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$Heart failure with preserved ejection fraction - European Heart Journal$

HR response during exercise test and cardiovascular mortality 583 week or more frequently. Of these men, 595 used b-blockers that reduce HR at rest and during exercise. After excluding these subjects, the final study sample included 1378 men free of CHD and not using b-blockers. None of the subjects reported using HR-blunting calcium blockers, such as verapamil and diltiazem. The study protocol was approved by the Research Ethics Committee of the University of Kuopio, and it complies with the Declaration of Helsinki. Each participant gave a written informed consent. Assessment of HR and other exercise test variables A maximal, symptom-limited exercise test was performed at baseline using an electrically braked cycle ergometer as described previously. 22,23 The primary aim of the study was to explore HR data from rest to maximal workload systematically instead of using arbitrarily chosen parts of recorded HR data. For that purpose, each subject’s exercise test was divided into five consequent periods of equal duration, and HR value was extracted from corresponding time points, i.e. rest, 20, 40, 60, 80, and 100% of maximal workload. For 556 men examined before June 1986, the testing protocol comprised a 3-min warm-up at 50 W followed by a step-by-step increase in the workload by 20 W/min. The remaining 822 men were tested with a linear increase in the workload by 20 W/min. Because two different protocols were used during the first 50 W, only the values at or .50 W were included into the analysis. Relative intensities of 20% were not considered in final analyses, because for 528 men examined before June 1986, the first workload of 50 W exceeded 20% of their maximal workload. For safety reasons and to obtain reliable information, the test was supervised by an experienced physician with the assistance of a trained nurse. The most common reasons for stopping the exercise test were leg fatigue (787 men), exhaustion (237), breathlessness (128), and pain in the leg muscles, joints, or back (51). The test was discontinued because of cardiorespiratory symptoms or abnormalities in 98 men. These included dyspnoea (39), arrhythmias (37), a marked change in systolic or diastolic blood pressure (8), dizziness (6), chest pain (4), and ischaemic electrocardiographic changes (4). HR was recorded from electrocardiogram (ECG) at rest, at the end of each 30-s interval during the exercise test, and at peak exercise. To express HR as a relative value, HRR was calculated as maximal HR 2 resting HR. Resting HR was expressed as the lowest HR value, whether measured in lying position before the test or while sitting on bicycle at the initiation of the test. Systolic blood pressure response to exercise was calculated as maximal systolic blood pressure 2 resting systolic blood pressure, and the response was also related to the duration of the test. Maximal oxygen uptake (VO 2max ) was defined as the highest value recorded over a 30-s interval. The criteria for myocardial ischaemia during exercise test were ischaemic changes in ECG defined as horizontal or downsloping ST depression .1.0 mm at 80 ms after the J-point. Assessment of other risk factors CVD history was defined as a history of cardiomyopathy, heart failure, stroke, or claudication. Cigarette smoking was defined as cigarette-years, which denotes the lifelong exposure to smoking and was estimated as the product of years smoked and the number of cigarettes smoked daily at the time of examination. 24 Diabetes was defined as a history of taking medication for diabetes or fasting blood glucose 6.7 mmol/L. The collection of blood specimens and the assessment of other risk factors, including alcohol consumption, body mass index (BMI), serum lipoproteins, and systolic and diastolic blood pressure at rest, have been described elsewhere. 22–24 Ascertainment of follow-up events Deaths were ascertained by computer linkage to the national death registry using a social security number that every Finn has. There were no losses to follow-up. All deaths that occurred between study enrolment from 20 March 1984 to 5 December 1989 and 31 December 1998 were included. CVD and CHD deaths were coded according to the Ninth International Classification of Diseases (code nos 390–459 and 410–414, respectively) or the Tenth International Classification of Diseases (code nos I00–I99 and I20–I25, respectively). CVD and CHD deaths were used as the primary endpoints and all-cause death as the secondary endpoint. We used CVD and CHD deaths as the primary endpoints because HR response during exercise primarily reflects cardiovascular status and most likely predicts CVD mortality. Statistical analysis The analysis of variance (ANOVA) for repeated measures, adjusted for age and the length of follow-up, was used to detect whether the slopes of HR increase of men who died during follow-up and survivors differed from the beginning of the test or only later during the test. In order to eliminate dispersion from compound symmetry assumption (equal correlations between measurements), Greenhouse-Geisser corrected degrees of freedom were used when testing the effects in ANOVA. The Helmert contrasts, which compare HRs at each relative workload with the mean HRs of the next relative workloads, were used to locate the phase of the test (rest, 40, 60, 80, and 100% of maximal workload) where the HR slopes of men who died during follow-up and survivors started to diverge. The statistically most significant contrast was used to construct a new variable. Differences in baseline data between those who died and survivors were tested with linear- and logisticregression analyses and Mann–Whitney U test by adjusting for age and length of follow-up. The new HR variable constructed according to ANOVA for repeated measures was entered into forced Cox-proportional hazards’ regression models. If possible, covariates were entered as uncategorized into Cox models. Two different sets of covariates were used: (i) age and examination year; (ii) age, examination year, alcohol consumption, BMI, cigarette smoking, CVD history, diabetes, serum LDL-cholesterol, systolic blood pressure at rest, and myocardial ischaemia during exercise. To compare the predictive value of HR40–100 and other exercise test variables, a stepwise Cox-regression analysis was used. Relative hazards, adjusted for risk factors, were estimated as antilogarithms of coefficients from multivariable models. Their confidence intervals (CIs) were estimated under the assumption of asymptotic normality of the estimates. To detect the best cut-off point for a new variable, the dichotomization cut-off point that maximized the log-rank test statistics was sought, and the predictive power of this categorized variable was tested by using Cox models. Finally, we tested potential interactions of the new HR variable with other risk factors for death with Cox models by adjusting for age and examination year. All tests for statistical significance were two sided. Statistical analyses were performed by using SPSS 11.5. for Windows (SPSS, Inc., Chicago, IL, USA). Results At the beginning of the follow-up, the median age of the subjects was 54 years (range 42–61 years). In ANOVA for repeated measures, the slope of HR increase was steeper in survivors when compared with those who died due to CVD during follow-up (F ¼ 12.9; df ¼ 1.757; P , 0.001 for interaction effect adjusting for age and length of followup) (Figure 1). By using Helmert contrasts, the difference in the steepness of HR slope between the groups was the strongest at interval 40–100% (F ¼ 19.6; P , 0.001). On the basis of these results, a new variable called HR40–100 was constructed as maximal HR 2 HR at 40% workload. The average HR40–100 was 54 b.p.m. (SD 13 b.p.m.) in the whole study population, 55 b.p.m. (SD 13 b.p.m.) in Downloaded from http://eurheartj.oxfordjournals.org/ by guest on August 30, 2013
584 K.P. Savonen et al. Figure 1 Heart rate (mean + SD) as a function of relative intensity (percentage of maximal workload reached in exercise test) in those who died due to CVD during follow-up (dashed line) and survivors (continuous line). survivors, and 45 b.p.m. (SD 13 b.p.m.) in those who died due to CVD during follow-up (P , 0.001 for difference between survivors and deceased). Baseline characteristics in survivors and those who died of CVD during the followup are shown in Table 1. HR40–100 correlated negatively with resting HR (r ¼ 20.33; P , 0.001) and positively with HR reserve (r ¼ 0.79; P , 0.001) and maximal HR (r ¼ 0.66; P , 0.001). HR increment between 40 and 100% of maximal workload and all-cause and CVD mortality The average follow-up time to any death or the end of follow-up was 11.4 years (range 0.3–14.8 years). In the present sample, a total of 146 (10.6%) deaths occurred during the follow-up period. There were 56 CVD deaths (4.1%), of which 37 were due to CHD (2.7%). When adjusted for age and examination year, CVD mortality decreased by 45% (95% CI 28–58; P , 0.001), CHD mortality decreased by 56% (95% CI 38–68; P , 0.001), and all-cause mortality decreased by 37% (95% CI 26–46; P , 0.001) with 1 SD (13 b.p.m.) increment in HR40–100. To investigate independent associations of HR40–100, it was entered simultaneously with age, examination year, and known risk factors for CVD death into Cox models (Table 2). CVD mortality decreased by 26% (95% CI 1–44; P ¼ 0.04), CHD mortality decreased by 41% (95% CI 16–59; P ¼ 0.004), and all-cause mortality decreased by 25% (95% CI 10–37; P ¼ 0.002) with 1 SD (13 b.p.m.) increment in HR40–100. HR40–100 predicted also death due to non-cardiovascular causes: mortality decreased by 24% (95% CI 5–39; P ¼ 0.02) with 1 SD (13 b.p.m.) increment in HR40–100. HR increase from rest to 40% of maximal workload was not associated with CVD (P ¼ 0.65), CHD (P ¼ 0.86), or all-cause mortality (P ¼ 0.27). HR increment between 40 and 100% of maximal workload, CVD mortality, and other exercise test-derived variables The associations of HR40–100 with mortality were compared also with those of VO 2max , resting HR, maximal HR, HR reserve, and systolic blood pressure response. All variables were considered as continuous variables, and relative risks were calculated for 1 SD increment. HR40–100 significantly predicted mortality after adjustment for known risk factors (Table 2). When entered into the same model, other exercise test variables had weaker associations with CVD and CHD mortality than HR40–100 but VO 2max was a stronger predictor of all-cause death than HR40–100 (Table 3). When HR40–100 and each of the other exercise test variables were entered into the fully adjusted model using stepwise method, HR40–100 remained in the model for CVD and CHD mortality, whereas other exercise test variables did not. In the corresponding model for all-cause mortality, both VO 2max and HR40–100 were included in the model but VO 2max was a stronger predictor (P ¼ 0.008) than HR40–100 (P ¼ 0.05). The best cut-off point of HR40–100 for predicting CVD mortality was 43 b.p.m., and 272 subjects (20%) had low HR40–100 (,43 b.p.m.). When HR40–100 was entered as a dichotomous variable into a Cox model, the strongest predictor of CVD death was smoking (P , 0.001) followed by a low HR40–100 (RR 2.4; 95% CI 1.4–4.2; P ¼ 0.002), myocardial ischaemia during exercise (P ¼ 0.007), high systolic blood pressure at rest (P ¼ 0.007), high age (P ¼ 0.01), and CVD history (P ¼ 0.05). The strongest predictor of CHD death was a low HR40–100 (RR 4.3; 95% CI 2.1–8.7; P , 0.001) followed by myocardial ischaemia during exercise (P ¼ 0.001) and smoking (P ¼ 0.002). Analyses stratified according to known risk factors for CVD death are presented in Table 4. A low HR40–100 predicted CVD death in all subgroups except in men with lower serum LDL-cholesterol levels (,3.5 mmol/L; n ¼ 428; P ¼ 0.51). Discussion The main finding of the present study is that a blunted HR increase between 40 and 100% of maximal workload (HR40–100) during an exercise test was associated with increased CVD, CHD, and all-cause mortality in a population-based sample of middle-aged men free of CHD. The magnitude of the association was comparable with that of other major CVD risk factors. In the present study, CVD mortality was associated with HR increment from 40 to 100% of maximal workload, whereas an association was not found with HR increase from rest to 40% of maximal workload. HR40–100 was a better predictor of CVD death than HR reserve (HR increase from rest to maximum) or a variable quantifying a submaximal HR increment by Lauer et al., 17 both previously established predictors of CVD death 13,16 or incident CHD. 17 A possible reason for this is that HR40–100 does not include the early portion of an HR slope, whereas HR reserve and HR variable by Lauer et al. 17 include also HR range ,40% of maximal workload. During dynamic exercise, the initial rise in the HR is mainly due to the withdrawal of vagal tone until HR approaches 100 b.p.m., whereas from that HR level onward, the more slowly responding sympathetic system begins to dominate the control of HR up to maximal values. 25,26 In the present study, a mean HR at 40% of maximal workload was 100 b.p.m. (Table 1). This suggests that a reduced ability to increase sympathetic activity may be the underlying factor mediating the association between a low increment of HR .40% of maximal workload and increased CVD mortality. Instead, a vagally mediated early Downloaded from http://eurheartj.oxfordjournals.org/ by guest on August 30, 2013
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