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(Hypertension. 1995;26:10-14.)
© 1995 American Heart Association, Inc.

Articles

The Arterial System in Hypertension

A Prospective View

Michel E. Safar; Edward D. Frohlich

From the Department of Internal Medicine and INSERM (U337), Broussais Hospital, Paris, France, and the Alton Ochsner Medical Foundation, New Orleans, La.

Correspondence to Pr M. Safar, Service de Medicine 1, Hôpital Broussais, 96 rue Didot, Paris, Cedex 75674, France.

	Abstract

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Abstract Hypertension has long been considered a hemodynamic disorder, the hallmark of which is an increased total peripheral resistance that is more or less uniformly distributed in the arterioles of the component organ circulations. In recent years, because of the introduction of innovative technologies and methods, it is now possible to obtain a meaningful assessment of the physiological role of the larger arteries, thereby providing an index of arterial distensibility and compliance and a new means to assess the role of pulsatile pressure and arterial stiffening in hypertension and its comorbid diseases (eg, arteriosclerosis, diabetes mellitus). This discussion addresses these newer methodological aspects in assessing arterial stiffening in systemic hypertension and other cardiovascular disorders. In addition, the epidemiological, the molecular biological, and genetic, as well as certain therapeutic, aspects of pulse pressure in these circumstances are discussed.

Key Words: hemodynamics • arteries • compliance • epidemiology • antihypertensive therapy • molecular biology • genetics

	Introduction

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Hypertension is usually defined hemodynamically in terms of a simple model of the circulation assuming steady flow and pressure. This model indicates that hypertension is characterized by an increased mean arterial pressure and total peripheral resistance reflecting a reduced arteriolar caliber. This definition neglects the fact that, in living animals and humans, flow and pressure are not steady but pulsatile. Based on arterial hemodynamic principles developed by McDonald and later by Nichols and O'Rourke,¹ a nonlinear model of the circulation may provide a better characterization of hypertension. This model takes into account not only mean arterial pressure but also pulsatile pressure. Pulsatile pressure is influenced at any given time during ventricular ejection by large arterial stiffening. According to this view, pulsatile pressure and arterial stiffening should be introduced into the altered hemodynamic pattern of hypertensive vascular disease. Therefore, for a given cardiac performance, it is not only the arteriolar constriction that controls the level of blood pressure but also the degree of arterial stiffness and the resulting changes in amplitude and timing of the arterial wave reflections.

This modern aspect of hypertension research has important implications for a more fundamental understanding of the disease. Thus, in clinical hypertension, alterations of the large arteries may be directly related to the classic complications involving the central nervous system, heart, and kidney, and this process may be analyzed independently of age and of the atherosclerotic lesions. Furthermore, arterial stiffening is importantly involved in a more comprehensive understanding of hypertension in the elderly. In experimental hypertension, introduction of large arterial alterations in the definition of the disease should also significantly modify existing basic concepts. For practical reasons related to the size of the blood vessels, most experimental studies dealing with cellular mechanisms of hypertension have been performed on large arteries, particularly the aorta. In most instances, the cellular mechanisms in the aorta have been extrapolated to the resistance function of arterioles. However, it is more appropriate to recognize that aortic cellular changes should be related to the buffering rather than resistance function in the vasculature. In reality, such approximations are no longer tenable because (1) hypertension is established usually by arterial pressure measurements obtained at the site of large and not small arteries; (2) large arteries should be integrated directly into the definition of the hypertensive disease; and (3) the larger and smaller arteries (including the arterioles) constitute two major compartments of the vascular system that have different and distinct structural and functional features in vascular biology: a buffering function for larger arteries and a resistance function for the arterioles. Thus, the primary objectives of the Second Workshop on Structure and Function of Large Arteries were to introduce and discuss current hemodynamic concepts of hypertension into the definition and understanding of the disease and to publish these newest developments in the pathophysiological mechanisms underlying hypertensive disease.

	Methodological Aspects

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Until recently, the rigidity of larger arteries has been evaluated experimentally using in vitro technology.^{1 2 3} By using strips and rings of the larger arteries, pressure-volume relationships were assessed, admittedly with the limitations inherent in the absence of pulsatile flow while using a steady driving pressure (Table). In vivo studies were performed using appropriate models of the arterial circulation,⁴ but direct measurements were not yet available. As reported in this issue of Hypertension, the recent development of high-resolution echo-Doppler technique permits noninvasive experimental and clinical determination of pulsatile pressure and diameter changes in vivo. Thus, various indexes of arterial stiffness can be measured directly, thereby permitting in vivo recognition of the great heterogeneity of the arterial tree. However, comparisons between older and recent findings may be difficult to perform because of certain methodological differences (Table).

View this table: [in this window] [in a new window]   Table 1. Study of the Pressure-Volume Relationship of a Given Arterial Vessel: Differences in Approach Between the Classic and New Techniques

One major technical advance was the noninvasive means to determine pulsatile pressure.^{1 5 6} This innovation established that, in clinical and experimental hypertension, pulse pressure increased markedly from central to peripheral arteries without substantial change in mean arterial pressure. Moreover, this pulse pressure gradient disappears with age because of concomitant changes in the amplitude and timing of arterial pressure wave reflections within the ascending aorta. Since these alterations in pulse pressure are due chiefly to an increase of systolic pressure, this hemodynamic pattern has several important implications. First, in any given patient or experimental animal, it is not possible to describe a single blood pressure curve for the totality of the arterial tree; several phenotypic aspects are observed and should be taken into account in any genetic studies. Second, in experimental hypertension (eg, in rats), systolic pressure at the tail artery is by definition physiologically amplified in contrast to thoracic systolic pressure. Therefore, this can be a misleading approach for a more precise hemodynamic evaluation of the severity of hypertensive disease. Third, in clinical hypertension, systolic and pulse pressure measured within the ascending aorta may be significantly reduced by drug treatment, whereas brachial systolic and pulse pressure may remain poorly modified.⁶ Nitrates, angiotensin-converting enzyme (ACE) inhibitors, and the ß-blocking agent dilevalol may selectively provide this hemodynamic pattern (in contrast to propranolol and atenolol).⁶ Pulse pressure changes may also have important implications in cardiovascular pharmacology. Because recent studies have suggested that pulsatile pressure can attenuate both peripheral and central components of baroreflex adaptation and resetting,⁷ the pulse pressure changes may contribute to sustained baroreflex responses observed in vivo, particularly after drug treatment.

The most important technical advance in recent years was the ability to determine transcutaneously in vivo the thickness of peripheral arteries (eg, human carotid and brachial). In this fashion, hypertrophy of large arterial vessel wall was at last demonstrable noninvasively in living hypertensive patients.^{8 9 10} Moreover, regression of hypertrophy in arterial segments of the radial artery has been observed after antihypertensive drug treatment.¹⁰ Furthermore, from the determination of arterial thickness, in vivo evaluation of Young's modulus can be obtained easily with a high degree of reproducibility.

Finally, mechanical factors acting on the arterial wall are no longer limited to blood pressure and tensile stress determinations. Adequate velocity profiles may be obtained, thereby permitting determination of pulsatile shear stress and its potential relationships with endothelial function.¹¹ Shear force, one of the vital mechanical factors contributing to changes in arterial structure and function, is now an important field for clinical and experimental research.

	Arterial Stiffening in Hypertension and Other Cardiovascular Disorders

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These methodological advances have steadily modified our understanding of arterial stiffening in hypertension for several reasons. First, arterial stiffening may be estimated in various arterial segmental territories with different results, depending on the organ circulation involved. Second, at the site of radial and carotid arteries, arterial stiffness may be studied under similar transmural conditions in normotensive and hypertensive subjects.^{12 13} The most important aspect of these determinations is that arterial stiffness can be measured in vivo (in rats and humans) using pulsatile and not static pressure-volume relations. This methodology is vastly different from the older and more classic conventional approaches, in which static compliance and distensibility have been measured from steady-state pressure determinations and with interrupted blood flow (Table). Obviously, the factors governing static and dynamic (pulsatile) compliance conditions are markedly different (Table).^{1 2} Static compliance is dependent mainly on smooth muscle tone and on the structural characteristics of the arterial wall; pulsatile compliance is frequency dependent and is importantly modified by changes in arterial viscosity, a factor governed principally by the connections between smooth muscle and extracellular matrix. This important and novel aspect of arterial stiffening is now measurable and thus able to stimulate much necessary fundamental research that will provide a more comprehensive understanding of the mechanical factors that act on the arterial wall.

During this workshop, in addition to hypertension, several physiological and other pathological situations were described in which arterial stiffness is known to be altered. For example, hemodynamic observations may be obtained routinely in such clinical situations as chronic renal failure¹⁴ and congestive heart failure.¹⁵ However, in several metabolic conditions (eg, obesity, atherosclerosis, abnormalities of lipid or glucose metabolism) in which hemodynamic parameters are still generally believed to be unaltered, it is now possible to detect and assess alterations in arterial stiffness, in vessel relaxation, or in shear stress. This field will undoubtedly grow in the forthcoming years and will provide new pathophysiological insight for new applications for diagnosis and treatment.

Finally, until recently, the stresses involved in cardiovascular diseases were chiefly evaluated in terms of mean blood flow or level of systolic and diastolic pressures. With newer technologies, direct measurements of tensile and shear stress now permit more precise and detailed in vivo steady-state as well as pulsatile data. Moreover, the variability of each mechanical stress component can be considered,¹⁶ including peak systolic and end-diastolic pressures.

	Epidemiological Impact of Pulse Pressure

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Alterations of the arterial pressure-diameter relation in subjects with hypertension have only recently been recognized. Indexes of arterial stiffness are now known to be influenced not only by the level of systolic and diastolic pressure but also by other factors, including sodium intake, serum high-density lipoprotein cholesterol, daily energy expenditure in physical activity, and serum insulin levels.¹⁷ These findings suggest that many modifiable constitutional and lifestyle characteristics could significantly contribute to aortic stiffness, independent of the height of arterial pressure. For these reasons, it is now necessary to evaluate more comprehensively these epidemiologically assessable aspects of arterial stiffness and pulse pressure of various populations.

Several years ago in Paris, the relationship of the two components of blood pressure, mean arterial pressure and pulse pressure, with cardiovascular risk was investigated in 18 336 men and 9351 women aged 40 to 69 years.¹⁸ Using cross-sectional analytic techniques, the pulsatile component of arterial pressure was exclusively and independently related to changes in left ventricular hypertrophy. In addition, the specific role of the pulsatile component of arterial pressure as an independent risk factor was confirmed by a 10-year survival analysis. This was shown to be operable particularly in women older than 55 years, in whom the pulsatile component of arterial pressure was an independent predictor of coronary but not cerebrovascular deaths.

In another recent study, the prognostic value of pretreatment pulse pressure was shown to be an important predictor of myocardial infarction.¹⁹ In that prospective hypertension control program, 2207 hypertensive patients with a pretreatment diastolic pressure 95 mm Hg were grouped according to pulse pressure textile. Myocardial infarction rates per 1000 person-years were related directly to the magnitude of pulse pressure as a predictor of myocardial infarction. As in the Paris study, a high pretreatment pulse pressure (63 mm Hg) was associated with subsequent cardiovascular complications (ie, myocardial infarction). Thus, these findings clearly indicated that the level of pulse pressure may be an independent predictor of cardiovascular risk, particularly for coronary disease. Further epidemiological studies are necessary to evaluate whether arterial stiffness per se may be an early predictor of cardiovascular risk.

	Aortic Stiffness and Molecular Genetics of Hypertension

Top Abstract Introduction Methodological Aspects Arterial Stiffening in... Epidemiological Impact of Pulse... Aortic Stiffness and Molecular... Therapeutic Effects References

 
There are few reports on the relationship between the genetics of hypertension and aortic stiffness. However, as suggested by some clinical and experimental studies,^{20 21} a genetic factor may be implicated in the mechanism of increased pulse pressure and arterial stiffness.

Regarding sodium and arterial stiffness, it has been reported that in genetic Dahl rats the stiffness of the carotid artery was increased independently of the height of arterial pressure and the level of sodium intake but could be related to the genetic trait.²² In patients with borderline hypertension, similar findings have been recognized recently: arterial compliance and distensibility are much more reduced in salt-sensitive than in non–salt-sensitive individuals.²³

In clinical hypertensive disease, whereas blood pressure and aortic stiffness were not linked to the ACE gene, a strong association has been reported between increased aortic stiffness and the presence of angiotensin II type 1 receptor gene.²⁴ Because collagen tissue is a major determinant of aortic stiffness and because angiotensin II may promote collagen production from aortic smooth muscle cells in cultures,²⁵ it could be hypothesized that specific angiotensin genes might influence the structure and the function of the hypertensive arterial wall through changes in connective tissue.

For many years, the renin-angiotensin system has been considered only as a producer of arteriolar constriction in hypertensive disease. Recent genetic and pharmacological investigations have emphasized that much more important links may be observed between this pressor system and the large arteries. Genetic studies have related ACE deletion polymorphism to large-artery damage, as produced by coronary ischemic disease and myocardial infarction.²⁶ Also, from the association of increased plasma ACE and increased carotid intima-media thickness,²⁷ plasma ACE has been shown to be more related to arterial than arteriolar changes. Pharmacological studies have shown that, independent of blood pressure reduction, ACE inhibition has specific effects on the heart and large vessels,^{28 29 30 31} in the latter producing an increase in arterial diameter and compliance. Moreover, several reports^{32 33 34} have indicated that ACE blockade has specific effects on the arterial connective tissue, producing substantial modifications in fibronectin expression and in collagen content. The latter changes were shown to be more related to ACE inhibition in arterial tissue than to arterial pressure reduction. Finally, in the case of large vessels, the existence of local angiotensin-induced production in connective tissue raises questions relating to mechanisms of increased aortic stiffness and the disproportionate increase in systolic pressure in elderly hypertensive subjects.

	Therapeutic Effects

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Because most earlier therapeutic trials in hypertension³⁵ have used diastolic pressure as the principal criterion of entry, the question has been raised recently as to whether other pressure-related criteria such as systolic or pulse pressure, arterial compliance or distensibility, or other indexes of arterial stiffness may be of additional value in evaluating antihypertensive drug effects on cardiovascular morbidity and mortality. The results of the Systolic Hypertension in the Elderly Program (SHEP)³⁶ obviously showed that the exclusive use of diastolic pressure created strong bias³⁷ and suggested the need to evaluate other arterial changes more extensively with the use of newer methodological advances. Furthermore, it has been shown that as the result of treatment of hypertension, cardiac and arterial changes may differ, even with the same magnitude of arterial pressure reduction, according to the agent used.^{38 39}

One line of evidence has already focused on the reversal of structural changes in hypertension, involving not only the large arterial vessels but the structure and the function of the heart as well.^{38 39 40} In other words, the quality of the heart-vessel coupling should be maintained (or even improved) after drug treatment.³⁹ One important line of investigation was the evaluation of changes in heart-vessel coupling regarding modifications in wave reflections induced by drug therapy.^{6 14 41 42} The recent finding that altered amplitude and timing of wave reflections may be an initiating and determining factor for cardiac hypertrophy⁴³ and may be reversed by some, but not all, antihypertensive agents⁴⁴ brings new insight into studies concerned with reversal of cardiac and vascular hypertrophy in hypertension.^{1 6}

A major issue of this workshop was the demonstration of the reversibility of the structural vascular changes observed in patients with hypertension. Experimental studies have shown that such reversibility in hypertensive rats may be obtained in the larger^{28 29 30 31 32 33} as well as smaller^{45 46} arteries. However, at this time, there is little evidence for extrapolation to clinical hypertension. Investigations of heart, large arteries, or resistance arterioles have shown that the reversal may be extremely difficult to obtain.^{46 47} Recently, hypertrophy of the radial arterial wall, in which only smooth muscle cells are involved, has been shown to be reduced in isolated systolic hypertension in the elderly.^{9 10} Clearly, much study remains to be done to confirm this important aspect of the treatment of hypertension; the objective of this workshop was focused to this end.

	Acknowledgments

 
This study was performed with support from a Biomed grant of the European Community.

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