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Skip Navigation Linksראשי > רשימת כתבי עת > Cardiology Updates And Reviews - גליון מס' 3 > Management of Arterial Stiffness
אוקטובר 2009 October | גיליון מס' 3 .No
צור קשר
חברי מערכת
רשימת גליונות קודמים
שער הגליון

Management of Arterial Stiffness


Relu Czernes, Reuven Zimlichman, Marina Shargorodsky

 
Abstract
Cardiovascular (CV) disease is the commonest cause of mortality in hypertensive and diabetic patients. Arterial stiffness of the large arteries is a usual feature of aging and is increased by a number of disorders such as hypertension, diabetes, and renal disease. Arterial stiffness is an independent predictor of CV mortality and can be measured through non-invasive techniques involving computed tomography, pulse-wave contour analysis, ultrasound, echocardiography, plethysmography, and pulse wave velocity. Consequently, this review summarizes lifestyle changes and therapies that improve arterial compliance, including weight loss, exercise, salt reduction, alcohol consumption, and neuroendocrine-directed therapies, such as those targeting the renin-angiotensin aldosterone system, bisphosphonates, insulin modulators, as well as novel therapies that target advanced glycation end products and matrix metalloproteinases.
Key words: Arterial Stiffness; Therapy; Diet; Hypertension; Arterial Compliance

Lifestyle Modifications and Nonpharmacologic Therapies
Several dietary changes can ameliorate arterial compliance. Flavonoids are antioxidant substances abundant in fruit, vegetables and dark chocolate that may reduce arterial stiffness (1,2). Restriction of dietary sodium, moderate alcohol consumption and reducing cigarette and cigar passive and active smoking also have a beneficial effect on arterial compliance. Apart from water, tea and coffee are the most widely consumed beverages worldwide, but one of them improves arterial compliance and the other decreases it. More than three cups of coffee consumption has a detrimental effect on aortic stiffness and wave reflections in healthy subjects. When smoking follows caffeine intake, it augments the unfavorable effect on aortic compliance (3,4). Black and green tea consumption rich in antioxidant flavonoids has a beneficial effect on endothelial function (5,6).
 Regular aerobic exercise (walking, jogging or swimming) may also result in better arterial elasticity (1,7). In healthy sedentary adults, aging is associated with increased stiffness (reduced compliance) of large elastic arteries, impaired vascular endothelial function, including reduction in endothelium-dependent dilatation and increased intima-media wall thickness (IMT). Habitual physical activity/increased aerobic exercise capacity is associated with a lower risk of CV diseases. Compared with their sedentary peers, adults who regularly perform aerobic exercise demonstrate smaller or no age-associated increases in large elastic artery stiffness, reduction of vascular endothelial function, and an increase of femoral artery IMT (8). A modest increase in exercise intensity and frequency has a hypotensive effect in sedentary hypertensive patients. Long-term training improves endothelium-dependent dilatation of the aorta and resistance of cardiac arteries, whereas short-term training increments endothelial function in coronary conduit arteries (9). Acute mental stress results in prolonged deterioration of aortic stiffness and wave reflection. Mental stress is an inherent element of everyday life. Chronic and acute mental stress is associated with higher pulse wave velocity, atherosclerosis, and coronary artery disease and may even lead to myocardial infarction or sudden cardiac death. Conversely, positive behavior and laughter decrease pulse wave velocity and augmentation index (10,11).
 Rapid weight loss in patients with morbid obesity and cardiovascular risk factors who underwent laparoscopic adjustable gastric banding, was found to be associated with improvement of small artery compliance (12). Data on the long-term vascular impact of intentional weight loss are limited. A very recent prospective study evaluated the effect of weight loss induced by nutritional and exercise intervention on arterial compliance, metabolic and inflammatory parameters in obese patients who participated in a weight reduction program. Arterial elasticity was evaluated using pulse-wave contour analysis (HDI CR-2000, Eagan, Minnesota) at baseline and at the end of the study. Moderate weight loss induced by nutritional and exercise intervention improves small and large artery elasticity. Augmentation of arterial elasticity was associated with improvement in glucose and lipid homeostasis as well as inflammation markers (13).
 The clinical benefits of enhanced external counterpulsation therapy in chronic stable refractory angina patients who fail to respond to conventional therapy, like percutaneous coronary intervention or bypass surgery combined with aggressive antianginal medication, include reduction of angina episodes, nitrate use and improvement in exercise tolerance and quality of life. In a recent study enhanced external counterpulsation treatment improved the augmentation index (AI) and pulse wave velocity (PWV) (14).

Current Antihypertensive Drugs
Interventional studies regarding the effect of drugs on arterial compliance are rare. Captopril, propranolol and amlodipine significantly reduced PWV compared with placebo, whereas verapamil had no acute effect on arterial stiffness (15,16). Nitroglycerin had a highly significant effect on AI, but only a minor effect on PWV, suggesting that the former parameter may be more useful in pharmacological studies (17). Nebivolol, a selective beta1-adrenoreceptor blocker with antioxidant properties, lowers mean aortic pressure and amplifies arterial compliance (18). Spironolactone prevents accumulation of aortic and myocardial collagen, independent of BP changes, in spontaneous hypertensive rats. The selective mineralocorticoid receptor blocker eplerenone diminishes arterial stiffness of resistant arteries, decreases collagen/elastin ratio and reduces circulating inflammatory mediators in hypertensive patients after one year of treatment (19,20).
 In hypertensive patients assessing the multiple effects of the RAA (Renin-Angiotensin-Aldosterone) axis on the endothelium, RAA inhibition seems particularly attractive in reducing arterial stiffness. Compared with a thiazide diuretic, losartan significantly improved AI. In patients with essential hypertension, both ACE inhibition and blockade of angiotensin receptor 1 reduced arterial stiffness. Valsartan ameliorates arterial compliance of both large and small vessels in patients with essential hypertension (21). Treatment with high doses of candesartan (32 mg) lessens arterial stiffness to a greater extent than conventional doses of candesartan (16 mg), despite comparable changes in blood pressure (22).
 The complementary vascular mechanism of dihydropyridine calcium channel blockers and inhibitors of the renin-angiotensin system have been shown to be more effective in improving endothelial dysfunction than treatment with drugs from either class alone (23). Different blood pressure (BP)-lowering drugs could have different effects on central aortic pressure and thus cardiovascular outcome, despite similar effects on brachial BP. The Conduit Artery Function Evaluation (CAFE) study, a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), examined the impact of 2 different BP lowering-regimens (atenolol-thiazide based versus amlodipine-perindopril based therapy) on derived central aortic pressures and hemodynamics. Radial artery applanation tonometry and pulse wave analysis were used to derive central aortic pressures and hemodynamic indexes on repeated visits for up to 4 years. Despite similar brachial systolic BPs between treatment groups, there were substantial reductions in central aortic pressures with the amlodipine regimen. BP-lowering drugs can have substantially different effects on central aortic pressures and hemodynamics despite a similar impact on brachial BP, and differences in central aortic pressures may be a potential mechanism explaining why the amlodipine-based regimen prevented more major cardiovascular events than the atenolol-based regimen (24,25).
 The synergic effect is also pronounced by the “dual” blockade of the RAA system (26,27). One year of dual blockade with candesartan and lisinopril in type 2 diabetic patients significantly decreased pulse pressure when compared with high-dose monotherapy with lisinopril (28). Telmisartan has been shown to be characterized by antihypertensive efficacy fully covering the 24-hour period, thereby allowing antagonizing the adverse effects of early morning BP rise on cardiovascular risk. Furthermore, it has a favorable metabolic profile (particularly on insulin sensitivity) and neutral effects on sympathetic cardiovascular function. Due to these properties, telmisartan diminishes cardiac and vascular organ damage, lowers arterial stiffness, improves vascular distensibility and reverses endothelial dysfunction (29). It was hoped that that the addition of ramipril to telmisartan would provide better heart and kidney protection. However, the recent findings in the ONTARGET (Renal Outcomes With Telmisartan, Ramipril, or Both, in People at High Vascular Risk) study of significantly more doubling of creatinine and dialysis in the combination arm despite less albuminuria argues against nephroprotective effects of the dual renin-angiotensin system (RAA blockade). In heart failure, dual RAA blockade was associated with more hypotension, worsening of renal function, and hyperkalemia than was angiotensin-converting enzyme inhibitor therapy alone (30).

Other Drugs
Treatment with rosiglitazone has reduced hyperinsulinemia and improved small artery elasticity with a tendency to improve large artery elasticity, in hypertensive as well as in normotensive patients. Rosiglitazone causes better insulin receptor sensitivity (IRS), a finding which supports the hypothesis that hyperinsulinemia and IRS participate in the mechanisms of tissue injury and their improvement induces improvement in arterial elasticity (31). Prolonged treatment with rosiglitazone improves arterial elasticity. However, significant deterioration in large and small artery compliance is observed in patients who discontinue rosiglitazone. The beneficial vascular effect of rosiglitazone on arterial elasticity is independent of glycaemic control (32).
 Therapy with statins also may improve arterial stiffness. Recent investigations have shown that PWV improved after fluvastatin and atorvastatin treatment in hypertensive patients, with or without end stage renal disease (ESRD) (33).
 Accumulating evidence suggests that osteoporosis and coronary artery disease have epidemiologic similarities. Moreover, the anti-atherogenic effects of bisphosphonates have been observed in vitro and in animal models. Prolonged treatment with risedronate improves arterial elasticity of small and large arteries, and decreases systemic vascular resistance. These beneficial vascular effects were not related to changes in cardiovascular risk factors and may be attributed to direct effects of risedronate on the vascular wall (34).
 Omapatrilat, a combined inhibitor of ACE and neutral endopeptidase, has been shown to decrease pulse pressure and proximal aortic stiffness much more than an ACE inhibitor alone. This finding indicates the possibility that inhibition of neutral endopeptidase may improve aortic elastic characteristics by affecting bradykinin, natriuretic peptides and metalloproteinases (35).
 A novel approach to vascular stiffness is treatment with the PDE5a inhibitor sildenafil which is used to treat erectile dysfunction. In the vascular wall sildenafil increases cGMP activation, and results in inhibition of fibrosis and vascular relaxation (36).
 Renal transplantation is the preferred method of renal replacement therapy in most patients with ESRD, because renal transplantation largely restores renal function and the patient’s quality of life, and considerably improves survival, including CV morbidity and mortality, compared with dialysis patients (37,38). AI and PWV in living renal transplant recipients were significantly lower than in HD patients (39,40). Cyclosporine A treatment, known as a possible factor in renal vasoconstriction, did not induce an acute increase in arterial stiffness by using applanation tonometry, but chronic treatment with cyclosporin A and tacrolimus increase PWV in cadaveric renal transplant recipients (38,41).
 Arterial stiffness seems to have a genetic component, which is largely independent of the influence of blood pressure and other cardiovascular risk factors. Clinical studies of hypertensive humans have shown that the anti-stiffening effect of converting enzyme inhibition is more pronounced in the presence of the c variant of the AT1R receptor gene polymorphism. Hypertensive patients with this type of polymorphism derive more benefit from converting enzyme inhibitors than from treatment with other hypertensive drugs (42). The association between I/D polymorphism of angiotensin-converting enzyme (ACE) gene and arterial stiffness in healthy, low-risk population was recently studied. In apparently healthy individuals, D allele is associated with lower aortic stiffness, whereas there is no association of the ACE polymorphism with wave reflections (43). Two interesting studies, REGRESS (Regression Growth Evaluation Statin Study) and LOCAT (Lopid Coronary Angiography Trial), showed that subjects with certain genotypes ( 5A/6A and 6A/6A) and taking statins experienced fewer clinical events that placebo groups. Perhaps in the future, management of vascular patient will be based on the genetic milieu (44). Recent studies on animals and humans have looked for the structural and genetic bases of arterial stiffness. They have shown that several genes and molecules are associated with vascular wall stiffening and have illustrated the consequences of changes in these genes and molecules under various clinical conditions. There is strong evidence that arterial stiffness is affected by the amount and density of stiff wall material and the spatial organization of that material. To identify these molecules and their signaling pathways is important for the development of future drug treatments of arterial stiffness (45). Extensive presentation of the genetic characteristic of arterial stiffness is beyond the scope of this chapter; for an excellent overview of this issue, see Laurent et al (45).
 Antihypertensive therapy ameliorates arterial stiffness mainly by reducing BP, as a major determinant of diminished arterial compliance. Currently used antihypertensive drugs that potentially alter arterial stiffness involve the risk of inappropriately decreasing diastolic BP, thus jeopardizing coronary reserve. Moreover, high BP alone definitely does not determine arterial stiffness, which is also influenced by BP-independent structural modifications of large artery walls (46). Therapeutic studies focusing on structural improvement in vessel walls are just beginning. Endogenous matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitor of metalloproteinases (TIMPs), are important mediators of extracellular matrix remodeling, which is integral to plaque progression in coronary artery disease. To establish a balance between matrix synthesis and degradation, there are some pharmacological methods to be followed: diminishing cellular expression of MMP; augmenting TIMP expression and inhibiting active MMP. One of the targets is prostaglandin E2, a very strong inductor of MMP-9 synthesis. One study shows an association between treatment with non-steroidal anti-inflammatory drugs and reduction of aortic aneurism progression. There are three types of MMP inhibitors in studies: pseudopeptides, nonpeptides and tetracycline analogues. Doxycycline is both an antibiotic and a nonselective MMP inhibitor. A retrospective study showed that doxycycline can reduce graft intimal hyperplasia in patients after aortic aneurysm operation. Future studies will complete our knowledge about MMP specific functions and activities in the extracellular matrix (47,48).
 Promising targets in this respect are the matrical proteins. During degenerative processes of the arterial wall, these proteins establish nonenzymatic links to glucose (and other similar molecules), and generate advanced glycation end products (AGEs). These AGEs accumulate slowly at the level of low-turnover proteins, such as collagen and elastin, increasing arterial (and myocardial) stiffness. Reducing AGE generation may improve arterial compliance (49). A recent clinical trial found that a breaker of AGE (ALT-711), a thiazolium derivate, improves vascular elasticity and ventricular diastolic distensibility (50,51).
 New drugs that enhance elastin by blocking serine elastase appear to suppress inflammation, cardiac dilatation, and dysfunction after a myocardial infarct, but the study was limited by toxicity of these drugs (52).
Conclusion
Arterial stiffness measurements serve as an important tool in identifying patients at a higher risk of cardiovascular disease. Although there has been an increase in hypertension and diabetes awareness, the adverse consequences of age-related arterial stiffness still receive little attention in everyday clinical practice.
 Recent developments, however, suggest that improved clinical recognition of age-related vascular stiffening will lead to better therapy and better outcomes for patients with hypertension, diabetes mellitus and hyperlipidemia.
 
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