The pulsatile component of blood pressure – Its role in the pathogenesis of atherosclerosis

Abstract

Pulse pressure (PP) is traditionally believed to increase cardiovascular risk because of an increase in afterload leading to left ventricular hypertrophy. It has also been emphasized that low diastolic blood pressure, being in part responsible for high PP, leads to an impairment of myocardial perfusion with all its adverse consequences. More recently, however, a direct role of pulsatile blood pressure changes in the pathogenesis of atherosclerosis and its complications has become better known. Experimental studies indicate that there is a cause‐and‐effect type of relationship between the pulsatile component of blood pressure and atherosclerotic process. A significant relationship between the parameters of the pulsatile blood pressure component and the extent of coronary atherosclerosis was also demonstrated. Currently the presence of a bidirectional link between atherosclerosis and PP is commonly postulated, meaning that an increased PP may be both a cause and an effect of atherosclerosis. This may result in a vicious circle wherein the pulsatile blood pressure component induces/enhances the development of atherosclerosis, which in its turn reduces the arterial compliance and enhances pulse wave reflection, thereby leading to an increase in PP. Currently new drug classes are being investigated, which might reduce the pulsatile blood pressure component without changing mean blood pressure level. Their clinical usefulness should become known over the next few years.

• Atherosclerosis
• blood pressure
• coronary artery disease
• hypertension
• pulsatility

Introduction

Hypertension is one of the major risk factor for cardiovascular and all‐cause mortality in the world. In an analysis published in 2005, high blood pressure was found to be the most important risk factor for morbidity and mortality in the general European population as well as in Central and Eastern Europe [1]. The above may be related to a high prevalence of hypertension on one hand, and, on the other hand, to a strong association between blood pressure level and the risk of death. There is also a need to emphasize that most people with hypertension die because of complications of atherosclerosis.

First epidemiological studies on hypertension have shown a significant relationship between diastolic pressure and cardiovascular risk [2]. Because of that, it was diastolic blood pressure that early became the primary target of hypertension diagnosis and treatment [2]. It was only in late 1980s when the view became widely accepted that increased systolic blood pressure causes a similar, if not bigger, increase in the risk of cardiovascular complications when compared with diastolic blood pressure [2]. Although many studies have demonstrated the independent link between pulse pressure (PP) and cardiovascular risk [2], [3], there have been some which have not confirmed it, in particular in younger age groups [4]. Currently systolic blood pressure is believed to be the most useful of blood pressure parameters in predicting cardiovascular risk [5].

Steady and pulsatile components of blood pressure

Two main components of blood pressure can be distinguished: the steady and pulsatile component [6]. The former is represented by mean arterial pressure and it depends mainly on the cardiac output and on peripheral resistance [6]. The pulsatile component is determined by many factors, most importantly by stroke volume of the left ventricle, heart rate, compliance of large arteries and the reflection of the pulse wave from arterial bifurcations and resistance arterioles [6]. Systolic blood pressure and PP both increase with age, which is mainly due to the increase in the stiffness of the wall of large arteries, leading to a reduced buffering of blood pressure oscillations by the aorta (Windkessel mechanism) and an accelerated return of reflected pulse wave. Recently, additional mechanism of the PP increase with age has been suggested in older subjects, i.e. higher energy of the reflected wave.

PP is traditionally believed to represent the pulsatile component of blood pressure [6]. However, PP was shown to be significantly correlated with mean arterial pressure (Figure 1), which confirms that, apart from being an index of cyclic, within‐beat variations of blood pressure, PP contains also some information on the absolute blood pressure level [7], [8]. On the other hand, it was demonstrated that pulsatility (PP divided by mean blood pressure) and pulsatility index (PP divided by diastolic blood pressure) are not correlated with mean arterial pressure [7], [9], which indicates that these parameters may be devoid of the information on absolute blood pressure level. Importantly, these two indices have no units (being ratios). Indeed, while PP represents absolute changes in blood pressure, pulsatility and pulsatility index are related rather to relative changes. This observation may be of particular relevance in studies on the pathogenesis of atherosclerosis and its complications.

Figure 1 Correlation between mean arterial pressure and pulse pressure, pulsatility and pulsatility index[9].

Pulsatile component of blood pressure and the pathogenesis of atherosclerosis

The mechanism traditionally considered responsible for the association between PP and cardiovascular morbidity and mortality is related to an increased afterload of left ventricle, which leads to its hypertrophy [6]. Left ventricular hypertrophy may in turn cause left ventricular diastolic dysfunction and, subsequently, lead to cardiovascular death. It is also an established fact that left ventricular hypertrophy is related to a higher risk of life‐threatening arrhythmias [10]. On the other hand, an increased PP is in part (if the level of systolic blood pressure is constant) a result of low diastolic blood pressure. Since the myocardial perfusion occurs predominantly in diastole, low diastolic blood pressure leads to low perfusion pressure and, as a consequence, to a reduced blood supply to the myocardium with all its adverse consequences [8]. The involvement of neurohormonal mechanisms (mainly an increased activity of the adrenergic system) in the pathogenesis of cardiovascular complications is also postulated in subjects with low diastolic blood pressure [11]. Recently, the evidence has been accumulating that pulsatile blood pressure component has a direct influence on the development of atherosclerosis and its complications [6], [8].

Blood vessels are exposed to two kinds of mechanical forces. One of them is shear stress and the other is the cyclic strain of the vascular wall, which, according to the Laplace's law, is mainly determined by cyclic change of blood pressure [12]. While shear stress affects predominantly endothelial cells, blood pressure changes (and the resulting changes in arterial wall tension) influence all structures of the arterial wall. These changes in the intramural tension have recently been recognized as an important factor in the pathogenesis of atherosclerosis [13], [14]. Recent studies have shed some light on the mechanisms of transduction of mechanical stimuli to biochemical signals that lead to changes in cellular function and morphology [13], [14]. It was shown that cyclic changes in intramural tension (corresponding to cyclic changes in blood pressure) may lead to different changes in endothelium and vascular musculature than constant pressure in the vessel lumen does [15], [16]. Cyclic strain may also cause proliferation of vascular smooth muscle cells as well as an increased production of elastin, collagen and glycosaminoglycans, which may in turn lead to an increase in atherosclerotic plaque volume [12], [13], [17]. Smooth muscle cells proliferation is stimulated among others by insulin‐like growth factor (IGF), platelet‐derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), the production of which depends in part on cyclic changes of wall tension [18]. Evidence is also available that expression of PDGF [one of the main factors stimulating migration and proliferation of smooth muscle cells in the vascular wall [18]] is increased by elevated blood pressure [19]. Cyclic strain leads also to the activation of α‐receptor for PDGF [13], [20].

Cyclic strain initiates cell proliferation also directly, without cytokine mediation [21]. These forces open gadolinium‐sensitive calcium channels, leading to an increase in intracellular calcium concentration [13], [18]. They also increase the activity of protein C kinase [13], [22]. The information on cyclic strain is also transduced into the cells by means of transmembrane proteins (integrins) activation, in particular of integrin β₁ and β₃[13], [23]. In some conditions, the changes in wall tension may also induce vascular smooth muscle cells' apoptosis [13], [23], [24]. Moreover, cyclic strain stimulates the expression of adhesion molecules in the endothelial cells, which facilitates the migration of inflammatory response cells into the vascular wall [25]. Sakamoto et al. [26] have shown that cyclic strain (at 1 Hz frequency) increases the production of scavenger receptors, thereby facilitating the transformation of macrophages into foam cells.

The previously discussed effects of cyclic changes in arterial wall tension depend in part on the changes in gene expression as demonstrated in a number of studies [16], [27], [28]. Such changes in gene expression caused by mechanical factors may also lead to changes in the directions of cell differentiation, which may be of importance in the pathogenesis of atherosclerosis, as well as in mediating plaque instability [14].

In a recently published paper, Kiefer et al. have shown that high PP may be an important factor conditioning the infiltration of arterial wall by lipids [29]. Importantly, in this study, no such relationship was shown for systolic, diastolic or mean arterial pressure [29]. This is further supported by the results published by Tropea et al. who, in an animal model, have demonstrated that cyclic stretch of arterial wall induces development of atherosclerotic lesions, while an elevated mean blood pressure level with a small extent of wall stretch does not accelerate their development [30]. A similar phenomenon occurs in humans, which is illustrated by the fact that intramyocardial coronary arteries are usually free of atherosclerotic lesions despite severe atherosclerosis in epicardial arteries [31]. This is explained by the fact that the intramyocardial arterial wall cells are only modestly stretched during the heart cycle, because the increasing pressure of blood in the artery is counterbalanced by increasing pressure within the contracting myocardium. Therefore, the oscillations of transmural pressure (the difference between pressures in the artery lumen and in the outside tissue) are being buffered, which markedly reduces the damage to the artery wall due to its cyclic stretching. Recently, it has been postulated that elevated PP (an index of pulsatile blood pressure component) is one of the two factors necessary for the development of atherosclerosis alongside low‐density lipoproteins [29], [32].

Cyclic strain and unevenly deformation of atherosclerotic plaque are the main mechanisms leading to plaque rupture [33], [34]. Plaque rupture is in turn the most important and most frequent cause of acute coronary syndromes [12], [34]. It has to be emphasized that plaque rupture is also an important mechanism leading to plaque progression [35]. Interestingly, in studies on subjects who died suddenly, hypertension was not associated with plaque rupture frequency [36–38]. However, these studies were based on autopsy data and thus they could not assess the relationship between the pulsatile blood pressure component and the risk of plaque rupture [36–38]. The above demonstrates that an increased blood pressure may not always be associated with cardiovascular risk by itself. On the other hand, the highest frequency of plaque rupture was observed in men who died during physical exercise, which may confirm the importance of pulsatile blood pressure changes (increased during exercise) in the pathogenesis of acute coronary syndromes [37].

As the cyclic deformation of the plaque is the largest on the border between atherosclerotic plaque and healthy arterial wall, this region is the area most prone to rupture [33], [34]. Moreover, macrophages tend to migrate to this area [12]. Lee et al. have shown a significant correlation between a local cyclic strain and the tissue activity of metalloproteinase‐1 (collagenase) [39], produced by macrophages in response to various factors, including the changes in the strain of tissue were they reside [14], [39]. This suggestion was further confirmed in the study of Yang et al., who demonstrated that monocytes exposed to cyclic strain after only few hours increase several times the synthesis and secretion of metalloproteinase‐1 (collagenase) and metalloproteinase‐3 [40]. The same group of investigators has also observed that collagenase production increases proportionally to the size of strain changes to which the monocytes are exposed [40]. Migration and accumulation of monocytes in the places characterized by largest strain changes is mediated, among other factors, by monocyte chemotactic protein (MCP‐1) secreted by vascular smooth muscle cells and endothelial cells in response to cyclic vascular wall deformation [14], [16]. Ion channels (e.g. potassium channels) opened by cell membrane stretching have been found in the macrophage cell membrane [41]. It is believed that these channels may participate in the transduction of information about the strain changes into the cell [40]. Recently published studies confirm that the change of pressure outside the macrophage may influence the type and quantity of cytokines it secretes and may also stimulate phagocytosis [28], [42].

The role of the pulsatile component of blood pressure in the pathogenesis of coronary heart disease was confirmed by the study of Heidland & Strauer, who reviewed retrospectively the data of 106 patients and analyzed the factors influencing the atherosclerotic plaque progression, their rupture and ulceration within 6 months from the first coronary angiography [43]. Subjects in whom the second coronary angiography revealed a complicated plaque (among the criteria were: at least 25% plaque progression, its ulceration, presence of thrombus) have higher pulsatility during the first procedure (p = 0.07). The multivariate analysis revealed that the pulsatility increase by 1.0 was related to 81% higher risk of complicated plaque [43]. This study has certainly a number of limitations, including low sample size and the problems related to the definition of complicated plaque. Nevertheless, the importance of the pulsatile component of blood pressure in the progression of atherosclerosis was further confirmed by an analysis of the ERA (Estrogen Replacement in Atherosclerosis) trial [44].

The role of pulsatile blood pressure component in the pathogenesis of atherosclerosis was also documented by other studies focusing on the relationship between blood pressure parameters and the extent of coronary atherosclerosis. In these studies, PP, pulsatility and pulsatility index measured invasively in the ascending aorta independently predicted the presence and the extent of atherosclerosis in the coronary arteries [7], [9], [45–49] (Table I). No such correlation was found for mean arterial pressure. A relationship between central PP and the extent of atherosclerotic changes was also seen when PP in the carotid artery was measured non‐invasively [50]. Recently, ascending aortic pulsatility was shown to be related to the extent of coronary atherosclerosis irrespectively of the presence of hypertension [51]. Although central PP was not correlated with coronary atherosclerosis in a group of patients with impaired left ventricular systolic function [52], this finding could probably be attributed to diminished stroke volume in patients with severe atherosclerosis rather than lack of PP–atherosclerosis association.

Table I. Studies assessing the relationship between pulsatile blood pressure component and coronary atherosclerosis.

Study	n	Parameter	Result
Nishijima et al. [45]	293	Central pulsatility	Increase in pulsatility by 0.1 increases the probability of a significant stenosis by 36%
		Peripheral pulsatility	No significant relationship
Nakayama et al. [46]	406	Central fractional diastolic pressure	Increase by 0.1 was associated an the increase in the probability of a significant stenosis by 38%
		Central fractional systolic pressure	No significant relationship
Danchin et al. [47]	280	Central pulsatility	Pulsatility was higher in subjects with coronary heart disease
Jankowski et al. [48]	447	Central pulsatility and pulsatility index	Pulsatility and pulsatility index were higher in subjects with coronary heart disease. In multivariate analysis, the relationship was significant only in women.
Jankowski et al. [7]	445	Central fractional systolic pressure	A significant correlation with the number of stenosed coronary arteries. Probability of three‐vessel disease increased by 28% when parameter increased by 0.1
		Central fractional diastolic pressure	A significant correlation with the number of stenosed coronary arteries. Probability of three‐vessel disease decreased by 39% when parameter increased by 0.1
		Peripheral fractional systolic pressure	No significant relationship
		Peripheral fractional diastolic pressure	No significant relationship
Jankowski et al. [9]	423	Central pulsatility and pulsatility index	A significant correlation with the number of stenosed coronary arteries. Probability of three‐vessel disease increased by 18% when pulsatility increased by 0.1 and by 11% when pulsatility index increased by 0.1
		Peripheral pulsatility and pulsatility index	No significant relationship
Guray et al. [49]	262	Central pulsatility	Increase in pulsatility by 0.1 was associated with an increase in the probability of a significant stenosis by 80% in women

In conclusion, currently there is no doubt as to the existence of significant relationship between the pulsatile blood pressure component and coronary atherosclerosis. When the results of previously cited experimental studies are considered, it has to be assumed, that the cause‐and‐effect relationship between the pulsatile component of blood pressure and coronary atherosclerosis is highly probable. At present, the relationship between large artery compliance and atherosclerosis is believed to be bidirectional [8]. Increased PP may thus be both the cause and the effect of atherosclerosis: on one hand the presence of atherosclerotic changes may impair their elastic properties, while on the other hand a reduced large artery compliance enhances the pulsatile component of blood pressure, which leads to the progression of atherosclerotic changes [8]. These mechanisms may lead to a vicious circle wherein the pulsatile blood pressure component causes/enhances the progression of atherosclerosis, which in turn, through a reduced arterial compliance and an enhanced wave reflection augments the pulsatile blood pressure component [8]. According to this concept, a therapeutic interference with this vicious cycle might improve patients' prognosis.

Predictive value of central PP

The doubts as to the predictive value of PP (especially in the younger age groups) are most likely derived from the fact that PP is conventionally measured at peripheral arteries. The difference between the level of systolic and PP between the aorta and the upper extremity arteries may exceed 20 mmHg in young subjects [53], [54]. Since the values of PP are several times smaller that those of systolic blood pressure, the above difference has proportionally higher impact on the predictive value of PP than is the case for systolic blood pressure.

In recent years, a number of studies were carried out to assess the prognostic value of central PP. Safar et al. studied patients with renal failure and found a significant correlation between PP measured in the carotid artery and the risk of death, but no such relationship for PP measured by sphygmomanometer on the brachial artery could be found [55]. These results have demonstrated (confirming earlier suggestions) that it is central blood pressure that is responsible for serious cardiovascular complications, while this relationship is less evident for peripheral blood pressure. Roman et al. [56], during American Heart Association Congress in 2005, have shown the results of over 3 years' follow‐up of 2662 subjects with no symptoms of cardiovascular disease (48% had diabetes, 54% hypertension). In this group, central PP (estimated from an analysis of peripheral pulse waveform) was an independent predictor of cardiovascular complications [56]. Interestingly, when carotid intima‐media thickness was included in the analysis, peripheral pressure (as well as the parameters of vascular stiffness such as Young modulus or augmentation index) was not related to the occurrence of complications [56]. On the other hand, Dart et al. reported peripheral PP to be superior compared to central PP in predicting outcome in older hypertensive women [57], whereas in the population studied in the CAFE study central PP–major complication risk association was not significantly stronger then peripheral PP–cardiovascular risk relationship [58]. The above studies have used non‐invasive methods to assess central PP. Recently, Chirinos et al. have published the results of an observation of over 300 men with angiographically confirmed coronary heart disease, in whom intra‐aortic pressure was measured invasively at baseline and found that a 10‐mmHg increase of PP in the ascending aorta may be associated with an increase in all‐cause mortality by 15% [59]. However, the authors did not consider in the analyses several important confounders including the extent of coronary atherosclerosis at baseline or the treatment following coronary angiography (percutaneous or surgical revascularization). In particular, the former might have influenced the results, since it has been shown that subjects with advanced atherosclerosis have higher intra‐aortic PP [7–9], [49]. Finally, in the Aortic Blood Pressure and Survival (ABPS) study, in 1112 subjects with confirmed or suspected coronary heart disease who were followed for over 4.5 years, the pulsatile component of blood pressure measured in the ascending aorta was the most important predictor of cardiovascular complications after adjusting for potential confounders (unpublished data of the authors of the review).

Summary

Over recent years, the pulsatile component of blood pressure was shown to be related to the pathogenesis of atherosclerosis development and progression. Its role in the pathogenesis of complications of atherosclerosis such as myocardial infarction or stroke has also been documented. Still, the results of cohort studies published so far are not unequivocal, which may be due to the fact that peripheral rather than central blood pressure parameters were evaluated in most studies. The studies in which central blood pressure was measured prove beyond all doubt that in high cardiovascular risk patients, the parameters characterizing the pulsatile blood pressure component (PP, pulsatility, pulsatility index) are better predictors of cardiovascular complications than mean arterial pressure level. Recently, in a consensus document, experts advised against using brachial PP as a surrogate for central PP [60]. Currently, new drug classes are being investigated, which might reduce the pulsatile blood pressure component without influencing mean arterial pressure. One of these classes is called AGE (advanced glycation end‐products) cross‐link breakers, which increase arterial compliance [61]. Alagebrium (a drug from this class) was showed to increase arterial compliance, reduce PP and pulsatility [61]. The study of these drugs in large clinical trials might help testing the hypothesis that a reduction of pulsatile blood pressure parameters such as pulsatility or pulsatility index improves prognosis.