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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.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.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.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.

PurposeThe 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.ParticipantsIn 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 dateThe 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 plansRecently, 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.

There is no consensus on the definition of an exaggerated increase in systolic blood pressure (SBP) during exercise. The aim was to explore a potential threshold for exercise SBP associated with increased risk of coronary heart disease in healthy men using repeated exercise testing. Two thousand fourteen healthy white male employees were recruited into the Oslo Ischemia Study during early 1970s. At follow-up 7 years later, 1392 men were still considered healthy. A bicycle exercise test at 100 W workload was performed at both visits. Cox regression analyses were performed with increasing cutoff levels of peak exercise SBP at 100 W workload (SBP100W) from 160 mm Hg to 200 mm Hg, adjusted for cardiovascular risk factors and physical fitness. Participants with SBP100W below cutoff level at both baseline and first follow-up were compared with participants with SBP100W equal to or above cutoff level at both visits. Compared with participants with SBP100W below all cutoff levels between 165 and 195 mm Hg, coronary heart disease risk was increased among participants with SBP100W equal to or above cutoff at all levels. There was no evidence of a distinct threshold level for coronary heart disease risk, and the relation between SBP100W and coronary heart disease appears linear. When investigating exercise SBP at moderate workload measured at 2 exercise tests in healthy middle-aged white men, there is increasing risk of coronary heart disease with increasing exercise SBP independent of SBP at rest. The association is linear from the low range of exercise SBP, and there is no sign of a distinct threshold level for increased coronary disease risk.

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.

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.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.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.

Background— Low resting heart rate (HR) has been associated with atrial fibrillation (AF) in athletes. We aimed to study whether low HR at rest or during exercise testing was a predictor of AF in initially healthy middle-aged men. Methods and Results— A total of 2014 healthy Norwegian men participated in a prospective cardiovascular survey, including a standardized bicycle exercise test in 1972 to 1975. During ≤35 years of follow-up (53 000 person-years of observation), 270 men developed incident AF, documented by scrutiny of health charts in all Norwegian hospitals. Risk estimation was analyzed with Cox proportional hazard models. Low exercise HR after 6 minutes exercise on the moderate workload of 100 W (HR100W) was a predictor of incident AF. Men with HR100W Conclusions— Our data indicate that low exercise HR on a moderate workload is a long-term predictor of incident AF in healthy middle-aged men. Elevated baseline blood pressure substantially amplifies this risk. The present results suggest a relationship between increased vagal tone, high stroke volumes and incident AF, and particularly so in physically fit men.

Aims To examine the impact of physical fitness (PF) on the association between fasting serum triglycerides (FTG) and diabetes risk and whether temporal changes in FTG predict diabetes risk in healthy middle-aged men. Methods FTG and PF (bicycle exercise test) were measured in 1962 men aged 40–59 years in 1972–1975 (Survey 1) and repeated in 1387 still healthy men on average 7.3 years later (Survey 2). Diabetes was diagnosed according to WHO 1985-criteria. Results During 35 years follow-up 202/1962 (10.3%) men developed diabetes. Compared with the lowest, the upper FTG tertile had a 2.58-fold (95% CI: 1.81–3.74) diabetes risk adjusted for age, fasting blood glucose and maternal diabetes, and a 2.29-fold (95%CI: 1.60–3.33) when also adjusting for PF. Compared with unchanged (±25%) FTG levels (n = 664), FTG reduction of more than 25% (n = 261) was associated with 56% lower (0.44; 95% CI: 0.24–0.75) diabetes risk, while FTG increase of more than 25% (n = 462) was associated with similar risk. These associations were unchanged when adjusted for PF and PF change. Conclusions High FTG-levels predicted long-term diabetes risk in healthy middle-aged men, and the association was only modestly weakened when adjusted for PF. A reduction in FTG was associated with decreased diabetes risk.

Exercise systolic blood pressure (SBP) predicts coronary heart disease (CHD) in the general population. We tested whether changes in exercise SBP during 7 years predict CHD (including angina pectoris, nonfatal myocardial infarction, and fatal CHD) and mortality over the following 28 years. Peak SBP at 100 W workload (=5.5 METS [metabolic equivalents]; completed by all participants) was measured among 1392 apparently healthy men in 1972–75 and repeated in 1979–82. The men were divided into quartiles (Q1–Q4) of exercise SBP change. Relative risks were calculated using Cox proportional hazard regression adjusting for family history of CHD, age, smoking status, resting SBP, peak SBP at 100 W, total cholesterol at first examination (model 1), and further for physical fitness and change in physical fitness (model 2). The highest quartile, Q4, was associated with a 1.55-fold (95% confidence interval, 1.17–2.03) adjusted (model 1) risk of CHD and a 1.93-fold (1.24–3.02) risk of coronary heart death compared with the lowest, Q1. Q4 had a 1.40-fold (1.06–1.85) risk of CHD and a 1.70-fold (1.08–2.68) risk of coronary heart death using model 2. Q4 was associated with increased risk of cardiovascular death and all-cause death compared with Q1 in model 1, but not in model 2. Our results indicate that an increase in exercise SBP at 100 W over 7 years is independently associated with increased long-term risk of CHD and substantiate our previous finding that high exercise SBP is an important risk factor for CHD in healthy men.

The incidence of both atrial fibrillation (AF) and obesity is increasing in the community, and lifestyle intervention is recommended. We aimed to test whether the predictive effect of body mass index (BMI) and weight change from age 25 years to midlife on incident AF were influenced by physical fitness. In 1972 to 1975, 2,014 healthy middle-age men conducted a bicycle exercise electrocardiographic test as a part of a cardiovascular survey program, defining physical fitness as work performed divided by body weight. During 35 years of follow-up, 270 men developed AF, documented by scrutiny of the health files in all Norwegian hospitals. Risk estimation was analyzed using Cox proportional hazard models and tested for age-adjusted physical fitness above and below the median. The mean BMI of 24.6 kg/m(2) defined a lean baseline cohort. The men with a baseline BMI of ≥28 kg/m(2) (11%) compared to a BMI28 kg/m(2) had a 1.68-fold risk of AF (95% confidence interval 1.14 to 2.40) and men reporting weight gain of ≥10 kg (24%) compared to weight loss (11%) of 1.66-fold (95% confidence interval 1.00 to 2.89), respectively. The dichotomy into men with age-adjusted physical fitness above and below the median, demonstrated statistically significant risk associations only for men with low fitness. The overall risk of AF was reduced by 23% in the fit men. In conclusion, within our lean baseline cohort of healthy middle-age men, a BMI of ≥28 kg/m(2) and weight gain of ≥10 kg from age 25 to midlife were long-term predictors of incident AF in men with physical fitness below the population median. The fit men had an overall slightly reduced risk of AF.

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.

Bodegard J, Skretteberg PT, Gjesdal K, Pyorala K, Kjeldsen SE, Liestol K, Erikssen G, Erikssen J (Oslo University Hospital, Oslo; University of Oslo, Oslo; University of Eastern Finland, Kuopio; University of Oslo, Oslo; Oslo University Hospital, Oslo). Low-grade systolic murmurs in healthy middle-aged individuals: innocent or clinically significant? A 35-year follow-up study of 2014 Norwegian men. J Intern Med 2012; 271: 581–588. Objective. To determine whether a low-grade systolic murmur, found at heart auscultation, in middle-aged healthy men influences the long-term risk of aortic valve replacement (AVR) and death from cardiovascular disease (CVD). Setting and subjects. During 1972–1975, 2014 apparently healthy men aged 40–59 years underwent an examination programme including case history, clinical examination, blood tests and a symptom-limited exercise ECG test. Heart auscultation was performed under standardized conditions, and murmurs were graded on a scale from I to VI. No men were found to have grade V/VI murmurs. Participants were followed for up to 35 years. Results. A total of 1541 men had no systolic murmur; 441 had low-grade murmurs (grade I/II) and 32 had moderate-grade murmurs (grade III/IV). Men with low-grade murmurs had a 4.7-fold [95% confidence interval (CI) 2.1–11.1] increased age-adjusted risk of AVR, but no increase in risk of CVD death. Men with moderate-grade murmurs had an 89.3-fold (95% CI 39.2–211.2) age-adjusted risk of AVR and a 1.5-fold (95% CI 0.8–2.5) age-adjusted increased risk of CVD death. Conclusions. Low-grade systolic murmur was detected at heart auscultation in 21.9% of apparently healthy middle-aged men. Men with low-grade murmur had an increased risk of AVR, but no increase in risk of CVD death. Only 1.6% of men had moderate-grade murmur; these men had a very high risk of AVR and a 1.5-fold albeit non-significant increase in risk of CVD death.

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.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.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 ESR6 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 ESR6 mm/h.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.

We appreciate the comments of Morris et al and share their curiosity about the pathophysiological mechanisms that lead to atrial fibrillation (AF). Our cohort of initially healthy middle-aged men demonstrated that those with high fitness and low heart rates at a modest workload (

The prognostic value of an isolated J-point depression, or rapidly upsloping ST-segment, on an exercise ECG has long been assumed to be a benign variant. However, little or no data supporting this assumption may be found in the literature. Our task was to examine if a rapidly upsloping ST-segment on an exercise ECG is associated with changes in risk of dying from CHD in 2014 healthy middle-aged men followed for 35 years.A group of healthy middle-aged men (n = 2014) participated in a cardiovascular survey. They underwent an examination programme including a symptom-limited ECG bicycle exercise test. Exercise induced ST-segments were categorised in three groups: normal ST-segment (n = 1383), rapidly upsloping (n = 401), and ST-depression (n = 230). Survival analyses were adjusted for smoking status, total cholesterol, systolic blood pressure, maximal heart rate, and physical fitness. The mean follow-up time was 35 years.The rapidly upsloping group had a 30% decreased risk of CHD death (hazard ratio, HR, 0.70, 95% CI 0.51-0.95) compared to the normal ST-segment group. The risk of CVD-death was numerically lower in the rapidly upsloping group (HR 0.82, 95% CI 0.65-1.04) compared to the normal ST-segment group. The ST-depression group had a 1.45-fold (HR 1.45, 95% CI 1.09-1.90) increased risk of CHD death compared to the normal ST-segment group.The rapidly upsloping ST-segment was a common finding (20%) on exercise ECG among healthy middle-aged men and was associated with a 30% reduced risk of dying from CHD compared to individuals with normal ST-segment. A rapidly upsloping ST-segment on exercise ECG may represent the true healthy state.

Hypertension is the most prevalent risk factor for incident atrial fibrillation (AF). Recently, even high normal blood pressures (BPs) have been established as predictive of AF in women. We aimed to study the long-term impact of upper normal BP on incident AF in a population-based study of middle-aged men. From 1972 to 1975, 2014 healthy Norwegian men were included in a prospective cardiovascular survey and underwent a comprehensive clinical examination including standardized BP measurements. During up to 35 years of follow-up, 270 men were documented with AF by scrutinizing all hospital discharges. Risk estimations for incident AF were analyzed in quartiles of BP using multivariate adjusted Cox proportional hazards. Men with baseline systolic BP ≥140 mm Hg and upper normal BP 128 to 138 mm Hg had 1.60-fold (95% CI 1.15–2.21) and 1.50-fold (1.10–2.03) risk of AF, respectively, compared with men with BP

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.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.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.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.

Takotsubo cardiomyopathy (TTC) is a diagnostic entity that is increasingly being recognized. Data from cardiac magnetic resonance (CMR) imaging and its impact on differential diagnosis are limited.After 26 months, coronary angiography revealed normal coronary arteries and left ventriculography and/or echocardiography left ventricular dysfunction with apical ballooning in 20 patients with acute coronary syndrome (ACS). Four patients were excluded from CMR and in three patients an alternative diagnosis was revealed. Thirteen patients (all female; 60 ± 8 years) with TTC underwent a multisequential CMR, in which all showed myocardial oedema with an elevated T2 ratio in the apical region (2.4 ± 0.4; p0.001 vs. healthy controls), and five patients an elevated global relative enhancement (gRE; 3.7 ± 1.4; p0.05 vs. healthy controls). No late gadolinium enhancement (LGE) was detected on CMR. Follow-up after 132 ± 33 days showed a normalized left ventricular ejection fraction, myocardial mass, T2 ratio, and gRE in all patients.TTC is a small but definite group among patients with ACS and normal coronary arteries. CMR allows differentiating TTC from other causes such as myocarditis and cardiomyopathies, as well as to identify the transient increase of myocardial mass and resolution of myocardial oedema as the systolic dysfunction improves. Therefore, CMR might add valuable information for the differential diagnoses and therapeutic decision-making in patients with suspected TTC.

Objective:A hypertensive response to exercise at moderate workload is associated with future risk of coronary heart disease (CHD) and mortality. Yet there is still no consensus regarding the cut-off value for an inappropriate increase in exercise systolic blood pressure. We have previously shown tha

Exercise systolic blood pressure (SBP) predicts coronary heart disease (CHD) in the general population. We tested if changes (?) in exercise SBP through seven years predict CHD over 28 years. Exercise SBP was measured among 1,392 men, apparently healthy in 1972-75 and at re-examination 1979-82. All