Kristian Engeseth

Low Heart Rates Predict Incident Atrial Fibrillation in Healthy Middle-Aged 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 <100 beats per minute (n=260) were characterized by high physical fitness, low resting and low maximum HR, and they had 1.60-fold AF risk (95% confidence interval, 1.11–2.26) compared with men with HR100W ≥100 beats per minute when adjusted for age, systolic blood pressure, and physical fitness. Additional adjustment for relative heart volume slightly reduced the association. The subgroup of men (n=860) with hypertensive blood pressure measurements at baseline had the highest risk difference between low and high HR100W with hazard ratio 2.08 (1.19–3.45). 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.

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.

Seven-Year Increase in Exercise Systolic Blood Pressure at Moderate Workload Predicts Long-Term Risk of Coronary Heart Disease and Mortality in Healthy Middle-Aged Men

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.

2D.01: EXERCISE SYSTOLIC BLOOD PRESSURE >/=190 MMHG AT MODERATE WORKLOAD PREDICTS CORONARY HEART DISEASE IN HEALTHY, MIDDLE-AGED MEN.

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 that exercise blood pressure at 100W workload (SBP100W) > 200 mmHg is associated with increased risk of CHD and mortality. We now aimed to investigate the possible association between SBP100W >/= 190mmHg and risk of CHD over up to 28 years follow-up. Design and method: Of the 1999 apparently healthy, middle-aged men who underwent thorough medical examination and laboratory testing, including a symptom-limited bicycle ergometer test, during 1972–1975, 1392 men were still healthy at survey 2 seven years later and completed a workload of 100 W at both surveys. Systolic blood pressure was measured near completion of the 100W stage (SBP100W). By comparing subjects having SBP100W >/=190 mmHg at baseline, follow-up or both(n=365) with subjects having SBP100W < 190 mmHg at both surveys (n = 1027), we estimated the risk of CHD (angina pectoris, non-fatal myocardial infarction and death from coronary heart disease). Results: The combined endpoint of CHD occurred in 452 of the 1392 men; 243 events among the 365 men with SBP100W >/= 190 mmHg. When adjusting for survey 1 smoking status, age, systolic blood pressure at rest, total cholesterol and family history of coronary heart disease, there was a 1.38-fold (CI 1.11–1.71, p < 0.005) increased risk of CHD. When further adjusting for physical fitness, SBP100W >/=190mmHg was associated with a 1.35-fold (1.08–1.65) increased risk of CHD. Conclusions: Our findings indicate that a systolic blood pressure of 190 mmHg or more at moderate workload is associated with future risk of CHD among apparently healthy middle-aged men. Figure. No caption available.

Long-term predictors of stroke in healthy middle-aged men:

Background There are few data on risk factors for stroke during long-term follow-up of healthy individuals. Aims We aimed to investigate the long-term predictive impact on stroke risk of baseline variables including hemodynamic variables measured at rest and during exercise in middle-aged, healthy men. Methods We performed a prospective cohort study of 2014 healthy Norwegian men aged 40–59 years, recruited during the period 1972–1975 and followed until 2007. Participants underwent a comprehensive clinical assessment at baseline, including a bicycle exercise test. Data on stroke, transient ischemic attack, and death were collected on all participants from follow-up visits, medical records, and the National Cause of Death Registry. We used Cox regression for analysis and estimated hazard ratios with 95% confidence intervals, adjusting for traditional risk factors and hemodynamic variables measured at rest and during exercise. Results During 35 years’ follow-up, 316 participants (16%) had stroke, of which 287 (91%) were ischemic and 29 (9%) were hemorrhagic. Age (hazard ratio 2.70 per increase in one standard deviation, 95% confidence interval 2.13–3.43), resting systolic blood pressure (hazard ratio 1.24, 95% confidence interval 1.11–1.39), body mass index (hazard ratio 1.14, 95% confidence interval 1.02–1.29), and atrioventricular conduction time (hazard ratio 1.11, 95% confidence interval 1.03–1.19) were significantly associated with long-term risk of stroke, as were maximal systolic blood pressure and heart rate during exercise (hazard ratio 1.28, 95% confidence interval 1.13–1.46, and hazard ratio 0.86, 95% confidence interval 0.74–0.99, respectively). Conclusions Hemodynamic variables at rest and during exercise testing add to the predictive value of clinical variables in healthy, middle-aged men, and should be included in the assessment of long-term risk of stroke, when available.

Exercise systolic blood pressure at moderate workload predicts cardiovascular disease and mortality through 35 years of follow-up in healthy, middle-aged men

Abstract Objective: There is an association between exercise systolic blood pressure (SBP) and cardiovascular disease and mortality. The aim of this study was to investigate this association, with 35 years of follow-up. Methods: Through 1972–75, 2014 healthy, middle-aged men underwent thorough medical examination and a bicycle exercise test. 1999 participants completed six minutes at 100 W. SBP was measured manually, both before the test and every two minutes during the test. Highest SBP measured during the first six minutes (SBP100W) was used in further analyses. Results: Participants were divided into quartiles (Q) based on their SBP100W; Q1: 100–160 mm Hg (n = 457), Q2: 165–175 mm Hg (n = 508), Q3: 180–195 mm Hg (n = 545) and Q4: 200–275 mm Hg (n = 489). After 35-years follow-up, there was a significant association between exercise SBP at baseline and cardiovascular disease and mortality. In the multivariate analysis adjusting for resting SBP, age, smoking status, total serum cholesterol and family history of coronary heart disease, as well as physical fitness, there is a 1.39-fold (CI: 1.00–1.93, p = 0.05) increased risk of cardiovascular mortality in Q4 compared to Q1. When not adjusting for physical fitness, there is a 1.29-fold (CI: 1.03–1.61, p = 0.02) increase in risk of cardiovascular disease between Q1 and Q4. Conclusions: The results of this study suggest that the association between exercise SBP at moderate workload and cardiovascular disease and mortality in middle-aged men extends through as long as 35 years and into old ages.

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.

ELEVATED SYSTOLIC BLOOD PRESSURE AT MIDDLE-AGE REMAINS A SIGNIFICANT CARDIOVASCULAR RISK FACTOR THROUGHOUT LIFE

Objective: Systolic blood pressure, prevalence of smoking, family history of coronary heart disease, cholesterol and cardiorespiratory fitness are well established as cardiovascular risk factors. In the present study we aimed to investigate how one measurement these variables at middle-age influenced risk of cardiovascular death during the first, intermediate and late part of a 35-year observation period, respectively. Figure. No caption available. Design and method: Systolic blood pressure, prevalence of smoking, family history of coronary heart disease, cholesterol and cardiorespiratory fitness were measured in 2014 apparently healthy, middle-aged Caucasian men by clinical examination, blood tests and an ECG-monitored, symptom-limited bicycle test. End points were registered after 35 years in a nationwide scrutiny of charts in all hospitals, and from the national Cause of Death registry. Early cardiovascular death was defined as event before 12 years of observation, intermediate event between 12 and 23 years of observation and late event between 23 and 35 years of observation. Impact of predictors and relative risks were estimated using Cox proportional hazards models. When estimating risks of intermediate and late cardiovascular death, men who died within 12 and 23 years were excluded. Results: We found 80 events of early, 207 events of intermediate and 241 events of late cardiovascular death. Age, systolic blood pressure, smoking status, and cholesterol were significant predictors of early, intermediate and late cardiovascular death. Baseline physical fitness was a significant and independent predictor of early and a borderline significant predictor of intermediate cardiovascular death but had no predictive impact on late cardiovascular death. Family history of coronary heart disease was a significant and independent predictor of early and intermediate, but not late cardiovascular death (Table1). Conclusions: Systolic blood pressure, smoking, and cholesterol measured at a median age 49 years were strong predictors of early, intermediate and late cardiovascular death during 35 years. Physical fitness at middle age and family history of coronary heart disease were only associated with risk of cardiovascular death before reaching 72 years. Risk factors for CV death have different persistence throughout life and systolic blood pressure at middle-age remains a significant cardiovascular risk factor until old ages.

IMPACT OF EXERCISE BLOOD PRESSURE ON STROKE RISK IN PHYSICALLY FIT AND UNFIT MEN. RESULTS FROM 35 YEARS FOLLOW-UP OF HEALTHY MIDDLE-AGED MEN

Objective: Resting blood pressure is one of the major risk factors for stroke. Our group recently showed that maximal blood pressure during exercise testing is a strong predictor of stroke in this cohort, independently of resting blood pressure. In the present study we investigate if maximal systolic blood pressures ability to predict stroke is influenced by a persons level of cardiorespiratory fitness. Design and method: The study enrolled 2014 healthy men aged 40–59 years between 1972–1975. The baseline examination included a maximal exercise test and the men were followed for a total of 35 years. Data on first-time stroke were collected from follow-up visits, hospital medical records from all national hospitals, and the national Cause of Death Registry. For data analyses, we grouped the men according to high or low fitness level (above/below median, values adjusted for age) and further for quartiles of maximal blood pressure. Multi-adjusted Cox regression analyses (including adjustment for resting blood pressure) were used to estimate risks for stroke. Results: During a median follow-up of time 31.9 years 316 first-time strokes occurred. There were no losses to follow-up. Fitness levels correlated positively with maximal systolic blood pressure. Among men with high fitness level, the highest quartile of maximal blood pressure had a higher risk of stroke than the lowest quartile (hazard ratio 1.75, confidence interval 1.06–2.94, p = 0.03). Among men with low fitness level, the highest quartile of maximal systolic blood pressure had a non-significantly higher risk of stroke than the lowest quartile (hazard ratio 1.50, confidence interval 0.91–2.63, p = 0.11). When resting systolic blood pressure was omitted from the models, maximal systolic blood pressure predicted stroke significantly in both fit and unfit men. Figure. No caption available. Conclusions: In healthy middle-aged men, maximal systolic blood pressure predicted stroke in men with high cardiorespiratory fitness, independently of resting systolic blood pressure. In men with low cardiorespiratory fitness the association was not significant, but there was no evidence of a qualitative different effect in this subgroup, and further research is needed to assess if maximal blood pressure has a predictive value for stroke in men, independently of fitness levels.

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.