HIGHLIGHTED TOPIC Physiology of the Aging Vasculature Arterial aging is risky

CARDIOVASCULAR DISEASES, i.e., hypertension, coronary heart disease, congestive heart failure, and stroke are the leading causes of morbidity, mortality, and disability in industrialized countries. Epidemiological studies have unequivocally shown that age is the dominant risk factor for these cardiovascular diseases. This cardiovascular disease epidemic is occurring worldwide despite unprecedented advances in the diagnosis and treatment of these conditions, and this situation is only expected to worsen because the world population is aging. Most research efforts to date have focused on developing interventions that target “traditional” risk factors for coronary heart disease (e.g., hypertension, hypercholesterolemia, etc.), whereas little attention has been devoted to aging because age has usually been viewed as an unmodifiable, unpreventable, or untreatable risk factor. This view exposes our major shortcoming in understanding why age is such a potent risk factor for cardiovascular diseases, namely our poor insight into the specific elements that constitute the risky components of aging vis a vis the cardiovascular system. The structure and function of arteries change throughout the lifetime of humans and animals. It is reasonable to hypothesize that specific mechanisms that underlie the arterial substrate that has been altered by an “aging process” are intimately linked to cardiovascular diseases. These changes include lumenal dilation, diffuse intimal and medial thickening, increased stiffness, reduced compliance of central arteries, endothelial dysfunction, and impaired arterial wound repair and angiogenesis. Elucidation of cellular and molecular mechanisms that underlie age-associated alterations in central and peripheral arterial structure and function in health is essential to unravel agedisease interactions and to target the specific characteristics of arterial aging that render it the major risk factor for the aforementioned diseases. Recent studies reveal a profile of arterial cell and matrix properties that emerges with advancing age within the grossly normal appearing aortic wall of both animals and humans that resembles a proinflammatory state. A “megacept” emerges with the realization that this age-associated profile within the arterial wall is strikingly similar to the inflammatory state that develops in arteries of younger animals in response to experimental induction of early atherosclerosis or hypertension. Thus “aging” and these “diseases” are fundamentally intertwined at the cell and molecular levels. In humans, other well known risk factors, e.g., altered lipid metabolism, smoking, and lack of exercise, interact with this age-associated proinflammatory arterial substrate, a fertile soil for facilitation of the initiation and progression of arterial diseases. This Highlighted Topics series, integrating perspectives that range from humans to molecules, briefly reviews selected recent advances in cardiovascular biology that provide insights into the mechanisms that may underlie arterial aging and its increased risks for arterial disease. The interaction of the arterial system with the left ventricle, termed arterial-ventricular coupling, is a central determinant of cardiovascular performance and cardiac energetics. Chantler et al. (3), provide an overview of the concept of arterial-ventricular coupling, using the arterial elastance (EA)/left ventricular end systolic (ELV) ratio and examine the effects of age, hypertension, and heart failure on EA/ELV and its components (where EA is a measure of the net arterial load exerted on the left ventricle and ELV is a load independent measure of LV chamber performance). In healthy individuals at rest, EA/ELV is maintained within a narrow range, which allows the cardiovascular system to optimize energetic efficiency at the expense of mechanical efficacy. During stress, e.g., exercise, an acute mismatch between the arterial and ventricular systems occurs (due to a disproportionate increase in ELV/EA) to ensure that sufficient cardiac performance is achieved to meet the increased energetic requirements of the body. As a result, EA/ ELV decreases from its resting level. Mechanistic insights that can be derived from studying arterial-ventricular coupling are highlighted. Recent studies have discovered an association between excessive pressure pulsatility due to stiff central arteries and microvascular remodeling and impaired regulation of local blood flow, leading to diffuse microscopic tissue damage and many forms of kidney disease and cognitive impairment. Mitchell (6) summarizes age-related changes in central aortic and peripheral arterial function and discusses potential mechanisms that link age-associated changes in properties of large arteries to excessive pressure pulsatility, abnormal microvascular structure and function, and end-organ dysfunction and damage. Arterial calcification modifies arterial wall stiffness and may have clinically significant consequences on cardiac function and downstream circulatory control. The calcium content of the arterial wall increases with age. The process and functional consequences of medial elastocalcinosis are reviewed by Atkinson (1). One of the major conceptual advances in our understanding of the pathogenesis of age-associated cardiovascular diseases has been that age-related oxidative stress may promote arterial inflammation even in the absence of traditional risk factors associated with atherogenesis. Oxidative stress affects the availability and/or balance of key regulators of vascular hoAddress for reprint requests and other correspondence: E. G. Lakatta, Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224. J Appl Physiol 105: 1321–1322, 2008; doi:10.1152/japplphysiol.91145.2008.