Intrinsic Changes in the Cardiovascular System: What is Normal Aging and What is Disease?
ACCEL | What is normal aging and what is disease? There is vascular aging and extreme vascular aging. Take a look at a healthy eight-year-old’s carotids and you see normal layers of artery that look like a smooth roadway, with the intima and adventitia setting the boundaries of the road and the media itself defining the “open road.” By age 52, aging has caused changes to the intima media thickness leaving less of a roadway and the look of more of a gently rolling hills; by 85, that once-narrow open road now looks like a graphic relief map of the Rocky Mountains.
Due to advancing age in general, and the rate of calcification in particular, there are changes in arteries over time. The question is: What is normal aging and what is disease?
In the past, vascular stiffening and an increase in systolic and pulse pressure have been considered part of normal aging. However, increasing evidence points to arterial stiffness as a critical precursor of disease.
Of course, arterial stiffness increases with age independently of the presence of cardiovascular risk factors or other associated conditions, but the extent of this increase may depend on several environmental or genetic factors, as demonstrated in a large body of work by Francesco Mattace-Raso, MD, PhD, head of geriatric medicine at Erasmus University Medical Center, Rotterdam, Netherlands.
Vascular stiffening and the subsequent increase in systolic and pulse pressure have, in the past, been considered a part of normal aging. Aside from aging, however, high arterial stiffness has also been associated with hypertension, diabetes mellitus, end-stage renal disease, and atherosclerosis. Emerging evidence has also shown an association between increased arterial stiffness and incident CVD in patients with hypertension and end-stage renal disease. Growing insights into the mechanisms underlying stiffness make it a potential target for intervention and prevention of cardiovascular disease.
Mattace-Raso and colleagues have contributed much to our current understanding of arterial (especially aortic) stiffness and associated risk factors:
- In a large population of nearly 3,300 elderly subjects, renal impairment was associated with aortic stiffness and was independent of cardiovascular risk factors.1
- In a large, untreated population (n=4,088) in the Rotterdam study, individuals with isolated systolic hypertension (ISH: defined as systolic blood pressure [SBP] of at least 140 mm Hg but diastolic BP (DBP) <90 mm Hg) had higher values of aortic stiffness compared to individuals with combined SBP and DBP hypertension, a difference that was most pronounced at older age. The results suggest that aortic stiffness contributes to ISH in older individuals who are not being treated for hypertension.2
- Dr. Mattace-Raso and a consortium of researchers studied 20,570 subjects from nine European and US cohorts, and found that the risk factors of metabolic syndrome (MetS) accelerated the age-associated increase in pulse wave velocity (PWV) levels at any age and did so similarly in men and women even after controlling for age, sex, smoking, cholesterol levels, and diabetes mellitus.3
- In 560 older persons (72.6 ± 5.5 years of age), homocysteine was associated with aortic stiffness, predominantly in the oldest old. This suggests that the strong association between homocysteine and cardiovascular mortality in the elderly may be mediated by aortic stiffness.4
- It has been suggested that arterial stiffening exposes the small vessels in the brain to highly pulsatile pressure and flow and, as such, may contribute to the pathogenesis of cerebral small vessel disease. Arterial stiffness was evaluated in 1,460 individuals and found to be associated with white matter lesions in the brain.5 The associations were independent of CV risk factors. The study suggests the importance of identifying persons with high arterial stiffness and to treat high blood pressure in these persons appropriately.
- Again from the Rotterdam study, an analysis of 3,178 subjects showed that moderate alcohol consumption is associated with lower arterial stiffness independently of CV risk factors and atherosclerosis in women; in men, although the same trend was observed, the estimates lacked statistical significance. The association was U-shaped and stronger for wine consumption. How does it work? It appears that alcohol exposure increases the production of vasoactive substances, like nitric oxide (NO), thereby inducing endothelium-dependent vasodilatation. Exposure of blood vessels to alcohol can promote NO generation and subsequent vasodilatation. Moreover, NO can convey vasoprotection by inhibiting platelet aggregation and platelet adhesion to the vascular wall. In this way, the vascular wall is not only protected against thrombosis, but also against the release of platelet-derived growth factors that stimulate smooth muscle proliferation and its production of matrix molecules.
Extreme Vascular Aging
In brief, vascular aging is a normal process that influences long- and short-term risk, but in the presence of specific factors, the result is extreme vascular aging that increases morbidity and mortality.
Dr. Mattace-Raso and his team have studied elastin, the connective tissue that allows many tissues in the body to resume their shape after stretching or contracting. With age, there is a thinning and fracturing of elastin and increased collagen deposition, resulting in an increased stiffening of the vessel walls that is more pronounced in the central, predominantly elastic arteries, compared to the distal, predominantly muscular arteries.
With age alone, elastin maintains most of its integrity for 50 years. It essentially has a half-life of 50 years; that means by 80 years of age elastin has lost a substantial amount of its natural integrity. Looking at it another way, beyond 50 years, age alone greatly impacts the integrity of elastin. Other variables will impact elastin, too: a higher mean arterial pressure, for example, stretches elastin and collagen fibers in the arterial wall, making the arteries less distensible. Overall, the specifics of what causes these “aging effects” remain largely unclear. Dr. Mattace-Raso suggests large population-based studies to determine whether age-related hormonal changes, nutritional patterns, physical activity, and possible interactions of genetic and environmental factors can influence functional vascular properties.
One step in that direction: Mattace-Raso et al. were the first to establish reference and normal values for carotid–femoral PWV, using almost 17,000 European subjects and patients and standardizing results for different methods of PWV measurement.6 On the basis of the distribution of PWV within each age and BP category, it is now possible to identify those people at higher risk than others in a certain age group and in which percentile of reference (or normal) population an individual subject stands.
Overall, Dr. Mattace-Raso said generalized arterial stiffness should no longer be considered an innocent expression of vascular aging, but rather a sign of increased cardiovascular risk. Measurement of PWV is noninvasive, easy to apply, allows a functional assessment of the arterial tree, and should be considered as an additional tool to identify subjects at high risk of cardiovascular disease.
- Sedaghat S, Dawkins Arce FG, Verwoert GC, et al. Age Ageing. 2014;43:827-33.
- Verwoert GC, Franco OH, Hoeks AP, et al. J Hypertens. 2014;32:1606-12.
- Scuteri A, Cunha PG, Rosei EA, et al. Atherosclerosis. 2014;233:654-60.
- van Dijk SC, Smulders YM, Enneman AW, et al. J Hypertens. 2013;31:952-9.
- Poels MM, Zaccai K, Verwoert GC, et al. Stroke. 2012;43:2637-42. Mattace-Raso F, Hofman A, Verwoert GC, et al. Eur Heart. J 2010;31:2338-50.
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