Heart rate response during exercise test and cardiovascular ...

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

HR response during exercise test and cardiovascular mortality 585 Table 1 Baseline characteristics according to CVD death during follow-up in 1378 men with no history of CHD or use of b-blockers at baseline Characteristics Mean/median (SD/range) or proportion P-value for difference All men (n ¼ 1378) Men who died of CVD during follow-up (n ¼ 56) Survivors (n ¼ 1322) between groups a Age (years) 54 (42–61) 54 (42–61) 52 (42–61) 0.003 BMI (kg/m 2 ) 26.5 (3.4) 27.8 (3.9) 26.5 (3.3) 0.01 Cigarette smoking (cigarette-years) b 147 (301) 315 (465) 140 (290) 0.02 Alcohol consumption (g/week) 74 (113) 120 (191) 72 (108) 0.12 CVD history (%) c 14.7 28.6 14.1 0.01 Diabetes (%) d 3.7 8.9 3.5 0.18 Serum LDL-cholesterol (mmol/L) 3.98 (0.97) 4.30 (1.04) 3.97 (0.96) 0.001 Systolic blood pressure at rest 133 (16) 143 (19) 132 (15) ,0.001 (mmHg) Maximal oxygen uptake (L/min) 2.6 (0.6) 2.3 (0.5) 2.6 (0.6) 0.03 Exercise test duration (s) 627 (137) 543 (121) 631 (137) 0.002 Myocardial ischaemia during 13.8 33.9 12.9 ,0.001 exercise (%) e Systolic blood pressure 76 (24) 77 (25) 76 (24) 0.50 response (mmHg) f Systolic blood pressure 7.5 (2.7) 8.6 (3.1) 7.5 (2.6) 0.02 response in relation to test duration (mmHg/min) Resting HR (b.p.m.) 74 (13) 78 (15) 74 (13) 0.02 Chronotropic incompetence (%) g 10.1 14.3 9.9 0.55 Maximal HR (b.p.m.) 163 (17) 154 (18) 163 (17) 0.003 HR reserve (b.p.m.) h 89 (20) 76 (19) 89 (19) ,0.001 HR at 40% of maximal workload 108 (13) 109 (14) 108 (13) 0.34 (b.p.m.) HR increment between 40 and 100% of maximal workload (b.p.m.) 54 (13) 45 (13) 55 (13) ,0.001 a Differences between groups were adjusted for age and length of follow-up and tested with logistic-regression analysis for CVD history, chronotropic incompetence, diabetes, and myocardial ischaemia during exercise and with linear-regression analysis for rest of the variables. An age difference between groups was tested with Mann–Whitney U test. b Cigarette-years denotes the lifelong exposure to smoking which was estimated as the product of years smoked and the number of cigarettes smoked daily at the time of examination. 24 c CVD was defined as a history of cardiomyopathy, heart failure, stroke, or claudication. d Diabetes was defined as a history of taking medication for treatment of diabetes or fasting glucose 6.7 mmol/L. e 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. f Systolic blood pressure response was calculated as maximal systolic blood pressure 2 resting systolic blood pressure. g Chronotropic incompetence was defined as an inability to reach 85% of the age-predicted (220 2 age in years) maximal HR. h HR reserve was calculated as maximal HR 2 resting HR. Downloaded from http://eurheartj.oxfordjournals.org/ by guest on August 30, 2013 increment of HR does not seem to be informative from the predictive point of view. In contrast, a resting HR, which is also largely defined by vagal activity, has previously been associated with an increased risk of premature CVD death, 1–12 and a similar trend was found also in this study. Patients with advanced CHD and heart failure show a high resting HR and a poor ability to increase HR during exercise. 27–29 These findings have been attributed to a low number of b-adrenergic receptors and desensitization of myocardial b-adrenergic receptors secondary to increased sympathetic activity. 27–29 A low HR40–100 together with a high resting HR in the present study may indicate a milder autonomic nervous system aberration frequently found in cardiac patients. 13 Experimental data show that cardiac autonomic regulation plays an important role in occurrence of life-threatening arrhythmias during acute cardiac ischaemia. 30 Other mechanisms by which an impaired HR response could be associated with increased CVD mortality include exercise-induced myocardial ischaemia 31 and a decreased cardiorespiratory fitness. 17 An impaired HR response has also been speculated to be a parasympathetic reflex triggered by irritation of mechanoreceptors in the left ventricular wall (the Bezold–Jarisch reflex) subsequent to deteriorated myocardial contractility. 32,33 However, a low HR40–100 predicted CVD and all-cause mortality independent of exercise-induced ischaemia. First, the strength of our study is that we have a representative population-based sample of middle-aged men. Secondly, the participation rate was high and there were
586 K.P. Savonen et al. Table 2 Risk factor for CVD, CHD, and all-cause death in 1378 men with no history of coronary heart disease or use of b-blockers at baseline a Risk factor Death due to CVD Death due to coronary heart disease All-cause death Relative risk (95% CI) P-value Relative risk (95% CI) P-value Relative risk (95% CI) P-value Age (for each increment 1.08 (1.02–1.16) 0.02 1.04 (0.97–1.12) 0.31 1.08 (1.04–1.13) ,0.001 of 1 year) Alcohol consumption 1.14 (0.62–2.09) 0.68 0.97 (0.45–2.09) 0.94 1.52 (1.06–2.19) 0.02 91 g/week (highest fourth vs. others) BMI (for each increment 1.20 (0.93–1.54) 0.16 1.19 (0.88–1.60) 0.26 1.07 (0.91–1.26) 0.42 of 3.4 kg/m 2 ) CVD history (yes vs. no) 1.81 (0.98–3.34) 0.06 1.66 (0.77–3.57) 0.20 1.02 (0.66–1.58) 0.93 Cigarette smoking (for each 1.43 (1.19–1.72) ,0.001 1.41 (1.11–1.78) 0.004 1.43 (1.29–1.60) ,0.001 increment of 301 cigarette-years) Diabetes (yes vs. no) 1.29 (0.48–3.47) 0.62 1.14 (0.33–4.00) 0.84 1.25 (0.64–2.45) 0.52 Myocardial ischaemia during 2.35 (1.32–4.19) 0.004 3.32 (1.68–6.59) 0.001 1.25 (0.83–1.90) 0.29 exercise (yes vs. no) Serum LDL-cholesterol 1.16 (0.89–1.51) 0.28 1.26 (0.92–1.72) 0.15 1.01 (0.86–1.18) 0.92 (for each increment of 0.97 mmol/L) Systolic blood pressure at rest 1.36 (1.09–1.70) 0.008 1.19 (0.89–1.58) 0.24 1.28 (1.11–1.49) 0.001 (for each increment of 16 mmHg) HR increment between 40 and 100% of maximal workload (for each increment of 13 b.p.m.) 0.74 (0.56–0.99) 0.04 0.59 (0.41–0.84) 0.004 0.75 (0.63–0.90) 0.002 a From Cox-regression model adjusted for age, examination year, and all variables, as shown. Except for age, alcohol consumption, CVD history, diabetes, and myocardial ischaemia, the relative risks were calculated for a change of 1 SD, as shown. Abbreviations as in Table 1. Table 3 Exercise test variables as a risk factor for CVD, CHD, and all-cause death in 1378 men with no history of CHD or use of b-blockers at baseline a Risk factor Death due to CVD Death due to CHD All-cause death Maximal oxygen uptake (for each increment of 0.6 L/min) Systolic blood pressure response (for each increment of 24 mmHg) Systolic blood pressure response in relation to test duration (for each increment of 2.7 mmHg/min) Resting HR (for each increment of 13 b.p.m.) Maximal HR (for each increment of 17 b.p.m.) HR reserve (for each increment of 20 b.p.m.) Relative risk (95% CI) P-value Relative risk (95% CI) P-value Relative risk (95% CI) P-value 0.74 (0.52–1.06) 0.10 0.57 (0.36–0.90) 0.02 0.66 (0.53–0.83) ,0.001 1.18 (0.90–1.54) 0.23 1.19 (0.85–1.66) 0.31 0.90 (0.76–1.06) 0.21 1.16 (0.94–1.44) 0.17 1.24 (0.95–1.61) 0.11 1.05 (0.90–1.22) 0.56 1.21 (0.94–1.55) 0.14 1.35 (1.01–1.81) 0.04 1.08 (0.92–1.27) 0.37 0.98 (0.74–1.30) 0.90 0.90 (0.64–1.27) 0.55 0.78 (0.65–0.94) 0.007 0.84 (0.63–1.12) 0.23 0.70 (0.49–1.00) 0.05 0.76 (0.64–0.91) 0.003 Downloaded from http://eurheartj.oxfordjournals.org/ by guest on August 30, 2013 a From Cox-regression model adjusted for age, examination year, alcohol consumption, BMI, cigarette smoking, CVD history, diabetes, serum LDL-cholesterol, systolic blood pressure at rest, and myocardial ischaemia during exercise. The relative risks were calculated for a change of 1 SD, as shown. Abbreviations as in Table 1. no losses to follow-up. Thirdly, we have reliable data on mortality because deaths were ascertained by National Death Registry using a social security number. Next, comprehensive assessment of health habits and cardiovascular risk factors allowed us to investigate the independent association of HR40–100 with CVD mortality. Finally, cardiorespiratory fitness was measured objectively by direct expiratory gas analysis instead of using predicted values. A limitation of the study is that only men were enrolled. Therefore, generalization of the present findings to female populations should be done with caution. The extent to
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