coronary angiography in northern Finland. All subjects treated with revascularization of LMCA stenosis (n=287) were included and followed up for a mean of 12±6 months. Results. From 287 patients, 238 underwent CABG, and 49 had PCI with DES. The incidence of 1-year mortality was 4% among the PCI-treated and 11% among CABG-treated patients (P=0.136). After the first month, mortality among PCI- or CABG-treated patients did not differ statistically significantly (2% versus 7%, P=0.133). The most significant independent predictor of mortality was reduced left ventricular systolic function (hazard ratio 14.9, 95% CI 5.5–40.0, P<0.001). Conclusions. PCI with DES for selected LMCA disease patients results in short- and midterm outcomes comparable to results of CABG in general. PCI is a viable therapeutic option in selected patients with LMCA stenosis.

Duration of QRS Complex in Resting Electrocardiogram Is a Predictor of Sudden Cardiac Death in Men

Background— Previous studies indicate that increased QRS duration in ECG is related to the risk of all-cause death. However, the association of QRS duration with the risk of sudden cardiac death (SCD) is not well documented in large population-based studies. Our aim was to examine the relation of QRS duration with SCD in a population-based sample of men. Methods and Results— This prospective study was based on a cohort of 2049 men aged 42 to 60 years at baseline with a 19-year follow-up, during which a total of 156 SCDs occurred. As a continuous variable, each 10-ms increase in QRS duration was associated with a 27% higher risk for SCD (relative risk, 1.27; 95% confidence interval, 1.14–1.40; P<0.001). Subjects with QRS duration of >110 ms (highest quintile) had a 2.50-fold risk for SCD (relative risk, 2.50; 95% confidence interval, 1.38–4.55; P=0.002) compared with those with QRS duration of <96 ms (lowest quintile), after adjustment for established key demographic and clinical risk factors (age, alcohol consumption, previous myocardial infarction, smoking, serum low- and high-density lipoprotein cholesterol, C-reactive protein, type 2 diabetes mellitus, body mass index, systolic blood pressure, and cardiorespiratory fitness). In addition to QRS duration, smoking, previous myocardial infarction, type 2 diabetes mellitus, cardiorespiratory fitness, body mass index, systolic blood pressure, and C-reactive protein were independently associated with the risk of SCD. Conclusions— QRS duration is an independent predictor of the risk of SCD and may have utility in estimating SCD risk in the general population.