Info

Stiff Compliant

Fig. 2. The change in hyperemic coronary blood flow following percutaneous coronary intervention in patients categorized as having a stiff aorta (central pulse wave velocity ~9 m/s), and as having a compliant aorta (central pulse wave velocity ~6 m/s). Data are presented as mean ± SEM. * p = 0.002 [adapted from 8].

Fig. 2. The change in hyperemic coronary blood flow following percutaneous coronary intervention in patients categorized as having a stiff aorta (central pulse wave velocity ~9 m/s), and as having a compliant aorta (central pulse wave velocity ~6 m/s). Data are presented as mean ± SEM. * p = 0.002 [adapted from 8].

induces endothelial dysfunction as indexed by acetylcholine reactivity [27] and may thus be an antecedent of coronary atherosclerosis.

Regardless of whether large artery stiffness is a marker of coronary atherosclerosis or actually contributes to its development, it would be expected to also have independent detrimental effects on the relationship between myo-cardial blood supply and demand. Elevated pulse pressure secondary to large artery stiffening could affect coronary outcomes through increased systolic pressure and thus afterload [28]. Chronic afterload elevation would likely lead to development of left ventricular hypertrophy [29-31] and a reduction in capillary to myocyte ratio [32]. Coronary perfusion is also likely to diminish secondary to diastolic pressure reduction. Indeed, it has been elegantly demonstrated in a dog study that ejection into a stiff aortic bypass increases pulse pressure and the energetic cost to the heart to maintain adequate cardiac output [33]. In addition, subendocardial perfusion was particularly compromised when ejection was into a stiff aorta in the setting of an applied coronary stenosis [34] [ These data demonstrate that elevation in aortic stiffness tightens the link between cardiac systolic performance and myocardial perfusion [35]. The clinical relevance of this experimental modeling has recently been demonstrated by Leung et al. [8]. In patients undergoing routine percutaneous coronary intervention, those with stiffer aortas had lower coronary blood flow, lower hyperemic coronary blood flow response and a smaller improvement in the hyperemic coronary blood flow after a successful intervention [8] [ In this

Fig. 3. Univariate correlations between arterial stiffness indices and time to ST segment depression of 1.5 mm (time to ischemia). All data are adjusted to the mean age of the group (62 years) using the slope of the univariate relationship between each variable and age. The full regression equations for SAC («) and AI (b) are: Time to ischemia = -7.47 • age + 179 • SAC + 738; Time to ischemia = -7.90 • age - 2.53 • AI + 910. AI = Augmentation index; SAC = systemic arterial compliance [adapted from 9].

Fig. 3. Univariate correlations between arterial stiffness indices and time to ST segment depression of 1.5 mm (time to ischemia). All data are adjusted to the mean age of the group (62 years) using the slope of the univariate relationship between each variable and age. The full regression equations for SAC («) and AI (b) are: Time to ischemia = -7.47 • age + 179 • SAC + 738; Time to ischemia = -7.90 • age - 2.53 • AI + 910. AI = Augmentation index; SAC = systemic arterial compliance [adapted from 9].

study the patients were dichotomized into those with low (~6 m/s) and high (~ 9 m/s) pulse wave velocity. Those with lower pulse wave velocity (more compliant arteries) had a dramatic threefold greater coronary hyperemic response after their percutaneous coronary intervention (fig. 2). That this mechanism impacts on physical capacity has been demonstrated by the finding that for any given degree of coronary disease, patients with stiffer large arteries have a lower ischemic threshold during a standard treadmill test [9] (fig. 3). In this study, when the mean systemic arterial compliance of 0.43 was increased to 0.53, the average time to ischemia would increase by 18 s (calculations made for the population mean age of 62 years, fig. 3a), whereas a reduction in the mean augmentation pressure of 23% to 18% increased time to ischemia by 13 s (fig. 3b). Thus the influence of stiffness on ischemic time was modest, but nevertheless measurable. Large artery stiffness is therefore likely to contribute to ischemic risk and be a potential therapeutic target for individuals with coronary disease.

The importance of large artery stiffening as an ischemic mechanism also depends on the prevalence of isolated systolic hypertension and its co-occurrence with coronary artery disease. Isolated systolic hypertension affects 26% of the population over 55 years of age [36], and is a strong predictor of cerebrovascular and cardiac events [28, 37-39]. For males and females aged between 25 and 64 with isolated systolic hypertension, the relative coronary risk is 1.5 and 2.2 respectively, compared to normotensive subjects [28]. The incidence of isolated systolic hypertension amongst those with clinically significant coronary disease is more difficult to quantify. As discussed in the previous section, the close relationship between large artery stiffness and atherosclerotic coronary disease suggests that the majority of coronary patients would have elevated large artery stiffness and therefore pulse pressure. While this elevation will not always fall into the range to be categorized as isolated systolic hypertension, pulse pressure elevation would nevertheless influence ischemic threshold.

Arterial Stiffness as Therapeutic Target in Ischemic Coronary Artery Disease

At present there are no clinically available agents which specifically target the large arteries. However, many conventional cardiovascular therapies, both pharmacological and non-pharmacological, reduce large artery stiffness, and clinical trials of more specific agents are underway. Arterial stiffness can be reduced both via passive (functional) mechanisms and through structural changes to the arterial wall. Functional reduction in arterial stiffness can be achieved through lowering mean arterial pressure or through vasodilation, which alters the relative loading of collagen and elastin in the arterial wall [40]. All antihypertensive and vasodilator agents reduce arterial stiffness via this mechanism. Many agents in these classes and others also influence arterial wall structure and thus biomechanical properties directly. The following section will briefly discuss the interactions of drugs commonly prescribed for treatment of the symptoms of ischemic coronary disease with respect to large artery stiffness and the implications for ischemia and outcome. In addition to their more direct actions, those agents which reduce large artery stiffness are likely to have additional benefit with regard to raising ischemic threshold. This would relate to reduction in pulse pressure and afterload and elevation in coronary perfusion. In the long term this hemodynamic profile might also be favorable with respect to limiting atherosclerotic progression and reducing risk of coronary plaque destabilization and rupture. The effect of drugs used to treat risk factors to improve cardiovascular outcomes are discussed in Section IV of this book.

Nitrates

Nitrates are an important anti-ischemic therapy which are thought to act, at least in part, through release of nitric oxide, although there is currently some controversy surrounding this issue [41, 42]. There is good evidence that under basal conditions, nitric oxide acts to lower both pulse wave velocity and arterial wave reflection [43]. Nitrate drugs would therefore be expected to reduce large artery stiffness and wave reflection. Acute administration of isosorbide dinitrate to untreated hypertensive individuals increased systemic arterial compliance and reduced peripheral wave reflection [44]. This effect was likely secondary to a reduction in mean arterial blood pressure [44]. Similarly, glyceryl trinitrate reduces arterial stiffness acutely in hypertensive patients [45]. In a double-blind randomized placebo-controlled study, isosorbide dinitrate resulted in a reduction in office and ambulatory pulse pressure following 8 weeks of treatment, without a reduction in diastolic blood pressure [46] in patients with isolated systolic hypertension. Similar hemodynamic findings have also been observed with the use of nitroglycerin or molsidomine (a glycosidase-ac-tivated nitric oxide donor) in hypertensive patients [47]. The fact that nitrates decrease pulse pressure whilst having no effect on diastolic blood pressure suggests that these agents act mainly on large arteries rather than on small resistance vessels. The blood pressure-lowering effects of chronic nitrate therapy would certainly be expected to mediate reduction in large artery stiffness [48]. In addition, studies in minipigs suggest that chronic nitrate therapy may also improve the viscoelastic properties of the arterial wall [49].

Potassium Channel Openers

Like nitrates, the ATP-sensitive K+ channel opener, nicorandil, causes vasodilation with subsequent reduction in preload and afterload, and an increase in coronary blood flow. Only a single study has examined the effect of nicorandil on biomechanical artery properties and this was in the periphery. Acute administration of nicorandil reduced brachial artery stiffness as demonstrated by a decrease in brachioradial pulse wave velocity [50]; This was likely mediated by a reduction in mean arterial blood pressure.

f5-Blockers

P-Blockers improve symptoms of angina and are commonly prescribed for the treatment of ischemic heart disease. It is generally accepted that P-blockers with vasodilator actions including pindolol, dilevalol, celiprolol and nebivolol have greater efficacy in reducing large artery stiffness than non-va-sodilating P-blockers (e.g., atenolol) [51-55]; It is likely that blood pressure reduction may provide benefit, including ischemic protection through reduction in arterial stiffness [53]. Chronic therapy with dilevalol or atenolol for 12 weeks reduced arterial stiffness, while the vasodilator actions of dilevalol had the added benefit of reduction in wave reflection [53]. The selective p1-block-ing agent, bisoprolol, has also been shown to reduce both blood pressure and artery stiffness with chronic treatment [56]. Vasodilating (highly-selective P1-adrenoceptor antagonist) P-blockers such as nebivolol, but not atenolol which is non-vasodilating, reduce arterial stiffness in sheep [57]. P-Blockers are also commonly prescribed in Marfan syndrome to limit aortic dilation. However, the effect of P-blockade on arterial stiffness in this population is somewhat controversial. In both acute [58] and long-term studies of aortic stiffness [59] in Marfan syndrome, P-blockers reduce wall stiffness only in those patients with normal or mildly increased aortic dimensions. In patients with significant aortic dilatation, an increase in wall stiffness is seen with P-blockade. Such an effect could be potentially detrimental in these patients [58]; Thus from the perspective of arterial stiffness, P-blockers with vasodilating activity are likely to be most effective in patients with normal or only mildly elevated aortic dimensions.

Calcium Antagonists

Calcium antagonists cause dilation of epicardial conduit vessels (thus relieving vasospastic angina) and of arterial resistance vessels. They also reduce systemic vascular resistance and arterial pressure and thereby myocardial oxygen demand. Chronic calcium antagonist therapy is generally accepted to reduce arterial stiffness on par with other antihypertensive agents including an-giotensin-converting enzyme inhibitors and diuretics [39, 60, 61]; However, there is some evidence that calcium channel blockers may have structural effects on the arterial wall and reduce stiffness by mechanisms additional to blood pressure reduction. In a study comparing 12 weeks of treatment with the calcium channel blocker felodipine or the diuretic hydrochlorothiazide in hypertensive patients, felodipine reduced central and peripheral pulse wave velocity, whereas hydrochlorothiazide did not [62]. Both drugs had similar effects on blood pressure, suggesting that calcium channel blockers may exert direct arterial wall effects. Similarly, peripheral compliance was improved by the calcium channel blocker nicardipine but not by the ^-blocker atenolol in hypertensive patients following 8 months of treatment eliciting similar blood pressure effects [63].

Antiplatelet Therapy

Few studies have examined the effects of chronic aspirin therapy on arterial properties. While aspirin treatment at 325 mg/day for 1 week has been associated with a detrimental effect on wave reflection [64], chronic low dose aspirin (100 mg/day) had no significant effect on augmentation index and wave reflection patterns in two studies [64, 65]. On the other hand, low-dose aspirin has slight antihypertensive effects when administered in the evening [66]. Such an effect would be expected to contribute to a reduction in large artery stiffness. It is possible that aspirin could mediate effects on arterial stiffness via its anti-inflammatory actions which decrease arterial tone [67]. It has recently been shown that inflammation caused by Salmonella typhi vaccination increases pulse wave velocity [68]. In reducing acute inflammation, aspirin may therefore reduce arterial stiffness . 68]. Whether other antiplatelet agents affect arterial properties is unknown.

Experimental Therapies Which May More Directly Target the Large

Arteries

Compliance of the arterial wall is dependent on two primary scaffolding proteins, collagen and elastin. Dysregulation in the production and degradation of these two molecules can lead to overproduction of abnormal collagen and reduced quantities of normal elastin, contributing to increased arterial stiffness. In addition, irreversible non-enzymatic cross-linking of arterial matrix components can be caused by advanced glycation end products (AGEs) [69]. Drugs which prevent cross-link formation or break existing cross-links are in development. Aminoguanidine, which inhibits cross-link formation, improves arterial compliance and reduces pulse wave velocity; however, high doses can result in glomerulonephritis [70]. Alagebrium or ALT-711 is an AGE cross-link breaker and reverses arterial stiffening without influencing blood pressure in animal models [71]. Furthermore, in a randomized, clinical trial in patients with elevated pulse pressure, ALT-711 significantly reduced pulse pressure and pulse wave velocity and increased arterial compliance [72]. AGE breakers would be expected to have particular efficacy in patients with diabetes. However, non-diabetic individuals with coronary disease are known to have elevated AGE levels proportional to the number of diseased vessels [73] and these individuals may also benefit. Clinical trials are currently underway to examine the effect of ALT-711 on large artery stiffness in patients with coronary artery disease, diabetes and isolated systolic hypertension [74]. Finally, since genetic modulation of extracellular matrix components and matrix me-talloproteinases contribute to atherosclerotic differences in large artery mechanical properties, these proteins may be important targets for therapy [23, 24, 75].

To summarize: Large artery stiffening is closely related to coronary atherosclerosis and outcome. Parallels in atherosclerotic burden between these beds likely explain part of this relationship. In addition, large artery stiffness per se promotes an unfavorable hemodynamic profile which may cause endo-thelial disruption, which further promotes the atherosclerotic process. Furthermore, studies in both animals and man indicate that large artery stiffening promotes a mismatch in cardiac blood supply and demand through pulse pressure elevation. Many agents commonly used to treat ischemic heart disease symptoms including nitrates, aspirin, vasodilating adrenergic antagonists, calcium antagonists and potassium channel openers, reduce large artery stiffness, at least in part, through reduction in mean arterial pressure. Some of these agents may also have structural effects on the arterial wall which influence arterial biomechanical properties. AGE breakers such as ALT-711 have shown promise in directly reducing large artery stiffness via structural effects. It remains to be determined whether agents specifically targeted to reduce large artery stiffness provide ischemic protection in the setting of coronary disease.

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Bronwyn Kingwell, A/Prof. Baker Heart Research Institute PO Box 6492, St Kilda Road Central Melbourne, Vic 8008 (Australia)

Tel. +61 3 9276 3261, Fax +61 3 9276 2461, 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 139-149

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