Inflammation, Oxidation, and Atherogenesis in the Elderly
Moderator: David G. Harrison, MD
- A. Lipids, inflammation, and atherosclerosis
Paul M. Ridker, MD, MPH
- B. Aging and vascular function: molecular mediators and clinical implications
Gary Gibbons, MD
- C. Role of reactive oxygen species in vascular disease
David G. Harrison, MD
In the past decade, abundant laboratory and clinical data have accumulated linking inflammation and atherosclerosis. Indeed, as pointed out by Dr Ridker, inflammation appears to be involved in all stages of the atherosclerotic process and is likely to play a major role in plaque vulnerability. In addition, biomarkers of inflammation, such as high-sensitivity C-reactive protein (hsCRP) and interleukin 6, have been shown to independently predict incident cardiovascular disease across all strata of total and low-density lipoprotein (LDL) cholesterol levels. Similarly, elevated hsCRP level has been associated with increased risk for developing the metabolic syndrome and diabetes mellitus. Moreover, reduction in inflammatory markers appears to significantly contribute to the favorable effects of regular exercise on incident cardiovascular disease. There is also evidence that the beneficial effects of statins in reducing cardiovascular risk may be mediated in part by attenuation of inflammatory processes. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, for example, statin therapy had the greatest benefit in reducing the risk of death or myocardial infarction among patients who achieved both an LDL cholesterol level <70 mg/dL and an hsCRP level <2 mg/L. More recently, the JUPITER trial demonstrated a significant reduction in cardiovascular disease events among individuals with LDL cholesterol levels <130 mg/dL but with hsCRP levels ≥2 mg/L, suggesting that patients with evidence for active inflammation may benefit from statin therapy even when the LDL cholesterol levels are within the target range recommended by current guidelines. In summary, although additional research is required to elucidate the molecular and vascular biological mechanisms responsible for the association between inflammation and atherosclerosis, the clinical importance of this link is clearly established, and there is emerging evidence that inflammation per se may serve as an appropriate therapeutic target for reducing cardiovascular disease risk.
The interaction between aging and vascular function is complex, involving genetic, environmental, and behavioral factors, with further modulation by comorbid conditions. As discussed by Dr Gibbons, aging is associated with increased vascular stiffness and endothelial dysfunction, mediated in part by oxidative stress, inflammation, and angiotensin II. Obesity accelerates these processes, leading to premature vascular aging, even during childhood and adolescence. Similarly, hypertension, dyslipidemia, and diabetes mellitus facilitate the development of atherosclerosis. Conversely, findings from the Heart Outcomes Prevention Evaluation (HOPE) and European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA) trials suggest that angiotensin-converting enzyme inhibitors may exert favorable effects on vascular function. The influence of genomic and epigenomic variations on the vasculature is an area of ongoing investigation, and preliminary evidence suggests that blood vessels may have an “epigenetic memory” that could modulate vascular aging and therefore serve as a potential therapeutic target. Additional research is needed, however, to further characterize the relationships between aging, traditional cardiovascular risk factors, diet, environmental factors, and genomic and epigenetic variations with respect to their impact on the vascular transcriptome and vascular function.
Hypertension, diabetes mellitus, dyslipidemia, cigarette smoking, and aging all contribute to increased oxidative stress through generation of superoxide radicals and hydrogen peroxide. As discussed by Dr Harrison, the production of oxidative moieties is mediated by several enzymes, including xanthine oxidase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and nitric oxide synthases. Increased oxidative stress, in turn, leads to lipid oxidation, adhesion molecule expression, matrix metalloproteinase activation, growth of vascular smooth muscle cells, altered vasomotion, and apoptosis, all of which contribute to endothelial dysfunction and atherogenesis. However, despite the strong association between oxidative stress and atherosclerosis, clinical trials of antioxidant vitamins, including vitamin C, vitamin E, and beta-carotene, have failed to show a beneficial effect of these agents on cardiovascular outcomes. These observations have led to a reassessment of the mechanisms underlying the relationship between oxidative stress and vascular disease. In this regard, recent studies from Dr Harrison’s laboratory suggest that tetrahydrobiopterin (BH4) may play an important role in regulating the response to oxidative stress, and that therapy with BH4 reduces blood pressure in both hypertensive mice and humans. Other recent studies focusing on NADPH oxidase isoforms have provided novel insights into the role of these enzymes in the pathogenesis of oxidative stress-mediated vascular dysfunction. In addition, studies in mice and humans indicate that a feedback mechanism contributes to the regulation of the interaction between endothelial nitric oxide synthase (eNOS) and extracellular superoxide dismutase (ecSOD), and that regular exercise significantly increases both eNOS and ecSOD expression, perhaps contributing to the beneficial effect of exercise on atherogenesis.
Additional basic research is needed to elucidate the fundamental molecular, biochemical, and cellular mechanisms responsible for the complex interactions between aging, inflammation, oxidative stress, endothelial dysfunction, and atherogenesis. Improved understanding of the mechanisms whereby hypertension, diabetes, dyslipidemia, smoking, obesity, physical inactivity, and other novel risk factors, as well as common comorbid conditions (eg, renal insufficiency, heart failure, pulmonary disease, arthritis), modulate the relationship between age and vascular function is also needed. Additional investigation to discern the influence of genomic and epigenomic factors on vascular aging and their role as potential therapeutic targets is also warranted. Similarly, further characterization of the potential role of specific therapies for reducing oxidative stress and their impact on clinical outcomes is needed. Clinical trials are needed to determine the effects of novel anti-inflammatory agents on vascular disease and clinical outcomes, to better define which patients might benefit from such therapies, to determine optimal levels of biomarkers (eg, LDL cholesterol, hsCRP) for reducing cardiovascular risk across a broad range of patient populations (including octogenarians and beyond), and to assess the long-term cost-effectiveness of these interventions. Pending the results of preliminary investigations, clinical studies will also be required to determine the effectiveness of novel therapies aimed at modulating age-related endothelial dysfunction and the deleterious effects of oxidative stress; such studies should include adequate representation of older patients of both sexes and all major racial and ethnic groups.