Edward D. Frohlich Dink Susic
Ochsner Clinic Foundation, New Orleans, La., USA
It is generally accepted that the increased cardiovascular morbidity and mortality in hypertension are related to target organ damage. Classically, the target organs are heart, brain, and kidneys. This brief report examines whether high arterial pressure may also affect other organs, such as aorta and large arteries. An attempt was also made to elucidate the relationship between disorders of the aorta and large arteries and other cardiovascular risk factors to the pathophysiology and treatment of patients with hypertension and its severe comorbid disease, atherosclerosis.
Copyright © 2007 S. Karger AG, Basel
High Blood Pressure and Disorders of the Aorta and Large Arteries
The positive correlation between arterial pressure and adverse cardiovascular events is certainly well documented. It was Sir George Pickering who vigorously opposed the idea of dividing blood pressure into normotension and hypertension stating that '...the various complications, like myocardial infarction and stroke, are also quantitatively related to arterial pressure...' . Furthermore, current therapeutic approaches to cardiovascular disorders are firmly based on this relationship. It thus seems prudent to start the discussion on the relationship between blood pressure and pathophysiology of large arteries by exploring the pressure as a risk factor.
The two most common disorders affecting aorta and large arteries are atherosclerosis, which starts with patchy intimal changes eventually leading to ischemic events distally, and arteriosclerosis, usually consisting of diffuse changes in the media leading to increased vessel stiffness and impairments in conduit and 'windkessel' functions of aorta and large arteries. Both conditions are common in older individuals and often coincide. Still open is the question whether the two diseases may exacerbate one another. Theoretically, there are reasons to believe they do but, since they usually coexist, causality is not easy to prove. Thus, arteriosclerosis increases systolic and pulse pressure, which could intensify endothelial damage and in this way may facilitate the formation of plaques. Similarly, atherosclerosis affects morphology and vascular function, and this may affect arteriolar stiffness. It should be noted, however, that since atherosclerosis may be a patchy disease throughout the aorta and large arteries, and non-invasive techniques are used to estimate and measure stiffness in large segments, all of the plaques probably do not affect actual measurements unless they are very abundant, coalescent, and calcified. On the other hand, the hyperlipidemias adversely affect endothelial function and may therefore increase arterial stiffness. However, in young patients with familial hypercholesterolemia, as well as in the early stages of experimental diet-induced atherosclerosis, aortic distensibility may be actually increased, not decreased [2, 3], Similarly, arterial wall stiffness has been shown to be reduced around lipid-laden plaques . Yet, later in the course of experimental atherosclerosis  as well as in older hypercholesterolemic patients , aortic disten-sibility is decreased. A number of other studies reported controversial results leading to a present conclusion that the interaction between arteriolosclerosis and atherosclerosis still remains to be clarified.
Atherosclerosis is a chronic inflammatory condition that results in formation of an atherosclerotic plaque which, in turn, compromises circulation distally, by vascular occlusion as result of its bulk or by thromboembolic events after rupturing. Hypertension is a known risk factor for atherosclerosis . The compelling link between the two is the vascular endothelium. Atherosclerosis is an extremely complex process that is initiated by endothelial damage facilitated by, among other factors, an increased arterial pressure . The first step in the process is the formation of fatty streaks subendothelially. This pathological derangement starts with lipoprotein (LDL) transport into the arterial wall and its subsequent entrapment in the extracellular matrix. The entrapped LDL is then oxidized and stimulates endothelial cells to secrete various adhesion molecules and chemokines. These attract monocytes that first adhere to the endothelium and then migrate into the subendothelium where they accu mulate lipids and transform into foam cells. The activated monocytes release mitogens and chemokines which attract more monocytes and vascular smooth muscle cells. These events lead to formation of atherosclerotic plaques which contain foam cells and activated macrophages and which are structurally unstable due to epithelial injury and the presence of inflammatory cells. Hemo-dynamic shearing forces, that are even more intense in hypertension and when pulse pressure is increased, can induce plaque rupture, usually at its more proximal point where the shearing forces are intensified. Rupture of the plaque predisposes the flowing blood to the highly thrombogenic constituents of the plaque, thereby leading to thrombus formation and possible embolization. Plaque formation, rupture, and subsequent thrombosis are therefore the major causes of acute cardiovascular events (myocardial infarction, stroke, death).
Decreased distensibility of the aorta and large arteries is routinely found in hypertensive patients regardless of the site or method of measurement . Whether this reduction in distensibility is merely due to an increased distending pressure, or is true increased stiffness due to hypertension-induced structural modifications of the arterial wall, remains a matter of considerable debate and investigation . The reasons for the divergent findings are numerous. Apart from the fact that different indexes (pulse pressure, pulse wave velocity, augmentation index, etc.) and different devices are used to estimate arterial stiffness, there are also many other factors that may affect the results. Thus, different vessels may be affected differently by the disparate factors that participate in the two diseases. In one study, a comparison of the properties of common carotid and femoral arteries in normotensive and hypertensive subjects was made . Diameter-pressure curves in carotid and femoral arteries were first determined and, from these measurements, effective compliance and distensibility at the prevailing pressure of each subject and isobaric compliance and distensibility at the same standard pressure in all subjects were calculated. The results demonstrated that, in the carotid artery, hypertensive patients had isobaric compliance and distensibility values that were similar to those of normotensive subjects. However, when determined at actual pressures, the vessels had lower effective compliance and distensibility. On the other hand, hypertensive patients had both effective and isobaric femoral compliance and distensibility values which were lower than normotensive subjects . It is also possible that additional co-existing conditions can affect the distensibility of large arteries in the hypertensive population. Thus, one very recent study indicated that the 'metabolic syndrome' may adversely affect aortic stiffness in hypertensive patients . This study population involved never-treated, non-diabetic, middle-aged patients with essential hypertension who were classified according to the presence or absence of the metabolic syndrome. As an estimate of stiffness, pulse wave velocity was determined in the aorta and upper limb. Aortic pulse wave velocity was found to be higher in a group with metabolic syndrome, whereas upper limb velocity did not differ between the groups. Interestingly, this same study demonstrated that central, but not general, adiposity was an important determinant of aortic stiffness.
It also appears that the effect of high blood pressure on arterial distensibil-ity is not uniform. Thus, some earlier studies [12-14] demonstrated that arterial compliance may be different within different hypertensive populations. Two studies evaluated arterial compliance using three indices: pulse wave velocity, pulse pressure/stroke volume and analysis of diastolic pressure decay [12, 13]. The results demonstrated decreased compliance in hypertensive patients, particularly in the elderly . Moreover, signs of impaired compliance were found even in patients with borderline hypertension . Another study  examined pulse wave velocity, compliance, and impedance of brachial artery in normotensive subjects and patients with uncomplicated essential hypertension. Compared to normotensive controls, hypertensive patients were found to have increased pulse wave velocity. However, when the results were related to diastolic pressure and age of the subjects, the data of the majority of hypertensive patients fell within nomograms obtained from normotensive subjects. Yet, a subgroup of hypertensive individuals still demonstrated higher pulse wave velocity, decreased arterial compliance, and increased impedance, suggesting excessive arterial stiffness. This non-uniform change in arterial stiffness in hypertensive individuals may be due to individual differences but it may also reflect differences in the duration of hypertension. Recently, results of the Bogalusa Heart Study clearly indicated that childhood blood pressure predicted arterial stiffness in adulthood . This particular study was conducted in over 800 black and white adults of both sexes who had at least four measurements of traditional risk factors with an average follow-up period of over 26 years. As an estimate of arterial stiffness, brachial-ankle pulse wave velocity was determined. The results further demonstrated that pulse wave velocity was higher in males than in females and in blacks than in whites. When multiple regression analysis was applied, systolic blood pressure in childhood was found to be an independent predictor of increased pulse wave velocity in young adults, in addition to serum cholesterol and triglyceride concentrations and a history of smoking . These findings underscore the importance of the height of arterial pressure over the long term in the evolution of arterial stiffness. Two other earlier studies further support these findings [16, 17]. Data from the Framingham Heart Study showed that untreated hy pertension may accelerate the rate of large artery stiffness . Thus, when compared with normotensive subjects, middle-aged and elderly patients with untreated hypertension were more likely to present with an age-related increase in pulse pressure, suggesting increased arterial stiffness . A more recent, longitudinal study compared the progression of aortic stiffness over a 6-year period in treated hypertensive and normotensive subjects and evaluated the determinants of this progression . Carotid-femoral pulse wave velocity was used as an index of aortic stiffness. The results indicated that the annual rates of progression in aortic stiffness were significantly higher in hypertensive than in normotensive subjects. The exceptions were hypertensive subjects with well-controlled arterial pressure levels which were similar to the stiffness progression of normotensives. In addition to high arterial pressure, other determinants of stiffness progression were a faster heart rate and a higher serum creatinine concentration.
In addition to the evidence that hypertension leads to accelerated arterial stiffening, there is also strong evidence that arterial stiffness may affect the development of high blood pressure. Thus, one very recent study  demonstrated that aortic stiffness in normotensive individuals was a predictor of future hypertension after correction for risk factors including systolic pressure, age, sex, body mass, heart rate, total serum cholesterol concentration, diabetes, smoking, alcohol consumption, and physical activity. This relationship was noted in younger and older subjects and for both sexes. Thus, elevated arterial pressure and arterial stiffness may apparently aggravate each other, establishing a vicious circle that is ultimately responsible for the adverse age- and pressure-related cardiovascular events.
The observed direct correlation between arterial pressure and stiffness of large arteries later in life provides some important implications. An analysis of the life course in terms of total life expectancy or life expectancy with or without cardiovascular disease was made in over 3,000 Framingham Heart Study participants according to their arterial pressure level at the age of 50 . As compared with hypertensive subjects, total life expectancy was 5.1 and 4.9 years longer for normotensive men and women, respectively. Furthermore, the normotensive men survived 7.2 years longer without cardiovascular disease compared with hypertensive subjects . These findings clearly indicate that increased arterial pressure in adulthood is associated with a large reduction in life expectancy and increased prevalence of cardiovascular disease. As already stated, high blood pressure in adulthood is also associated with greater arterial stiffness later in life. Thus, increased arterial stiffness may be related to lower life expectancy and higher cardiovascular morbidity that was observed in hypertensive subjects .
Arterial Stiffness, Target Organ Damage, and Risk of Atherosclerotic
Until recently, large artery stiffening with consequent increases in systolic and pulse pressures has been considered as a part of normal aging. However, over time, evidence has accumulated to demonstrate that arterial stiffness is a strong independent predictor of adverse cardiovascular events. Numerous studies in different populations, particularly in the elderly, have shown that it is a major risk factor for stroke, coronary heart disease, cardiovascular and total mortality [21, 22]; Furthermore, in addition to being an established risk factor, increased vascular stiffness is now becoming a potential therapeutic target, particularly in patients at risk of cardiovascular disease. Of course, even before vascular stiffness becomes a legitimate therapeutic target, it should be clearly demonstrated that reduction of arterial stiffness also reduces cardiovascular risk independent of the effects of treatment. Thus far, there have been few large-scale reports that have conclusively demonstrated that reduction of vascular stiffness reduces the adverse cardiovascular events irrespective of other effects. The one exception that indirectly supports this notion is a study that involved 150 patients with end-stage renal disease who were given antihypertensive medication ; Pulse wave velocity was measured in all patients before and during treatment. Fifty-nine deaths occurred during the study, 40 related to cardiovascular and 19 to non-cardiovascular causes. There were several predictors of all causes, with cardiovascular mortality with absence of pulse wave decrease in response to arterial pressure lowering being the strongest. These findings clearly indicated that arterial stiffness is a cardiovascular risk factor independent of arterial pressure.
A number of cardiovascular drugs have been shown to affect arterial stiffness. Many of these agents also lower arterial pressure which, by itself, also increases arterial distensibility. Therefore, this effect must be differentiated from any functional or structural effects of these drugs on arterial wall stiffness. The angiotensin-converting enzyme (ACE) inhibitors, angiotensin (type 1) receptor antagonists, and some of the calcium antagonists have been shown to be effective in improving vascular stiffness, although the ACE inhibitors seem to be more effective than others ; On the other hand, the dual ACE and neutral endopeptidase inhibitor omapatrilat was shown to be more effective than enalapril in reducing aortic stiffness ; Statins have also demonstrated the ability to reduce arterial stiffness ; Most of these drugs also improve endothelial dysfunction and this effect may actually mediate their effect on vascular distensibility. There are also some novel approaches to treating arterial stiffness. Thus, advanced glycation end-product crosslinks are considered significant contributors to increased arterial stiffness in the elderly. A crosslink breaker has been shown to improve arterial distensibility in older patients . In old spontaneously hypertensive rats the same crosslink breaker was shown to increase aortic distensibility and improve survival .
In summary, this report examined the relationship between the disorders of the aorta and large arteries and some other cardiovascular risk factors. Evidence was presented to demonstrate that hypertension aggravates age-related stiffening of the aorta and large arteries. Available data also suggest that arterial stiffness is an independent cardiovascular risk factor. Finally, the effects of commonly used cardiovascular drugs were briefly discussed.
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Edward D. Fröhlich, MD Ochsner Clinic Foundation 1514 Jefferson Highway New Orleans, LA 70121 (USA)
Tel. +1 504 842 3700, Fax +1 504 842 3258, E-Mail [email protected]
Section II - Arterial Stiffness, Atherosclerosis and End-Organ Damage
Safar ME, Frohlich ED (eds): Atherosclerosis, Large Arteries and Cardiovascular Risk. Adv Cardiol. Basel, Karger, 2007, vol 44, pp 125-138
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