Effects of Statins on Vascular Elasticity

Determinant of Vascular Elasticity and Compliance

Vascular elasticity or compliance or stiffness is a major determinant of vascular resistance. The elasticity is determined by all components of the vessel wall, including the endothelium, SMCs, and the interstitium composed primarily of fibroblasts.

Table 2. Evidence for blood pressure-lowering effect of statins

Author

Study outline

Statin used

Outcome

Abetel et al. [49]

23 patients with hypertension and hyperlipidemia

Fluvastatin 40 mg for 3 months

Fluvastatin lowered blood pressure by 8-16 mm Hg

Borghi et al. [40]

Patients with hypertension and hyperlipidemia

Statins (pravastatin or simvastatin) in addition to antihypertensive treatment

Additive benefit of statins in lowering blood pressure

Glorioso et al. [50]

25 patients with hypertension and hyperlipidemia

Pravastatin 20-40 mg vs. placebo for 32 weeks

Pravastatin decreased systolic blood pressure by 8 mm Hg

O'Callaghan et al. [38]

25 patients with hypertension and hyperlipidemia

Pravastatin vs. placebo for 12 weeks

Pravastatin did not lower blood pressure

Sposito et al. [39]

Patients with hypertension and hyperlipidemia

ACE inhibitor (enalapril or lisinopril) alone or with statin (lovastatin or pravastatin)

Additive blood pressure-lowering effect of the combination compared to ACE inhibitor alone

Tonolo et al. [51]

26 microalbuminuric hypertensive type 2 diabetic patients

Simvastatin in addition to antihypertensive treatment

Simvastatin exerted additional blood pressure-lowering effect and also reduced 24-hour urinary albumin excretion

Ferrier et al. [53]

22 normolipidemic patients with stage I isolated systolic hypertension

Atorvastatin therapy (80 mg/day) and placebo for 3 months in crossover design

Intensive cholesterol reduction with atorvastatin reduced large artery stiffness and blood pressure in normo-cholesterolemic patients with stage I isolated systolic hypertension

The effects of statins on endothelium have been amply described, and include an increase in eNOS expression (and activity). Statins also reduce the generation of oxidant species in endothelial cells. These effects appear to be dose-dependent and are shared by all statins with minor inter-statin variability. Schmalfuss et al. [41], in our laboratory, examined the effects of different statins on vascular endothelial cell growth. Whereas atorvastatin and simvas-tatin reduced endothelial cell growth in culture, pravastatin did not affect it.

Increase in endothelial progenitor cells or neovascularization has been described with all statins with increasing regularity. How this phenomenon correlates with alteration in elasticity is not clear. Cooke [42] suggested that lower dosages of statins may be pro-angiogenic whereas the higher doses may be anti-angiogenic. The precise mechanism of increase in vascularity with statins is not known, but activation of protein kinase B/Akt, the cell survival signal related to generation of NO, has been thought to be responsible for this phenomenon.

Increased formation and activity of NO may influence arterial SMC contractile activity and proliferation. The reduction in vascular SMC proliferation and disarrayed growth may also be involved in salutary effects of statins on vascular compliance. In this regard, decrease in AT1R expression may also contribute to the improvement of the contractile response of vascular SMCs.

The interstitium, consisting primarily of fibroblasts, affects vascular compliance by generation of collagen and collagen-degrading enzymes. Reduced vascular elasticity (and loss of compliance) is often observed in hypertension, diabetes mellitus and aging. Dechend et al. [43] showed that cerivastatin reduced pro-fibrotic response in the hearts of rats made transgenic for human renin and angiotensinogen. Patel et al. [44] also showed reduced fibrosis in response to simvastatin in ^-myocyte heavy-chain transgenic mice. The studies on improvement in cardiac diastolic as well as systolic function, a reflection of cardiovascular system compliance with statins, were reviewed recently by Reddyet al. [45].

Although there are very few studies relating to arterial compliance and elasticity with statins, one study is particularly noteworthy. Dougherty et al. [46] examined the effect of Ang II infusion on aortic anatomical changes in the aorta and noted formation of microaneurysms. Interesting, the formation of microaneurysms was greater in hypercholesterolemic mice, showing the importance of cross-talk between dyslipidemia and RAS.

The effects of statins on elasticity are not as well studied, and there is paucity of literature in this area. Ichihara et al. [47] recently reported the differential effect of statins on aortic stiffness. In this single-blind, randomized prospective study, 85 hyperlipidemic, hypertensive patients were followed for 12 months. Aortic stiffness was assessed by measuring pulse wave velocity every 3 months. Patients were randomly allocated to groups treated with pravastatin, simvastatin, fluvastatin, or a non-statin antihyperlipidemic drug. During the 12-month treatment period, pulse wave velocity did not change in the pravastatin group or the non-statin group, but it was transiently reduced in the sim-vastatin group and significantly decreased in the fluvastatin group. Notably, the doses of the statins used in this study were lower than the usually prescribed dose. All four antihyperlipidemic drugs significantly decreased serum cholesterol levels without affecting blood pressure, ankle brachial index, or serum triglyceride levels. These results suggest that long-term use of statins in hyperlipidemic, hypertensive patients is associated with a significant reduction in aortic stiffness without any effect on blood pressure.

Raison et al. [48] assessed arterial stiffness in 23 patients, aged 32-70 years, who had hypertension and hypercholesterolemia. Subjects received either ator-vastatin or a placebo. Aortic stiffness was measured from aortic pulse wave velocity after a 12-week treatment. The results revealed that atorvastatin did not change blood pressure; however, it significantly lowered plasma total and LDL cholesterol and increased aortic pulse wave velocity by +8 vs. 2% under placebo. The percentage changes in plasma total and LDL cholesterol and in pulse wave velocity were significantly and negatively correlated, independent of blood pressure level. These results support the possibility that statins might contribute to a change in arterial stiffness independent of blood pressure level.

Kontopoulos et al. [52] assessed the effect of atorvastatin on aortic stiffness in hypercholesterolemic patients free of arterial hypertension and diabetes mellitus. Thirty-six patients (18 with coronary artery disease and 18 without coronary artery disease) received atorvastatin for a 2-year period. As expected, total cholesterol, LDL cholesterol, triglycerides and high-density lipoprotein cholesterol levels changed favorably. Aortic stiffness was assessed by transthoracic echocardiography at baseline and 2 years later. After 2-years' treatment with atorvastatin, aortic stiffness was significantly reduced by 14% (p = 0.019) which was similar in patients with or without coronary artery disease. Ferrier et al. [53] investigated the effect of high-dose atorvastatin on large artery stiffness and blood pressure in normolipidemic patients with isolated systolic hypertension. Atorvastatin 80 mg/day and placebo were used for 3 months in a randomized, double-blind, cross-over study design. Systemic arterial compliance was measured non-invasively using carotid applanation to-nometry and Doppler velocimetry of the ascending aorta. Systemic arterial compliance was higher after treatment (placebo vs. atorvastatin: 0.36 8 0.03 vs. 0.43 8 0.05 ml/mm Hg, p = 0.03) whereas brachial systolic, mean and dia-stolic blood pressures were lower after treatment.

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