Paradigm of Vascular Aging: Conceptual Strides Slowed by Technical Limitations

In the last decade, focus on the vasculature and its role in disease and aging has emerged as a clinical and research priority. Paradigms of cardiac disease have expanded to include key components of vascular anatomy and physiology, and complex cardiac-vascular coupling relationships underlying health and disease have been identified.1, 2 With aging, typical vascular changes fundamentally increase propensity to experience functional limitations and disease. Included among age-related vascular changes are increased afterload, diminished coronary perfusion, abnormal vasomotor regulation, greater vascular stiffness, autonomic dysfunction, and a host of other liabilities that increase susceptibility to coronary ischemia, heart failure, arrhythmias, falls, and other cardiac sequelae. Furthermore, ramifications of vascular aging extend beyond the heart to essentially every other perfused organ. Impaired cerebral, renal, and skeletal muscle performance are among the systemic effects of normal vascular aging, especially in the context of cardiac and autonomic abnormalities that often exacerbate age-related perfusion abnormalities. Goals to improve the health of our growing older population have therefore been increasingly oriented to efforts to improve vascular health. Related research is typically premised on hypotheses that enhanced vascular performance will lead to improvements in general health and function.3 This issue of the Journal of the American Geriatrics Society features two contributions in this burgeoning area of investigation, one study focuses on the effects of homocysteine on vascular performance in older adults and the other focuses on utility of exercise training to modify vascular function in older adults. Nevertheless, despite the enormous relevance and appeal of these inquiries for our expanding population of older patients, questions regarding the techniques used to assess vascular function must temper enthusiasm for their data and conclusions. Hirsch et al.4 study the effects of hyperhomocysteinemia on endothelial performance in older and younger adults by measuring flow-mediated diameter changes of the brachial artery. The study uses an ultrasound-based technique that was first introduced by Deanfield et al.5 that has become a popular index of endothelial health. An endothelial stimulus is created, first by occluding blood flow in the distal forearm using a pneumatic cuff. After 5 minutes of inflation the cuff is released, creating a reactive hyperemic blood flow and an associated shearing of blood cells against the endothelial cells that line the vessel lumen. The shear stress induces healthy endothelial cells to synthesize nitric oxide (NO) and associated vasodilation. Because poorly functioning endothelial cells synthesize inadequate NO, flow-mediated responses become blunted or even constrictive. Hirsch et al. demonstrate such that flow-mediated dilation is particularly dampened in older adults with high levels of homocysteine. The investigators conclude that hyperhomocysteinemia adversely affects endothelial performance, and they conclude with additional hypotheses that dietary interventions designed to augment homocysteine metabolism (B12 and folic acid supplements) would probably benefit older people. Wang et al. focus on the benefits of exercise training with Tai Chi Chuan (TCC) to improve endothelial performance.6 In contrast to Hirsch et al.'s investigation, these investigators use a novel assessment of vascular endothelial response entailing transdermal iontophoresis of acetylcholine (a pharmacological stimulus of endothelial NO) to measure the NO-mediated vasodilation of the leg's cutaneous microcirculation. Using a cross-sectional study design, 10 older men who regularly engaged in TCC for at least 3 years were compared with 10 sedentary men. Compared with sedentary controls, the older TCC group demonstrated significantly greater acetylcholine-mediated skin flow, suggesting that exercise training was associated with greater intrinsic endothelial NO production. In complementary assessments, the older TCC athletes demonstrated higher baseline arterial flow in the leg (measured by impedance plethysmography) and greater cuff-induced hyperemic flow. Older TCC athletes also had relatively higher leg venous capacity, tone, and blood flow than their sedentary counterparts. The investigators conclude that TCC modifies age-related vascular changes with enhanced endothelial-mediated dilation in skin vasculature and improved parameters of arterial flow and venous compliance in the leg. These studies are similar in that the each promotes a paradigm of prevention in geriatric healthcare. Vitamins and exercise may potentially forestall and even reverse the customary tolls of vascular aging. Both studies also promote noninvasive indices of vascular performance with which to prove their hypotheses and to substantiate elegant physiological rationales regarding mechanisms of endothelial performance. Nevertheless, both studies also critically fail to clarify the shortcomings of their methodology, which may lead readers to question the confidence of their conclusions. Hirsch et al. study only 24 older adults (12 with homocysteine levels ≥ 15 mumol/L and 12 with homocysteine levels ≤ 13/L). Although the investigators report that endothelial-dependent vasodilation was significantly lower in older people with hyperhomocysteinemia, the data depicted graphically show wide variation in outcomes. Furthermore, the data show flow-mediated responses that exceed those typically reported in the medical literature, which is particularly surprising, because flow-mediated responses are usually reduced with age.7 In addition, these investigators placed the pneumatic cuffs around subject's distal arms (their forearms), a position that usually induces relatively lower flow-mediated responses than placing the pneumatic cuffs more proximally (around the upper arms), which leads to even greater concern about the magnitude of flow-mediated diameter responses that are reported. Many have described the limitations of brachial flow–mediated responses as an index of vascular health. The resolution of ultrasound technology is barely adequate to measure accurately a vessel typically measuring 3 to 4 mm. Moreover, the almost inevitable movements of the sonographer and subject compound the potential for inaccuracy during the 7- to 8-minute protocol. Even the slightest tilt or slide of the transducer will change the field of interrogation or image quality, significantly compromising data accuracy. Among the efforts to compensate for these limitations are higher frequency of ultrasound transducers (for greater resolution), increased frequency of image sampling, and protocols that entail averaging several consecutive images for each diameter measurement.8 Surprisingly, such steps were not incorporated in the protocol used for this study, nor was their absence accounted for in its discussion. Wang et al.'s study is similarly subject to criticism of its methods. This study is especially problematic in that it focuses on cutaneous microcapillary vascular responses, an index that is not often used in the literature. Because differences in vessel anatomy (size, composition, number of branch points) have all been demonstrated to effect endothelial flow-mediated responses, it is difficult to know how cutaneous vascular responses correspond to conclusions regarding endothelial function oriented to the coronary arteries, brachial arteries, and other vascular beds.9 To some extent, the investigators address this issue by correlating the cutaneous vascular indices to measurements of lower extremity arterial flow and venous tone. However, these arterial and venous measurements also depend on a novel techniques; the investigators do not use the more-customary strain-gauge plethysmography, nor do they compare cutaneous responses with brachial or coronary artery endothelial responses that are better established in the literature. The reader's confidence in one technique is not bolstered when it is built upon the foundation of another poorly understood approach, particularly when the study population is small. There are other problems with the Wang et al. study in regard to the selection bias of the remarkable TCC training group. Ten subjects exercised for a mean ± standard deviation of 11.2 ± 3.4 years in a moderate-intensity protocol 5 ± 1.5 times weekly, with their vascular data compared with 10 age-matched sedentary controls. It is hard to know how to interpret data from such a select group of athletes and to relate the conclusions to the vast majority of older adults for whom such an exercise regimen would be inconceivable.10 In conclusion, both studies presented in this issue of the Journal provide a glimpse of the exciting field of vascular biology and add to the preventive health paradigm for older adults. Although each study is limited by cross-sectional design, selection bias, and limitations in techniques, they both raise important questions and add to a growing momentum toward more-definitive solutions.