The walls of major arteries, particularly the aorta, lose flexibility over time, resulting in increasing arterial stiffness. Arterial stiffening is caused, at least in part, by the slow breakage and loss of elastin fibers in the arterial wall, as well as the buildup of stiffer collagen fibers. Increased arterial stiffness is associated with an increased risk of hypertension as well as other disorders such as chronic renal disease and stroke.
Arterial stiffness is a rising problem that is linked to an increased risk of cardiovascular events, dementia, and mortality. Reduced central vascular compliance affects cardiac function and coronary perfusion by altering arterial pressure and flow dynamics.
Stiffness in the larger central arterial system, such as the aortic tree, contributes significantly to cardiovascular disease in older people and is associated with systolic hypertension, coronary artery disease, stroke, heart failure, and atrial fibrillation, which are the leading causes of mortality in developed countries.
The functional impacts of arterial stiffness include changes in the fundamental mechanical behavior of the artery wall's material properties, as well as the influence of wall characteristics on changes in geometry and wall tension.
While generalized vasculature stiffening has been recognized as a hallmark of normal aging since ancient medical texts, systematic scientific evaluation of arterial stiffening, particularly the type that affects the central arterial axis, has only recently matured as a clinical and research discipline.
The incidence and frequency of surrogate measures of vascular stiffness, generally pulse pressure and isolated systolic hypertension, are increasing in these situations.
Vascular stiffness affects the stress placed on the ventricles, the efficiency of ventricular ejection, and the perfusion of the heart itself. For the same net stroke volume, hearts ejecting into a stiffer arterial system must produce greater end-systolic pressures. As a result, for a certain amount of expelled flow, the energy required increases. Even at identical levels of mean arterial pressure (MAP)., chronic ejection into a stiffer vasculature causes ventricular hypertrophy .
Vascular stiffness also alters the way the heart is perfused. Because normal coronary flow is largely diastolic, variations in systolic pressure have minimal effect on mean perfusion. Coronary perfusion in hearts ejecting into a stiff arterial system, on the other hand, exhibits considerably greater systolic flow associated with the elevated systolic perfusion pressure.
Increased central arterial stiffness is a symptom of numerous diseases, including diabetes, atherosclerosis, and chronic renal impairment. As a result, the frequency and prevalence of clinical surrogate indicators of vascular stiffness, such as pulse pressure and isolated systolic hypertension, rise significantly with age and these related diseases.
Arterial stiffness is also associated with an increased risk of cardiovascular illness, such as myocardial infarction, heart failure, and overall mortality, as well as stroke, dementia, and renal disease. Vascular stiffness not only adds to these clinical consequences and lowers the threshold for their symptoms by modifying resting and stress-induced hemodynamics and energy expenditure, but it also likely leads to increased dyspnea with exercise and orthostatic hypotension in older adults.
Although the anatomical and cellular alterations that cause arterial stiffness may predispose the vasculature to additional insult from atherosclerotic disease, the mechanisms behind this relationship are currently being studied. Wang and Fitch present a current synopsis of the alleged association between arterial stiffness and atherosclerosis.
In general, vascular stiffening develops as a result of a complex interaction of various independent and interdependent processes. Thus, the stiffening or hardening of the arterial wall with age is a macroscopic reflection of hemodynamic stresses, hormonal milieu, salt consumption, and the individual's glycemic status, as well as the overall deterioration in cellular systems and function.
Arterial stiffness is caused by biological aging and arteriosclerosis. Inflammation has a significant part in the development of arteriosclerosis, and as a result, it is a key contributor to the stiffness of big arteries.
Although vascular stiffening is a universal change associated with aging, it is also a characteristic in illnesses such as hypertension and diabetes, where complex cellular pathways conspire to exacerbate arterial wall hardening.
The structural components of the arterial wall, particularly elastin and collagen, as well as vascular smooth muscle tone and transmural distending pressure, are the primary determinants of arterial stiffness. Endothelium appears to have a role in the regulation of arterial stiffness via the effect of smooth muscle tone via the production of vasoactive mediators, according to growing data.
Indeed, the effect of basal nitric oxide generation and endothelin-1 on common iliac artery stiffness in an ovine model has recently been shown. Furthermore, atrial natriuretic peptide and, to a lesser extent, brain natriuretic peptide have been demonstrated to affect iliac artery stiffness in this animal model.
Increased arterial stiffness increases the stress on the heart since it needs to do more work to maintain stroke volume. This increased strain induces left ventricular hypertrophy and remodeling over time, which can lead to heart failure. Increased exertion may also be related with a greater heart rate, a proportionally longer length of systole, and a comparative decrease in diastole duration.
This reduces the amount of time available for perfusion of heart tissue, which occurs mostly during diastole. As a result, the hypertrophy heart, which has a higher oxygen demand, may have a reduced supply of oxygen and nutrients.
The time it takes for pulse wave reflections to return to the heart may also be affected by arterial stiffness. The pulse wave is reflected as it passes through the circulation at locations where the transmission characteristics of the arterial tree vary (i.e. sites of impedance mismatch). These reflected waves go in the opposite direction of the heart. Because the speed of propagation increases in stiffer arteries, reflected waves arrive to the heart early in systole. This puts more strain on the heart during systole.
The role of collagen and elastin
The state of two key scaffolding proteins, collagen and elastin, affects vessel wall compliance. Normally, there is a strictly controlled equilibrium between the production and breakdown of these two proteins.
Anomalies exist in this regulating mechanism, such as those caused by inflammatory changes, in which collagen is overproduced and elastin production is impaired. This type of asymmetry adds to vascular stiffness. Furthermore, increasing luminal pressure (as seen in hypertension) favors collagen formation at the expense of elastin.
Indeed, histological study of post-mortem artery tissue appears to demonstrate that the thickness of the tunica medium doubles or triples between the ages of 20 and 90 (the broadest range of human lifespan). A stunning variety of histological alterations are noticed when stiffened arteries are viewed microscopically.
These include aberrant and disordered endothelial cells, increased collagen, fragmented and decreased elastin, smooth muscle cell infiltration, macrophage infiltration, mononuclear cell infiltration, and enhanced matrix metalloproteases.
In fact, there is an increase in transforming growth factor (TGF)-, intercellular adhesion molecules (ICAM), and cytokines in the vessel wall. In addition to wall thickening, there appears to be a constant rise in vessel diameter with increasing age, amounting to around 9% each decade from 20 to 60 years in the ascending aorta.
Arterial stiffness precedes hypertension
Although the relationship between increased arterial stiffness and hypertension is complicated due to several confounding factors (e.g., aging, food, concomitant disease, lifestyle, etc.), recent human and animal research show that increased arterial stiffness can precede hypertension. According to research conducted in five distinct animal models, arterial stiffness precedes high blood pressure.
The phrase "arterial stiffness" refers to the loss of arterial compliance and/or changes in vessel wall characteristics. According to the traditional view, compliance of large arteries, particularly the thoracic aorta, represents their ability to dampen the pulsatile nature of ventricular ejection and to convert a pulsatile pressure at the ascending aorta into a continuous pressure downstream at the site of arterioles.
This reduces energy consumption during organ perfusion while also protecting tiny arteries in target organs (mostly the brain and kidney) from the harmful effects of pressure pulsatility. During ventricular contraction, a portion of the stroke volume is sent immediately to the peripheral tissues, while the remainder is temporarily held in the aorta and central arteries, straining the artery walls and raising local blood pressure.
A more recent viewpoint holds that arterial compliance is an important thermodynamic optimization of cardiovascular energetics. A portion of the heart's energy is redirected to the artery wall's distension. During systole, this energy is "stored" in the artery walls, and during diastole, it recoils the aorta. This effect forces the stored blood forward into the peripheral tissues, resulting in diastolic flow.
This phenomenon is effective due to the stiffness and shape of the arteries. When stiffness is low (young healthy man), a considerable amount of cardiac energy is transferred during diastole, which helps decrease post-load and improve organ perfusion during diastole .
A greater pressure is required in senior hypertensives to stretch a more stiff vascular system. As a result, a greater proportion of the stroke volume passes into the arterial system and peripheral tissues during systole.
The major effects include intermittent flow and pressure, exacerbated flow and pressure pulsatility at the distal small resistance location, and a shortened capillary transit time. The latter decreases metabolic exchanges. These processes together cause harm to target organs.
Clinical Measurement of Arterial Stiffness
Arterial stiffness may be measured at three different levels: systemic, regional, and local. Only circulation models can be used to assess systemic arterial stiffness. Regional and local arterial stiffness, on the other hand, may be assessed immediately and non-invasively at various locations along the arterial tree.
One significant benefit of their evaluation is that it is based on direct measurements of factors that are highly related to wall stiffness. A great number of reviews on methodological issues have been published.
Local artery stiffness measurements, acquired either with well-established high-resolution echo tracking devices or, more recently, with magnetic resonance imaging, are better appropriate for pathophysiological and pharmacological research.
Non-pharmacological treatments that are able to reduce arterial stiffness include:
- Weight loss,
- Exercise training,
- Dietary changes,
- Low salt diet,
- Moderate alcohol consumption, and
- Hormone replacement therapy.
Pharmacological treatments which are able to reduce arterial stiffness in humans include:
- Antihypertensive treatment, such as diuretics in old people, beta-blockers, ACE inhibitors, angiotensin receptor blockers (ARBs), and calcium channel antagonists;
- Treatments of congestive heart failure, such as angiotensin converting enzyme (ACE) inhibitors and vasopeptidase inhibitors
- Hypolipidemic agents such as statins;
- Antidiabetic agents, such as thiazolidinediones; and
- Advanced glycation end products (AGE)-breakers, such as alagebrium.
The reduction in arterial stiffness in response to antihypertensive medication may be attributed only to blood pressure reduction, but other BP-independent effects may also be involved. However, other research conclusively demonstrated that antihypertensive therapy might reduce arterial stiffness and/or wave reflections irrespective of brachial BP reduction.
This has been observed with the administration of a calcium channel blocker, long-term ACE inhibition, or angiotensin-receptor blockade. Furthermore, several medications that do not target blood pressure can reduce arterial stiffness (for example, statins, anti-diabetics, and anti-inflammatory agents), demonstrating that arterial stiffness can regress even when there is no change in BP.
Whether lifestyle adjustments and pharmacological therapies are helpful in lowering arterial stiffness to younger participants' levels in the elderly, and whether the reduction in arterial stiffness translates into a reduction in cardiovascular events. To the best of our knowledge, no big randomized clinical study has been conducted in a specific cohort of senior hypertensives above the age of 60 or 70.
Isolated systolic hypertension and arterial stiffness
Isolated systolic hypertension (defined as a systolic blood pressure more than 140 and a diastolic blood pressure greater than 90 mm Hg) and increased pulse pressure (PP=systolic blood pressurediastolic blood pressure) are two clinical indications of reduced vascular distensibility.
The prevalence of hypertension rises with age, with more than 60% of people over the age of 65 having hypertension with a systolic blood pressure greater than 140 mm Hg and/or a diastolic blood pressure greater than 90 mm Hg; older blacks have a higher prevalence of hypertension than whites in all age groups.
Chronically elevated mean blood pressure causes thickening of the artery wall, most notably in the media. Remodeling caused by hypertension is a compensatory process that normalizes elevated wall stress. In contrast to the effects of age, the inherent stiffness of wall material in hypertensive persons may not differ from that of normotensive controls, and hypertension-related wall hypertrophy is at least partially reversible with appropriate mean pressure reduction.
It is sometimes difficult to distinguish the effects of pharmaceutical and lifestyle treatments on blood pressure reduction from their direct effects on arterial wall characteristics. Changes in MAP are more closely related to changes in arterial compliance than changes in systolic blood pressure.
Interventions that lower blood pressure and are linked with a reduction in cardiovascular risk are related with a reduction in arterial stiffness measurements. They may, however, have no direct influence on the structural components of the vessel wall that contribute to rigidity.
Is arterial stiffness reversible?
Human and animal research have both shown that arterial stiffness can be reversed. When mice were treated to moderate-intensity exercise, the physicians discovered that there was a considerable reduction of an age-associated rise in TG2 activity, which was coupled with enhanced nitric oxide bioavailability and decreased collagen depositions in the extracellular matrix.
Interestingly, these biochemical alterations did not result in a substantial change in vascular stiffness, suggesting that the TG2 crosslinks may have a long half-life in the vascular matrix once established. As a result, it appears that the reversibility of vascular stiffness may be restricted to a certain stage or kind of vascular disease that causes stiffness.
In humans, 3 months of short-term aerobic exercise decreased arterial stiffness in older individuals (> 65 years) with type 2 diabetes, potentially lowering the risk of cardiovascular morbidity and death. A recent study also shown that moderate-to-vigorous physical exercise can reverse vascular stiffness in overweight or obese young individuals.
Furthermore, several antihypertensive drugs (e.g., angiotensin converting enzyme inhibitors or angiotensin II receptor I antagonists) have been demonstrated to considerably improve arterial stiffness. Thus, vascular stiffness caused by some medical problems can be reversed with a change in lifestyle or medication.
In recent decades, efforts to minimize the morbidity and mortality associated with cardiovascular disease have concentrated on atherosclerosis. The consistent drop in age-adjusted mortality in high-income nations is evidence of the effort's effectiveness.
However, as the population ages, the cardiovascular disease spectrum shifts to include arterial disease issues other than those induced by blockage and ischemia, such as gradual stiffness of the aorta and central elastic arteries.
There is substantial evidence that arterial stiffness is associated with negative outcomes independent of atherosclerosis, and while the underlying process manifests as systolic hypertension, the pathophysiological causes of damage extend well beyond this.
Arterial stiffness is a significant therapeutic target, but two areas of study are urgently needed to advance the present evidence basis. To begin, the mechanism behind arterial stiffness must be well understood in order to identify prospective locations for treatment. This need large, well-characterized prospective cohorts beginning at a young age before stiffness acceleration develops.
The recent discovery of novel genetic markers reveals that there is still much to learn about what drives the stiffening process. Second, well-designed interventional studies with equal blood pressure decrease across arms are required. If these results show that modifying stiffness is related with improved outcomes, measuring pulse wave velocity will shift from the borders to a routine clinical diagnostic.
Stiffness in the greater central arterial system, such as the aortic tree, contributes considerably to cardiovascular illness in older people and is related with systolic hypertension, coronary artery disease, stroke, heart failure, and atrial fibrillation.
Central arterial stiffness is now well acknowledged as a significant aging effect that has been linked to detrimental vascular phenotypes in illnesses such as diabetes, atherosclerosis, and renal failure, among others.
The increasing frequency and risk of arterial stiffness give a huge impetus to better understand the underlying molecular, cellular, and genetic causes, as well as the resulting physiological impact.
Because currently available antihypertensive drugs fall short of enhancing the compliance of the central artery arteries, understanding these processes will assist in more precisely focused therapeutic approaches.
Reducing arterial stiffness in these bigger arteries is predicted to have a considerable influence on morbidity and mortality in older persons, diabetics, and those with chronic renal illness, as well as enhance quality of life in these groups.
Weight loss, exercise, salt reduction, alcohol consumption, and neuroendocrine-directed therapies, such as those targeting the renin-angiotensin-aldosterone system, natriuretic peptides, insulin modulators, and novel therapies targeting advanced glycation end products, are all presented as ways to reduce arterial stiffness.