Elevated resting heart rate is an independent risk factor for cardiovascular disease in healthy men and women

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1 Coronary Artery Disease Elevated resting heart rate is an independent risk factor for cardiovascular disease in healthy men and women Marie Therese Cooney, MB, BCh, BAO, MRCPI, a Erkki Vartiainen, MD, PhD, b Tinna Laakitainen, MD, PhD, b Anne Juolevi, MsC, b Alexandra Dudina, MB, a and Ian M. Graham, MB, BCh, BAO, FESC, FRCPI a Dublin, Ireland; and Helsinki, Finland Background Elevated resting heart rate (RHR) is known to be associated with reduced survival but inconsistencies remain, including lack of significance in most studies of healthy women, lack of independence from systolic blood pressure (SBP) in some, and the suggestion that RHR is merely functioning as a marker of physical inactivity or other comorbidities. We aimed to clarify these inconsistencies. Methods We analyzed the effect of RHR on end points in the National FINRISK Study; a representative, prospective study using Cox proportional hazards model. Ten-thousand five-hundred nineteen men and 11,334 women were included, excluding those with preexisting coronary heart disease, angina, heart failure, or on antihypertensive therapy. Results The hazard ratios for cardiovascular disease (CVD) mortality for each 15 beats/min increase in RHR were 1.24 ( ) in men and 1.32 ( ) in women, adjusted for age, gender, total cholesterol, physical activity (categorical), SBP, body mass index, and high-density lipoprotein cholesterol. This relationship remained significant after exclusion of those with comorbidities and events occurring within first 2 years of observation. Relationship with coronary mortality was stronger and with total mortality was slightly weaker. Inclusion of nonfatal end points weakened the relationship. Conclusions A strong, graded, independent relationship between RHR and incident CVD was demonstrated. This was consistent in healthy men and women. We have clarified that the relationship is independent of SBP and that the temporal sequence would be compatible with a causal relationship. New findings include independence from both a validated measure of physical activity and comorbidities and the demonstration of a stronger effect for fatal than nonfatal events, supporting increased arrhythmogenicity of one of the mechanisms. (Am Heart J 2010;159: e3.) Faster resting heart rates (RHRs) are associated with shorter life expectancies. 1 Epidemiologic studies 2-19 have demonstrated that elevated RHRs increase the risk of mortality, from cardiovascular disease (CVD) in particular. The relationship has been demonstrated in diverse subgroups, including the general population, 2-11,19 hypertensives, 3,18,20 and those with established coronary artery disease (CAD) Resting heart rate has previously been shown to fulfill several of the criteria for causality. 21,22 In men, the relationship has been shown to be strong and graded. 4,8,9 Animal studies have demonstrated reduced rates of atherogenesis post experimental heart rate reduction. 23,24 In addition, several biologically plausible From the a Department of Cardiology, Adelaide Meath Hospital, Tallaght, Dublin 24, Ireland, and b Department of Health Promotion and Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland. Submitted June 24, 2009; accepted December 14, Reprint requests: Ian M. Graham, Cardiovascular Medicine, Trinity College Dublin, Preventive Cardiology, Royal College of Surgeons, Dublin, Adelaide Meath Hospital, Tallaght, Dublin 24, Ireland. ian.graham@amnch.ie /$ - see front matter 2010, Mosby, Inc. All rights reserved. doi: /j.ahj mechanisms for the effect of elevated RHR have been proposed including the antiischemic and antiarrhythmic benefits of a low heart rate and the atherogenic hemodynamic effects of an elevated heart rate; a faster heart rate will necessarily impose more shear stresses than a slow one. However, a number of inconsistencies require clarification, particularly regarding the effect in women. Many of the earlier general population studies did not include women. 2,7-11 Of those that did, 3-6,19,25-27 an independent relationship between RHR and coronary heart disease (CHD) or CVD end points was only demonstrated in women in 3 prospective studies 5,6,25 and in 2 of these the relationship was only significant in a specific age range. 5,25 Another large prospective study assessing the effect of RHR on coronary events in healthy women showed a significant association with CHD incidence. 28 However, it cannot be considered to have demonstrated a truly independent effect because systolic blood pressure was not adjusted for as a continuous variable. 28 Independence has not been firmly established. In some of the larger studies, RHR did not remain an independent significant risk factor after inclusion of

2 Cooney et al 613 systolic blood pressure in the model. 5 Some studies demonstrated independence from physical activity; however, only dichotomous variables were used. 3,6-8,11,19 Comorbid conditions may be associated with elevated RHRs, and adjustment for these potential confounders has been limited in previous studies. The temporal sequence is another important factor to consider because elevated heart rate may be a consequence of subclinical heart disease causing a reduction in left ventricular function. Although, heart rate reduction has shown benefit in those with established CAD or heart failure. 17,29,30 The benefit of RHR reduction in the general population has not yet been investigated. Aim In this analysis, we aim to examine the relationship between RHR and CHD, CVD and total mortality and nonfatal myocardial infarction (MI) in the National FINRISK study. This extensive, standardized, prospective study provides enough information on potential confounders to clarify many of the inconsistencies outlined above and to establish whether there are gender differences in the relationship. In addition, we will examine the associations between RHR and other CV risk factors. Methods Study population The National FINRISK study is a large prospective populationbased observational study. 31 Full methodological details have been described elsewhere. 31 Briefly, collection of baseline data began in Subsequent studies began in 1977, 1982, 1987, 1992, 1997, 2002, and Random, representative population samples were drawn from population registers. Initially, those aged 30 to 59 years were recruited, this was extended in subsequent surveys with individuals 25 to 74 years recruited in Follow-up to end of 2003 is available and was collected in accordance with MONICA methodology, 32 meaning the followup in these analyses ranges from 6 to 27 years. The follow-up was based on the mortality register by Statistics Finland, which is linked to the risk factor surveys using social security numbers. Information on nonfatal events was based on the national hospital discharge data. Funding Finnish Foundation for Cardiovascular Research funded the National FINRISK Study Irish Heart Foundation Servier unrestricted educational grant End point definitions The eight, ninth, and tenth revision of the International Classification of Diseases (ICD) were used to identify CHD mortality, defined as ICD-9 codes and CVD mortality, which included in addition , , 798.1, and 798.2, with exclusion of the following definitely nonatherosclerotic causes of death: 426.7, 429.0, 430.0, 432.1, 437.3, 437.4, and The corresponding ICD-10 codes were used. These correspond to the definition of end points in the SCORE project. 33 Nonfatal MI was defined as ICD-9 codes and corresponding ICD-10 codes. The end point any CHD event includes both nonfatal MI and CHD mortality. Risk factor information collection The survey methods followed the WHO MONICA protocol from These were comparable with the methods used in 1972 and The questionnaire addressed medical history, medications, smoking history, and physical activity. A validated 34 assessment of leisure time physical activity was used; full details can be found in the online Supplementary Material. For this analysis, current smokers were defined as currently smoking or having quit b6 months previously; noncurrent smokers were defined as those who never smoked and those who quit smoking N6 months previously. Examination included measurement of weight, height, blood pressure, and waist circumference (1987 and later). Resting heart rate was measured by palpation of the radial artery pulsation N30 seconds, in the sitting position after 5 minutes of rest. Venous blood sample was taken for measurement of total cholesterol, high-density lipoprotein (HDL) cholesterol (1982 onwards), triglycerides (1972, 1992, and onwards) which were analyzed in a central laboratory. Exclusions Those with previous myocardial infarction, angina, or heart failure were excluded from the analysis. Those on antihypertensive medications were also excluded because these medications may have modified heart rate. Univariable analysis of the effect of RHR The population was divided into gender-specific quintiles of RHR. The levels of other available CV risk factors were examined within each RHR quintile. The rates (per 1,000 person years) were calculated within each gender-specific quintile and category of RHR, defined as 60, 60 to 90, and N90 beats/min, separately in men and women. Multivariable analysis of the effect of RHR The effect of RHR as a continuous variable (per 15 beats/min increase) on each end point was calculated using Cox proportional hazards methods. All of the analyses were performed separately in men and women and stratified by year of study and area of Finland. The covariables introduced into the model were age, smoking status (current or noncurrent smoker), systolic blood pressure, total cholesterol, self-reported diabetes, body mass index (BMI), HDL cholesterol, and physical activity (categorical variable). The time variable was time from study entry to first event. In the case of nonfatal MI, individuals were considered to have left the study after the first event. For all of the analyses in the main article, we included only the study years 1982 to 1997 because these have information on HDL cholesterol, which is included as a covariable in the in Cox analysis.

3 614 Cooney et al American Heart Journal April 2010 Table I. Baseline characteristics in each quintile of RHR in men and women included in models 1 and 2 RHR quintile n Age TC SBP Smokers DM BMI HDL PA1 PA2 PA % 1% % 43% 41% % 1% % 50% 27% % 2% % 52% 22% % 2% % 51% 17% % 2% % 53% 13% All % 2% % 50% 25% % 1% % 52% 24% % 1% % 54% 18% % 1% % 54% 16% % 1% % 52% 14% % 2% % 55% 10% All % 1% % 53% 17% TC, Total cholesterol; SBP, systolic blood pressure; smokers, percentage of current smokers; DM, percentage with diabetes; PA1, minimal physical activity; PA2, moderate physical activity; PA3, heavy physical activity. Table II. CVD, CHD, and total mortality rates (unadjusted) in each gender-specific quintile of RHR in men and women HR quintile HR range n Age CVD mortality rate CHD mortality rate Total mortality rate Fatal or nonfatal CHD event ( ) 0.9 ( ) 4.9 ( ) 2.8 ( ) ( ) 1.3 ( ) 6.2 ( ) 4.0 ( ) ( ) 1.5 ( ) 7.4 ( ) 5.1 ( ) ( ) 1.9 ( ) 8.6 ( ) 4.5 ( ) ( ) 3.5 ( ) 11.8 ( ) 6.6 ( ) ( ) 0.2 ( ) 2.7 ( ) 1.0 ( ) ( ) 0.5 ( ) 3.2 ( ) 1.2 ( ) ( ) 0.4 ( ) 3.0 ( ) 1.2 ( ) ( ) 0.5 ( ) 3.8 ( ) 1.4 ( ) ( ) 1.1 ( ) 5.6 ( ) 2.4 ( ) The above analyses were repeated for the effect of RHR as a categorical (categories: RHR b60, 60-90, N90). To assess if RHR was functioning as a marker of preexisting subclinical disease, the analyses were repeated with events occurring in the first 2 years excluded from the dataset. The effect on hazard ratio for RHR as a continuous variable for CVD mortality after addition of each covariable into the model is shown in the online Supplementary Material. To assess for an interaction effect between gender and RHR, men and women were included together and an interaction term included in the model. The multivariable adjusted effect on RHR on CVD mortality was assessed in all strata of physical activity. To allow sufficient numbers for this analysis, men and women were analyzed together and gender was included as a risk factor. To examine whether RHR was merely functioning as a marker of preexisting comorbidities, we repeated the analyses (CVD mortality end point only) having excluded all those with any of the following comorbidities: asthma, emphysema, rheumatoid arthritis, or cancer. The effect of RHR on CVD mortality was also examined in those with and without baseline elevated SBP. An analysis to assess impact of length of follow-up is described in the online Supplementary Material. All statistical analyses were undertaken using Stata version 9 (StataCorp, College Station, Tx). Results This analysis is limited to the 28,047 individuals in the study years from 1982 onward (because HDL cholesterol was measured in these years). Exclusion of those with previous MI, angina, heart failure, or pharmacologic treatment of hypertension (4,978) and those with missing data left 10,519 men and 11,334 women. Baseline characteristics are shown in Table I. The median duration of follow-up was 12 years. As shown in Table I, there was a trend toward higher total cholesterol levels, higher blood pressures, higher rates of smoking, higher BMI, higher levels of physical inactivity, lower levels of heavy physical activity, and

4 Cooney et al 615 Figure 1 Rates of each end point in each quintile of RHR in men and women. lower HDL cholesterol levels with increasing RHR quintile. This was seen in both men and women. Univariable analyses In men, on univariable analysis CVD, CHD, and total mortality rates increased with each successive increase in RHR quintile. Rate ratio comparing extreme quintiles was 3.87 ( ) for CVD mortality. For the fatal and nonfatal MI end point, the relationship was not as strong or graded. The rates are shown in Table II and illustrated in Figure 1. In women, on univariable analysis, the associations with mortality end points were also strong with a hazard ratio of 3.29 ( ) comparing extreme quintiles for

5 616 Cooney et al American Heart Journal April 2010 Table III. Age and multivariable adjusted hazard ratios for each end point for RHR as a continuous variable (per 15 beats/min increase) Hazard ratios adjusted for age only Hazard ratios adjusted for all risk factors Number included (events) (372) Hazard ratio for CVD mortality 1.50 ( ) 1.24 ( ) Hazard ratio for CHD mortality 1.63 ( ) 1.34 ( ) Hazard ratio for total mortality 1.36 ( ) 1.19 ( ) Hazard ratio for fatal and nonfatal CHD events 1.28 ( ) 1.06 ( ) Number included (events) (140) Hazard ratio for CVD mortality 1.45 ( ) 1.32 ( ) Hazard ratio for CHD mortality 1.71 ( ) 1.50 ( ) Hazard ratio for total mortality 1.28 ( ) 1.21 ( ) Hazard ratio for fatal and nonfatal CHD events 1.35 ( ) 1.20 ( ) CVD mortality. However, in general, the relationships were less strongly graded than in men. Again, the relationship with fatal and nonfatal MI together was weaker. These rates are not adjusted for age; there was a slight increase in median age as RHR quintile increased, as shown in Table II. The rates of each end point in each category of RHR are shown in Supplementary Table I and illustrated in Supplementary Figure 1 (Appendix online). Rate ratios comparing b60 beats/min to N90 beats/min were 3.80 ( ) for men and 6.16 ( ) for women for the CVD mortality end point. Multivariable analyses In multivariable analyses (Table III), RHR as a continuous variable remained a significant predictor of CVD mortality after full adjustment. As shown in Table III, the hazard ratio for RHR was attenuated after the addition of the other CV risk factors. For example, the hazard ratio for CVD mortality in women reduced from 1.50 to 1.24 in men after adjustment and from 1.45 to 1.32 in women. Most of the attenuation occurred with the introduction of systolic blood pressure into the model. However, in men particularly, introduction of the smoking variable also attenuated the hazard ratio, as did introduction of the physical activity variable in both genders (full data shown in online Supplementary Table II). Inclusion of waist circumference and triglycerides where these variables were available made no appreciable difference to the hazard ratio for resting heart rate (data not shown, available on request). As shown in Table III, RHR also remained an independent predictor of the other mortality end points (CHD and total mortality). In both men and women, the relationship was strongest for the CHD mortality end point and additional of nonfatal MIs to the end point resulted in a substantial reduction in the strength of the relationship in both men and women, which lost statistical significance in men. Table IV. Fully adjusted hazard ratios for CVD mortality for RHR as a continuous variable (per 15 beats/min increase) in men and women with high and normal baseline systolic blood pressure Baseline systolic blood pressure 140 mm Hg Baseline systolic blood pressure >140 mm Hg 1.31 ( ) 1.23 ( ) 1.50 ( ) 1.28 ( ) To investigate whether elevated RHR was an independent risk factor or merely a marker of subclinical disease, we reanalyzed the effect excluding all fatal events that occurred within the first 2 years of follow-up. This resulted in virtually no difference in the hazard ratios. Multivariable adjusted hazard ratios per 15 beats/min increase in RHR were 1.27 ( ) in men and 1.28 ( ) in women for the CVD mortality end point. The effect of RHR category on risk of each end point was also calculated as this is particularly clinically relevant, as shown in the online Supplementary Table III. There was no significant interaction between gender and effect of RHR on CVD mortality (P =.742). Resting heart rate remained a predictor of CVD mortality in both the inactive and the moderately active strata of physical activity. However, statistical significance was lost in those who undertook heavy physical activity (event numbers in this group were small). Fully adjusted hazard ratios per 15 beats/min increase in RHR were 1.24 ( ) in the inactive group, 1.30 ( ) in the moderate activity group, and 1.11( ) in the heavy activity group. After exclusion of those with comorbidities, the relationship between RHR and CVD mortality remained essentially the same. Hazard ratios per 15 beats/min increase in RHR were 1.23 ( ) and 1.28 ( ) in men and women, respectively. Analyses by blood pressure subgroup showed a stronger effect of RHR in those with baseline blood pressure b140 mm Hg in both men and women. As

6 Cooney et al 617 shown in Table IV, fully adjusted hazard ratios were significant in both blood pressure subgroups. As shown in the online Supplementary Table IV, RHR had a stronger effect on CVD outcomes when the observation time was shorter. For example, the risk associated with each 15 beats/min increase in RHR in men was 1.19 ( ) when the full observation time was included (up to 27 years), but this increased to 1.40 ( ) when the observation time was truncated at 5 years. There was also a statistically significant relationship between RHR and non-cvd mortality also. The fully adjusted hazard ratios for each 15 beats/min increase in RHR were 1.17 ( ) in men and 1.18 ( ) in women. Discussion This analysis has clearly demonstrated the association between resting heart rate and CVD, CHD, and total mortality. We have confirmed the strength of the relationship. For example, in men, RHR N90 beats/min compared to RHR b60 beats/min was associated with an almost 2-fold increased risk of CVD mortality in men and 3-fold increased risk in women. This effect was independent and similar in magnitude to the risk associated with current smoking (data not shown). These estimates are similar to those of previous studies, which ranged from 1.5- to 3.3-fold increased risk in the higher RHR category. 3,4,6,8,10,11,25 We have confirmed the graded nature of the relationship, particularly in men. The risk seems to increase more steeply in the highest quintile of RHR, in line with the findings of previous studies. 28 Previously, there was inconsistency regarding the effect in women. Earlier, possibly underpowered studies, showed either an insignificant or less important effect in women than men. Only 4 studies in the general population have actually shown a significant relationship between CVD or CHD outcomes in women, 5,6,25 and of note, one of these 28 did not adjust for systolic blood pressure as a continuous variable. We have demonstrated that RHR functions as a significant independent predictor of mortality outcomes in women as well as men, with no evidence of a gender interaction. Thus, our analysis adds to the scientific understanding of RHR as a risk factor in women. An analysis of the effect of RHR on outcome in the placebo group of the BEAUTIFUL trial showed a very similar result to ours, despite a substantial difference in study population (CAD patients with impaired left ventricular function). The hazard ratio for cardiovascular death for each 5 beats/min increase in baseline RHR was Previously, there was doubt concerning the independence of the effect, particularly regarding possible confounders such as blood pressure, physical activity, and comorbidities. 19 This analysis has demonstrated that RHR is strongly related to other risk factors including smoking, SBP, BMI, total cholesterol, HDL cholesterol (inversely), and physical activity levels. Because of these associations, the effect of RHR on CVD end points attenuated on addition of the other CV risk factors to the model. However, despite this, the effect of RHR on CVD end points remained statistically significant even after inclusion of all of the risk factors, including physical activity as a categorical variable and persisted within strata of physical activity. In addition, the relationship remained after exclusion of those with comorbidities, which could potentially have been confounding the relationship. The effect of RHR was not substantially altered by the addition of waist circumference and triglycerides into the model in subgroups where these variables were available (data not shown). This is the fourth largest study of the effect of RHR on outcome in the general population. In the only 3 larger studies, 5,19,28 either did not adjust for systolic blood pressure 28 or the relationship did not persist once other CV risk factors were introduced into the model, either in women 19 or in both genders. 5 Preexisting or even subclinical CVD may lead to elevations in RHR. In this way, reverse causality could account for the relationship between RHR and the future development of CVD. Our demonstration of the persistence of the relationship after exclusion of events occurring in the first 2 years demonstrates a temporal sequence consistent with causality. There are a number of possible explanations for the finding of a stronger effect of RHR with shorter follow-up times. One may postulate that reverse causality is responsible. The increase in relative importance of stroke (on which elevated RHR has a weaker effect) with ageing is a likely explanation, which has been suggested previously. 19 In an etiologic analysis, such as this, considering the shorter follow-up time seems more reasonable because many of the individuals will have been started on antihypertensive medication within 10 years, this will also have reduced RHR in many cases. The mechanism through which elevated RHR exerts its deleterious effect is unknown. Possibilities include predisposing to ischemia, arrhythmia, and plaque rupture or by promoting atherogenesis by increasing the absolute number of sheer stresses to which the vessel wall is exposed. Our demonstration of the stronger effect on fatal than nonfatal events supports proarrhythmogenicity as one of the mechanisms, as do previous studies showing a particularly strong effect of elevated RHR on sudden cardiac death. 8,9 The main strengths of this analysis are the large size of the dataset, prospective design, the standardization of the methods for data collection and follow-up, the long observation time (up to 27 years), and the representativeness of the sample of the general population. The use of clinic-based resting heart rate measurement as opposed

7 618 Cooney et al American Heart Journal April 2010 to ambulatory heart rate could be considered a limitation. However, a previous prospective study has shown a high degree of correlation between the 2 measurements and that ambulatory heart rate did not add prognostic information to that provided by clinic heart rate. 35 We have adjusted only for physical activity as a categorical variable and not for exercise capacity as measured by cardiopulmonary testing. However, the physical activity questions used have been shown to correlate with predicted maximal oxygen uptake. 34 Heart rate variability and heart rate response to exercise are also associated with CVD outcomes, 9 these were not available in this dataset. Only baseline RHR measurements were available; therefore, we could not assess the effect of change in RHR, which has recently been shown to be a predictor of CVD death in men 36 or adjust for regression dilution bias; this could lead to underestimation of the effect. None of the current risk estimation systems for primary prevention of CVD currently include RHR as a risk factor. 33 Our findings indicate that those with high RHRs should be considered at higher risk than indicated by SCORE 33 or Framingham risk estimates. Several behavioral and lifestyle factors are associated with RHR. These include increased RHRs in the presence of psychological stress 37 or smoking 38 and lower RHRs in those who are physically fit 39 or consume greater amounts of oily fish or Ω-3 fatty acids These factors can be modified using conservative measures and many have been shown to be associated with prolonged survival. 40,43,44 However, because these conservative measures have other beneficial effects on the CV system, it cannot be concluded that their benefits are as a direct result of heart rate lowering per se. Whether benefit will result from lowering of elevated RHRs can only be assessed in a randomized controlled trial. This analysis signals the need for consideration of such a trial. Conclusion This large prospective cohort study confirms the strong and graded relationship between RHR and CVD, CHD and total mortality end points. We have clarified a number of previously disputed issues relating to fulfillment of the causal criteria, specifically independence, appropriate temporal sequence, and the consistency of the relationship in women. We have demonstrated, for the first time that RHR is a risk factor independent of a validated measure of physical activity. In addition, we have shown elevated RHR to be a stronger risk factor for the development of fatal as opposed to nonfatal MI, compatible with the possibility of a proarrhythmogenicity as one of the mechanisms. Resting heart rates N90 beats/min have been shown to be associated with at least a doubling of risk a similar effect to smoking. 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9 Cooney et al 619.e1 Appendix. Supplementary information on Methods Leisure time physical activity questionnaire A validated 34 assessment of leisure time physical activity was used. Participants were asked the following question: how much do you exercise and stress yourself physically in your leisure time? The answers were coded as follows: 1. In my leisure time, I read, watch TV, and work in the household with tasks that do not make me move much and that do not physically tax me. 2. In my spare time, I walk, cycle, or exercise otherwise at least 4 h/wk. This includes walking fishing and hunting, light gardening, and others but excludes travel to work. 3. In my spare time, I exercise to maintain my physical condition, for example, running, jogging, skiing, gymnastics, swimming, playing ball games, or I do heavy gardening or the like for at least 3 h/wk. 4. In my spare time, I regularly exercise competitive-wise several times a week, orienteering, skiing, swimming, or playing ball games or other heavy sports. For the purpose of these analyses, answers 3 and 4 were combined, due to small numbers (particularly of women) in the fourth category. Leisure time activity was chosen over activity at work as this has been shown to correlate better with CVD risk factors. 1 Supplementary analysis impact of length of follow-up In a supplementary analysis to assess the impact of length of follow-up on effect of RHR, we included the 1977 also, as this has follow-up of up to 27 years available. Using this enlarged data set (study years 1977 to 1997), we examined the multivariable association between RHR and both CVD and CHD mortality when the follow-up was full (up to 27 years) and truncated at 15, 10, 7, and 5 years of follow-up. Results are shown in Supplementary Table IV. Supplementary tables Supplementary Table I. CVD, CHD, and total mortality rates and fatal and nonfatal CHD event rates (unadjusted) in each RHR category in men and women Category n Age CVD mortality rate CHD mortality rate Total mortality rate Fatal and nonfatal CHD events b ( ) 0.9 ( ) 4.9 ( ) 2.8 ( ) ( ) 1.8 ( ) 7.9 ( ) 4.8 ( ) N ( ) 4.2 ( ) 13.8 ( ) 7.0 ( ) b ( ) 0.1 ( ) 2.4 ( ) 0.8 ( ) ( ) 0.5 ( ) 3.6 ( ) 1.4 ( ) N ( ) 1.5 ( ) 6.0 ( ) 2.8 ( ) Supplementary Table II. Hazard ratio for CVD mortality for RHR as a continuous variable (per 15 beats/min increase) with sequential addition of covariables into the model. ***pb0.001; **pb0.01 None 1.50*** 1.58*** Age 1.50*** 1.45*** SBP 1.38*** 1.37** Total cholesterol 1.36*** 1.37** Smoking 1.27*** 1.33** Diabetes 1.26*** 1.32** BMI 1.26*** 1.32** HDL 1.26*** 1.37** Physical activity 1.24*** 1.32** Number included No. of events

10 619.e2 Cooney et al American Heart Journal April 2010 Supplementary Table III. Age and multivariable adjusted hazard ratios for each end point associated with RHR categories CVD mortality 60 Reference Reference ( ) 1.34 ( ) N ( ) 1.93 ( ) CHD mortality 60 Reference Reference ( ) 1.49 ( ) N ( ) 2.37 ( ) Total mortality 60 Reference Reference ( ) 1.23 ( ) N ( ) 1.76 ( ) Fatal and nonfatal CHD events 60 Reference Reference ( ) 1.34 ( ) N ( ) 1.42 ( ) CVD mortality 60 Reference Reference ( ) 2.61 ( ) N ( ) 3.05 ( ) CHD mortality 60 Reference Reference ( ) 4.35 ( ) N ( ) 7.59 ( ) Total mortality 60 Reference Reference ( ) 1.30 ( ) N ( ) 1.71 ( ) Fatal and nonfatal CHD events 60 Reference Reference ( ) 1.45 ( ) N ( ) 1.97 ( ) Supplementary Table IV. Effect of varying observation time on hazard ratio for RHR as a continuous variable (per 15 beats/min increase), used for all variables in the multivariable analyses (except HDL-C not available in cohorts with longer follow-up) CVD mortality end point CHD mortality end point Full observation time (27 y) 1.19 ( ) 1.13 ( ) 1.23 ( ) 1.17 ( ) 15 y 1.20 ( ) 1.18 ( ) 1.25 ( ) 1.19 ( ) 10 y 1.29 ( ) 1.34 ( ) 1.34 ( ) 1.32 ( ) 7 y 1.37 ( ) 1.44 ( ) 1.35 ( ) 1.40 ( ) 5 y 1.40 ( ) 1.60 ( ) 1.47 ( ) 1.69 ( ) 1. Hickey N, Mulcahy R, Bourke G, et al. Study of coronary risk factors related to physical activity in 15,171 men. BMJ 1975;30:507-9.

11 Cooney et al 619.e3 Supplementary figure Supplementary Figure 1 Rates of each endpoint in each category of RHR in men and women.