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Michel E. Safar, MD
Department of Internal Medicine, Broussais Hospital, Paris, France.
Hypertension is usually considered as a cardiovascular (CV) syndrome in which the principal goal consists to identify specific causes: as stenosis of the renal artery, primary aldosteronism, and pheochromocytoma. High blood pressure (BP) is considered to be due to a reduction of the caliber of small arteries and arterioles, with resulting increase in total peripheral resistance and mean blood pressure (MBP). Two specific points of the BP curve, peak systolic (SBP) and diastolic BP (DBP), are widely used to define the disease. Because MBP approximates DBP plus one-third pulse pressure (PP) which is the difference between SBP and DBP, DBP is widely used as the main criterion for clinical management.
In the recent years, hypertension has been rather described as a powerful risk factor predicting CV morbidity and mortality. High BP is considered to act on the arterial wall with deleterious mechanical consequences, which are responsible for many CV events, mainly of cardiac, cerebral and renal origin. Since the goal of drug treatment of hypertension consists to prevent CV complications, it seems likely that the totality of the BP curve, and not only two arbitrary points as SBP and DBP, should be considered to define adequately hypertension.
In fact the BP curve is due to the summation of two different components, a steady component, MBP, and a pulsatile component, PP . MBP, the product of cardiac output multiplied by total peripheral resistance, is the pressure for the steady flow of blood and oxygen to peripheral tissues and organs and refers to arterioles. The pulsatile component, PP, is the consequence of the intermittent ventricular ejection from the heart. It is the role of large conduit arteries, mainly the aorta, to minimize the pulsatility. In addition to the pattern of left ventricular ejection, the determinants of PP (and SBP) are the cushioning capacity of arteries, and the timing and intensity of arterial wave reflections . Thus, in this conception, for a given cardiac function, both small and large arteries participate to the mechanisms of hypertension.
Over the past few years, there are several reasons explaining that arterial stiffness and wave reflections have been widely studied in hypertensive populations. Whereas DBP was considered in the past to be the better guide to stratify the severity of the disease, epidemiological investigations have directed attention to SBP as a more informative factor of CV risk , and it has been even shown that PP is an independent marker of CV risk . Over 50-60 years of age, PP is the most powerful mechanical factor available to predict those hypertensive subjects at greatest risk for subsequent myocardial infarction [4-6]. The predictive values of PP, has been noted even in hypertensive subjects under successful drug therapy, i.e., with BP very close to normal values [7-9]. Indeed, whereas drug control of DBP (< 90 mm Hg) is consistently obtained in large populations of hypertensive subjects, the ability to control SBP (< 140 mm Hg) is observed to a much lesser extent [10-12]. Furthermore, subjects with a persistently elevated SBP and PP, have been reported to have stiffer arteries than subjects of the same age and MBP but with adequately controlled of SBP and PP [8, 9, 13]. Finally, among the vascular factors influencing PP, two of them have been shown to be independent predictors of CV risk: aortic stiffness, measured from aortic PWV [14-16], and early wave reflections, evaluated from pulse wave analysis .
The purpose of this review, which is focused on PP and arterial stiffness in hypertensive subjects, was two-fold: (i) to delineate the specific roles of arterial stiffness, PP and wave reflections in the mechanisms of hypertension, and (ii) to analyze the recent therapeutic trials enabling to modify the therapeutic approach in hypertensive populations through a selective reduction of arterial stiffness, PP and alterations of wave reflections.
ARTERIAL STIFFINES AND WAVE REFLECTIONS IN THE MECHANISMS
The arteries have two distinct but interrelated functions: to deliver an adequate supply of blood to peripheral tissues (the conduit function) and to smooth out pressure oscillations due to intermittent ventricular ejection (cushioning function) [1, 18]. These two aspects of arterial function can be dealt independently since their functional alterations have different origins and consequences. Disorders of conduit function by narrowing the vessel lumen affect the tissues and organs downstream, while disorders of cushioning function by arterial wall stiffening have deleterious effects on the heart upstream.
Conduit function of arteries [1, 18]:
The efficiency of conduit function is related to the width of the arteries and the almost constancy of MBP along the arterial tree. The MBP drop between the ascending aorta and arteries in the forearm or leg does not exceed 2-3 mm Hg in the supine position. Arterial conductance is very efficient: since in conditions of increased demand, the blood flow can increase five to eight times over the baseline value. This physiological adaptability is mediated through acute changes in arterial flow velocity and/or diameter. Diameter changes are dependent on endothelium function which respond to alterations of shear stress or to direct action of vasoactive factors . Conduit arteries can be altered for functional reasons (endothelium-dependent vasodilation is limited in hypertension and mainly in cardiac failure, hypercholesterolemia, smoking) or due to structural remodeling and/or atherosclerotic process. In the case of chronic increase in flow, the arteries increase their internal dimensions and the reserves for such an increase are limited. Thus, the principal alterations of conduit function occur through narrowing or occlusion of arteries with restriction of blood flow and resulting ischemia or infarction of tissues downstream.
Atherosclerosis, which is characterized by the presence of localized plaques, is the most common disease that disturb conduit function. Atherosclerosis is primarily an intimal disease, focal and patchy in its distribution, occurring preferentially in the coronaries, femoral arteries, infrarenal aorta, and carotid bulb. Focal compensatory enlargement occurs at discrete sites of narrowing immediately adjacent to more or less normal areas. Mechanisms of atherogenesis are complex, including smoking, lipid disturbances, thrombogenesis, production of vasoactive substances and growth factors and mediators of inflammation. Besides these humoral factors, atherogenesis depends also on mechanical factors such as tensile stress and alterations in shear stress. The role of mechanical factors is assessed by the high prevalence of atherosclerosis in hypertension, with predilection of plaques for sites characterized by disturbances of flow pattern and shear stress, like orifices, bifurcations, bending and pronounced arterial tapering. However, atherosclerosis is a quite different from that occurs following alterations of cushioning function: arteriosclerosis.
Cushioning function of arteries [1,
The principal role of arteries as cushions is to dampen the pressure oscillations resulting from intermittent ventricular ejection ("Winkessel" effect). Physiologically, large arteries can instantaneously accommodate the volume of blood ejected from the heart, storing part of the stroke volume during systolic ejection and draining this volume during diastole, thereby ensuring continuous perfusion of organs and tissues. The cushioning function is very efficient in young and healthy humans and the extra energy lost on account of the intermittent ventricular ejection is only 10-15% greater than if the heart's output was continuous. The efficiency of Windkessel function depends on viscoelastic properties of arterial walls and the "geometric" characteristic of the arteries including their diameter and length. The viscoelastic properties of arteries are usually expressed in term of compliance (C), and distensibility (Di), or potentially incremental elastic modulus (Einc) [1, 18]. The compliance (C) is defined as the ratio between the change of arterial diameter (D D) induced by an increase in pressure (DP) and expressed as C = DD/DP. The distensibility (Di) is expressed as the relative change in arterial diameter (DD/D, where D is baseline diastolic diameter) induced by increase in pressure: Di = (DD/D x DP). All indexes of arterial stiffness are influenced by blood pressure level, decreasing with increased pressure. The viscoelastic properties of the arterial wall determine the amplitude of pressure waves as well as their propagation and reflections along the arterial tree [1, 18].
The principal alteration in cushioning function is due to the stiffening of arterial wall, with increase in SBP and PP as the principal consequences. Two different mechanisms should be described . The first, direct mechanism, involves the generation of a higher forward pressure wave by the left ventricle ejecting into a stiff arterial tree. The second mechanism is indirect, via the influence of increased arterial stiffness on the pulse wave velocity (PWV) and the timing of incident (forward) and reflected (backward) pressure waves. Indeed, ejection of blood into the aorta generates a pressure wave that is propagated to other arteries throughout the body. This forward travelling pressure wave is reflected at any points of structural and functional discontinuity of the arterial tree, generating a reflected ("echo") wave travelling backward towards ascending aorta. Incident and reflected pressure waves are in constant interaction and are summed up in a measured pressure wave. The final amplitude and shape of the measured aortic PP wave are determined by the phase relationship (the timing) between the component waves. The timing of incident and reflected pressure waves depends on the PWV, the travelling distance of pressure waves, and the duration of ventricular ejection. The desirable timing is disrupted by increased PWV due to arterial stiffening. With increased PWV, the reflecting sites appear "closer" to the ascending aorta and the reflected waves occur earlier, thus becoming more closely in phase with incident waves in this region. The earlier return means that the reflected wave impacts on the central arteries during systole and reduces aortic pressure during diastole. Hence the viscoelastic properties of the arterial system influence PP through the level of SBP as well as DBP.
An increase of arterial stiffness alters to left ventricular function. Through promoting an increased in pressure wave amplitude and early wave reflections, arterial stiffening increases peak-and end-systolic pressure in ascending aorta and myocardial oxygen consumption. Furthermore, increased SBP induces myocardial hypertrophy, impairs diastolic myocardial function and ventricular ejection. In addition increased SBP and PP accelerates arterial damage, increasing the fatigue of biomaterials, degenerative changes and arterial stiffening, thus creating a vicious circle. Taken together these alterations explain why PP, aortic stiffness and wave reflections are independent predictors of CV risk (see above in the introduction).
Cushioning function is primarily altered during aging process and in conditions associated with "sclerotic" remodeling of arterial walls, i.e. associated with increased collagen content and changes in extracellular matrix (arteriosclerosis) . Arteriosclerosis is principally a medial alteration which is generalized throughout the thoracic aorta and central arteries causing dilatation, diffuse hypertrophy and stiffening of arteries. Arteriosclerosis results in a diffuse fibroelastic intima thickening, an increase in medial ground substance and collagen, and fragmentation of elastic lamellae with secondary fibrosis and calcification of the media. These changes are more pronounced in the aorta and central arteries than in the limb arteries.
Several aspects similar to those of the aging process are observed in essential hypertension. Nevertheless, some differences characterize these two conditions. In hypertension the arterial dilation is not always observed and whereas aging is principally characterized by alterations and decreased content of elastin in the arterial wall, hypertension is principally characterized by increased collagen content .
Taken together, atherosclerosis is a condition that typically disturbs conduit function, while arteriosclerosis does not alter it in basal conditions. Nevertheless, in western populations these two conditions frequently coexist since both progress with aging and share several common pathogenic mechanisms making the distinction sometimes difficult. Moreover, increased intima-media thickness may be by itself a favoring condition for the development of atheromatous plaques and has been considered as a possible early marker of atherosclerosis.
THE KEY THERAPEUTIC TRIALS ON ARTERIAL STIFFNESS AND WAVE
To demonstrate the independent predictive roles of arterial stiffness and wave reflections on CV risk, specific interventional studies focusing on hypertensive subjects have recently been performed. They show that: (i) drugs may act on large artery structure and function independently of blood pressure changes, and (ii) prolongation of survival not only requires blood pressure reduction but also a significant decrease in arterial stiffness.
Nitrates are known to dilate larger rather than smaller arteries, whether or not the endothelium is intact [1, 18, 21]. Earlier studies showed that nitrates cause a selective decrease of SBP over DBP in healthy volunteers as well as in subjects with borderline or sustained essential hypertension . Since the baroreflex response following nitrate administration is attenuated with age, an acute and selective reduction of SBP is constantly observed in old subjects with systolic hypertension . Low-dose nitrates weakly modify stroke volume, venous tone and aortic PWV while aortic wave reflections, as a consequence of a significant increase of the diameter of peripheral (but not central) muscular arteries, play a major role in the mechanism of the SBP decrease, [1, 18, 21]. Taylor  previously showed that an increase of the arterial cross-sectional area at peripheral bifurcations could theoretically cause a delay of wave reflections with subsequent selective decreases of SBP and PP through changes of peripheral reflection patterns. In clinical situations, such changes of SBP and PP have been widely demonstrated in randomized studies [1, 21] but, in some cases, are difficult to detect. Indeed, under nitrates, PP transmission is modified from the central aorta to the brachial artery, making that the BP changes are more pronounced at the aortic than at the brachial artery level. Finally, a major point to consider is that a selective decrease of aortic SBP may be constantly obtained using nitrates, as a consequence of the change of muscular artery geometry and the subsequent modification of the reflection coefficient within the distal compartment of the arterial tree . This effect may be obtained not only acutely through vasomotor tone changes, (i.e., without any modification of the thickness and composition of the vessel wall)  but also in the long term. Duchier et al  have shown that nitrates given chronically in subjects with isolated systolic hypertension in the elderly are able to reduce selectively SBP with minor changes in DBP.
The key therapeutic trial demonstrating the role of arterial stiffness in the control of SBP and PP in hypertensive subjects was performed recently in patients with end-stage renal disease undergoing hemodialysis . The objective of the trial was to reduce CV morbidity and mortality through a therapeutic regimen involving successively salt and water depletion by dialysis; then, after randomization, angiotensin-converting-enzyme (ACE) inhibition or calcium-entry blockade, and finally the combination of the two agents and/or their association with a beta-blocker. Using this procedure, it was possible to evaluate over a long-term follow-up (51 months) whether the drug-induced MBP reduction was associated or not with a parallel decrease of arterial stiffness and the resulting consequences on CV risk. During follow-up, MBP, PP and aortic PWV were reduced in parallel in survivors. In contrast, in subjects who died from CV disease, MBP was lowered to the same extent as in survivors, but neither PP nor PWV were significantly modified by drug treatment. As a consequence, from the result of that trial, it appears that the lack of a aortic PWV attenuation despite the significant reduction of MBP was a significant predictor of CV death.
Taken together, these two therapeutic studies have demonstrated for the first time the need, in hypertensive subjects, to develop drugs acting specifically on the large artery walls, i.e., either on arterial stiffness or on wave reflections or on a combination of both, with a resulting potential lowering of CV risk .
Nowadays, the standard treatment of hypertension consists to shift the age-BP curve towards lower SBP, DBP and MBP values. Taken together, the recent epidemiological studies and therapeutic trials clearly indicate that, over 50 years of age, a novel objective of treatment should be to reduce the physiological SBP increase and DBP decrease with age, thus acting on the slope of the age-BP curve. This goal may be achieved only through action on large and not small arteries, thereby modifying arterial stiffness and wave reflections, and normalizing not only SBP, DBP and MBP, but also PP.
A first approach consists to use the standard antihypertensive drugs, since some of them have specific effects on the mechanical properties of large arteries. For instance, from experimental studies, it appears that aortic collagen accumulation may be prevented independent of BP by ACE inhibition or spironolactone . However, in hypertensive humans there is, no evidence that the doses of these drugs may be the same as those required for conventional antihypertensive drug treatment. Recent clinical pharmacology studies, particularly with the calcium-entry blocker mibefradil , suggest that the most effective doses for SBP and DBP may be not adequate for PP. Moreover, the level of brachial PP reduction may differ from that of aortic PP. Further investigations are needed to resolve these important aspects.
The second approach consists to develop
new antihypertensive agents acting on conduit arteries with specific profiles
acting not only on vasomotor tone but also on the composition of conduit artery
walls. These new agents might operate via mechanotransduction mechanisms acting
on cell-cell and cell-matrix attachments of the vessel wall [30, 31]. New approaches
for the drug treatment of hypertension are needed, with the development of therapeutic
trials capable to further attenuate CV morbidity and mortality through changes
of arterial stiffness and wave reflections.
This study was performed with the help of INSERM, Association Claude Bernard and GPH-CV. We thank Mrs. Anne SAFAR and for her skillful technical help.
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