Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com 

High blood pressure is only one risk factor

Preview: It is becoming increasingly clear that high blood pressure is not the sole cause of the high cardiovascular morbidity and mortality rates associated with hypertension. Reduction of blood pressure is of utmost importance, but many other factors contribute significantly to the risk of adverse cardiovascular events and death.

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Hypertension is a complex syndrome comprising many abnormalities, including obesity, abnormal lipid metabolism, insulin resistance, altered glucose metabolism, arterial stiffness, and renal disease (1-6) (figure 1: not shown). The importance of factors other than blood pressure is underscored by the relationship between blood pressure and adverse cardiovascular events. In patients with mild to moderate hypertension, the relationship between level of blood pressure and adverse outcomes is not linear. Furthermore, a meta-analysis of large-scale interventional studies (7) found that a reduction in blood pressure substantially decreases the risk of both fatal and nonfatal stroke but produces less-than-expected reductions in fatal and nonfatal coronary events.

“Normotensive hypertension”

Some studies have shown that the target-organ damage typically associated with hypertension can be detected before blood pressure is significantly elevated; this discovery has given rise to the term “normotensive hypertension” (8). Radice and colleagues (9) used B-mode echocardiographic studies to compare left ventricular structure and function in 51 adolescent boys with normotension who had at least one parent with hypertension and 55 boys with normotension who had parents with normotension. The sons of parents with hypertension had significantly greater intraventricular septum and posterior wall thickness, left ventricular mass, and cross-sectional area than the boys with normotension who had parents with normotension. Thus, target-organ damage–in this case, left ventricular hypertrophy (LVH)–was apparent prior to blood pressure elevation in young persons with a genetic predisposition to hypertension.

Neutel and colleagues (10) reported finding a number of abnormalities commonly associated with hypertension in subjects with normotension who were genetically predisposed to hypertension. These included increases in plasma insulin concentration, insulin-glucose ratio, plasma renin activity, total cholesterol level, creatinine clearance, and albumin excretion rate.

As noted, vascular remodeling and LVH are somewhat independent of the degree of elevated blood pressure and may even precede increased blood pressure. Some alterations in cardiovascular structure and function have been shown to precede a diagnosis of high blood pressure; these include LVH in children and young adults, coronary artery disease, and decreased arterial compliance (2,9,11). These myocardial and blood vessel changes do not always occur after blood pressure elevation, which suggests that they are not a response to that elevation. Rather, they appear to result from a complex array of genetic and environmental factors that also contribute to high blood pressure (9). Therefore, cardiac and vascular changes could be considered risk factors for cardiovascular disease rather than markers of established disease (8).

It appears that the combination of elements of the hypertension syndrome can determine the impact of elevated blood pressure for an individual patient. Several cardiovascular risk factors (eg, elevated cholesterol, LVH, obesity) are markedly more common in patients with borderline hypertension than in patients with normotension (table 1). This finding suggests that these pathologic abnormalities are associated with hypertension because of genetic or environmental factors.

In its sixth report, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (12) recommended either a beta-blocker or a diuretic as initial therapy for hypertension (table 2). However, the report also suggested that initial treatment selection should be modified if there are comorbid conditions such as diabetes, dyslipidemia, isolated systolic hypertension, or target-organ damage (evidenced by a history of myocardial infarction, heart failure, or renal damage). These conditions may occur in 50% to 90% of patients with hypertension. Thus, reduction of blood pressure is important but not optimal therapy in most–if not all–patients with hypertension. Indeed, the treatment goal should be reduction of as many risk factors as possible in patients with the hypertension syndrome.

Vascular remodeling

Accelerated atherogenesis is a key component of the hypertension syndrome. Pathologic changes in the blood vessels are seen in various other cardiovascular diseases. Hypertension also is associated with abnormalities in the small arteries, the major change being alterations in the media-lumen ratio (vascular remodeling) (8). Vascular remodeling can involve an increase in muscle mass (hypertrophy), which is an adaptive mechanism resulting from increased pressure, or by lumenal dilatation, the adaptive mechanism to increased flow. Both of these mechanisms are associated with rearrangements of cellular and noncellular elements (4). The changes occurring with vascular remodeling lead to shifts in compliance of the arterial wall.

Arterial compliance

Changes in vessel-wall function are described by many terms, including compliance, distensibility, stiffness, and elasticity (see box below). This review focuses on compliance, which is a function of distensibility, or elasticity. The compliance of an artery can be defined as the change in area or volume for a given change in pressure. Compliance depends on the ability of arteries to temporarily store the systolic blood volume to be delivered during diastole. This storage capacity converts intermittent flow to continuous flow, a phenomenon important at the tissue level. When the vessel wall loses its elasticity, pulse pressure is widened; this change is common in elderly patients and is characteristic of isolated systolic hypertension. Indeed, a widened pulse pressure has been associated with increased cardiovascular risk independent of systolic and diastolic blood pressures (13).

Left ventricular hypertrophy

Myocardial remodeling, most notably LVH, also is an important element in the hypertension syndrome. LVH is closely related to vascular remodeling and, as previously described, can occur with a reduction in vascular compliance. Epidemiologic evidence indicates that LVH is an important predictor of cardiovascular morbidity and mortality in patients with hypertension; the risk of adverse cardiovascular events increases with the severity of LVH (1).

Vascular change as a risk factor

Riley and associates (14) showed that decreased arterial elasticity was associated with other risk factors for cardiovascular disease, such as total serum cholesterol levels in adolescents who participated in the Bogalusa Heart Study. Furthermore, one measure of arterial stiffness, the pressure-strain elastic modulus, was associated with parental history of myocardial infarction or diabetes mellitus, or both, independent of both total cholesterol level and systolic blood pressure. This finding suggests that vascular elasticity (and thus remodeling) might be an important predictor of cardiovascular disease.

Ventura and colleagues (15) showed arterial compliance to be significantly reduced in patients with borderline hypertension. They found that arterial compliance became impaired very early in the disease process when blood pressure was only intermittently elevated; a 40% decrease in arterial compliance was associated with only a 14% rise in arterial pressure. Similarly, the recent Atherosclerosis Risk in Communities study of nearly 7,000 patients with normotension (16) found that a decrease of 1 SD in arterial elasticity increased the risk of hypertension by 15%, independent of baseline blood pressure and risk factors.

Reduced vascular compliance appears to be an early indicator of vascular disease, but it also is considered a possible mechanism in the initiation and progression of atherosclerosis and hypertension (6). It is important to distinguish changes in the la rterial compliance

Reduced compliance could be used as an early indicator of target-organ damage (eg, LVH) because it appears early in the course of hypertension. Bouthier and colleagues (17) showed that the left ventricular mass-volume ratio was significantly correlated with brachial artery compliance (but not diastolic blood pressure) in patients with hypertension.

Most methods of evaluating compliance are indirect. Brinton and associates (18) have developed a method to obtain pressure measurements by oscillometric recognition of the cuff signal pattern. Vascular compliance is derived from the incorporation of measurements of the rate of pressure change into a physical model of the brachial artery. Kim and Kim (19) measured changes in blood volume and pressure using impedance plethysmographic studies and a mercury sphygmomanometer, respectively. Compliance was then calculated by dividing the change in blood volume by the change in pulse pressure (systolic pressure minus diastolic pressure). Perret and colleagues (20) developed an ultrasonic device to determine arterial compliance as a function of blood pressure.

Other methods of determining compliance include pulse contour and Fourier analysis (21), pulse wave analysis with a modified Windkessel model (22), and evaluation of pressure wave contour from the carotid or radial site (23). There is no agreement on the best method. The only well-designed, large-scale prospective studies comparing abnormal compliance with cardiovascular outcomes are still in progress.

Antihypertensive therapy

Several types of antihypertensive therapy have shown some promise in improving arterial compliance.

• Diuretics

The effect of diuretics on arterial compliance is unclear. Girerd and colleagues (24) reported that 9 months of treatment with hydrochlorothiazide and amiloride in elderly hypertensive patients resulted in a significant increase in carotid artery compliance and a significant decrease in the thickness-radius ratio of the radial artery. However, Kool and associates (25) found that 6 months of treatment with the same combination of diuretics produced no significant change in the distensibility of the common carotid artery.

• Direct vasodilators

Direct vasodilators such as isosorbide dinitrate have promising beneficial effects on arterial compliance. Chau and colleagues (26) showed that administration of isosorbide dinitrate significantly increased arterial compliance, which probably resulted primarily from relaxation of vascular smooth muscle.

• Calcium antagonists

Calcium channel blockers, or calcium antagonists, have the potential to improve arterial compliance. Ting and colleagues (27) showed that treatment with nifedipine normalized aortic input impedance and increased compliance in patients with hypertension. However, Shimamoto and Shimamoto (28) found that 8 weeks of treatment with nifedipine was significantly less effective than the angiotensin-converting enzyme (ACE) inhibitor lisinopril in increasing compliance of the thoracic aorta in elderly patients with hypertension.

• Beta-Blockers

Beta-blocker therapy has shown variable effects on arterial compliance. Using a model of the arterial tree, Soma and colleagues (29) evaluated the effects of atenolol on arterial compliance in 30 patients with hypertension. After 4 weeks of therapy, arterial compliance increased by 42%. In contrast, Thybo and associates (30) reported that atenolol therapy had no significant effect on the media-lumen ratio of small arteries dissected from gluteal biopsy specimens.

• ACE inhibitors

Physiologic studies have shown that the ACE inhibitors captopril, lisinopril, and perindopril can greatly increase arterial compliance (24-26,28,30,31). As previously mentioned, Shimamoto and Shimamoto (28) saw a marked improvement in aortic compliance with lisinopril compared with nifedipine in elderly patients with hypertension. Chau and colleagues (26) found that captopril actively increased arterial compliance as a result of smooth-muscle relaxation. Kool and associates (25) found that 6 months of treatment with perindopril enhanced the compliance of the common carotid artery in patients with essential hypertension. Asmar and associates (31) reported similar results in 16 patients with hypertension who were treated for 3 months.

Thybo and colleagues (30) found that 12 months of perindopril therapy was associated with a significant reduction in the media-lumen ratio of small arteries. As previously mentioned, such an effect on vascular morphologic characteristics was not observed in patients treated with atenolol, even though this beta-blocker had a slightly greater blood pressure-lowering effect than perindopril. Sihm and associates (32) confirmed these findings and showed that the reduction in the media-lumen ratio with perindopril therapy had a significant correlation with a reduction in left ventricular mass as determined by echocardiographic studies.

The beneficial action of ACE inhibitors on hypertension and other cardiovascular diseases may be due to their action on the endothelium. The Trial on Reversing ENdothelial Dysfunction (33) showed that ACE inhibition with quinapril hydrochloride for 6 months improved endothelial dysfunction in patients with normotension who did not have severe hyperlipidemia or heart failure. The improvement in dysfunction may be due to attenuation of the contractile effects and superoxide-generating effects of angiotensin II and to enhancement of endothelial cell release of nitric oxide that occurs after decreased breakdown of bradykinin.

Summary and conclusion

Hypertension is part of a disease continuum that can begin with vascular or endothelial dysfunction and progress to elevated blood pressure and target-organ damage (figure 2: not shown). We now know that the hypertension paradigm is much more complicated than previously thought and can be a two-way street. Therefore, evaluation of arterial compliance can be important in the screening of patients at risk for hypertension and other cardiovascular diseases. Measurement of the compliance of both large and small vessels is now possible by several noninvasive methods, including impedance plethysmographic studies and sphygmomanometric measurements, ultrasound, oscillometric recognition of the cuff signal pattern, pulse contour analysis, and cuff sphygmomanometric studies. Evaluation of arterial compliance could allow early detection of vascular dysfunction and initiation of therapy to impede the process of vascular remodeling; the Treatment in Obese Patients With Hypertension substudy (34) is designed to address this possibility.

The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends either a diuretic or a beta-blocker as initial therapy for hypertension. However, the report also suggests that certain complications commonly associated with this disease should prompt selection of alternative therapies, including alpha-blockers, calcium antagonists, and ACE inhibitors. Studies suggest that arterial stiffness is another important consideration in the selection of antihypertensive therapy and that it should be added to the list of comorbid conditions that influence treatment selection.

Therapy with agents that can increase compliance and inhibit or reverse vascular remodeling has the potential to combat vascular dysfunction even before blood pressure is elevated. A formal cost-efficacy analysis of the use of therapy before blood pressure is elevated has not been performed, but therapy may be cost-effective in terms of cardiovascular events averted.

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