Pulse pressure and heart rate

Journal of Clinical Epidemiology 54 (2001) 735–740

Pulse pressure and heart rate: Independent risk factors for cancer? Frédérique Thomas, Louis Guize, Kathryn Bean, Athanase Benetos* Centre d’Investigations Préventives et Cliniques, 6/14 rue La Pérouse, 75784 Paris cedex 16, France Received 28 June 2000; received in revised form 12 September 2000; accepted 14 October 2000

Abstract In the present study, the roles of heart rate (HR) and pulse pressure (PP) on cancer mortality, after taking into account physical activity, cigarette smoking, alcohol consumption and other confounding factors or underlying disease, were examined in men. The study included 125,513 men aged 20 to 95 years who had a health check-up at the IPC Center between 1978 and 1988. HR and PP were classified into three groups:  60, 60–80,  80 bpm for HR and  50, 51–64,  65 mmHg for PP. Adjusted risk ratios related to the increment from one class of HR or PP to the next for all cancer mortality were 1.4 (1.2–1.5) and 1.3 (1.1–1.4), respectively. This relationship was independent of several known risk and confounding factors, especially cigarette smoking and physical activity, and could not be explained by the presence of underlying disease. © 2001, Elsevier Science Inc. All rights reserved. Keywords: Heart rate; Pulse pressure; Cancer mortality; Tobacco; Physical activity; Risk factors

1. Introduction Two decades ago, Dyer et al. [1] reported a relationship between blood pressure (BP) and cancer mortality, independent of age, smoking, and cholesterol. Since then, several prospective studies have examined this relationship but the results have been inconsistent. Some results showed a positive association [2,3], some showed no association [4], and others even showed an inverse relationship among elderly subjects [5]. Some studies reported a positive relationship between BP and certain types of cancer [2,3]. The relationship between BP and cancer seems to vary according to the site of the cancer, the length of the follow-up and the presence of other risk factors [3]. Other studies suggest that this relationship may be an indirect result, due to the presence of confounding factors such as tobacco, alcohol intake and lack of physical activity, which may also be associated with high BP. A study conducted among middle-aged men who were randomly selected among patients from general practices in various British towns [6] showed that elevated BP is associated with an increased risk of cancer in current smokers only. This strengthens the hypothesis that the relationship between BP and cancer is the result of interactions with confounding factors.

* Corresponding author. Tel: 331.53.67.35.02; fax: 331.47.20.44.58. E-mail address: [email protected]

The relationship between heart rate (HR) and cancer mortality was also examined. A majority of the findings reported a positive association between HR and cancer [7,8]. In 1981, Persky et al. [7] examined the relationship between HR and cancer in three epidemiological studies conducted in Chicago. Two of the three studies showed a positive association between HR and death from cancer. Because increased HR is associated with cigarette smoking and lack of physical activity [8,9], it has been suggested that the relationship between HR and cancer mortality may be due to the relationships between cancer and lack of regular physical exercise or smoking. In several studies, data for physical activity were not available, making it impossible to evaluate this hypothesis. However, in other studies, after taking into account physical activity and other risk factors such as tobacco, the association between HR and cancer mortality persisted [8,10]. When examined together, these results suggest that mechanical hemodynamic factors such as BP and HR could be associated not only with CVD mortality but also with nonCVD mortality. However, it is unclear whether these associations depend on the presence of confounding factors or underlying diseases. In the present study, we examined the role of HR and pulse pressure (PP  systolic-diastolic BP), the two main parameters of pulsatile hemodynamic stress, on the different types of cancer mortality in a large French cohort composed of 125,513 men. These associations were examined after taking into account physical activity, cigarette smoking, al-

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Table 1 Age-adjusted means (SEM) according to heart rate

Number Age (years) BMI (kg/m2) SBP (mmHg) DBP (mmHg) PP (mmHg) Cholesterol (g/l) Triglycerides (g/l) Gamma-Gt (g/l) Expiratory ratiob Physical activity (n) Smokers (n)

HR1a

HR2a

HR3a

P

24,543 41.2 (11.6) 24.3 (0.02) 130 (0.08) 80 (0.06) 50 (0.06) 2.14 (0.003) 0.92 [0.914–0.924] 22.8 (0.25) 1.01 (0.001) 47.5% (11,645) 29.1% (7148)

80,168 42.1 (11.4) 24.6 (0.01) 134 (0.05) 83 (0.03) 52 (0.03) 2.20 (0.001) 1.01 [1.006–1.013] 26.5 (0.14) 1.00 (0.0005) 33.1% (26,465) 34.1% (27,295)

20,745 41.7 (11.6) 24.7 (0.02) 142 (0.09) 87 (0.07) 55 (0.06) 2.25 (0.003) 1.11 [1.106–1.118] 35.8 (0.28) 0.98 (0.001) 24.4% (5045) 40.4% (8324)

– ns 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001

HR1 60 bpm; HR2 60–80 bpm; HR3  80 bpm. Ratio of observed expiratory volume/expected expiratory volume (according to age).

a

b

cohol consumption and other confounding factors or underlying disease. 2. Materials and methods 2.1. Population Subjects were examined at the IPC Center (Centre d’Investigations Préventives et Clinques), a medical center which is subsidized by the French national health care system (Securité Sociale-CNAM) and which provides all working and retired individuals and their families with a free medical check-up every 5 years. It is one of the biggest medical centers of this kind in France, having carried out approximately 15,000 examinations per year from 1970 to 1978 and approximately 25,000 per year after 1978, for people living in the Paris area. In this study, the population was composed of 125,513 men aged 20–95 years who had a health checkup at the IPC Center during the period of January 1978–December 1988. If a person had more than one examination, the first one was used for analysis. Supine BP was measured three times in the right arm using a manual sphygmomanometer, after a 10-minute rest period. The mean of the last two measurements was calculated. The first and the fifth Korotkoff phases were used to define systolic and diastolic pressures. A self-administered questionnaire containing dichotomic (yes or no) questions regarding tobacco use (current consumption of more than 10 cigarettes/day) and physical activity (  2 hours/week) was administered. Personal and family history of CV disease were also assessed with a self-administered questionnaire. Forced expiratory flow was measured with a spirometer and was adjusted for theoretical values according to corresponding tables. Biological parameters were measured under fasting conditions and electrocardiographic (ECG) measurements were also recorded. Resting heart rate was determined by ECG and classified into four categories:  60 bpm, 60–79 bpm; 80– 100 bpm and  100 bpm. Continuous values for HR were

not reported. Gamma-Gt level was used as a surrogate measure for evaluated alcohol consumption. Deceased subjects were identified from the mortality records of the “Institut National de Statistiques et d’Etudes Economiques” (INSEE). A patient from our cohort was classified as deceased when he had the same first name, last name, gender and date of birth as a person recorded in the INSEE mortality records. By using this matching procedure, the identification error was less than 1%. Only subjects with all four of these criteria were classified as deceased. Individuals matching for fender, last name and only one out of the other two criteria were excluded from the study. Data for an 8-year follow-up period were analyzed. Follow-up ended in December 1996. During the follow-up period, among the 2950 subjects from our cohort who were classified as having died, 1164 died from cancer (all-cause). Causes of mortality taken from the death certificates were provided by INSERM’s department of mortality (Unit SC 8). Causes of death were codified according to the International Classification of Disease (8th revision before 1978 and 9th revision thereafter). The following codes were used to identify the various causes of cancer mortality: 140–239 for cancer mortality; 140–149, 160–165 for broncho-pulmonary cancer; 150–159 for digestive cancer; and 179–189 for genito-urinary cancer. Cardiovascular mortality was also examined (codes 390 to 459).

Table 2 Number of deaths and mortality rates (%) according to heart rate group for 8 years of follow-up. HR1

HR2

HR3

Pa

All-cause cancer (%) 160 (0.65) 692 (0.89) 312 (1.57) 0.001 Broncho-pulmonary cancer (%) 48 (0.20) 232 (0.29) 136 (0.70) 0.001 Digestive cancer (%) 60 (0.24) 195 (0.24) 92 (0.47) 0.001 Genito-urinary cancer (%) 17 (0.07) 79 (0.10) 17 (0.08) 0.57 a

P for chi-square test.

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Table 3 Age-adjusted means (SEM) according to pulse pressure

Number Age (years) BMI (kg/m2) SBP (mmHg) DBP (mmHg) PP (mmHg) Cholesterol (g/l) Triglycerides (g/l) Gamma-Gt (g/l) Expiratory ratiob Physical activity (n) Smokers (n)

PP1a

PP2a

PP3a

P

33,770 41.4 (10.2) 24.3 (0.02) 124.3 (0.06) 82.6 (0.06) 41.7 (0.03) 2.18 (0.002) 0.996 [0.990–1.00] 25.1 (0.22) 1.00 (0.0080) 34.6% (11,663) 33.2% (11,323)

83,283 41.6 (11.4) 24.6 (0.01) 136.2 (0.03) 82.5 (0.03) 53.8 (0.02) 2.20 (0.001) 1.006 [1.002–1.010] 27.5 (0.14) 0.997 (0.0005) 34.9% (28,970) 34.3% (28,530)

8440 46.3 (16.4) 24.9 (0.03) 158.9 (0.1) 86.5 (0.01) 72.4 (0.05) 2.21 (0.004) 1.070 [1.057–1.082] 34.6 (0.45) 0.979 (0.0020) 29.8% (2507) 35.5% (2992)

– 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001

PP1 50 mmHg; PP2 50–64 mmHg; PP3 65 mmHg. Ratio of observed expiratory volume/expected expiratory volume (according to age).

a

b

2.2. Data analysis HR, measured by ECG, was classified into three groups:  60 bpm (HR1), 60–80 bpm (HR2) and  80 bpm (HR3). PP was also classified into three groups:  50 mmHg (PP1); 50–64 mmHg (PP2) and  65 mmHg (PP3). A multivariate analysis was used to compared biological and clinical parameters in each group of HR and PP after adjustment for age. Tobacco consumption and physical activity practice were compared using a chi-square test. Mortality rates were compared using a univariate analysis with no adjustments. A chi-square test was used to compare mortality rates in each group of HR and PP. A multivariate analysis using the Cox regression model was used to evaluate risk ratios (RR) related to the increment of one class of PP or HR for different causes of mortality. The following parameters were included in the model: age, BMI, gamma-Gt, tobacco, cholesterol, PP, HR, triglycerides and physical activity. RR were first determined by comparing PP1 to PP2, and PP1 to PP3. A second evaluation was made by calculating the mean effect of the increment of one class of PP. Similar evaluations were carried out for HR. RR were also evaluated after exclusion of the first 2 years of follow-up. Adjusted risk ratios for cancer mortality according to tobacco status (current smokers vs. non current smokers) and physical activity practice (2 hours/week vs. the others) were also evaluated with the same cox regression model described above. All statistical analyses were carried out using SAS software. This study received approval from the Comité National de l’Informatique et des Libertés (CNIL). All study participants gave their informed consent for their data to be used for epidemiological studies. 3. Results Table 1 presents age-adjusted means according to HR groups. Age did not differ between the groups. SBP, DBP,

PP, cholesterol, triglycerides, gamma-Gt levels and percentage of current smokers were positively associated with HR (P  0.001). Physical activity and expiratory volume ratio were lower among accelerated HR groups (P  0.001). Tables 2 shows mortality rates for cancer according to HR. Mortality rates were higher in the HR3 group than in the HR1 group. Analysis according to different types of cancer showed that this positive association was observed with broncho-pulmonary cancer mortality (mortality rate was 4 times greater in HR3 than in HR1) and with digestive cancer mortality (mortality rate was 2.5 times greater in HR3 than in HR1). No association between HR and genito-urinary cancer mortality was observed. Table 3 presents age-adjusted means according to PP groups. Parameters positively associated with PP groups were age, BMI, SBP, DBP, cholesterol, triglycerides and gammaGt (P  0.001). Physical activity and expiratory volume ratio were negatively associated with PP (P  0.001). Table 4 shows mortality rates for cancer according to pulse pressure. Cancer mortality rates were higher in the PP3 group than in the PP1 group. Analysis according to cancer type showed that this association was mainly observed for broncho-pulmonary cancer (mortality rates were 5 times higher in PP3 than in PP1). For digestive cancer and genito-urinary cancer the association was less pronounced. Tables 5 and 6 show risk ratios (RR) adjusted for age, body mass index, gamma-Gt, tobacco, cholesterol, triglycerides and

Table 4 Number of deaths and mortality rates (%) according to pulse pressure for 8 years of follow-up PP1

PP2

PP3

Pa

All-cause cancer (%) 225 (0.67) 740 (0.89) 200 (2.37) 0.001 Broncho-pulmonary cancer (%) 74 (0.22) 256 (0.31) 87 (1.03) 0.001 Digestive cancer (%) 76 (0.23) 216 (0.26) 55 (0.65) 0.001 Genito-urinary cancer (%) 20 (0.06) 74 (0.09) 19 (0.23) 0.001 a

P for chi-square test.

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Table 5 Adjusted risk ratioa (95% of confidence interval) related to the group of heart rate (bpm) for different causes of mortality

All-cause cancer Broncho-pulmonary cancer Digestive cancer Genito-urinary cancer Cardiovascular

HR2b

HR3b

HRc

HRd

1.18 [0.98–1.43] 1.25 [0.88–1.77] 1.00 [0.72–1.38] 1.23 [0.70–2.17] 1.20 [0.91–1.98]

1.33 [1.19–1.49] 1.52 [1.25–1.85] 1.23 [1.03–1.57] 0.86 [0.58–1.28] 1.31 [1.11–1.54]

1.37 [1.23–1.53] 1.55 [1.29–1.87] 1.30 [1.06–1.81] 0.98 [0.69–1.40] 1.35 [1.15–1.57]

1.36 [1.23–1.51] 1.45 [1.22–1.72] 1.40 [1.16–1.68] 1.03 [0.72–1.46] 1.51 [1.31–1.76]

a

Adjusted risk for age, body mass index, gamma-Gt, tobacco, cholesterol, PP, triglycerides and physical activity. Risk ratios vs. HR1 (for 8 years of follow-up). c Mean of risk ratios for increment from one class to the next for 8 years of follow-up. d Mean of risk ratios for increment from one class to the next after exclusion of the two first years of follow-up. b

physical activity related to HR and PP groups for cancer mortality and for cardiovascular mortality. Compared to the HR1 group, RR for cancer mortality increased by 18% (P  0.06) in the HR2 group and by 33% (P  0.001) in the HR3 group. Interestingly, RR observed for cardiovascular mortality was similar [1.20 (HR2 vs. HR1) and 1.31 (HR3 vs. HR1)] (Table 5). Significant associations were observed for both broncho-pulmonary cancer and digestive cancer mortality. No association was found between HR and genito-urinary cancer mortality. After exclusion of the first 2 years of follow-up, HR remained significantly associated with all-cause cancer mortality (P  0.01), broncho pulmonary cancer mortality, (P  0.01), digestive cancer mortality (P  0.01) and cardiovascular mortality (P  0.01) (Tables 5, last column). Risk for cancer mortality also increased with PP levels (Table 6). Compared to the PP1 group, all-cause cancer mortality increased by 14% in the PP2 (P  0.10) group and by 23% (P  0.05) in the PP3 group. The highest RR related to PP was observed for broncho-pulmonary cancer; the RR was similar to the risk for cardiovascular mortality. After exclusion of the first 2 years of follow-up, the associations between PP and cancer mortality, notably bronchopulmonary cancer, remained significant. The same observation was made for cardiovascular mortality. Regardless of the follow-up period (with or without the first 2 years) (Table 6, last column), no significant association between pulse pressure and digestive or genito-urinary cancer was found in this analysis.

We also evaluated the influence of tobacco consumption and physical activity on the association between cancer mortality and HR and PP. Figure 1 (upper panel) shows the mean adjusted RR for the increment from one class of HR to the next, according to smoking status and physical activity for all-cause cancer mortality. Adjusted RR did not differ among smokers [1.44 (1.10–1.88)] and non smokers [1.45 (1.31–1.60)]. Adjusted RR did not differ significantly among subjects with regular physical activity [1.38 (1.10–1.72)] and those without regular physical activity [1.42 (1.28–1.58)]. Figure 1 (lower panel) shows adjusted RR for the increment of one class of PP to the next according to tobacco consumption and physical activity for all-cause cancer mortality. Adjusted RR in smokers did not differ from the risk observed among non-smokers [1.29 (1.14–1.46)] vs. 1.22 (0.90–1.88)]. The RR was not statistically different among subjects with regular physical activity [1.48 (1.14–1.92)] and those without regular physical activity [1.23 (1.08–1.39)]. 4. Discussion The main result of our study was that both HR and PP were positively associated with cancer mortality. After taking into account other risk factors such as tobacco, alcohol consumption and physical activity, the positive relationship between these two factors and cancer mortality remained significant. An important remark is that the risk related to HR acceleration was similar for cancer mortality and CVD mor-

Table 6 Adjusted risk ratioa (95% of confidence interval) related to the group of PP (mmHg) for different causes of mortality

All-cause cancer Broncho-pulmonary cancer Digestive cancer Genito-urinary cancer Cardiovascular a

PP2b

PP3b

PPc

PPd

1.14 [0.96–1.34] 1.14 [0.85–1.51] 1.01 [0.76–1.35] 1.23 [0.70–2.16] 1.22 [0.94–1.58]

1.23 [1.09–1.39] 1.51 [1.25–1.82] 1.14 [0.92–1.42] 1.21 [0.81–1.82] 1.50 [1.27–1.78]

1.28 [1.14–1.43] 1.57 [1.30–1.90] 1.12 [0.91–1.37] 1.22 [0.85–1.74] 1.51 [1.22–1.77]

1.30 [1.05–1.47] 1.60 [1.30–1.97] 1.14 [0.91–1.42] 1.23 [0.84–1.81] 1.41 [1.87–1.69]

Adjusted risk for age, body mass index, gamma-Gt, tobacco, cholesterol, HR, triglycerides and physical activity. Risk ratios vs. PP1. c Mean of risk ratios for increment from one class to the next. d Mean of risk ratios for increment from one class to the next after exclusion of the two first years of follow-up. b

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Fig. 1. Adjusted risk ratios for cancer mortality according to smoking and regular physical exercise, related to heart rate (upper panel). Adjusted risk ratios for cancer according to smoking and regular physical exercise, related to pulse pressure (lower panel).

tality. The impact of PP was also equally important for both broncho-pulmonary cancer and cardiovascular mortality. HR and PP are hemodynamic factors which are the main determinants of cyclic strain of the arterial wall. PP was found to be a significant independent predictor of cardiovascular mortality, and especially of coronary mortality [11–14]. Recent studies have also shown that accelerated HR is an independent predictor of cardiovascular mortality [9,15–18]. These results could be explained by the fact that an increase in HR or PP contributes to the enhancement of left ventricular afterload, cardiac oxygen consumption and arterial fatigue, all of which lead to an acceleration of cardiovascular alterations and/or complications. However, it is difficult to explain why these hemodynamic parameters could be associated with noncardiovascular causes of death, especially cancer mortality. Several hypotheses should be considered to explain this relationship. The first one is that associations between PP, HR and cancer mortality are due to factors such as tobacco consumption, lack of physical activity and alcohol consumption that increase PP and/or HR, and at the same time cancer

mortality. However, the results of the present analysis showed that the observed associations between HR and/or PP and cancer mortality persisted after adjustment for these risk factors. Moreover, analysis in subgroups according to tobacco consumption and physical activity showed that the risks related to PP and HR for cancer mortality were not influenced by the presence or absence of these factors. Therefore, the results obtained from these two different approaches do not support this first hypothesis. It is possible that other factors play a role in this relationship. For example, social and psychological parameters could be underlying mechanisms which increase both cancer mortality and hemodynamic factors such as PP and HR. The results of the present study do not eliminate this hypothesis. Self-administered questionnaires provide incomplete information about a subject’s level of stress, socioeconomic status or educational level. Another hypothesis is that at the cellular and molecular levels, common elements such as growth factors could be associated with hemodynamic parameters and the evolution of cancer. Several reports suggest common mechanisms between hypertension

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and atherosclerosis on the one hand and hypertension and tumor formation on the other [19]. It is also possible that the increased PP and HR observed during the examination was a consequence of a pre-existing cancer. Indeed, frail health could be a contributing factor to increased PP and HR. In this case, there should be an increase in mortality rates in the first years of follow-up. In this study, risk ratios showed that the association between BP, HR and cancer mortality persisted after the first years of follow-up, suggesting that this relationship could not be explained only by hormonal changes induced by cancer. This confirms results obtained by Wannamethee et al. [8] who found that a positive relationship between HR and cancer mortality persisted after the exclusion of subjects who died in the first 5 years of follow-up. Finally, we cannot eliminate a causal relationship between hemodynamic factors and the evolution of malignant disease. Increased PP and HR may modulate the vascularization of tumors and may therefore influence the evolution of cancer. This hypothesis however could not be verified. One of the limitations of the study was that data concerning the incidence of malignancies were not available, therefore not permitting the evaluation of PP and HR as prognostic risk factors which influence case fatality after disease has occurred. In conclusion, in a large French male population, HR and PP were found to be independent predictors of cancer mortality, especially broncho-pulmonary cancer mortality. In fact, the present analysis enables the elimination of the hypothesis that the relationship between cancer mortality and HR or PP was mediated by confounding factors such as tobacco, alcohol consumption or physical inactivity. Further studies are necessary to more clearly establish the link between hemodynamic factors and cancer. Acknowledgments This study was performed with the help of INSERM (Paris, France). We thank the Caisse National d’Assurance Maladie (CNAM) for supporting the study. References [1] Dyer AR, Berkson DM, Stamler J, Lindberg HA, Stevens E. High blood pressure: a risk factor for cancer mortality. Lancet 1975;1:1051–6.

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