Abstract
Alongside cancer, cardiovascular disease (CVD) exhibits the highest rates of morbidity and mortality globally, in western society as well as in Asian countries. Aging is a serious problem for the Asian population as progression toward a super-aged society is moving at a remarkably high rate. This increased rate of aging leads to increased CVD risk and, consequently, high CVD incidence. However, aging is not the only deleterious factor of vascular problems; hypertension, hypercholesterolemia, diabetes mellitus, and kidney disease may induce atherosclerosis and arteriosclerosis (i.e., arterial stiffening), and the progression of these diseases ultimately leads to cardiovascular, cerebrovascular, chronic kidney, or peripheral artery disease. Despite the existence of several guidelines on the treatment of risk factors such as hypertension and CVD, there is still an ongoing debate regarding the clinical need for assessment of arteriosclerosis and atherosclerosis, which act as a bridge between cardiovascular risk factors and CVD. In other words, although arteriosclerosis and atherosclerosis are essential to our understanding of vascular diseases, the need for additional tests beyond the conventional diagnosis method remains disputed. This is presumably due to insufficient discussion on how to apply such tests in clinical practice. This study aimed to fill this gap.
Introduction
The English physician Thomas Sydenham (1624–1689) said, “man is as old as his arteries.” The increase in blood pressure that accompanies aging is the most important risk factor of vascular aging [1]. The heart contracts approximately 100,000 times a day, and at each contraction, the flow, pressure, and diameter changes exert stress on the blood vessels. Among these stress factors, the change in blood flow is by far the most prominent; however, blood flow varies depending on certain conditions and is not easily measured in a clinical setting. By contrast, changes in blood pressure are more frequently applied in clinical practice for monitoring and diagnostic purpose as they can be measured more conveniently. Specifically, the pressure in the arterial vessels is measured as systolic blood pressure (SBP; during heart contractions) over diastolic blood pressure (rest period between contractions). In the early stages of hypertension, the resistance to flow created at the small arterioles and resistance arteries with a 20–80 µm diameter increases diastolic blood pressure and mean arterial pressure. This was shown in a study of patients with mild hypertension without target organ damage, where the frequency of vascular remodeling with inward narrowing of resistance arteries was substantially high at 63–97%. This inward remodeling has been reported to precede target organ damage, such as cardiac hypertrophy or kidney damage resulting in proteinuria [2]. Vascular changes initiated in early small artery remodeling lead to increase in mean arterial pressure and large artery stiffening, and the formation and progression of large artery remodeling increase the pulse pressure in the central aorta and large conduit arteries. These changes lead to cardiac hypertrophy and increased wall thickness of the carotid artery and other large elastic arteries, and the consequent fibrous and fatty buildup induces the clogging of arteries by atherosclerotic plaques, which can eventually rupture. Moreover, the persistent increase in central pulse pressure further aggravates small artery remodeling and leads to coronary microvascular dysfunction, myocardial ischemia, microalbuminuria, declining renal function, and white matter lesions in the brain [3].
Large and small arteries have been observed to have closely connected endothelial function [4], such that small arteries interact with larger arteries – structurally or functionally – in hypertension. The question is whether blood pressure control is sufficient to restore the healthy state of blood vessels before hypertension. A reduction in blood pressure does not seem to improve blood vessel changes, and hypertension drugs display different effects on blood vessels. For example, beta-blockers can reduce blood pressure to levels similar to those achieved by renin-angiotensin or calcium channel blockers, although they show little to no improvement in the structure of blood vessels [5, 6]. Blood vessel changes induced by increased blood pressure cannot simply be reversed in structural or functional terms by a reduction in blood pressure. These different effects on blood vessels were shown to cause a marked difference in the onset of stroke in a long-term follow-up study [7]. Nevertheless, several studies have shown that hypertension treatment has impacts on arteries beyond lowering blood pressure [5, 7]. Similarly, hypercholesterolemia and diabetes mellitus treatments have also been found to impact the arteries beyond lowering blood cholesterol and glucose [8, 9]. Therefore, changes in arterial structure and function as well as their management strategies have been acknowledged as important cardiovascular risk factors for hypertension, hypercholesterolemia, and diabetes mellitus [7‒9].
There are many discrepancies in the reported usefulness of measuring atherosclerosis and arteriosclerosis among the recommendation papers and guidelines in western societies, and some have presented unfavorable assessments; therefore, the methods are only reluctantly applied in clinical settings [10‒13]. By contrast, the guidelines published in Asia are relatively more favorable toward the clinical utility of measuring arterial stiffness [14‒16]. This review sought practical examples of arterial stiffness measurement to explore more efficient ways to apply the methods in clinical practice.
Clinically Useful Diagnostic Tools to Detect Atherosclerosis and Arteriosclerosis
The vascular changes caused by atherosclerosis can be measured both structurally and functionally as shown in Figure 1. The atherosclerosis test most easily applied in clinical settings is the analysis of the intima-media thickness and plaque in the carotid artery, aorta, and femoral artery using ultrasonography [17]. This analysis is useful for evaluating and classifying or reclassifying cardiovascular risk in patients or apparently healthy subjects and is therefore commonly used in routine health checkups and at health clinics. The ankle-brachial index (ABI) is used to detect obstructive atherosclerosis in the upper and lower extremities based on the ratio of SBP between the ankle and brachial arteries [18]. Endothelial function testing measures functional changes in the blood vessels by measuring the endothelial cell response to certain stimulation in the coronary or peripheral arteries. As the endothelium plays a key role for the onset, development, and clinical course of atherosclerosis, endothelial function testing offers a reliable biomarker of the presence and level of progression of atherosclerosis [19]. Flow-mediated dilatation of the brachial artery using ultrasound is commonly used in clinical practice. Reactive hyperemia pulse amplitude tonometry of the fingertips is another widely used method, although it has proven difficult to standardize due to individual variations as well as several intercurrent factors that may influence the test [20]. For blood testing, measuring the levels of high-sensitivity C-reactive protein – in addition to blood glucose and cholesterol – can detect the proteins related to inflammation/leukocyte activation in the arteries to examine endothelial health [21]. The rheological behavior of blood may also be measured as an atherosclerosis test, as blood viscosity measurements can be used to estimate the resistance to blood flow within blood vessels. Furthermore, blood hyperviscosity is closely associated with macrovascular and microvascular complications of atherosclerosis [22]. Thus, the measurement of whole blood viscosity is likely to serve as a marker of endothelial functions related to vascular injury.
Commonly used methods of atherosclerosis and arteriosclerosis in clinic. cfPWV, carotid-femoral pulse wave velocity; baPWV, brachial-ankle pulse wave velocity; CAVI, cardio-ankle vascular index; hsCRP, high-sensitivity C-reactive protein.
Commonly used methods of atherosclerosis and arteriosclerosis in clinic. cfPWV, carotid-femoral pulse wave velocity; baPWV, brachial-ankle pulse wave velocity; CAVI, cardio-ankle vascular index; hsCRP, high-sensitivity C-reactive protein.
Among the methods for measuring arteriosclerosis (arterial stiffening), regional pulse wave velocity (PWV) and local distensibility or compliance are commonly used. The PWV measures the velocity of the pulse wave from each heart contraction along the blood vessel walls. In western society, the measurement of PWV between the carotid artery and femoral artery (cfPWV) is the gold standard, whereas, in Asia, the PWV between brachial and ankles (baPWV) and from the origin of the aorta to tibial artery (cardio-ankle vascular index, CAVI) are more commonly used to measure the arterial stiffness [23]. In theory, CAVI resembles the stiffness parameter β, which means that the test is independent of blood pressure [24]. The distensibility reflects elastic properties of the arterial wall and is calculated as the percent change in the arterial area (strain) for a given change in local pressure (stress). Arterial compliance reflects the buffering function of the arterial wall and is defined as the changes in the arterial area for a given change of arterial pressure. Local distensibility and compliance can be measured noninvasively with ultrasound-based techniques, commonly at the carotid, aorta, and femoral artery. Pulse wave analysis using the technique of applanation tonometry is another way to measure arterial stiffening. Pulse wave analysis can be used to measure central aortic pressure which reflects a more realistic pressure load on the left ventricle and central organs compared to peripheral (brachial) arterial pressure. Arterial-ventricular coupling can also be measured [25], although this method is not often applied in clinical practice. All methods have their strengths and limitations (Table 1).
Strengths and limitation of vascular function tests
. | Strength . | Limitation . |
---|---|---|
Arteriosclerosis | ||
Pulse wave velocity | Accepted as the gold standard of cardiovascular risk stratification and therapeutic efficacyCut-off value of high-risk and normal versus abnormalReproducible and inexpensive | Only provides the average PWV and does not provide the location of the arterial abnormalitiesCoarse approximations of the distance by external measurement, especially in tortuous arteries or in the presence of abdominal obesity |
Pulse wave analysis | Recognition of forward and reflected arterial wave and heart loadEstimation of central systolic pressure | Difficulty in location accuracyInfluenced by heart rate and vasoactive drugsOperator dependency |
Local distensibility/compliance | More precise evaluation of a short segment of arteryProbably early diagnostic tool to detect local biomechanical properties | Difficulty in accurate assessment of pulse pressure at the sitesAffected by many factors such as age and sex |
Atherosclerosis | ||
Endothelial function test | Well accepted as a marker of atherosclerosisEarly detection of cardiovascular diseaseEasy to track changes the effectiveness of treatments | Technically challenging in measurement of endothelial function testWeak fixed cutoff values between normal and cardiovascular riskLack of standardized protocols |
Ultrasound-based wall thickness/plaque | Well accepted predictable tool of cardiovascular risk and eventsNumerous outcome studies | Highly operator dependent in ultrasound qualityLimited resolution and false positives and negatives |
Blood viscosity | A key determinant to regulate vascular resistance | Insufficient clinical dataNo standard method to measure blood viscosity |
Inflammatory markers | Well-established concept in atherosclerotic disease process and atherosclerotic cardiovascular diseaseLarge body of clinical outcome studiesSimple with repeatability | Considerable within-individual variabilityLack of specificityPoor predictive valueLack of consensus on optimal cut-off values |
. | Strength . | Limitation . |
---|---|---|
Arteriosclerosis | ||
Pulse wave velocity | Accepted as the gold standard of cardiovascular risk stratification and therapeutic efficacyCut-off value of high-risk and normal versus abnormalReproducible and inexpensive | Only provides the average PWV and does not provide the location of the arterial abnormalitiesCoarse approximations of the distance by external measurement, especially in tortuous arteries or in the presence of abdominal obesity |
Pulse wave analysis | Recognition of forward and reflected arterial wave and heart loadEstimation of central systolic pressure | Difficulty in location accuracyInfluenced by heart rate and vasoactive drugsOperator dependency |
Local distensibility/compliance | More precise evaluation of a short segment of arteryProbably early diagnostic tool to detect local biomechanical properties | Difficulty in accurate assessment of pulse pressure at the sitesAffected by many factors such as age and sex |
Atherosclerosis | ||
Endothelial function test | Well accepted as a marker of atherosclerosisEarly detection of cardiovascular diseaseEasy to track changes the effectiveness of treatments | Technically challenging in measurement of endothelial function testWeak fixed cutoff values between normal and cardiovascular riskLack of standardized protocols |
Ultrasound-based wall thickness/plaque | Well accepted predictable tool of cardiovascular risk and eventsNumerous outcome studies | Highly operator dependent in ultrasound qualityLimited resolution and false positives and negatives |
Blood viscosity | A key determinant to regulate vascular resistance | Insufficient clinical dataNo standard method to measure blood viscosity |
Inflammatory markers | Well-established concept in atherosclerotic disease process and atherosclerotic cardiovascular diseaseLarge body of clinical outcome studiesSimple with repeatability | Considerable within-individual variabilityLack of specificityPoor predictive valueLack of consensus on optimal cut-off values |
Why Is It Important to Measure Vascular Aging?
Several studies have shown that vascular aging causes severe damage to vascular structure and function, inducing cardiovascular disease (CVD) [26]. In general, vascular age is a person’s age predicted by a best-fit multivariable regression model based on traditional cardiovascular risk factors, use of treatment, and PWV. Atherosclerosis is initiated in the first decade of life, but by the fifth decade, risk factors such as smoking, obesity, hypertension, diabetes mellitus, and hypercholesterolemia produce individual variations in vascular aging based on their presence and management, leading to substantial differences in the levels of vascular damage between individuals. Early vascular aging (EVA) refers to more severe vascular damage than what is expected of one’s chronologic age, whereas supernormal vascular aging (SUPERNOVA) is the opposite concept of EVA [27].
Rising blood pressure is possibly the most influential risk factor of EVA. Although hypertension begins with small artery remodeling [2], aging prompts its progression to atherosclerosis in the medium-to-large arteries and then induces arteriosclerosis [28, 29]. Ultimately, the interactions between the small arteries and medium-to-large arteries form a vicious circle in which they continue to aggravate one another. The vascular damage and accelerated vascular aging caused by hypertension – as seen in diabetes mellitus to a similar degree – result in vascular diseases such as chronic kidney disease and dementia. The pathophysiologic response initiated in small artery remodeling gradually raises the blood pressure further, aggravating atherosclerosis and arteriosclerosis in medium-to-large arteries, which, in turn, aggravates the vascular damage, forming a positive feedback cycle. An increase in blood pressure above that of normal vascular aging induces vascular disease at an earlier age. Hence, compared with chronological aging, vascular aging is a more important factor at the onset of cardiovascular events [30].
The measurement and management of blood pressure and blood glucose are common in current clinical settings for treating hypertension and diabetes mellitus, respectively – but how can we treat the biological aging of the vasculature, which happens naturally as individuals age? Although chronological aging cannot be stopped, is it possible to prevent and treat vascular and organ aging caused by biological aging? To do so, the progression of atherosclerosis and/or arteriosclerosis should be quantitatively and accurately measured and then restored to normal levels. This process is predicted to make a far greater contribution to the control of cardiovascular risks than the control of blood pressure and blood glucose for hypertension and diabetes mellitus, respectively. There are countless variables in the long journey from a rise in blood pressure, glucose, and cholesterol to serious CVD. However, compared with these risk factors, arteriosclerosis and atherosclerosis are more closely associated with CVD such that the quantitative assessment of these two conditions as a basis for therapeutic decision-making is predicted to be far more effective for CVD treatment and prevention. Quantitative measurements of arteriosclerosis and atherosclerosis will allow for quantitative and accurate assessment of accelerated vascular aging, enabling providers to choose accurate treatment options. Such methods will be even more valuable for individuals in the fifth decade of life, when EVA is more likely to start begin.
Accelerated or Premature Atherosclerosis in Patients with Cardiovascular Risk Factors
Atherosclerosis is a complex condition arising from the inflammatory response caused by injury. The endothelial dysfunction of the blood vessels by injury occurs in the early stages and then gradually progresses to fatty streaks, plaque formation, and its increased vulnerability, and finally plaque rupture. This process induces macrovascular complications, including atherosclerotic CVDs such as coronary artery, cerebrovascular, and peripheral artery diseases. The onset of atherosclerosis occurs far earlier than what may be expected. Fatty streaks are detected in the aorta of children, the coronary arteries of adolescents, and the peripheral arteries of young adults [31]. As previously mentioned, traditional CVD risk factors (e.g., hypertension, diabetes mellitus, hypercholesterolemia, smoking, obesity, and family history) accelerate atherosclerotic vascular disease and events. Diabetes mellitus is an independent factor that increases the risk of atherosclerosis as well as its pervasiveness and plaque instability [32]. Large genome-wide association studies have reported a genetic link between diabetes mellitus and atherosclerosis [32].
Traditional CVD risk factors, including hypertension, diabetes, and hypercholesterolemia, can be diagnosed and treated as per their respective guidelines. However, it is unclear what should be done with progressed atherosclerosis found in the carotid or abdominal artery in cases of mildly to moderately increased blood pressure, glucose, or cholesterol level. Hypertension is a critical CVD risk factor that induces carotid atherosclerosis and can increase the incidence of stroke when it progresses [33]. As an example, a patient visiting a clinic and displaying the unexpected progression of carotid atherosclerosis based on their blood pressure measured at the clinic warrants certain considerations. First, the patient should be examined for the presence of masked hypertension. The rate of masked hypertension is known to be 10–30% in the general population despite clinical measurements (i.e., favorable blood pressure) indicating adequate control [34]. Second, the patient’s blood pressure fluctuation and variability should be examined. Independent of the within-visit mean blood pressure, the risk of death as well as cardiovascular events and stroke has been found to increase when the levels of visit-to-visit blood pressure variability (BPV), as well as within-visit systolic BPV, are high [35, 36]. BPV is closely associated with arterial stiffening [37, 38], and raised BPV pointing to an unusual progression in arteriosclerosis could be reduced by medication with subsequent follow-up monitoring. Third, the individual should be examined for other diseases that can accelerate the progression of atherosclerosis. For instance, rheumatoid disease arises from a discordance between the innate and adaptive immune systems. Atherosclerosis involves an aberrant immune response caused by blood vessel injury as an important pathogenic mechanism. Thus, the progression of atherosclerosis is likely to be accelerated by an immune disorder that can worsen both atherosclerosis and rheumatoid disease [39]. Similarly, the recent pandemic of coronavirus disease 2019 (COVID-19) induces systemic inflammation and damages the immune system, further hastening the onset of atherosclerosis and, in the presence of underlying CVD risk factors (especially hypertension), increases the level of cardiovascular damage [40].
Accelerated Arteriosclerosis in Patients with Cardiovascular Risk Factors
Arteriosclerosis is arterial damage caused by a distinct aging process. It is an epidemic disease that increases the risks of cardiovascular events, dementia, and death [41, 42]. The progression of atherosclerosis is more rapid and occurs earlier than arteriosclerosis; thus, the presence of arteriosclerosis is likely to indicate substantial progression of atherosclerosis. Nevertheless, there may be cases of a notable progression of arteriosclerosis without high levels of traditional CVD risk factors such as hypertension, hypercholesterolemia, and hyperglycemia. To interpret these cases and determine which clinical approaches should be taken, it is important to consider the two most important determinants of arterial stiffening: age and blood pressure [43]. The aging process elevates blood pressure, increases pulsatile aortic wall stress, and induces aortic stiffening and dilation as well as the degradation and fracture of aortic elastic lamellae. These changes lead the pulse wave generated by heart contraction to undergo early reflection to the central aorta, which causes central systolic hypertension. An increase in central systolic pressure leads to cardiac overload on one axis, causing a typical cardiovascular atherosclerotic continuum that underlies left ventricular hypertrophy, myocardial ischemia, and heart failure; on the other axis, it causes pulse wave encephalopathy, pulse wave nephropathy, end-stage renal disease, and dementia. This is referred to as the cardiovascular aging continuum [44, 45]. Furthermore, carotid or aortic stiffness is associated with accelerated progression of blood pressure elevation that results in hypertension in normotensive subjects [46]. Thus, aging-related arterial stiffness and hypertension represent a “chicken or the egg” scenario [47].
When arteriosclerosis is found to have progressed further than what is expected for an individual’s age, there may be a problem in the aging processes in arteries. In a study conducted on normotensive participants and treated hypertensive patients, carotid-femoral PWV (an arterial stiffening marker) showed greater progression in hypertensive patients than in normotensive participants but cfPWV progression was similar in both groups when blood pressure was well controlled. However, despite identical blood pressure levels between the two groups, increased heart rate may have been a critical cause of aging-related vasculopathy [43]. Notably, for older patients, lowering the heart rate could help reduce age-related arteriosclerosis [43]. In patients with hypertension being treated with an antihypertensive drug, increases in arteriosclerosis or aging frequently led to deteriorating renal function in addition to an increase in uncontrolled blood pressure or heart rate. Another important factor in the acceleration of arteriosclerosis is high sodium intake [48] and metabolic syndrome [49]. In children, arteriosclerosis was shown to increase from the onset of obesity [50, 51]. It is thus necessary to determine which lifestyle factors can increase arterial stiffening to abnormal levels, especially in relation to sodium intake and childhood obesity [1]. Genetics also contribute to arterial stiffening with approximately 40% of the heritability of high cf-PWV [52].
The threshold of PWV indicative of high risk varies according to age and the method of measurement, and different guidelines offer different solutions. In the European guidelines, >10 m/s is considered a high-risk cfPWV [53]. In the Japanese guidelines, baPWV >18 m/s [54] and CAVI ≥9.0 m/s [55] are associated with an increase in cardiovascular events. In numerous studies, baPWV and CAVI, used widely in Asia, showed the association between clinical values of baPWV or CAVI and various risk factors as well as their ability to predict cardiovascular events [56]. In South Korea, mass screening of subclinical atherosclerosis and arteriosclerosis is currently underway, and PWV measurement in atherosclerosis is frequently conducted in clinical practice [57].
The following study may offer clues regarding how to use atherosclerosis and arteriosclerosis measurements in clinical settings. Of 124 stable patients (mean age, 67.4 years; men, 66.7%) with hypertension, diabetes mellitus, or CVD at an outpatient clinic, the proportion of high-risk patients displaying high baPWV (24.2%) and/or low ABI (8.1%) was approximately one-third, which exceeded the predicted level [58]. Follow-up monitoring of these patients with the addition of a drug, an increase or a decreased drug dose showed that SBP was reduced by 11 mm Hg and baPWV was reduced by 2 m/s, suggesting that vascular examination could improve care in clinical practice. PWV and ABI can allow vascular aging to be quantified, and such quantitative data on the level of vascular aging reversal in response to therapeutic change are likely to be valuable and highly achievable in clinical settings.
Next Steps in Clinical Practice
The potential benefits of using atherosclerosis and arteriosclerosis measurements in addition to traditional CVD risk factors may suggest directions for improving CVD management and prevention in clinical settings. First, atherosclerosis and arteriosclerosis should be assessed in addition to age in the general low-risk population to identify the difference between chronologic aging and vascular aging. Doing so will help identify EVA and SUPERNOVA and aid in the development of appropriate preventive measures. The age group of 40–50 years is presumed to be the best target for this assessment as CVD prevention could be initiated following clear signs of such differences.
Second, atherosclerosis and arteriosclerosis should be assessed in the intermediate- and high-risk populations to provide surrogate markers for the prediction of CVD risk to further clarify the risk stratification and allow patients to be re-stratified. Third, a vascular examination should be conducted for patients undergoing treatment for a CVD risk factor to detect residual arterial risk compared with conventional CVD risk given high levels of atherosclerosis and arteriosclerosis. Notably, the causes of renal dysfunction and autoimmune and inflammatory diseases – e.g., rheumatoid disease, connective tissue disease, uric acid increase [59], sleep apnea syndrome [60], and sarcopenia [61] – should be determined.
Fourth, although controlling blood pressure, glucose, and cholesterol is important following pharmacologic or non-pharmacological treatment of a significant CVD risk factor, follow-up monitoring should be conducted to determine whether the improvements to the traditional CVD risk factors contributed to improved arterial function and structure. In addition, the contribution of actual prevention of hard cardiovascular disease should be determined. If no change to arterial function and structure was induced despite improvements to CVD risk factors, including blood pressure, glucose, and cholesterol, or if further deterioration has been observed, a scrupulous effort should be made to identify other causes.
Finally, aging research is being conducted using various animal models [62]. In animals such as the naked mole-rat, the longest-living rodent, healthy cardiovascular structure, and function are maintained even at an age corresponding to 92 human years. Although this may be beyond the scope of this review, these animals may offer insights into the prevention of age-induced vascular stiffness in humans.
Acknowledgments
This was presented at the third webinar “2022 Highlights from Pulse.”
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The authors received no financial support for the research, authorship, and/or publication of this article.
Author Contributions
Jeong Bae Park contributes the writing of all parts of this review. Alberto Avolio contributes to the comments to the revision of the manuscript.