Macro and microvasculature in hypertension: therapeutic aspects

(2008) 22, 590 595 & 2008 Macmillan Publishers Limited All rights reserved 0950-9240/08 $30.00 www.nature.com/jhh REVIEW Macro and microvasculature in hypertension: therapeutic aspects ME Safar 1, D Rizzoni 2, J Blacher 1, ML Muiesan 2 and E Agabiti-Rosei 2 1 Faculty of Medicine, Diagnosis and Therapeutic Center, AP-HP, Hôtel-Dieu Hospital, Paris Descartes University, Paris, France; 2 Clinica Medica, Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy Macrovasculature, microvasculature and the heart determine the structure and function of the circulatory system. 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 the delivery of nutrients and oxygen to tissues steadily. 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 the origin of most of the wave reflections generating increased central systolic blood pressure (SBP) in the elderly. Nowadays many data of the literature suggest that hypertension-related damage to the micro and macrovascular system may be manageable through pharmacological agents. Among them, b-blocking agents and diuretics poorly modify microvascular structure, whereas angiotensin and calcium entry blockade has an opposite effect, thereby reducing central wave reflections and, finally, causing a selective SBP reduction. (2008) 22, 590 595; doi:10.1038/jhh.2008.43; published online 29 May 2008 Keywords: anti-hypertensive therapy; macrovasculature; microvasculature Introduction The heart and the vasculature determine the haemodynamics of the circulatory system. As the blood progresses through the arterial tree towards the periphery, the pulsatile pressure and its consequences that result from the intermittent ventricular ejection of the blood in the macrocirculation are smoothed out, thereby allowing a steady oxygen flow to the tissues (microcirculation). The blood pressure (BP) curve has two components: the constant mean arterial pressure (MAP), a measure of cardiac output and vascular resistance, and the pulse pressure (PP), a measure of the pressure fluctuations, the elasticity of large arteries, and the timing, velocity (pulse wave velocity, PWV), and the intensity of the arterial wave reflections. PP and mostly systolic blood pressure (SBP) vary across the arterial tree and increase peripherally with the decline in artery diameter, the increase in arterial stiffness and the transit of wave reflections. 1,2 Anti-hypertensive therapy largely prevents the cerebral and renal complications of hypertension as Correspondence: Professor ME Safar, Centre de Diagnostic et de Thérapeutique, Hôtel-Dieu, 1, Place du Parvis Notre-Dame, 75181 Paris Cedex 04, France. E-mail: Michel.Safar.Hotel-Dieu.Paris@wanadoo.fr Received 28 January 2008; revised 17 March 2008; accepted 8 April 2008; published online 29 May 2008 well as the development of congestive heart failure. The prevention of coronary ischaemic disease is more difficult to obtain. This aspect is important to consider because, during chronic treatment, it is difficult to normalize SBP (o140 mm Hg) and much easier to control adequately diastolic blood pressure (DBP) (o90 mm Hg). 3 This aspect is important to consider because, in the absence of treatment, two kinds of hypertension are usually defined: systolic (X140 mm Hg) diastolic (X90 mm Hg) hypertension in the middle age; systolic (X140 mm Hg) hypertension in older subjects, particularly in subjects with low (p90 mm Hg) DBP. International guidelines consider that the normalisation of SBP is nowadays a priority of anti-hypertensive drug therapy. This situation requires to fully investigate the principal pathophysiological mechanisms explaining increased SBP within large and small arteries. Our working hypothesis, in this editorial review, involves the following three propositions: (1) disturbed stiffness and wave reflections, which affect mainly the hypertensive large arteries (macrocirculation), are the two major factors determining SBP, mainly in subjects with systolic hypertension in the elderly, in the absence of heart failure, (2) wave reflections develop particularly at the site of arteriolar bifurcations, which are the major site of the structural arteriolar changes observed in the hypertensive microcirculation, and (3) it is expected that the reversibility of arteriolar structural changes

may be a major pre-requisite to obtain a selective reduction of SBP in subjects treated for hypertension. This editorial involves in hypertensive subjects two different descriptions: structure and function of the microcirculation; macrocirculation and control of SBP and PP under treatment. Note that the classical and arbitrary limit between macro and microvessels corresponds to an internal arterial diameter of 400 mm. Myogenic tone, which operates at the intersection of macro and microvasculature and is at the origin of organ autoregulation, will be considered as out of the scope of this review. Structure and function of the microvasculature in hypertension Vascular resistance and MAP are the main haemodynamic components that are determined by the microvasculature. The increase in MAP observed in subjects with hypertension of the middle age is known to be largely due to an increase in vascular resistance, causing a parallel increase in both SBP and DBP. As a consequence of the Poiseuille s law, increase in vascular resistance is considered to be the principal haemodynamic hallmark of hypertension. 4 Studies performed in animals and humans have determined that in response to the chronic increase in resistance, cells of the arteriolar vessels adapt structurally and functionally. Not only is the extracellular material re-arranged, but also the smooth muscle cells, which get activated, may migrate and proliferate. Together, these two events alter the thickness of the vascular wall. The overall result is a reduction in the calibre of small arteries and arterioles with an increase in the wall to lumen ratio. 4 Basic concepts on the hypertensive microvasculature Resistance vessel structure is a difficult quantity to measure. In vitro studies of isolated resistance vessels have the advantage of precise measurements of vascular dimensions without fixation artifacts. If measurements are confined to an evaluation of the ratio of wall thickness to lumen diameter ( wall: lumen ratio ), or, with measurements of tunica media thickness ( media:lumen ratio ), by general agreement this parameter is increased in hypertension, at least in the more proximal resistance vessels (internal diameter between 400 and 100 mm). In fact, the ratio between media thickness and internal diameter is considered, at present, the most reliable indicator of microvascular structure, as it is independent from vessels dimensions. In the past two decades, the presence of structural alterations in subcutaneous and omental small resistance arteries dissected from biopsies performed in essential hypertensive patients has been confirmed with a direct investigation using the micromyographic method. 4 In fact, patients with essential hypertension show the presence of an increased tunica media to lumen ratio, without any relevant increase of the total amount of wall tissue, as indicated by a media cross-sectional area similar to that observed in normotensive controls. The major part of the structural changes observed in essential systolic diastolic hypertension is the consequence of eutrophic remodelling (re-arrangement of the same amount of wall material around a narrowed lumen), without net cell growth. On the contrary, in patients with some forms of secondary hypertension (renovascular hypertension and primary aldosteronism), or diabetes mellitus a more evident contribution of cell growth, leading to the development of hypertrophic remodelling (vascular smooth muscle cell hypertrophy or hyperplasia), may be usually observed. It is now therefore widely accepted that structural abnormalities of microvessels are common alterations associated with chronic hypertension. 4 It has been proposed that this section of the arterial tree may be important in the development of hypertension, and may also contribute to its complications. However, interrelationships between BP and vascular structure are complex. At present there is no clear evidence about the possible role of vascular structural changes in initiating hypertension. It has been proposed that structural alterations in the resistance vasculature may act as a vascular amplifier, able to enhance the effects of any hypertensive stimulus, 5, but there is also some disagreement about this amplifier hypothesis. 6 A complex interplay between vascular structure and function as well as neurohumoral factors may be postulated. 7 Also the time course of the development of changes in morphological and mechanical aspects of resistance arteries in hypertension may be described but remains partially unclear. 8 Microvasculature and hypertensive CV risk A significant correlation between media to lumen ratio of subcutaneous small resistance arteries and SBP, DBP and MAP has been observed in a relatively large population of normotensive subjects and hypertensive patients. 8 Similar results were obtained in a small number of patients with and without left ventricular hypertrophy. 9 Recently, we have investigated possible relationships between subcutaneous small resistance artery structure, and BP values in a population of more than 200 normotensive subjects and hypertensive patients. Among the most important predictors of small artery structure there were clinic SBP, DBP and mean BP, 24-h SBP and DBP, and the ratio between the PP and stroke volume, taken as an indirect index of large artery distensibility (Figure 1; D Rizzoni and E Agabiti-Rosei, unpublished data). 591

592 M/L 0.30 0.25 0.20 0.15 0.10 0.05 0.00 Spearman correlation coefficient: 0.23, p=0.008 n=130 0 0.5 1 1.5 2 2.5 PP/SV Figure 1 Correlation between pulse pressure/stroke volume (PP/SV) ratio and media to lumen ratio of subcutaneous small resistance arteries (M/L) (D Rizzoni, unpublished data). and so on, did not enter the model. The relevant prognostic role of small resistance artery structure has been recently confirmed in a medium-risk hypertensive patients cohort. 12,13 We have also re-evaluated our prognostic data taking into account also the characteristics of the vascular remodelling. For the same values of internal diameter, those subjects who suffered CV events had a greater media-cross-sectional area, in comparison with those without CV events 14 (Figure 2). Therefore, it seems that, for the same size of the vessels explored, a more consistent cell growth (hypertrophic remodelling) means an even worse prognosis. It has also been recently proposed that alterations in the microcirculation may be involved in the abrupt rise of BP during the morning hours, which is, in turn, associated with increased incidence of CV events. 15 Figure 2 Possible role of hypertrophic remodelling in the occurrence of cardiovascular events in high-risk patients. 14 For any value of internal diameter, subjects and patients with cardiovascular events have a greater media cross-sectional area (MCSA) compared to those without cardiovascular events. Regardless of the presence or absence of a causal relationship between small artery structure and hypertension, 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 ischaemic 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 (CV) events, has been previously demonstrated in a relatively large population during a follow up of 5.6 years. 11 In this study the media to lumen ratio of subcutaneous small resistance arteries represented, together with clinic PP, the most potent predictor of CV events in a relatively high-risk population. 11 Brachial PP (macrovasculature) and media to lumen ratio of subcutaneous small arteries (microvasculature) were found to be significantly associated with the occurrence of CV events (Cox proportional hazard model). Other CV risk factors, including age, gender, cholesterol levels, left ventricular mass Microvasculature and chronic anti-hypertensive drug therapy According to the previously mentioned observations, the possible regression of vascular alterations in small resistance arteries of subjects with systolic diastolic hypertension is an appealing goal of antihypertensive treatment. Some intervention studies have demonstrated an improvement or even an almost complete normalisation of the structure of subcutaneous small resistance arteries with angiotensin converting enzyme (ACE) inhibitors (cilazapril, perindopril (Per) and lisinopril), 9,16,17 calcium channel blockers (nifedipine, amlodipine and irsradipine) and 16,17 angiotensin II receptor blockers (losartan, irbesartan, candesartan and valsartan). 16 18 On the contrary, the b-blocker atenolol and the diuretic hydrochlorothiazide had lesser effects on resistance vessels and on brachial PP, despite a BP reduction similar to that observed with ACE inhibitors. 16,17 Such findings are widely observed in systolic diastolic hypertension but have been poorly investigated in subjects with systolic hypertension, mainly when DBP is low (o90 mm Hg). In one of these studies, performed in hypertensive patients with non-insulin-dependent diabetes mellitus, 18 brachial PP 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, whereas no change was observed with atenolol. Brachial PP was correlated with age, duration of diabetes and hypertension. According to the authors of the study, 18 differences in haemodynamic actions could contribute to the heterogeneous impact of these drugs on small artery structure. Vasoconstriction may represent one of the mechanisms leading to eutrophic remodelling as the vasoconstricted state becomes embedded in the newly secreted extracellular matrix. Therefore, vasodilation rather than specific actions of the

anti-hypertensive agents used could be involved in the correction of eutrophic remodelling. 19 Valsartan acts as a vasodilator through inhibition of the vascular effects of angiotensin II, whereas the b- 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 remodelled 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 BP was equally well controlled in both the groups, at the end of the study brachial SBP was 5 mm Hg (P ¼ NS, not significant) higher in the atenolol than in the valsartan group. As previously mentioned, valsartan but not atenolol reduced brachial PP, a marker of arterial stiffness in the presence of preserved ejection fraction. 1,2 Stiffness of small arteries (evaluated by the stress strain relationships) was, in fact, enhanced in patients treated with atenolol, and a similar change may have also occurred in large arteries. 18 This may explain differences in brachial SBP and also different effects of the drugs on small artery remodelling at the end of the study. It should however be mentioned that no correlation was observed between changes in brachial PP and changes in vascular structure when all the available studies are considered together (D Rizzoni and E Agsbiti-Rosei, unpublished data). There is, in any case, a dissociation between control of brachial BP and effects on vascular structure, as there was no difference in brachial BP-lowering effect between effective (ACE inhibitors, angiotensin receptor blockers and calcium antagonists) or ineffective (b-blockers and diuretics) therapeutic strategies, although different drugs may possess different vasodilator properties. 19 None of these studies has, however, analysed in detail whether a relationship exists between decrease of media to lumen ratio of small arteries and BP components, that is, brachial and also central BP. This lack of data is particularly true regarding diuretic compounds (mainly thiazides) 2,8,16 when given in long-term treatment. 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. 20 This beneficial effect was associated with a normalisation of the media collagen/elastin ratio, thus suggesting that antihypertensive treatment may normalize mechanical alterations also in human small resistance arteries. Control of SBP and PP: role of macrovasculature and wave reflections Ventricular ejection in humans is associated with an acute shock of stroke volume against the aortic wall. Thereafter, the BP curve may be considered as a wave, which travels along the arterial tree at a given speed, the PWV. 1,2 The PWV level is an indirect measurement of aortic stiffness: the higher the PWV, the stiffer the arterial wall and the higher the SBP at any given value of stroke volume. Thereafter, two major events characterize the BP curve. First, at each discontinuity of the arterial wall, the incident pressure wave may be reflected. Second, the summation of the incident (coming from the heart) and the reflected (returning towards the heart) waves determine the shape of the BP curve at each site of the arterial tree. With age, this shape is more and more influenced by the timing and amplitude of the reflected wave, which returns towards the heart at the same PWV as the incident wave. 1,2 Thus, PWV is a major marker of biological aging. Pressure waves are reflected at every discontinuity of the arterial wall, but reflections predominate at the sites of arteriolar bifurcations, where the geometry and stiffness of vessel wall material determine the reflection angle and, therefore, the value of its coefficient. 21 23 Herein, the major factors to consider are not only the distensibility and the diameter of each arteriolar branch of the bifurcation, but also their exact location. With age, the reflection sites are closer to vital organs, such as the heart, brain and kidney, and even wave reflections may contribute particularly to organ damage. 1,2,24 Wave reflections may occur at any vascular site where vasomotor tone and pulsatility are still present. They disappear almost completely at pre-capillary and capillary levels (diameter: o150 mm), that is, when blood perfusion becomes almost completely steady. Macrovasculature and CV risk From a pathophysiological viewpoint, the reflected pressure wave is markedly influenced by vascular aging. 1,2 When subjects are young and have quite elastic conduit arteries (low PWV), the reflected wave returns slowly towards the heart, that is, during the diastolic period. Its principal consequence is to boost coronary perfusion during this period without changing the cardiac afterload. On the other hand, when the subjects are old and have stiff arteries, the reflected wave returns very rapidly towards the heart (high PWV), that is, during systole. 1,2 In this setting, coronary perfusion, which normally occurs only during diastole, is consistently reduced and favours coronary ischaemia. Furthermore, in the central arteries, the reflected pressure wave becomes superimposed on the forward wave during systole and causes an additive increase of SBP, called the augmentation pressure (mm Hg) or augmentation index (%PP). Consistent with this pathophysiological understanding of hypertension and end-organ damage, PP, aortic stiffness and pressure wave reflections have been shown to produce mainly systolic hypertension and to be 593

594 Table 1 Forward (P t ) and backward (P b ) wave reflections and reflection coefficients (P b /P t ) in normotensive and hypertensive patients under baseline conditions and in hypertensive patients after captopril administration 19 21 Parameter Normotensive (baseline) Hypertensive (n ¼ 12) Baseline P* Captopril P* Pressure wave components (mm Hg) Forward (P t ) 31.9±3.8 40.1±5.5 0.001 37.0±4.9z 0.007 Backward (P b ) 13.7±2.5 25.0±6.3 0.001 19.3±5.3w 0.002 P b /P t 0.43±0.07 0.62±0.09 0.001 0.52±0.09w 0.01 f 0 (Hz) 3.1±0.6 3.9±1.1 0.03 3.5±1.2 NS Abbreviation: NS, not significant. f 0 indicates first zero crossing of impedance phase angle. *Vs normotensive baseline. w Po0.005, z Po0.05 vs hypertensive baseline by paired t-test. independent predictors of CV risk (see reviews in2). For instance, in the Framingham Heart Study and in the Syst-Eur Study, brachial PP was shown to be superior to SBP as a predictor of coronary heart disease in subjects more than 60 years. 2 This relationship between brachial PP and CV risk is maintained in high-risk groups such as individuals with left ventricular dysfunction, end-stage renal disease, or diabetes mellitus. 2 Macrovasculature, wave reflections and anti-hypertensive therapy The role of arterial stiffness and wave reflections in the mechanisms of SBP reduction in subjects under anti-hypertensive drug therapy was primarily observed from the monitoring of brachial and carotid SBP and PP in the Reason Study 25 and further firmly confirmed. 26,27 This controlled trial compared the b-blocking agent atenolol to low doses of the combination of the diuretic indapamide (Ind) with the ACEI Per. After 1 year, for the same DBP reduction, Per/Ind lowered brachial (peripheral artery) and carotid (central artery) SBP and PP more than atenolol. 25 The reductions of carotid SBP and PP were significantly more pronounced than those of brachial SBP and PP, but this effect was seen exclusively with Per/Ind. Although carotid and aortic PP did not change significantly under atenolol, Per/Ind achieved a significant central PP reduction together with a selective reduction of cardiac hypertrophy. 28 The two drug regimens caused the same aortic PWV reduction as a result of the comparable decreases of MAP and DBP. The major difference between the two drug regimens was that Per/Ind lowered the carotid augmentation index, a classic marker of carotid wave reflections, 1,2 but atenolol did not. Nebivolol might have an intermediate effect. 29 The difference between Per/Ind and atenolol could be due exclusively to the atenolol-induced heart rate reduction, thereby causing the maintenance of disturbed wave reflections. 21 27 However, this result was observed only within the first 6 months of treatment. 25 After this period, the Reason Study showed that the mechanism of SBP reduction under Per/Ind was highly modified. After 1 year of drug treatment, structural arteriolar changes are known to be constantly and significantly reversed under ACEI by Per but never under atenolol or diuretics given alone. 1,2,16,17 We suggest that the reversion of structural arteriolar changes is responsible per se for the selective reduction of SBP and PP for two reasons. First, the selective reduction of SBP and PP becomes significant only after 1 year of treatment. 1,2,16 Second, ACEI, but not atenolol, is known to reduce reflection coefficients (Table 1). 21 23 In conclusion, there is hardly any doubt that CV events are the consequences of vascular damage at both the macro and microvascular level. Possible interrelationships between alterations in the macro and microvasculature and mechanisms possibly involved represent an extremely interesting topic, which deserve further and thorough investigation, also considering its relevant clinical impact, especially in terms of possible prevention or regression of the concerned alterations. An important possibility in the future is that regression of structural vascular changes should become a necessity, particularly at the site of microvasculature, to prevent the occurrence of CV events. There is a strong need of a study aimed at evaluating possible relationships between indicators of small resistance artery structure and of large artery distensibility (for example PWV, augmentation index and so on) both in basal condition and under anti-hypertensive drug treatment. Acknowledgements This review was prepared with the help of INSERM (Institut de la Santé et de la Recherche Médicale) and GPH-CV (Groupe de Pharmacologie et d Hémodynamique Cardiovasculaire), Paris. We thank Dr Anne Safar for helpful and stimulating discussions. Disclosures None.

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