Change in Body Weight and Long-Term Risk of Stroke and Death in Healthy Men.

Background and Purpose- The importance of weight change for the risk of stroke is not well known. We examined the associations between early- and mid-life weight change and risks of stroke and death during long-term follow-up of healthy men. Methods- We recruited healthy men aged between 40 and 59 years and performed a cardiovascular examination at baseline and again at 7 years. We collected data on weight change since the age of 25 (early-life weight change) and measured weight change from baseline to the visit at 7 years (mid-life weight change). For both weight change periods, participants were divided into the following categories: weight loss, weight gain 0 to 4.9 kg, weight gain 5 to 9.9 kg, and weight gain ≥10 kg. Data on stroke and death were collected up to 35 years, from study visits, hospital records, and the National Cause of Death Registry. We used Cox regression to analyze the associations between weight change during early-life and mid-life and risks of stroke and death. Results- Of the 2014 participants, 2014 (100%) had data on early-life weight change and were followed for a median of 30.1 years, while 1403 had data on mid-life weight change and were followed for a median of 24.6 years. During early-life, compared with those who had weight gain 0 to 4.9 kg, hazard ratio for stroke was 1.46 (95% CI, 1.09-1.95) among those with weight gain 5 to 9.9 kg, 1.39 (95% CI, 1.03-1.87) for those with weight gain ≥10 kg, and 1.46 (95% CI, 0.99-2.11) among those with weight loss. For all-cause death, the hazard ratios were 1.08 (95% CI, 0.92-1.23), 1.14 (95% CI, 0.98-1.33), and 1.29 (95% CI, 1.06-1.56), respectively. During mid-life, there were no significant differences in risk of stroke or death between the groups. Conclusions- Weight increase during early-life, but not mid-life, seems to be associated with increased long-term risk of stroke in healthy men. If these findings can be confirmed, efforts to prevent weight increase should target the younger population.

Cardioversion Safety - Are We Doing Enough?

There is a considerable periprocedural risk of thromboembolic events in atrial fibrillation patients undergoing cardioversion, and treatment with anticoagulants is therefore a hallmark of cardioversion safety. Based on retrospective subgroup analyses and prospective studies, non-vitamin K anticoagulants are at least as efficient as vitamin K-antagonists in preventing thromboembolic complications after cardioversion. The risk of thromboembolic complications after cardioversion very much depends on the comorbidities in a given patient, and especially heart failure, diabetes, and age >75 years carry a markedly increased risk. Cardioversion has been considered safe within a 48-h time window after onset of atrial fibrillation without prior treatment with anticoagulants, but recent studies have set this practice into question based on e.g. erratic debut assessment of atrial fibrillation. Therefore, a simple and more practical approach is here suggested, where early cardioversion is performed only in hemodynamically unstable patients.

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.

Change in Cardiorespiratory Fitness and Risk of Stroke and Death: Long-Term Follow-Up of Healthy Middle-Aged Men.

Background and Purpose- Low cardiorespiratory fitness is associated with increased risk of cardiovascular disease. The present study aims to assess whether change of fitness over time has any impact on long-term risk of stroke and death. Methods- We recruited healthy men aged 40 to 59 years in 1972 to 1975, and followed them until 2007. Physical fitness was assessed with a bicycle ECG test at baseline and again at 7 years, by dividing the total exercise work by body weight. Participants were categorized as remained fit, became unfit, remained unfit, or became fit, depending on whether fitness remained or crossed the median values from baseline to the 7-year visit. Outcome data were collected up to 35 years, from study visits, hospital records, and the National Cause of Death Registry. Risks of stroke and death were estimated by Cox regression analyses and expressed as hazard ratios (HRs) with 95% CIs. Results- Of 2014 participants, 1403 were assessed both at baseline and again at 7 years, and were followed for a mean of 23.6 years. Compared with the became unfit group, risk of stroke was 0.85 (0.54-1.36) for the remained unfit, 0.43 (0.28-0.67) for the remained fit, and 0.34 (0.17-0.67) for the became fit group. For all-cause death, risks were 0.99 (0.76-1.29), 0.57 (0.45-0.74), and 0.65 (0.46-0.90), respectively. Among those with high fitness at baseline, the became unfit group had a significantly higher risk of stroke (HR, 2.35; CI, 1.49-3.63) and death (HR, 1.74; CI, 1.35-2.23) than those who remained fit. Among those who had low fitness at baseline, the became fit group had a significantly lower risk of stroke (HR, 0.40; CI, 0.21-0.72) and death (HR, 0.66; CI, 0.50-0.85) than participants in the remained unfit group. Conclusions- Cardiorespiratory fitness at baseline and change in fitness was associated with large changes in long-term risk of stroke and death. These findings support the encouragement of regular exercise as a stroke prevention strategy.

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

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.

Body weight and risk of atrial fibrillation in 7,169 patients with newly diagnosed type 2 diabetes; an observational study.

BACKGROUND: Obesity, type 2 diabetes and atrial fibrillation (AF) are closely associated, but the underlying mechanisms are not fully understood. We aimed to explore associations between body mass index (BMI) or weight change with risk of AF in patients with type 2 diabetes. METHODS: A total of 7,169 participations with newly diagnosed type 2 diabetes were stratified according to baseline BMI, and after a second BMI measurement within 18 months, further grouped according to relative weight change as "weight gain" (>1 BMI unit), "stable weight" (+/- 1 BMI unit) and "weight loss" (<1 BMI unit). The mean follow-up period was 4.6 years, and the risk of AF was estimated using adjusted Cox regression models. RESULTS: Average age at diabetes diagnosis was 60 years and the patients were slightly obese (mean BMI 30.2 kg/m(2)). During follow-up, 287 patients developed incident AF, and those with overweight or obesity at baseline had 1.9-fold and 2.9-fold higher risk of AF, respectively, than those with normal BMI. The 14% of the patients with subsequent weight gain had 1.5-fold risk of AF compared with those with stable weight or weight loss. CONCLUSIONS: In patients with newly diagnosed type 2 diabetes, baseline overweight and obesity, as well as modest weight increase during the first 18 months after diagnosis, were associated with a substantially increased risk of incident AF. Patients with type 2 diabetes may benefit from efforts to prevent weight gain in order to reduce the risk of incident AF. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01121315.

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.

High prevalence of atrial fibrillation in long-term endurance cross-country skiers: echocardiographic findings and possible predictors--a 28-30 years follow-up study.

BACKGROUND: Lone atrial fibrillation (LAF) seems to be more common in endurance-trained male athletes than in men in the general population. The reason for this has not been found. AIM: To determine the prevalence of LAF in long-term endurance cross-country skiers and to examine possible predictors. METHODS: Of 149 healthy, long-term trained cross-country skiers from three different age groups who were invited, 122 and 117 participated in the studies in 1976 and 1981, respectively. At follow-up in 2004-2006, 78 men participated, with 33 in age group I (54-62 years), 37 in group II (72-80 years) and eight in group III (87-92 years), whereas 37 individuals had died and seven could not be tracked. The examination programme applied in 1976, 1981 and 2004-2006 consisted of an electrocardiographic monitoring during rest and exercise and a maximal exercise test. Echocardiography was performed in 2004-2006. RESULTS: A high prevalence (12.8%) of LAF was found. The only predictor from both 1976 and 1981 associated with LAF was a long PQ time (r=0.38, P=0.001 and r=0.27, P=0.02, respectively), whereas bradycardia was another predictor from 1981 (r=0.29, P=0.012). At follow-up, left atrial enlargement was a marker associated with LAF (P<0.001). CONCLUSION: Long PQ time, bradycardia and left atrial enlargement seem to be important risk factors for LAF among long-term endurance cross-country skiers.

Exercise Systolic Blood Pressure at Moderate Workload Is Linearly Associated With Coronary Disease Risk in Healthy Men.

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.

Effects of angiotensin receptor blockade on serial P-wave signal-averaged electrocardiograms after electrical cardioversion of persistent atrial fibrillation.

AIMS: To evaluate the effects of the angiotensin II type 1 receptor blocker candesartan on P-wave signal-averaged electrocardiogram (P-SAECG) after electrical cardioversion in patients with atrial fibrillation (AF). METHODS AND RESULTS: One hundred and seventy-one patients with persistent AF were randomized to receive candesartan 8 mg/day or placebo for 3-6 weeks before and candesartan 16 mg/day or placebo for 6 months after electrical cardioversion. P-SAECG was recorded in 114 patients (57 in each treatment group) after cardioversion and repeated in those with sinus rhythm at 1 and 6 weeks, and 3 and 6 months. Filtered P-wave duration (FPD), root-mean-squared (RMS) voltages of the terminal 40 ms of the filtered P-wave, RMS voltage of the entire filtered P-wave, and the integral of the voltages in the entire PD were analysed. No effects of candesartan were observed on any P-SAECG parameter at baseline. In the subgroup of patients in sinus rhythm after 6 months, FPD was significantly shorter both at baseline (151 +/- 16 vs. 163 +/- 16 ms) and at 6 months (143 +/- 12 vs. 153 +/- 15 ms) in the candesartan (n = 15) compared with the placebo group (n = 21). CONCLUSION: Treatment with candesartan was associated with a shorter FPD in patients remaining in sinus rhythm for 6 months.

SBP above 180 mmHg at moderate exercise workload increases coronary heart disease risk in healthy men during 28-year follow-up.

OBJECTIVE: We investigated the association between exercise SBP at a moderate workload and long-term risk of coronary heart disease (CHD) in men who were healthy when assessed by two bicycle exercise tests 7 years apart. METHODS: During 1972-1975, apparently healthy men (n = 1999) were initially enrolled following thorough medical examination and ECG-monitored bicycle exercise test. Participants (n = 1392) who were healthy also at a second exercise test 7 years later were included in the present study. They were divided into quartiles, Q1-Q4, according to the highest SBP during the initial 6 min of the exercise test on a moderate workload of 100 W (SBP100W) at 7 years and followed for up to 28 years. Adjusted Cox regression was used to estimate CHD risk defined as first occurrence of angina pectoris, nonfatal myocardial infarction or CHD mortality. RESULTS: During follow-up, 452 of the 1392 men suffered incident CHD, and unadjusted, there was increased risk of CHD with increasing SBP100 W, with significant differences between Q1-Q4. In the multivariate analysis adjusting for classical coronary risk factors, including SBP at rest, there was increased risk of CHD in Q3 (SBP100 W above 180 mmHg) and Q4 (SBP100 W above 200 mmHg) compared with Q1 (≤160 mmHg, lowest SBP100 W), hazard ratios 1.42 (CI 1.07-1.90) and 1.93 (CI 1.38-2.70), respectively. CONCLUSION: Healthy middle-aged men had increased long-term risk of CHD with exercise SBP above 180 mmHg at moderate workload. The prognostic impact of SBP above 180 mmHg at exercise is independent of classical coronary risk factors and blood pressure at rest.

The predictive value of transthoracic echocardiographic variables for sinus rhythm maintenance after electrical cardioversion of atrial fibrillation. Results from the CAPRAF study, a prospective, randomized, placebo-controlled study.

OBJECTIVES: The recurrence rate of atrial fibrillation after electrical cardioversion is disappointingly high. The aim of the present study was to prospectively investigate if standard echocardiographic variables at the day of cardioversion could predict sinus rhythm maintenance. METHODS: Transthoracic echocardiographic examination was performed within 4 h after cardioversion for all the patients in the CAPRAF (Candesartan in the Prevention of Relapsing Atrial Fibrillation) study. RESULTS: Cardioversion was successful for 137 patients not given specific antiarrhythmic therapy, and only 41 (30%) maintained sinus rhythm at 6-month follow-up. There were significant (p = 0.05) lower transmitral A wave velocities in the group with relapsing atrial fibrillation compared with the group with sinus rhythm at 6-month follow-up. All patients with the lowest A wave velocities had an early recurrence of atrial fibrillation. There were no differences between the groups regarding atrial dimensions or left ventricular function. The use of the angiotensin II receptor antagonist candesartan had no influence on the echocardiographic variables, nor on the recurrence rate of atrial fibrillation after cardioversion. CONCLUSIONS: Transthoracic echocardiographic examination performed a short time after electrical cardioversion of atrial fibrillation showed that only A wave peak velocities were significantly predictive of sinus rhythm maintenance 6 months after the procedure.

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.

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.

Effect of candesartan and various inflammatory markers on maintenance of sinus rhythm after electrical cardioversion for atrial fibrillation.

Inflammatory markers, their relation to maintenance of sinus rhythm after electrical cardioversion for atrial fibrillation (AF), and the effect of candesartan were investigated in a double-blind placebo-controlled study (CAPRAF). One hundred seventy-one patients with persistent AF were randomly assigned to receive candesartan 8 mg/day or placebo for 3 to 6 weeks before and candesartan 16 mg/day or placebo for 6 months after electrical cardioversion. Serum levels of high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha, interleukin-6, P-selectin, E-selectin, CD-40 ligand, and vascular cell adhesion molecule-1 were measured at baseline and end of study. Compared with patients with a relapse of AF, patients still in sinus rhythm at 6 months after cardioversion (n = 40) had lower baseline hs-CRP and E-selectin levels: median 2.36 mg/L (25th, 75th percentiles 1.28, 4.09) versus 3.44 mg/L (25th, 75th percentiles 1.66, 6.05, p = 0.031) and 32 ng/ml (25th, 75th percentiles 23, 42) versus 37 ng/ml (25th, 75th percentiles 28, 51, p = 0.042), respectively. Neither sustained sinus rhythm for 6 months nor treatment with candesartan had an impact on measured concentrations of markers of inflammation. In conclusion, low hs-CRP and E-selectin at baseline were associated with maintenance of sinus rhythm after electrical cardioversion.

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.