Ten-year prediction of cardiovascular disease in healthy Norwegian men, based on NORRISK-2. / Tiårsprediksjon av hjerte- og karsykdom hos friske norske menn basert på NORRISK-2.

BACKGROUND: Norwegian guidelines for primary prevention of cardiovascular disease recommend the use of the NORRISK-2 risk model, with some additions. We wished to investigate whether NORRISK-2 could predict cardiovascular disease in healthy Norwegian men who took part in the Oslo Ischaemia Study. MATERIAL: NORRISK-2 scores were calculated for 2 014 men in the age group 40-60 years who were included in the Oslo Ischaemia Study in 1972-75. Cox regression analyses were used to calculate the hazard ratio for death and cardiovascular disease within ten years of the participants' initial assessment. RESULTS: No participant was lost to follow-up of the 2 014 men, 125 died in the first ten years after inclusion, 61 of whom died from cardiovascular disease. Those who died were older than those who survived, with a larger proportion of daily smokers, and they had higher systolic blood pressure and resting pulse, increased total cholesterol and lower physical fitness. The majority of those who died from acute myocardial infarction and ischaemic stroke within ten years were classified in the high-risk group in NORRISK-2. INTERPRETATION: NORRISK-2 satisfactorily identified the high-risk persons in this cohort of healthy, middle-aged Norwegian men. This supports use of the Norwegian guidelines in the decision on possible primary protection against cardiovascular disease.

Novel insights into stroke risk beyond resting and maximal bicycle exercise systolic blood pressure.

OBJECTIVE: Previous research has shown an association between moderate workload exercise blood pressure (BP) and coronary disease, whereas maximal exercise BP is associated with stroke. We aimed to investigate the association between the increase in BP during maximal exercise and the long-term risk of stroke in healthy, middle-aged men. METHODS: Two thousand and fourteen men were included in the Oslo Ischemia Study in the 1970s. In the present study, we examined baseline data of the 1392 participants who remained healthy and performed bicycle exercise tests both at baseline and 7 years later. Cox proportional hazard was used to assess the risk of stroke in participants divided into quartiles based on the difference between resting and maximal workload SBP (ΔSBP) at baseline, adjusting for resting BP, age, smoking, serum cholesterol and physical fitness. Follow-up was until the first ischemic or hemorrhagic stroke through 35 years. RESULTS: There were 195 incident strokes; 174 (89%) were ischemic. In univariate analyses, there were significant positive correlations between age, resting SBP, resting DBP and SBP at moderate and maximal workload, and risk of stroke. In the multivariate analysis, there was a 2.6-fold (P < 0.0001) increase in risk of stroke in ΔSBP quartile 4 (ΔSBP > 99 mmHg) compared with ΔSBP quartile 2 (ΔSBP 73-85 mmHg), which had the lowest risk of stroke. ΔSBP quartile 1 had a 1.7-fold (P = 0.02) increased risk compared with quartile 2, suggesting a J-shaped association to stroke risk. CONCLUSION: Stroke risk increased with increasing difference between resting and maximal exercise SBP, independent of BP at rest, suggesting that an exaggerated BP response to physical exercise may be an independent predictor of stroke.

The Oslo Ischaemia Study: cohort profile.

PURPOSE: The Oslo Ischaemia Study was designed to investigate the prevalence and predictors of silent coronary disease in Norwegian middle-aged men, specifically validating exercise electrocardiography (ECG) findings compared with angiography. The study has been important in investigating long-term predictors of cardiovascular morbidity and mortality, as well as investigating a broad spectrum of epidemiological and public health perspectives. PARTICIPANTS: In 1972-1975, 2014 healthy men, 40-59 years old, were enrolled in the study. Comprehensive clinical examination included an ECG-monitored exercise test at baseline and follow-ups. The cohort has been re-examined four times during 20 years. Linkage to health records and national health registries has ensured complete endpoint registration of morbidity until the end of 2006, and cancer and mortality until the end of 2017. FINDINGS TO DATE: The early study results provided new evidence, as many participants with a positive exercise ECG, but no chest pain ('silent ischaemia'), did not have significant coronary artery stenosis after all. Still, they were over-represented with coronary disease after years of follow-up. Furthermore, participants with the highest physical fitness had lower risk of cardiovascular disease, and the magnitude of blood pressure responses to moderate exercise was shown to influence the risk of cardiovascular disease and mortality. With time, follow-up data allowed the scope of research to expand into other fields of medicine, with the aim of investigating predictors and the importance of lifestyle and risk factors. FUTURE PLANS: Recently, the Oslo Ischaemia Study has been found worthy, as the first scientific study, to be preserved by The National Archives of Norway. All the study material will be digitised, free to use and accessible for all. In 2030, the Oslo Ischaemia Study will be linked to the Norwegian Cause of Death Registry to obtain complete follow-up to death. Thus, a broad spectrum of additional opportunities opens.

Interaction between inflammation and blood viscosity predicts cardiovascular mortality.

OBJECTIVES: Inflammation and increased blood viscosity are associated with increased risk of cardiovascular mortality. Erythrocyte sedimentation rate (ESR) and hematocrit both influence blood viscosity whereas the first also is a marker of inflammation. We aimed to investigate ESR, hematocrit and the interaction between them as predictors of cardiovascular mortality during 26 years follow-up among healthy middle aged men. DESIGN: Four hundred and eighty eight men aged 40-59 were extensively examined in 1972-1975 and followed over a period of 26 years. Risk estimation was made in Cox proportional hazards and adjusted for age, smoking, systolic blood pressure, total serum cholesterol, and physical fitness. RESULTS: A 2.44-fold (95% CI 1.37-4.35) adjusted risk of cardiovascular mortality was found in the highest quartile of hematocrit compared to the lowest. Among the 265 men who had an ESR <6 mm/h (median), the adjusted risk of cardiovascular mortality was 3.05-fold (95% CI 1.49-6.23) in the highest quartile of hematocrit compared to the lowest. This association was not observed among the 223 men with ESR <6 mm/h. CONCLUSION: Elevated hematocrit is independently associated with increased long-term risk of cardiovascular mortality in men with high ESR. Our data suggest that the combination of inflammation and blood viscosity may improve the prediction of cardiovascular risk.

Fasting Serum Levels of Potassium and Sodium in Relation to Long-Term Risk of Cancer in Healthy Men.

PURPOSE: To examine whether serum levels of potassium and sodium were associated with long-term cancer risk in initially healthy men. PATIENTS AND METHODS: A cohort of 1994 initially healthy men with no use of medication, aged 40-59 years, was followed for cancer during 40 years of follow-up. Associations between fasting electrolyte levels and cancer risk were assessed with incidence rates and Cox proportional hazards models. RESULTS: Potassium, but not sodium, was linearly associated with cancer risk. This association remained significant after adjustment of several potential confounding factors, and also after excluding the first 10 years of follow-up. The age-adjusted risk of all-site cancer increased with 16% for each SD increase in potassium level. Men with hyperkalemia showed an incidence rate that was 40% higher than for men with normal potassium levels. CONCLUSION: Fasting serum potassium level in healthy men was positively associated with long-term cancer risk. Potassium or potassium ion channels may have a role in cell proliferation or differentiation. These findings might imply future cancer strategies for targeting individuals with high serum potassium levels.

Changes in midlife fitness, body mass index, and smoking influence cancer incidence and mortality: A prospective cohort study in men.

Cancer prevention efforts include modification of unhealthy lifestyle, such as smoking cessation and resisting gain in body weight. Although physical activity is inversely related to risk of several cancers, it is poorly studied whether changes in physical activity or fitness influence future cancer risk. Thus, we aimed to investigate whether changes in midlife cardiorespiratory fitness (CRF), body mass index (BMI), and smoking habits influence cancer incidence and mortality. The study cohort includes 1689 initially healthy men, aged 40-59 years. Measurements of CRF, BMI and information on smoking habits were collected in two repeated waves, 7 years apart. Cox regression models estimated associations as hazard rates (HR) with 95% confidence intervals (CI), between midlife changes in the modifiable lifestyle factors and cancer incidence and mortality. The men were followed prospectively for more than 30 years. Compared to CRF loss (>5%), improved CRF (>5%) was associated with lower cancer incidence (HR 0.81, 95% CI 0.67-0.98) and mortality (HR 0.70, 95% CI 0.54-0.92), and maintaining the CRF stable yielded lower cancer incidence (HR 0.76, 95% CI 0.61-0.95). No association was seen for BMI gain, but maintaining the BMI stable was related to lower cancer incidence (HR 0.77, 95% CI 0.60-0.98), compared to BMI loss. Continue smoking was associated with higher cancer incidence and mortality, compared to men who stopped smoking. In particular, this study adds new knowledge about the potential preventive role of CRF in cancer development and emphasizes lifestyle modification as a highly important effort in cancer prevention.

Physical fitness is a modifiable predictor of early cardiovascular death: A 35-year follow-up study of 2014 healthy middle-aged men.

Background Physical fitness has been shown to predict cardiovascular death during long-term follow-up. In the present study we aimed to investigate how physical fitness and other cardiovascular risk factors at middle-age influenced the risk of cardiovascular death during the early (0-11 years), intermediate (12-23 years) and late (24-35 years) parts of a 35-year observation period. Methods and results Age-adjusted physical fitness was calculated in 2014 apparently healthy, middle-aged men after maximal bicycle electrocardiogram-tests in 1972-1975 (Survey 1) and 1979-1982 (Survey 2). The men were assessed through 35 years after Survey 1, and 28 years after Survey 2 by Cox proportional hazards models. Low Survey 1 physical fitness was independently associated with increased risks of early and intermediate, but not late, cardiovascular death. Survey 1 to Survey 2 change in physical fitness, age, smoking status, systolic blood pressure and cholesterol impacted cardiovascular death risks in all periods. Family history of coronary heart disease impacted early and intermediate, but not late, cardiovascular death. Conclusions Most classical cardiovascular risk factors were strong predictors of early, intermediate and late cardiovascular death. Physical fitness measured at median age 50 years was independently associated with risk of early cardiovascular death, but the association weakened as time progressed. Change in physical fitness during middle-age impacted cardiovascular death risk in a full lifetime perspective. Thus, our data suggest that physical fitness is a modifiable cardiovascular risk factor with limited duration in contrast to the sustained impact of smoking, blood pressure and cholesterol on cardiovascular mortality.

Measured cardiorespiratory fitness and self-reported physical activity: associations with cancer risk and death in a long-term prospective cohort study.

Physical activity is inversely associated with risk of some cancers. The relation with cancer-specific death remains uncertain. Mainly, studies on relationships between physical activity and cancer are based on self-reported physical activity (SPA). Hereby, we examined whether measured cardiorespiratory fitness (CRF) is associated with cancer risk, mortality, and case fatality. We also describe relationships between SPA and these outcomes, and between CRF and SPA. A cohort of 1997 healthy Norwegian men, aged 40-59 years at inclusion in 1972-75, was followed throughout 2012. At baseline, CRF was objectively measured. SPA (leisure time and occupational) was obtained through a questionnaire. Relationships between CRF or SPA, and the outcomes were estimated using Cox regression, adjusted for age, body mass index (BMI), and smoking. Pearson correlation coefficients evaluated agreements between CRF and SPA. During follow-up, 758 men were diagnosed with cancer and 433 cancer deaths occurred. Analyses revealed lower cancer risk (Hazard ratio [HR] 0.85, 95% confidence intervals [CI]: 0.68-1.00), mortality (HR 0.68, 95% CI: 0.53-0.88), and case fatality (HR 0.74, 95% CI: 0.57-0.96), in men with high CRF compared to low CRF. Light leisure time SPA was associated with lower cancer risk (HR 0.70, 95% CI: 0.56-0.86) and mortality (HR 0.64 95% CI: 0.49-0.83), whereas strenuous occupational SPA was associated with higher risks (HR 1.42, 95% CI: 1.13-1.78 and HR 1.45, 95% CI: 1.09-1.93). Correlations between CRF and SPA were 0.351 (P < 0.001) and -0.106 (P < 0.001) for leisure time and occupational SPA, respectively. A high midlife CRF may be beneficial for cancer risk, cancer mortality, and case fatality.

Temporal Reduction in Chronotropic Index Predicts Risk of Cardiovascular Death Among Healthy Middle-Aged Men: a 28-Year Follow-Up Study.

BACKGROUND: Chronotropic index is a standardized measure of heart rate (HR) increment during exercise that reflects the combined effects of age, resting HR, and physical fitness. Low chronotropic index has been reported to predict disease and death. We tested whether temporal change in chronotropic index over 7 years influenced risk of cardiovascular death through up to 28 years. METHODS AND RESULTS: Chronotropic index was calculated ([achieved maximal HR-resting HR]/[age-predicted maximal HR-resting HR]) after a symptom-limited bicycle ECG exercise test in 1420 healthy men at 2 examinations 7 years apart, in 1972 and 1979. Events of cardiovascular death were registered by manual scrutiny of all participants' hospital charts and the Norwegian Cause of Death Registry. The participants were divided into quartiles of temporal change in chronotropic index, with quartile one having the most negative value. Cox proportional hazard regression models were used to estimate risks and adjusted for classical cardiovascular risk factors. Incidence of cardiovascular death was 310 (22%) during median of 21 years of follow-up. After multivariable adjustment, and comparison with quartile four (mean +0.11), quartiles one (-0.16), two (-0.04), and three (+0.02) were associated with hazard ratios 1.50 (95% CI 1.10-2.05), 1.10 (0.79-1.53), and 1.04 (0.74-1.45) for cardiovascular death. Results remained robust also after exclusion of 31 participants with exercise ECG-induced signs of coronary ischemia. CONCLUSIONS: Temporal reduction in chronotropic index was associated with increased long-term risk of cardiovascular death and might be a clinically important predictor when assessing risk in healthy individuals over a longer time.

Heart rate reserve predicts cardiovascular death among physically unfit but otherwise healthy middle-aged men: a 35-year follow-up study.

BACKGROUND: Heart rate reserve (HRR) has been reported to be inversely associated with cardiovascular (CV) disease and death. The impact of physical fitness (PF) on this relationship has not, however, been described in detail. We investigated how different levels of PF influenced the association between HRR and CV death during a 35-year follow-up. METHODS AND RESULTS: HRR and PF were measured in 2014 apparently healthy, middle-aged men during a symptom-limited bicycle exercise test in 1972-75. The men were divided into tertiles (T1-T3) by age-adjusted HRR. Morbidity and mortality data were registered from hospital charts through 2007 and the Norwegian Cause of Death Registry. Adjusted Cox proportional hazard regression models were used to calculate risks. Incidence of CV death was 528 (26%) during median 30 years of follow-up. Men with the lowest HRR had 41% (HR 1.41 [1.14-1.75]) increased risk of CV death compared with the men with the highest. We found a significant interaction between age-adjusted PF and HRR. After stratifying the men by PF, results were statistically significant only among men with the lowest PF, where the men with lowest HRR had a 70% (HR 1.70 [1.12-2.67]) increased risk of CV death compared with the men with the highest. CONCLUSIONS: Low HRR was independently associated with increased risk of CV death in apparently healthy, middle-aged men. The predictive impact of HRR on CV death risk was, however, confined to unfit men.

HDL-cholesterol and prediction of coronary heart disease: modified by physical fitness? A 28-year follow-up of apparently healthy men.

OBJECTIVE: High-density lipoprotein cholesterol (HDL) and physical fitness (PF) have both been shown to predict cardiovascular disease (CVD), particularly coronary heart disease (CHD). Increased PF is associated with increased HDL and may partly explain the benefit of HDL. We tested the hypothesis that PF influences the prognostic impact of HDL for CHD and also for CHD-, CVD- and all-cause death. METHODS: HDL was measured 1979-1982 in 1357 healthy men aged 44-69 years followed up to 28 years. PF was measured using bicycle exercise test. Hazard ratios (HRs) adjusted for age, smoking, systolic blood pressure, and total cholesterol and further for PF between HDL quartiles were calculated using Cox proportional survival model. RESULTS: The highest HDL quartile was associated with lower risk of CHD (HR: 0.57, 95% confidence interval [CI]: 0.43-0.74), fatal CHD (HR: 0.56, CI: 0.36-0.86), fatal CVD (HR: 0.64, CI: 0.46-0.88) and all-cause death (HR: 0.80, CI: 0.65-0.99) compared to the lowest quartile. Adjustments for PF or changes in PF over 8.6 years did not change the results except for all-cause death, which was not significantly different between HDL quartiles. We found no interaction between HDL and PF. CONCLUSIONS: HDL is a strong predictor of long term risk of CHD, fatal CHD and fatal CVD in healthy middle-aged men. Physical fitness or its changes had no impact on the ability of HDL to predict CHD.

Is there an association between severe job strain, transient rise in blood pressure and increased mortality?

BACKGROUND: Job strain may be associated with various diseases and increased mortality but there is little data available from prospective studies with long-term follow-up. OBJECTIVE: To assess the effect of heat exposure followed by severe job strain on blood pressure, heart rate and mortality. DESIGN: Prospective 19-year observational study (1982-2000) of a cohort of employees in a ferry alloy plant undergoing two economical crises. The participants were 218 healthy males aged 30-59 years. MEASUREMENTS: Annual standardized measurements of blood pressure, heart rate, serum cholesterol and registration of morbidity and mortality. RESULTS: Heat-exposed men (n = 25) and non-heat-exposed men (n = 193) had unchanged blood pressure from 1982 to 1984. Thereafter the plant underwent two serious economic crises, in 1985-87 and 1990-91, respectively. The first one was handled by decisions exclusively taken by the head office and included a gradual lay-off of 25% of the workers, and the second one was handled jointly between the local management, union leaders and employees and included a modest, voluntary lay-off. Thus, the two crises differed markedly in low vs high job control. Blood pressures gradually increased from 1985 to 1988 in the whole cohort until systolic blood pressure reached 15 mmHg and diastolic blood pressure 12 mmHg above baseline levels (p < 0.001). Thereafter blood pressures decreased to slightly above baseline levels and then remained unchanged for the next 5 years. However, heart rate increased from 62 +/- 12 beats/min in 1982-83 to 69 +/- 10 beats/min in 1988 (p < 0.01) and did not return to baseline. Total mortality by 31 December 2000 in the study cohort was significantly higher over the 19 years of follow-up than among age-matched, Norwegian men (p < 0.01). CONCLUSIONS: If a cause-effect relationship exists between the first economical crisis in the ferry alloy plant and the concomitant rise in blood pressure, job strain had a powerful but time-limited effect on blood pressure. Since the same phenomenon was not reproduced 5 years later, the marked difference in job control (high vs low) may constitute the difference. Alternatively, age-related effects or adaptive coping mechanisms may have prevented a similar second blood pressure rise despite exposure to a job strain of similar severity. However, there was also a high 19-year total mortality in the study population, which could be related to long-term health consequences of the first or both economic crises. This study provides some support for the notion that increased job strain elevates blood pressure and deteriorates outcome.

Early versus late morning measurement of blood pressure in healthy men. A potential source of measurement bias?

Standardization of blood pressure (BP) measurement is important for both clinical and epidemiological purposes. The aim of the present study was to investigate early vs late morning measurements of BP and heart rate in healthy subjects. During the years 1972-75, healthy men aged 40-59 years (n = 2014) participated in a cardiovascular survey in Oslo. Two to four men underwent the examination program per day; it included height/weight, a spirographic study, chest X-ray, a number of blood tests, case history, clinical examination, resting ECG and physical exercise testing. BP and heart rate measurements were meticulously standardized. When adjusting for age, smoking habits and season of year we found that men who were examined as number one in the row of two to four subjects each morning had higher systolic BP (3.6 mmHg, p < 0.001) and heart rate (3.6 beats/min, p < 0.001) at rest compared to others. They were virtually identical in all other aspects. These differences in systolic BP and heart rate at rest disappeared during bicycle exercise. Thus, we suggest that the increased BP and heart rate at rest represent a stress reaction to being number one in a row of subjects to be examined, i.e. a bias in BP and heart rate measurements, possibly of both clinical and epidemiological importance.