Smoking, blood pressure and cardiovascular risk

In this issue of the journal, Khalili et al. [1] present results from the Malmö Preventing Project, a large population-based study aimed at identifying and evaluating risk factors for cardiovascular disease. The specific aim of the analysis presented was to determine to what extent smoking modifies the cardiovascular risk resulting from elevated blood pressure in middle-aged men. More than 22 000 men, aged 25–63 years, representing more than 70% of the total male population of these age groups in the area, entered the study. The mean duration of follow-up was 17 years and the total number of person-years exceeded 375 000. This large population allows a powerful analysis of cardiovascular risk factors. The authors stratified patients according to quintiles of systolic blood pressure and identified a separate group of treated hypertensives. Cerebrovascular and cardiac events were analysed together. Similar to that previously demonstrated for North American populations, the cardiovascular event rate (first cardiovascular events) increased with rising systolic blood pressure [2]. The highest event rate was observed in treated hypertensive patients. These data confirm the results of other observations [3]. However, the data contrast with results from the Framingham study where, even if cardiovascular event rate was similar in patients with long-term sustained hypertension and long-term treatment and patients without long-term treatment, long-term antihypertensive treatment was associated with a substantial reduction of cardiovascular mortality [4]. The presented comparison of treated hypertensive patients with other participants is not conclusive. Treated hypertensives had blood pressure values as high as those patients in the highest quintile of systolic blood pressure (on average 144/97 mmHg) and tended to have a higher prevalence of diabetes. No information about the duration of treatment and adherence to treatment is provided. Moreover, no information on subsequent treatment after the sreening examination in treated hypertensives and other participants is provided. Clear evidence regarding the benefits of antihypertensive therapy in terms of reduced cardiovascular morbidity and mortality has been presented by Collins et al. [5]. The true benefit of antihypertensive treatment may even have been underestimated [6]. Smoking doubled the risk of cardiovascular events in all groups of systolic blood pressure, without significant differences between the quintiles. The effects of systolic blood pressure and smoking were additive, and there was no potentiation of the blood pressure-related cardiovascular risk by smoking. However, the excess risk of smoking in treated hypertensives was somewhat lower (relative risk 1.4). This could indicate that standard care antihypertensive treatment may attenuate cardiovascular risk, partly independent of blood pressure reduction. Interestingly, cardiovascular events had a similar incidence in current non-smokers, former smokers and never smokers. Thus, the smoking-related excess cardiovascular risk appeared to be reversible. In addition, the quantity of smoking did not influence the cardiovascular risk resulting from increased systolic blood pressure, except for the population in the highest quintile of systolic blood pressure. The study provides important insights into the inter-relationship between cardiovascular risk factors. As the authors correctly state, multiple risk factor intervention in hypertensive patients is mandatory. The complex interaction of risk factors may explain the relatively small effect of antihypertensive treatment alone on the cardiac event rate of hypertensive patients [7]. Prospective intervention studies aiming to influence multiple risk factors in hypertensive patients and patients with high cardiovascular risk promise to give further insight into the mutual relationship between cardiovascular risk factors and to help develop powerful therapeutic strategies [8–10]. The analysis of Khalili et al. [1] is limited to the evaluation of smoking and systolic blood pressure. In populations at risk for cardiovascular events, many individuals present multiple cardiovascular risk factors. Analyses from European and North American populations allow approximation of cardiovascular risk using risk charts. These charts are based on smoking habits, cholesterol levels and systolic blood pressure [11,12]. Further studies are required in order to quantify the exact contribution of each risk factor (e.g. hypercholesterolemia, diabetes, smoking, family history of cardiovascular disease, age, sex and blood pressure) to the overall cardiovascular risk. According to the current guidelines of the International Society of Hypertension, these risk factors have equal weight for risk stratification [13]. This may not be justifiable in selected populations (e.g. male versus female populations). Moreover, a more detailed understanding is required of how these risk factors influence the type of cardiovascular disease [2,14]. It is well known that blood pressure influences the risk of stroke to a far greater extent than the risk of cardiac events [15]. A detailed analysis of the contribution of individual risk factors to the event rate in separate vascular beds is mandatory. It is conceivable that cardiovascular risk factors are not independent but congregate in clusters in selected populations. Therefore, population-specific analyses and comparisons between different populations are important [11,16,17]. The major result emerging from the presented analysis is that smoking approximately doubles the cardiovascular risk resulting from increased systolic blood pressure. These findings are in accordance with data from other population surveys (e.g. the Augsburg MONICA project and the Framingham study) [11]. What might be mechanisms to explain the increase of blood pressure-related risk conveyed by smoking? First, activation of the sympathetic nervous system may have a fundamental role. Elevated blood pressure, particularly systolic blood pressure, is linked to increased sympathetic nerve activity, at least in subgroups of patients with increased heart rates, as a possible consequence of increased cardiac sympathetic drive [18]. Smoking has been shown to increase sympathetic nerve activity [19]. The potentiation of blood pressure-related increases in sympathetic outflow by smoking may account for elevated cardiovascular risk. Elevated sympathetic nerve activity is associated with end organ damage in essential hypertension [20] and is a predictor of cardiovascular mortality in selected patient collectives [21,22]. Because sympathetic activation is related to current smoking and is reversible after smoking cessation, increased sympathetic nerve activity as a substantial mediator of smoking-related excess cardiovascular risk might explain the lack of increased cardiovascular risk in former smokers compared to never smokers. Second, hypertension and smoking have synergistic deleterious effects on large artery structural and functional wall properties. Data from the Cardiovascular Health Study show that hypertension, smoking and other risk factors interact in their influence on left ventricular geometry and large artery intima media thickness and elastic wall properties [23]. Moreover, hypertension and smoking are additive in their detrimental effects on endothelial function [24,25]. Furthermore, increased sympathetic nerve activity related to elevated blood pressure and smoking may contribute to impaired large artery elastic wall properties [26]. Finally, it has been convincingly shown that both impaired large artery elasticity [27] and disturbed endothelial function [28] in hypertensive patients are important predictors of their cardiovascular morbidity and mortality. In summary, a comprehensive population-specific and vascular territory-specific analysis of the individual contribution of different risk factors to cardiovascular morbidity and mortality is fundamental to establish new concepts for multiple risk factor intervention in cardiovascular disease.