High Blood Press Cardiovasc Prev (2015) 22:119–128 DOI 10.1007/s40292-015-0086-3
REVIEW ARTICLE
Interactions Between Macro- and Micro-Circulation: Are They Relevant? Damiano Rizzoni1 • Carolina De Ciuceis1 • Massimo Salvetti1 • Anna Paini1 Claudia Rossini1 • Claudia Agabiti-Rosei1 • Maria Lorenza Muiesan1
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Received: 25 February 2015 / Accepted: 27 March 2015 / Published online: 14 April 2015 Ó Springer International Publishing Switzerland 2015
Abstract Macrovasculature, microvasculature, and the heart are the main determinants of the structure and function of the circulatory system. Due to viscoelastic properties of large arteries, the pulsatile pressure and flow that result from intermittent ventricular ejection are smoothed out, so that microvasculature mediates steadily the delivery of nutrients and oxygen to tissues. The disruption of this function, which occurs when microvascular structure develops, mainly in response to hypertension, leads to endorgan damage. Microvascular structure is not only the site of vascular resistance but probably also the origin of most of the wave reflections generating increased central systolic blood pressure in the elderly. Many data of the literature suggest that hypertension-related damage to the micro and macrovascular system may be corrected by pharmacological agents. Among them, b-blocking agents and diuretics have a negligible effect on microvascular structure, while renin-angiotensin system antagonists and calcium entry blockers have favorable actions, improving large artery mechanics and possibly reducing central wave reflections. Central pulse pressure, indicative of changes in large conduit arteries is an independent determinant of vascular remodelling in small resistance arteries and might represent a main target of antihypertensive treatment. Keywords Antihypertensive therapy Macrocirculation Microcirculation
& Damiano Rizzoni
[email protected] 1
Clinica Medica, Department of Clinical and Experimental Sciences, University of Brescia, c/o 2a Medicina, Spedali Civili, 25100 Brescia, Italy
1 Microvascular Structure in Hypertension Resistance arteries (internal diameter \350 lm) and capillaries (internal diameter \7 lm) are key elements in the control of blood pressure [1]. Thus, structural changes in the microcirculation may directly and strongly affect blood pressure values. In fact, it is now widely accepted that structural abnormalities of microvessels are common alterations associated with chronic hypertension [1, 2]. A thickened arterial wall together with a reduced lumen (a process known as remodelling) may play an important role in the increase of vascular resistance, and may also be an adaptive response to the increased haemodynamic load. In the last few years, several evidences have suggested that hypertensive injury of small arteries may participate also in the pathophysiology of its complications [3]. Hence, the study of structural and mechanical alterations of resistance vessels in essential hypertension, the possibility of their regression with antihypertensive treatment as well as their contribution to the prognosis of patients with essential hypertension should be considered of great clinical and scientific interest. Starting from the late eighties, newer techniques for direct visualization and in vitro examination of the vessels have been developed, allowing a better understanding of vascular remodelling. In particular, a direct investigation of changes in small resistance arteries obtained from subcutaneous and omental fat tissue of essential hypertensive patients has been made possible by using the wire or pressure micromyographic methods [2, 4, 5]. The majority of the available data indicates that, in patients with essential hypertension, the resistance arteries show a greater media thickness, a reduced lumen and external diameter with increased media to lumen ratio, without any significant change of the total amount of wall
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tissue, as indicated by an unchanged media cross sectional area. Therefore, the major part of the structural changes observed in these patients is the consequence of inward eutrophic remodelling (re-arrangement of the same amount of wall material around a smaller vessel lumen) [6], without net cell growth. In contrast, in patients with some forms of more severe hypertension or of secondary hypertension (such as renovascular hypertension and primary aldosteronism) [7] and in diabetic patients [8], the development of hypertrophic remodelling with a more evident contribution of cell growth including vascular smooth muscle cells hypertrophy (volume increase) or hyperplasia (cell number increase) was detected [9]. Experimental studies have indicated that changes of small artery structure in hypertension are the consequence of a dual process of remodelling and growth [6]. However, the molecular events involved in the development of the remodelling processes in systemic hypertension are still poorly understood, and, in particular, the mechanisms leading to eutrophic remodelling are presently uncertain, although changes in the extracellular matrix/integrins might be involved. Also the renin-angiotensin-aldosterone system plays an important pathophysiological role in the development of vascular structural alterations, in particular of hypertrophic remodelling, as documented by the observation performed in small subcutaneous small resistance arteries of patients with pronounced activation of the system [7, 9]. Angiotensin II, the major effector peptide of the renin-angiotensin-aldosterone system, promotes oxidative stress, and has proliferative, pro-inflammatory and proatherogenic activity [2]. Angiotensin II is thus a central player in the development of hypertension and early vascular change. These findings suggest that inhibition of angiotensin II activity has the potential to prevent or reverse vascular remodelling and inflammatory cardiovascular disease. 1.1 Small resistance artery structure and cardiovascular risk An important consequence of the presence of structural alterations in small resistance arteries and arterioles may be an impairment of organ vasodilator reserve [10]. The presence of structural alterations in the microcirculation may represent an important link between hypertension and ischemic heart disease, cerebral damage or renal failure. In fact, a relationship between structural alterations in the subcutaneous small resistance arteries and the occurrence of cardiovascular events, has been previously demonstrated in a population of hypertensive and diabetic patients at a relatively high cardiovascular risk, during a follow up of 5.6 years [11]. The presence of structural alterations in the microcirculation may be considered an important link
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between hypertension and ischemic heart disease, heart failure, cerebral ischemic attacks, and renal failure. It was previously demonstrated that structural alterations in the microcirculation (as indicated by greater values of media to lumen ratio in subcutaneous small resistance arteries) is probably the most powerful predictor of cardiovascular events in a high-risk population of hypertensive patients [11]. In a multivariate Cox regression analysis, microvascular structure and pulse pressure were the only two predictors of cardiovascular events, even when all traditional risk factors were included in the model [11]. The relevant prognostic role of small resistance artery structure has been confirmed in medium cardiovascular risk hypertensive patients cohorts [12, 13]. Also the characteristics of the vascular remodelling seem to matter. For the same values of internal diameter, those subjects who suffered cardiovascular events had a greater media cross sectional area, in comparison with those without cardiovascular events [3]. Therefore, it seems that, for the same size of the vessels explored, a more consistent cell growth (hypertrophic remodelling) means an even worse prognosis. Therefore, smooth muscle cell growth seems to be a less efficient compensatory mechanism of increased blood pressure values compared with eutrophic remodelling [3], with relevant consequence in terms of cardiovascular events. It has been also suggested that alterations in the microcirculation may be involved in the abrupt rise of blood pressure during the early morning hours, which is, in turn, associated to increased incidence of cardiovascular events [14]. More recently, Buus et al. [15] demonstrated a prognostic role of changes of microvascular structure, as evaluated by the media to lumen ratio of subcutaneous small resistance arteries during antihypertensive treatment. This demonstration of the prognostic role of changes in microvascular structure during treatment, independently of the extent of blood pressure reduction, could substantially support the idea to consider microvascular structure as an intermediate endpoint in the evaluation of the benefits of antihypertensive treatment [16]. 1.2 Effect of Treatment on Small Artery Structure Some intervention studies with specific drugs have demonstrated an improvement or even an almost complete normalization of the structure of subcutaneous small resistance arteries with angiotensin converting enzyme (ACE) inhibitors (cilazapril, perindopril, lisinopril), calcium channel blockers (nifedipine, amlodipine, irsradipine), angiotensin II receptor blockers (losartan, irbesartan, candesartan, olmesartan and valsartan) [2, 17, 18]. On the contrary, the b-blocker atenolol and the diuretic
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hydrochlorothiazide were devoid of effects on resistance vessels, despite a blood pressure reduction similar to that observed with ACE inhibitors [2, 17, 18]. More than 300 patients were investigated in these intervention studies, using a reliable and precise micromyographic approach [4, 7, 18]. ACE inhibitors proved to be significantly more effective than the b-blocker atenolol in terms of changes in media to lumen ratio [18]. The same result was obtained comparing dihydropyridinic calcium channel blockers and atenolol, or angiotensin receptor blockers and atenolol [18]. Interestingly enough, when the effects of calcium channel blockers and ACE inhibitors were compared, no significant difference was observed, although a trend to observe a more pronounced effect with ACE inhibitors was present [17]. The comparison between the effects of diuretics and the remaining drug classes was limited by the low number of studies and the heterogeneity of drugs investigated (eplerenone and hydrochlorothiazide). However, diuretics were less effective than ACE inhibitors [17]. Several reasons may be advocated to explain the disparate effects of different drug classes on small artery structure. It is possible that ACE inhibitors and angiotensin receptor blockers possess growth inhibiting and antioxidant properties that may be responsible for their beneficial effect on the microcirculation [2]. Additional possible reasons are the lack of vasodilator properties of b-blockers [19], and the heterogeneous effect of drug treatments on small and large vessels stiffness and distensibility. In one study, performed in hypertensive patients with non-insulin dependent diabetes mellitus [20], brachial pulse pressure (a rough marker of arterial stiffness) was significantly higher in patients than in normotensive subjects before random assignment and it was significantly reduced only by the angiotensin receptor antagonist valsartan, while no change was observed with atenolol. As previously mentioned, vasoconstriction may represent one of the mechanisms leading to eutrophic remodelling as the vasoconstricted state becomes embedded in the newly secreted extracellular matrix. Angiotensin receptor blockers seems also to be particularly effective in reducing vascular stiffness and collagen content in small resistance arteries [21, 22] while stiffness of small arteries (evaluated by the stress-strain relationships) was, in fact, enhanced in patients treated with atenolol [23]. Recently, a significant reduction in small resistance artery stiffness was observed in essential hypertensive patients treated with a selective mineralocorticoid receptors blocker eplerenone, but not in those treated with atenolol [23]. This beneficial effect was associated with a normalization of the media collagen/elastin ratio, thus suggesting that antihypertensive treatment may normalize mechanical alterations also in human small resistance arteries. However, no significant improvement in the media to lumen ratio was observed in the above-
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mentioned study after treatment with eplerenone [23]. The effects of olmesartan on vascular remodelling have been studied in the Vascular Improvement with Olmesartan medoxomil Study (VIOS) [24]. This randomised, parallel group study compared the effects of antihypertensive therapy based on olmesartan or atenolol on vascular remodelling in subcutaneous small resistance arteries nondiabetic patients with stage I hypertension. After one year of treatment, olmesartan had decreased the wall:lumen ratio from 14.9 to 11.1 %, a value that was similar to that of the control group of normotensive patients (11.0 %). In contrast, atenolol-based treatment did not affect vascular remodelling. Similarly augmentation index, an index of large artery compliance, was improved by olmesartan, but not by atenolol [24]. The effects of a1-adrenergic receptor blockers, such as doxazosin, on subcutaneous small resistance artery structure were never evaluated to date. Similarly, almost all studies have used the b-blocker atenolol as a comparator. No data are available about effects of newer b-blockers, such as nebivolol, bisoprolol or carvedilol, which, theoretically, could have different properties and different effects, compared with atenolol, on hemodynamics lipidic and glycemic metabolisms, on endothelial function, and, possibly, on microvascular structure. In addition, few data are presently available about the effect of antihypertensive treatment on small artery structure in high-risk patients. In patients with complicated hypertension (patients with left ventricular hypertrophy or concomitant diabetes mellitus), a reduction, but not a full normalization of the media to lumen ratio of subcutaneous small resistance arteries could be obtained by effective antihypertensive treatment [17, 18]. In fact, media to lumen ratio remained significantly higher in respect to what observed in normotensive controls.
2 Mechanical Properties of Large Arteries in Hypertension Arterial stiffness plays a key role in the pathophysiology of the cardiovascular system. During systole, the left ventricle increases the pressure in large vessels, that, due to their elastic properties, may store a significant part of the left ventricle ejection volume [25]. After the closure of the aortic valve, the recoil of the large vessels to their diastolic dimensions pushes the blood towards the periphery. This mechanism allows to reconcile the intermittent contraction of the left ventricle with the permanent need of tissues for oxygen and nutriments [25]. This phenomenon is quantitatively larger in healthy and younger subjects [26]. Arterial compliance favours left ventricular function as it reduces left ventricular workload, and enhances diastolic
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perfusion, crucial to the delivery of blood to the myocardium through the coronary vessels. As the propagation of the pressure wave in elastic tubes occurs at a definite velocity, it is possible to measure arterial stiffness through the pulse wave velocity (PWV). Aortic stiffness is approached by the carotid to femoral PWV (normal values: \10 m/s) [27, 28]. In addition, the pressure wave can reflect from the peripheral vasculature (branching, resistance sites, stenosis), and return towards the heart [25]. When stiffness is high, the returned wave may add to the ejection pressure. In physiological conditions, the reflected pressure wave returns in diastole, explaining why the systolic and pulse pressures measured close to the heart (central blood pressure) is lower than at the periphery [29]. Age and blood pressure are the two major determinants of increased arterial stiffness [25, 30]. Molecular determinants of arterial stiffness are related to the fibrotic components of the extracellular matrix, mainly elastin, collagen and fibronectin. Increased arterial stiffness was consistently observed in conditions such as hypertension, dyslipidemia and diabetes [25]. As blood vessels become stiffer because of age-related processes, the pulse wave is transmitted more rapidly and returns to the heart during left ventricular contraction, resulting in a greater augmentation of the central aortic systolic pressure. It is therefore possible to quantify this effect through the calculation of the augmentation index. Alterations in the mechanical properties of large arteries have a clear pathophysiological link with clinical outcome. In addition to being a measure of the cumulative influence of identified and unidentified cardiovascular risk factors on target organ damage, changes of large artery phenotype may be causative in the pathogenesis of cardiovascular events [25]. An expert consensus document on arterial stiffness has been previously published [27]. In this document, more than 11 longitudinal studies have been listed demonstrating that a simple measure of aortic stiffness through carotid-femoral PWV yielded prognostic values beyond and above traditional risk factors [27], and this was recently confirmed in a large meta-analysis [31]. In addition, increased aortic augmentation index is associated with coronary artery disease [29]. Central pressures also correlate with cardiovascular risk not only in patients with atherosclerotic disease but also in apparently healthy subjects. The late systolic augmentation of the central pressure waveform is associated with an increase in left ventricular mass index independent of age and mean blood pressure [29] and carotid systolic blood pressure is an independent determinant of left ventricular wall thickness. Moreover, central pressure is also more closely related than brachial pressure to other important cardiovascular intermediate end points, such as vascular hypertrophy, extent of carotid atherosclerosis, and ascending aorta diameter [29].
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As mentioned, an increased stiffness of the aorta and large arteries leads to an increase in pulse pressure through a reduction in arterial compliance and effects on wave reflection. A number of factors are known to influence arterial wall behavior and, therefore, pulse pressure. In addition to the effects of aging and blood pressure on arterial wall elasticity, there is some evidence that atherosclerosis, per se, amplifies these effects. Thus, the relationship between PP and coronary disease may be bidirectional [32].
3 Relationships Between Structural Changes in the Microcirculation and Macrocirculation Due to the viscoelastic properties of large arteries, the pulsatile pressure and flow that result from intermittent ventricular ejection is smoothed out, so that microvasculature mediates steadily the delivery of nutrients and oxygen to tissues [33]. The disruption of this function, which occurs when microvascular structure develops in response to hypertension, leads to end-organ damage. Microvascular structure is not only the site of vascular resistance but also, probably, the origin of most of the wave reflections generating increased central systolic blood pressure in the elderly [33], although the proper location of a reflection site may be elusive [34]. On the other end increased pulsatility of conduit arteries is transmitted to small arteries and may contribute to vascular injury in the resistance vasculature [35]. When the possible prognostic role of small artery remodelling in hypertension was evaluated, only the media to lumen ratio of subcutaneous small arteries and pulse pressure (a rough index of large artery stiffness) entered the model, thus suggesting that, at least in these high risk subjects, structural changes in the microcirculation and alterations on mechanical properties of large arteries are the two most important factors in predicting outcome [11]. Possible relationships between subcutaneous small resistance artery structure and blood pressure values were investigated in a population of more than 200 normotensive subjects and hypertensive patients [36]. Among the most important predictors of small artery structure there were clinic systolic, diastolic and mean blood pressure, 24-h systolic and diastolic blood pressure, and the ratio between pulse pressure and stroke volume, taken as a rough index of large artery compliance (Fig. 1). Recently, possible relationships between indices of large arteries stiffness and media to lumen ratio (M/L) of subcutaneous small resistance arteries have been investigated [37]. M/L ratio was significantly related to brachial systolic blood pressure and pulse pressure (r = 0.36 and 0.31, P \ 0.01, respectively) and to central systolic and pulse
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Fig. 1 Determinants of the structure of resistance-sized arteries in hypertensive patients (n = 130): correlation between pulse pressure/ stroke volume (PP/SV), an index of large artery distensibility and media to lumen ratio of small resistance arteries (M/L). From Ref. [36]
Fig. 2 Pulsatile hemodynamics and microcirculation: evidence for a close relationships in hypertensive patients: univariate correlation between media to lumen ratio (M/L) and carotido-femoral pulse wave velocity (CF-PWV). From Ref. [37]
pressure (r = 0.41 and 0.37, P \ 0.01, respectively). A positive correlation was observed between M/L ratio and carotid-femoral pulse wave velocity (r = 0.45; P \ 0.001) (Fig. 2); this correlation remained statistically significant after adjustment for age and mean blood pressure. M/L ratio was also associated to aortic augmentation index (r = 0.33; P = 0.008), and this correlations remained statistically significant after adjustment for potential confounders. Large artery stiffening was also demonstrated to be related to cerebral lacunar infarctions [38], or to large white matter hyperintensities [39] which are usually expression of cerebral microvascular disease. Elderly subjects with high intracranial pulsatility display smaller brain volume
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and larger ventricles, supporting the notion that excessive cerebral arterial pulsatility harms the brain [40]. Pulse pressure and pulse wave velocity, markers of arterial stiffness, have been associated with stroke, dementia, and lowered levels of cognitive function, and it was suggested that aggressive treatment of risk factors associated with greater arterial stiffness may help preserve cognitive function with individuals’ increasing age [41]. Also pulsatility index was associated with lower memory scores and worse performance on tests assessing executive function. When magnetic resonance imaging measures (grey and white matter volumes, white matter hyperintensity volumes and prevalent subcortical infarcts) were included in cognitive models, haemodynamic associations were attenuated or no longer significant, consistent with the hypothesis that increased aortic stiffness and excessive flow pulsatility damage the microcirculation, leading to quantifiable tissue damage and reduced cognitive performance. Marked stiffening of the aorta is associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains [42]. Middle cerebral artery pulsatility was also demonstrated to be the strongest physiological correlate of leukoaraiosis, independent of age, and was dependent on aortic diastolic blood pressure and pulse pressure and aortic and middle cerebral artery stiffness, supporting the hypothesis that large artery stiffening results in increased arterial pulsatility with transmission to the cerebral small vessels resulting in leukoaraiosis [43]. Therefore, it seems that a close relationship has been established between microvascular damage in brain and kidney and indices of age and hypertension (pulse pressure, aortic pulse wave velocity, and augmentation index) [44]. A possible pathophysiological explanation of this link can be offered on the basis of differential input impedance in the brain and kidney, compared with other systemic vascular beds: torrential flow and low resistance to flow in these organs expose small arterial vessels to the highpressure fluctuations that exist in the carotid, vertebral, and renal arteries. Such fluctuations, measurable as central pulse pressure, increase three- to fourfold with age. Exposure of small vessels to highly pulsatile pressure and flow explains microvascular damage and resulting renal insufficiency and intellectual deterioration [44]. Therefore, the logical approach to prevention and treatment requires reduction of central pulse pressure [43]. Because the aorta and large arteries are not directly affected by drugs, this entails reduction of wave reflection by dilation of conduit arteries elsewhere in the body [43]. This can be accomplished by regular exercise and by drugs such as nitrates, calcium channel blockers, angiotensin-converting enzyme
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inhibitors, and angiotensin receptor blockers [44]. This hypothesis may account for greater and earlier vascular damage in diabetes mellitus (relative microvascular fragility) and is similar to that given for vascular changes of pulmonary hypertension caused by ventricular septal defects and other congenital vascular shunts [44]. In summary, loss of cognitive function and hypertension are two common conditions in the elderly and both significantly contribute to loss of personal independency. Microvascular brain damage—the result of age-associated alteration in large arteries and the progressive mismatch of their crosstalk with small cerebral arteries—represents a potent risk factor for cognitive decline and for the onset of dementia in older individuals [45]. Recently, a non-invasive approach for the evaluation of retinal arteriolar morphology (Scanning laser Doppler flowmetry) was proposed [46] and validated [47]. The wall to lumen ratio of retinal arteries (evaluated non-invasively), is strongly correlated with the gold standard measurement of the media to lumen ratio of subcutaneous small arteries, obtained with locally invasive bioptic techniques (wire micromyography) [47]. Using this non-invasive approach, Ott et al. [48] could very recently demonstrate that wall to lumen ratio of retinal arterioles correlated with central pulse pressure, central augmentation index normalized and pulse pressure amplification (peripheral pulse pressure/central pulse pressure). Multiple regression analysis revealed an independent relationship between wall to lumen ratio and central pulse pressure, but not with other classical cardiovascular risk factors. Even more recently, using the same technique, it was demonstrated that wall to lumen ratio of retinal arterioles was significantly related to clinic systolic and pulse pressure, to 24-h systolic and pulse pressure, and to central systolic and pulse pressure [49]. In addition, a significant correlation was observed between wall to lumen ratio of retinal arterioles and carotid-femoral pulse wave velocity (Fig. 3) [49]. Thus, central pulse pressure, indicative of changes in large conduit arteries, is an independent determinant of vascular remodelling in small retinal arterioles [48, 49]. Such a relationship indicates a coupling and crosstalk between the microvascular and macrovascular changes attributable to hypertension [50]. In fact, increased wall to lumen ratio and rarefaction of small arteries are major factors for an increase in mean blood pressure; then the higher mean blood pressure, in turn, may increase large artery stiffness through the loading of stiff components of the arterial wall at high blood pressure levels; finally the increased large artery stiffness may be a major determinant of the increased pulse pressure, which, in turn, damages small arteries in different organs (heart, brain, retina,
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Fig. 3 Correlation between wall to lumen ratio of retinal arterioles (WLR) and carotido-femoral pulse wave velocity (PWV). From Ref. [49]
Target organ damage - Myocardial ischemia - Reduction in GFR - Microalbuminuria - White matter lesions
Small artery remodelling wall/lumen ratio and rarefaction
Target organ damage - LVH - Carotid IMT - Plaque rupture
central PP
mean BP
arterial stiffness Large artery remodelling
Fig. 4 Large/small artery cross talk in hypertension. From Ref. [50]
kidney) and, in general, favors the development of target organ damage [50]. Thus, the cross-talk between the small and large artery exaggerates arterial damage, following a vicious circle [50] (Fig. 4).
4 Targeting Central Blood Pressure As previously mentioned, some intervention studies have demonstrated an improvement or even an almost complete normalization of the structure of subcutaneous small resistance arteries with angiotensin converting enzyme
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(ACE) inhibitors (cilazapril, perindopril, lisinopril) [18], calcium channel blockers (nifedipine, amlodipine, isradipine) [18], angiotensin II receptor blockers (losartan, irbesartan, candesartan and valsartan) [18]. On the contrary, the b-blocker atenolol and the diuretic hydrochlorothiazide were devoid of effects on resistance vessels and on brachial pulse pressure, despite a blood pressure reduction similar to that observed with ACE inhibitors [18]. In one of these studies, performed in hypertensive patients with non-insulin dependent diabetes mellitus [20], brachial pulse pressure was significantly higher in patients than in normotensive subjects before random assignment and it was significantly reduced only by the angiotensin AT1 receptor antagonist valsartan, while no change was observed with atenolol. Valsartan acts as a vasodilator through inhibition of the vascular effects of angiotensin II, whereas the beta blocking agent atenolol may induce vasoconstriction and may reduce blood flow. In addition, under atenolol the ‘‘downstream’’ increase in impedance at the level of the remodeled arteries may cause early reflected waves and an ‘‘upstream’’ increase in transmural pressure at the level of central elastic arteries that may lead to increased SBP and arterial stiffness. Although during the study blood pressure was equally well controlled in both groups, at the end of the study brachial systolic blood pressure was 5 mmHg higher in the atenolol than in the valsartan group. As previously mentioned, valsartan but not atenolol reduced brachial pulse pressure, a marker of arterial stiffness in the presence of preserved ejection fraction [20]. Stiffness of small arteries (evaluated by the stress-strain relationships) was, in fact, enhanced in patients treated with atenolol, probably due to changes in extracellular matrix associated with hypertension [51] and a similar change may have also occurred in large arteries [20]. This may explain differences in brachial systolic blood pressure and also different effects of the drugs on small artery remodelling at the end of the study. Antihypertensive treatment with angiotensin converting enzyme (ACE) inhibitors, angiotensin-receptor blockers and calcium channel blockers was effective also on arterial stiffness and wave reflections [52, 53]. Similarly to what observed in microcirculation, diuretics and atenolol had fewer effect on pulse wave velocity, carotid stiffness, and wave reflections. The effects of antihypertensive treatment with angiotensin converting enzyme (ACE) inhibitors on arterial stiffness and wave reflections were investigated by evaluation of brachial and carotid systolic blood pressure and pulse pressure (indirect indices of arterial stiffness) in the REASON Study (preterax in REgression of Arterial Stiffness in a contrOlled double-bliNd study) [54] and further firmly confirmed [55]. The REASON Study was a controlled trial that compared the b-blocking agent atenolol
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to a low dose combination of the diuretic indapamide with the ACE inhibitor perindopril. After 1 year, for the same diastolic blood pressure reduction, the combination of perindopril and indapamide induced a more pronounced reduction of brachial (peripheral artery) and carotid (central artery) systolic blood pressure or pulse pressure than atenolol [54]. The more evident reduction of central pulse pressure induced by the combination perindopril-indapamide was associated to a more pronounced reduction of cardiac mass [56]. The two drug regimens induced the same aortic PWV reduction as a result of the comparable decreases of mean or diastolic arterial pressures [33]. The major difference between the two therapeutic approaches was that perindopril/indapamide but not atenolol reduced carotid augmentation index, a reliable marker of carotid wave reflections [33]. Several mechanisms may be involved in the observed differences between the two therapeutic approaches. The atenolol-induced heart rate decrease may have caused the maintenance of disturbed wave reflections [33], since it has been previously demonstrated that a slow heart rate can also affect PWV and augmentation of central aortic systolic pressure [33]. It is possible that perindopril, but not atenolol, may have improved micro and macrovascular structure, by preventing structural alterations at different levels. In addition, ACE inhibitors, but not atenolol, are known to reduce reflection coefficients [33], thus reducing the reflection of waves from the microcirculation toward large arteries. In the CAFE study (Conduit Artery Function Evaluation) [55], the different effects of atenolol/hydrochlorotiazide and amlodipine/perindopril on central blood pressure accounted probably for a significant part of the different effect on cardiovascular outcome observed in the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial), in which an advantage of the combination ACE inhibitorcalcium channel blocker was clearly observed. In fact, amlodipine/olmesartan could have been more effective than atenolol/hydrochlorotiazide both on microvascular damage and on augmentation index/large artery compliance [55]. A more pronounced and favourable effect of calcium channel blockers, diuretics and ACE inhibitors compared with b-blockers on central aortic systolic blood pressure or central augmentation pressure was also observed by Morgan et al. [57].
5 Conclusion In conclusion, there is hardly any doubt that cardiovascular events are the consequence of vascular damage at both the macro and microcirculatory level. The relationship between large stiffening artery and microvascular disease
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may be bidirectional, since wave reflection from microvascular sites could increase systolic blood pressure and pulse pressure, while transmission of increased arterial pulsatility to microvessels could represent a mechanism of damage. Therefore, both central blood pressure and microvascular structure represent targets of hypertensive treatment, since reduction of central blood pressure is associated with an improved prognosis, while drugs acting on smooth muscle of distributing arteries, might induce a relaxation that has little effect on peripheral resistance but may cause substantial reduction in the magnitude of wave reflection [58]. In addition to vasodilating drugs, frequently used in the treatment of hypertension and cardiac failure, also regular exercise could be useful in this regard [58]. Thus, interrelationships between alterations in the macro and microcirculation and mechanisms possibly involved represent an extremely interesting topic, which deserve further and thorough investigation, also considering its relevant clinic impact, especially in terms of therapeutic targets and possible prevention or regression of such alterations.
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