Smoking and cardiovascular risk

In this issue of the journal, Dalla Vecchia et al. [1] provide important new insights into the cardiovascular effects of cigarette smoking. In a comprehensive study, they evaluated the effects of acute and chronic smoking on the skin microcirculation in normal subjects. Skin microcirculatory responses to smoking were assessed using an integrated strategy comprising combined use of laser Doppler flowmetry, simultaneous blood pressure measurement and iontophoresis of acetylcholine and nitroprusside. Compared to non-smoking controls, smokers had clear evidence for baseline microcirculatory changes, whereas acute cigarette smoking was associated with a complex impairment of peripheral microcirculatory regulation in both non-smokers and regular smokers. How do these findings of skin microcirculatory responses advance our understanding of mechanisms linking acute and chronic smoking to cardiovascular risk? Smoking and cardiovascular risk Smoking is an important risk factor for cardiovascular disease, in particular for acute events such as myocardial infarction, stroke and sudden death [2–4]. Among smokers, cardiac ischaemia is five times more likely when patients are actually smoking than when they are not smoking [5]. The risk of myocardial infarction in smokers is much higher than the risk in non-smokers with more extensive coronary artery disease [6]. The risk of sudden death increases more than ten-fold in men and five-fold in women who smoke [7]. These findings indicate that smoking-related cardiovascular events cannot be attributed solely to progression of atherosclerosis and other mechanisms, both acute and chronic, are likely to be implicated. Acute haemodynamic effects of smoking The acute haemodynamic responses to smoking include increases in heart rate, systolic and diastolic blood pressure and myocardial contractility [8,9]. These acute responses occur within 1–2 min of the act of smoking and result in increased myocardial oxygen demand. Pressor and tachycardic effects of smoking last for at least 30 min [9,10]. Acute cigarette smoking decreases arterial compliance in both large elastic and medium-sized muscular arteries [11]. Smoking and risk for hypertension Despite the acute pressor effect of cigarette smoking, several epidemiological studies failed to confirm an independent link between smoking and risk of hypertension in young to middle-aged subjects. However, recent evidence suggests that smoking is associated with increased risk of systolic hypertension in elderly men [12,13]. The vast majority of these studies were based on office measurements in subjects abstaining from smoking. Blood pressure measured in the office is probably consistently lower than the blood pressure to which subjects are exposed during actual smoking. Indeed, ambulatory daytime blood pressure is higher in hypertensive smokers than in non-smokers with similar office blood pressure. The increase in ambulatory blood pressure observed after smoking is evident in both young and elderly hypertensives [14,15]. Thus, in young subjects, although smoking is associated with transient increases in blood pressure detectable only with ambulatory monitoring, smoking may be a risk factor for chronic blood pressure elevation in elderly subjects. Acute effects of smoking on autonomic function and cardiovascular variability The sensitivity of the arterial baroreflex is markedly reduced by acute smoking [16]. This impairment of baroreflex function may be directly linked to smoking-related reduced arterial distensibility and the consequent loss of stretch receptor responsiveness [11]. Impaired baroreflex function may contribute in part to any increase in blood pressure variability [9], and decrease in heart rate variability [16], during smoking. Effects of cigarette smoking on muscle sympathetic activity While smoking increases blood pressure and heart rate, there is a dramatic reduction in muscle sympathetic nerve activity (Fig. 1a) [10,17]. These findings have been cited as evidence that cigarette smoking does not elicit an increase in efferent sympathetic nerve traffic [18].Fig. 1: Recordings of muscle sympathetic nerve activity before smoking and during smoking without infusion of nitroprusside (a) and during smoking with infusion of nitroprusside (b) in a normal subject. Smoking without nitroprusside was associated with a marked increase in mean arterial pressure (MAP) and with a decrease in muscle sympathetic nerve activity (a). When the smoking-induced elevation in blood pressure was attenuated with nitroprusside, muscle sympathetic nerve activity increased strikingly (b). Adapted with permission [19].Increased blood pressure in response to smoking, acting via the baroreflexes, may itself elicit sympathetic inhibition, and may thus obscure any sympathetic excitatory property of cigarette smoke [19]. Indeed, when the blood pressure increase in response to cigarette smoking is blunted by simultaneous infusion of sodium nitroprusside, there is a striking increase in sympathetic nerve traffic (Fig. 1b) [19]. Sympathetic activity may reach levels two- to three-fold higher than those seen before smoking. Thus, the arterial baroreflexes, responding to increases in blood pressure during smoking, may exert a protective effect by blunting the sympathetic excitatory effects of cigarette smoke. Effects of cigarette smoking on skin sympathetic activity By contrast to muscle sympathetic activity, skin sympathetic activity is not attenuated by increased blood pressure and baroreflex activation. Acute smoking causes a marked increase in skin sympathetic nerve activity (Fig. 2) [19]. The increases in skin sympathetic activity, muscle sympathetic nerve activity and heart rate with smoking suggest that cigarette smoke may act centrally to cause a uniform increase in sympathetic nerve traffic, to blood vessels, to skin and to the heart.Fig. 2: Recordings of skin sympathetic nerve activity before and during smoking in a normal subject. Smoking caused a marked increase in skin sympathetic nerve activity. Adapted with permission [19].Relevance of the findings of Dalla Vecchia et al. [1] By contrast to previous studies evaluating the effects of acute cigarette smoking on endothelial function in the brachial artery [20], Dalla Vecchia et al. [1] did not detect any acute impairment of endothelium-dependent vasodilation of the skin microvascular bed in non-smokers. This is consistent with the concept that the effects of risk factors on endothelial function may differentially affect different vascular beds. Sympathetic neural mechanisms may help to explain the contrasting effects of smoking on endothelial function in the macrocirculation and in the skin microcirculation. Sympathetic stimulation significantly impairs the flow-mediated response in brachial artery [21]. By contrast, sympathetic activity has no significant influence on endothelial function in the human skin [22]. Thus, smoking-related increases in sympathetic outflow may interfere with flow-mediated dilation of the brachial artery but not of the skin microvascular bed. Dalla Vecchia et al. [1] report several intriguing findings in chronic smokers. As noted by the authors, their study was not designed to evaluate the underlying mechanisms. However, several important observations with mechanistic implications emerge from their data. First, both endothelium-dependent and endothelium- independent vasodilation were impaired in habitual smokers. This suggests that chronic smoking impairs the skin microcirculation independently of the endothelium. Second, chronic smoking was associated with resting (pre-smoking) skin vasodilation. It appears plausible that impaired vasodilator reactivity may be countered to some extent by the resting vasodilation in chronic smokers. In other words, maximally dilated skin vessels have a limited capacity for any further dilation above baseline levels. Acute smoking resulted in paradoxical improvement of endothelium-dependent vasodilation in chronic smokers. As suggested by the authors, this finding may reflect the direct effect of nicotine on nitric oxide release. Alternatively, endothelial nitric oxide release may be secondary to haemodynamic changes associated with smoking. Acute cigarette smoking increases arterial stiffness in the macrocirculation [11,23] and thus may increase pulse pressure and shear stress in smaller arteries. Increased shear stress may contribute to endothelial nitric oxide release [24] and be responsible for paradoxical recovery of vasodilation after smoking. Vasodilatation of skin vessels may conceivably help to buffer smoking-related increases in blood pressure. On the other hand, this vasodilation may theoretically have deleterious effects because it would permit pulsatility of the macrocirculation to penetrate deeper into the microvasculature [24]. Changes in the microvasculature are found in subjects with early and subtle elevations in blood pressure or fasting plasma glucose [25]. Smoking-related changes in cardiovascular regulation may further contribute to the microvascular damage. Conclusions Although the independent chronic effects of smoking on the risk of hypertension are relatively small, the overall cardiovascular risk of a hypertensive patient is greatly increased by smoking. Therefore, the effects of smoking on blood pressure levels may contribute only modestly to cardiovascular morbidity and mortality in hypertensive patients. The cardiovascular responses to smoking represent a complex interplay between the macrocirculation, microcirculation, autonomic nervous system and multiple vasoactive mediators, including nitric oxide and inflammatory factors. Dalla Vecchia et al. [1] have shown that cigarette smoking has a powerful effect on the microcirculation even in young subjects. Furthermore, they confirm that non-invasive testing of microvascular function may provide new insights into the pathogenesis of cardiovascular disease, insights which may not be evident from more traditional macrocirculation studies. Smoking cessation is probably the single most powerful lifestyle measure for the prevention of cardiovascular events in hypertensive patients [26]. Potential benefits of smoking cessation are similar to those of antihypertensive-treatment [26]. Therefore, while searching for new mechanisms linking smoking to cardiovascular events, we should also focus on more effective programmes for smoking cessation.