Most physicians are interested in vascular aging because it is associated with longevity. Measurements evaluating vascular stiffness have been found to predict cardiovascular (CV) events better than standard brachial artery blood pressure (BP) testing in large population studies. Central (aortic) and brachial (peripheral) systolic and pulse pressures diverge as a result of pulse wave amplification because of vascular compliance and wave reflection.1 Vascular stiffness amplified by increasing age and atherosclerosis risk factors can be indirectly derived by measurements of central, brachial systolic, and pulse pressures.2,3 Central arterial pressure more closely reflects the load placed on the left ventricle and coronary and cerebral vasculature. Consequently, central BP is considered a more accurate marker of CV risk and an appropriate target for assessment of treatment strategies. Sir William Osler probably had it correct when he was quoted saying “you’re only as old as your arteries.”4
At a pathobiological level, aortic wall stiffness has been associated with processes involving wall matrix, inflammation, and mechanical stress. Increased collagen content and extracellular matrix (arteriosclerosis) is commonly seen in hypertension and aging. In contrast, atherosclerosis relates to endovascular inflammation, increased cellular oxidative stress, and plaque formation; however, both processes can lead to increased vascular stiffness.5 Patients with increased aortic stiffness have increased aortic pulse wave velocity and reduced arterial compliance.6 The clinical implication of increased aortic stiffness results in increased afterload on the left ventricle; alteration in coronary perfusion, which affects cardiac diastolic relaxation; and increased myocardial oxygen consumption. Moreover, these surrogates have been tested in multiple trials with important CV outcomes data. Based on the studies so far, it is evident that increased aortic pulse wave velocity is a strong independent predictor of CV risk, regardless of whether it plays a causative role in CV risk or merely serves as a marker of CV disease already present.
One example is found in the Strong Heart Study,7 which evaluated 2405 patients without CV disease at entry with a 5-year follow-up. During this period, 344 patients had CV events that were significantly associated with high central pulse pressure, thus associating high central pulse pressure with increased arterial stiffness.1 Another study, the Conduit Artery Function Evaluation (CAFE) trial8 substudy (on behalf of the Anglo-Scandinavian Cardiac Outcomes Trial [ASCOT] Investigators), evaluated the differential impact of BP-lowering drugs on central aortic pressure and clinical outcomes. The study enrolled 2073 patients from 5 ASCOT centers after being on treatment for about 1 year. A total of 19,257 patients were enrolled in the ASCOT trial. All patients had hypertension and 3 additional risk factors. They were randomized in a 2 × 2 factorial design to receive 1 of 2 antihypertensive regimens: amlodipine (5/10 mg) with or without perindopril (4/8 mg) or atenolol (50/100 mg) with or without a diuretic. Despite similar brachial arm systolic BPs in the two treatment arms, there was a significant decrease in both central aortic pulse pressure and central aortic systolic pressure in the angiotensin-converting enzyme (ACE) inhibitor/calcium channel blocker (CCB) arm vs the β-blocker/diuretic arm. This study suggested that ACE inhibitor/CCB treatment was significantly better. In addition, using the Cox proportional hazards modeling, they determined that central aortic pulse pressure was significantly associated with a post hoc–defined composite outcome of total CV events (unadjusted P<.0001; P<.05 after adjustment for baseline variables). Based on these data, it can be inferred that arterial stiffness and its components do affect CV outcomes. The vascular etiologies of these vessel wall changes require a closer look.
In a recent paper by Wang and associates,9 low-density lipoprotein (LDL) cholesterol was independently associated with aortic stiffness, and high-density lipoprotein (HDL) cholesterol was independently inversely associated with aortic stiffness. These findings are in part supported by a similar report by Giral and colleagues10 in 105 normotensive patients, where they found a significant relationship with HDL cholesterol and aortic pulse wave velocity. Among the studies in which arterial stiffness was improved, one of the studies by Barinas-Mitchell and associates11 stands out. They studied 38 diabetes patients who lost 9.4 kg in the placebo arm over a period of 1 year. They found a significant (P<.01) reduction in arterial stiffness. Other beneficial effects attributed to weight loss were significant reductions in glucose, LDL and HDL cholesterol, interleukin 6, tumor necrosis factor, high-sensitivity C-reactive protein, plasminogen activator inhibitor 1, and fibrinogen.
Furthermore, in a study by Greenfield and associates12 involving 684 female twins, central abdominal adiposity (surrogate marker of insulin resistance) was a significant determinant of arterial stiffness independent of age, heart rate, and genetic factors. Additionally, infused insulin in healthy individuals can reduce systemic arterial stiffness13; however, in insulin-resistant obese individuals,14 type 2 diabetic patients,15 and patients with central abdominal obesity, aortic stiffness is increased.16 Together with the current studies, these reports highlight the importance of body fat distribution in determining systemic arterial stiffness and offer a potential mechanism linking these factors to adverse CV outcomes.
To date, the best treatment strategies to reduce arterial stiffening involve mainly lifestyle changes such as exercise, weight loss, decreased salt intake, and moderate alcohol consumption. Among these, reducing salt intake probably is the most beneficial.17 Among the antihypertensive drugs we have today, very few have been shown to consistently decrease central BP. Newer pharmacologic approaches are evolving and involve targeting nitric oxide pathways, anti-oxidants, transforming growth factor β inhibitors, 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, and renin-angiotensin-aldosterone RAAS inhibitors.17
The etiology of vascular stiffness from a cellular level is affected by genetics, environment, risk factors, inflammation, matrix, and oxidative stress.18 Better understanding of the molecular, cellular, genetic, and environmental influences on arterial stiffness will one day result in targeted therapeutic options to improve vascular stiffness and, in turn, decrease CV and all-cause mortality. For now, healthy lifestyle still appears to be the best treatment for happy blood vessels.