Focus on the assessment and prevention of vascular aging

With the increasing aging of the population, China has officially entered an aging society. Population growth and aging alone are expected to increase the number of cardiovascular events by more than 50% from 2010-2030. Currently, the incidence of Cardiovascular diseases is increasing year by year, and together these diseases account for approximately 39.6% of age-related diseases. There is growing evidence that age is a major risk factor for the development and progression of cardiovascular disease, and that vascular aging plays an important role in this. Vascular aging, also known as vascular degenerative changes, refers to the physiopathological process of functional degeneration and structural aging of blood vessels as they age, due to the combined effects of other factors. Diseases caused by vascular aging that result in damage to target organs such as heart, brain and kidney are called vascular degenerative diseases. It is important to pay attention to vascular aging for the prevention and treatment of cardiovascular and cerebrovascular diseases.

I. Mechanism of vascular function degeneration and structural aging
Healthy large arteries have a strong buffering capacity and can provide stable blood flow to microvessels despite the diastolic and intermittent ejection of blood from the heart, thus protecting them from the harmful effects of pressure fluctuations. However, with aging and in response to various cardiovascular risk factors, blood vessels undergo aging, with structural remodeling and dysfunction, which is primarily characterized by increased vascular stiffness. The stiffened aorta has a significantly impaired buffering capacity for the heartbeat, with excessive transfer of pulse wave energy from the heartbeat to the low-impedance target organ microvasculature and abnormal ventricular-arterial interactions, ultimately leading to target organ damage, facilitated left ventricular structural remodeling, dysfunction, and even failure.

Compared to Atherosclerosis, vascular aging-induced atherosclerosis is distinctly different in mechanism and leads to more extensive structural remodeling of the vessel wall. In age-related structural remodeling of the blood vessels, changes in the intima and mesima cause thickening of the vessel wall. In the absence of atherosclerosis, vascular aging causes mainly intimal thickening, especially a significant increase in intima-media thickness (IMT), and the mechanisms of vessel wall thickening are mainly proliferation and migration of vascular smooth muscle cells, impaired elastin fiber integrity and deposition of extracellular matrix. Functionally, vascular aging causes endothelial cell damage and dysfunction, leading to a significant reduction in vascular nitric oxide (NO)-dependent diastolic effects, and this endothelial dysfunction is also closely associated with microvascular dysfunction, which promotes elevated blood pressure, large artery sclerosis, and structural remodeling of small arteries, all of which ultimately lead to multi-organ damage in the elderly. Structural remodeling and dysfunction interact to ultimately promote atherosclerosis.

Second, pay attention to vascular degenerative diseases
When the stiffness of large arteries such as the aorta and carotid artery increases due to aging, but the peripheral muscular arteries do not show significant changes, the energy of the pulse wave is transmitted more to the microcirculation at this Time, and this phenomenon leads to damage to organs with high-flow, low-resistance vascular beds, such as the heart muscle, kidney, and brain, causing corresponding vascular degenerative diseases.

(i) Heart damage

The pulse wave generated by the left heart ejection propagates not only forward but also reflects backward. Under normal conditions, the reflected pulse wave reaches the coronary artery during diastole and thus can help fill the coronary artery. When the aorta becomes sclerotic due to aging, the propagation velocity (PWV) of the pulse wave increases and reaches the coronary artery earlier at the end of systole, thus leading to a decrease in coronary perfusion pressure and an increase in left ventricular afterload, promoting left ventricular remodeling, dysfunction, and even left ventricular failure, even when left ventricular failure occurs. even if coronary artery disease has not yet developed. Some studies have also found that direct measurement of carotid-femoral pulse wave velocity may independently predict the onset of heart failure.

(ii) Renal damage

High pulse wave pressure and high blood flow into the renal microcirculation can lead to microvascular damage such as small artery wall stretching, small aneurysm rupture and microthrombosis, causing glomerular damage, resulting in decreased glomerular filtration rate and proteinuria, and ultimately end-stage renal disease. Chronic kidney disease, in turn, can promote vascular sclerosis through a variety of mechanisms, including promotion of vascular calcification, secretion of more inflammatory factors, decreased ability to handle sodium load, deleterious activation of the renin-angiotensin-aldosterone axis, and sympathetic hyperactivity.

(iii) Brain damage

The brain is richly supplied with blood and densely vascularized, and maintaining stable, good perfusion is necessary for normal cognitive and other physiological functions; local perfusion abnormalities may be key to the progression of cognitive dysfunction and dementia. When vascular aging occurs, abnormally enhanced PWV that is conducted into the microcirculation of the brain may promote cerebral microvascular damage and remodeling, and the concomitant age-related microvascular loss can lead to increased susceptibility of the brain to hypoperfusion and reduced efficiency of oxygen and energy delivery. Carotid-femoral PWV was found to be associated with cognitive impairment, cognitive decline, and episodic dementia, and was associated with localized brain atrophy and imaging manifestations of cerebral small vessel disease, including elevated white matter density, lacunar infarction, cerebral microhemorrhage, and perivascular gap enlargement. A meta-analysis also found that carotid-femoral PWV was a risk factor for stroke independent of classical cardiovascular disease risk factors and aortic stiffness .

Image source: Starko Helo

III. Accelerating the exploration of assessment tools for vascular aging
Since vascular aging is mainly manifested by increased stiffness of large arteries, the assessment of vascular aging is mainly done by evaluating the risk factors that promote the development of vascular aging and measuring the sclerosis of large arteries.

(i) Assessment of risk factors that promote vascular aging

In addition to age, hypertension is the main factor that directly promotes vascular sclerosis. Although studies have shown that vascular stiffness increases before the onset of hypertension, hypertension is also a risk factor for atherosclerosis, and one study showed that PWV increased more rapidly in hypertensive patients than in normotensive people, even with antihypertensive therapy. Therefore, continuous assessment of blood pressure can help estimate the rate of progression of atherosclerosis.

In addition, there are a number of metabolic and lifestyle factors that can contribute to the development of vascular aging. Obesity, which has long been recognized as a promoter of aging in many tissues and organs, also promotes vascular aging. Studies have shown that body mass index, waist circumference, waist-to-hip ratio, and fat mass percentage independently predict the progression of carotid-femoral PWV. In addition to lipid metabolism, abnormalities in glucose metabolism can also contribute to vascular aging. Studies have shown that glycosylated hemoglobin and insulin resistance indices are associated with carotid-femoral PWV progression after adjusting for physiological confounders and cardiovascular risk factors. In terms of lifestyle, alcohol consumption and smoking promote PWV, while exercise may slow the progression of PWV elevation. In conclusion, a comprehensive assessment of all aspects of metabolism and lifestyle is important to predict the rate of progression of atherosclerosis.

(ii) Detection of vascular structural aging

An increase in IMT is a hallmark structural change in vascular aging, and the distance between the carotid lumen-intima interface and the intima-epima interface is usually measured clinically using a high-frequency B-mode ultrasound probe. The IMT tends to increase progressively with age, and the IMT of the common carotid artery is an independent predictor of cardiovascular disease risk.

(C) Detection of vascular function degeneration

The degeneration of vascular function is mainly manifested by impaired diastolic function and increased stiffness. Vascular diastole is mainly achieved by the production of NO by endothelial cells and its relaxation by smooth muscle cells. If endothelial cell function is impaired, the release of NO is reduced in response to stimulation. Based on this principle, ultrasound measurements of temporary changes in brachial artery diameter in response to shear stress are commonly used to assess arterial flow-mediated vasodilatory function.

PWV measurements are the most commonly used method to assess arterial stiffness. For peripheral arteries ultrasound or manometry can be used to measure interstitial or single point PWV of the carotid-femoral, carotid-radial, main femoral, brachial-ankle, carotid, and brachial arteries as well as the cardio-ankle artery index, whereas for PWV measurements of the aorta or aortic arch magnetic resonance imaging techniques are mostly used. Among the PWV measurements, carotid-femoral PWV is considered the Gold standard, but because of the complexity of the procedure, measurement of brachial-ankle PWV is mostly chosen clinically to assess the stiffness of the large and middle arteries.

(iv) Detection of blood biomarkers of vascular aging

There are several indicators related to metabolic, oxidative stress or inflammatory responses in blood that can be used to assess the risk of vascular changes, such as glucose, lipids, trimethylamine oxide, glutathione, superoxide dismutase, C-reactive protein, interleukin-6, and many others. In addition, there are a number of biomarkers that directly reflect the degree of vascular aging.

When vascular endothelial cells become damaged, apoptotic or fibrotic, they release a complex vesicular structure, the endothelial microparticles, which account for 5-15% of all particles in the circulation. Its levels in the blood have been found to be an independent predictor of adverse events in patients with cardiovascular disease. Its elevated blood levels can reflect endothelial cell damage and therefore can be used as a biomarker to assess vascular aging.

In addition, endothelial progenitor cells of bone marrow origin play an important role in the repair of vascular endothelial injury. Circulating endothelial progenitor cells can migrate into the subendothelial region, directionally differentiate and replace damaged endothelial cells, and regulate the differentiation of surrounding stromal cells and promote the proliferation and migration of endothelial cells. The percentage of CD34+KDR+ cells in peripheral blood mononuclear cells, as detected by flow cytometry, can indicate whether vascular aging has occurred.

There is still a need to further search for specific molecular markers for the evaluation of aging of vascular components.

IV. Active research on prevention and treatment of vascular aging
In view of the risk factors promoting vascular aging and the characteristics of vascular aging, many interventions have been studied and validated, and these interventions can be divided into three main types, lifestyle interventions, drug therapy and physical therapy.

(I) Lifestyle interventions

Many risk factors that promote vascular aging are closely related to poor lifestyles, so lifestyle interventions are important interventions, mainly through exercise and diet, in addition to the recognized smoking cessation and alcohol restriction.

In the 1990s, studies on the delay and even reversal of vascular aging through exercise began. Results from a rigorously screened cross-sectional survey showed that aerobic exercise attenuates atherosclerosis that worsens with age. Another non-randomized interventional study showed that exercise training increased arterial compliance. Subsequently, an increasing number of studies have focused on the effects of various forms of exercise on PWV indicators in different populations. Although the results vary between studies, most of them confirm the role of exercise, especially aerobic exercise, in delaying vascular aging.

Dietary interventions are mainly calorie restriction and sodium restriction. Caloric restriction for a year or less can result in significant weight loss in PWV and a significant reduction in systolic blood pressure. However, longer-term caloric restriction requires attention to possible side effects, such as loss of bone mineral density. Sodium restriction, which is commonly used to control blood pressure, has also been shown to improve vascular stiffness, and a meta-analysis showed that sodium restriction may reduce arterial stiffness in addition to changes in blood pressure.

(ii) Pharmacological interventions

In addition to the application of antihypertensive, hypoglycemic, and lipid-lowering drugs to slow vascular aging in response to traditional risk factors such as hypertension, hyperglycemia, and hyperlipidemia, a number of drugs that intervene by acting directly on vascular tissue are also under development. These drugs inhibit calcification, inhibit collagen cross-linking, promote collagen breakdown, inhibit elastase, promote the release or supplementation of NO, activate classical anti-aging pathways such as Sirtuin, anti-inflammatory, anti-fibrotic and other mechanisms of action to inhibit structural aging and functional degeneration of blood vessels and reduce vascular stiffness.

(iii) Physiotherapy

Vascular contraction and diastole are mainly regulated by endothelin-1 and NO released from vascular endothelial cells, and endothelial shear stress is the main regulator of this function of endothelial cells. Based on this theory, extracorporeal counterpulsation has been developed to physically lower systolic blood pressure and increase diastolic blood pressure in the aorta, increasing the endothelial shear stress of blood flow. Studies have shown that extracorporeal counterpulsation therapy significantly increases plasma NO levels, decreases endothelin-1 levels, and enhances the ability of endothelial cells to promote vasodilation.

In conclusion, vascular aging with age and a combination of factors can cause damage to multiple target organs and lead to the development of vascular degenerative diseases, posing a serious threat to the health of the middle-aged and elderly. Accurate assessment of the degree of vascular aging and the rate of progression, early intervention of relevant risk factors, and strengthening of protective factors will contribute to the prevention and treatment of vascular degenerative diseases and promote the implementation of the development strategy of a healthy China.

Author: Yu-Cong Zhang, Cun-Tai Zhang
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