Review Article
Pluse
Pluse 2023;11:1–8
DOI: 10.1159/000530616
Arteriosclerosis and Atherosclerosis
Assessment in Clinical Practice:
Methods and Significance
Jeong Bae Park a Alberto Avolio b
a
JB Lab and Clinic and Department of Precision Medicine and Biostatistics, Yonsei University, Wonju College of
Medicine, Seoul, Republic of Korea; bMacquarie Medical School, Faculty of Medicine, Health and Human
Sciences, Macquarie University, Sydney, NSW, Australia
Keywords
Arteriosclerosis · Atherosclerosis · Cardiovascular disease ·
Cardiovascular disease risk factors
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 prob-
lems; hypertension, hypercholesterolemia, diabetes mel-
litus, and kidney disease may induce atherosclerosis and
arteriosclerosis (i.e., arterial stiffening), and the progres-
sion of these diseases ultimately leads to cardiovascular,
cerebrovascular, chronic kidney, or peripheral artery dis-
ease. 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
karger@karger.com © 2023 The Author(s).
www.karger.com/pls Published by S. Karger AG, Basel
This article is licensed under the Creative Commons Attribution-
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Received: September 7, 2022
Accepted: March 24, 2023
Published online: April 12, 2023
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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. © 2023 The Author(s).
Published by S. Karger AG, Basel
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 approx-
imately 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 pres-
sure in the arterial vessels is measured as systolic blood
pressure (SBP; during heart contractions) over diastolic
Correspondence to:
Jeong Bae Park, mdparkjb @ gmail.com
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 hyper-
trophy 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 mel-
litus treatments have also been found to impact the
arteries beyond lowering blood cholesterol and glucose
[8, 9]. Therefore, changes in arterial structure and func-
tion as well as their management strategies have been
acknowledged as important cardiovascular risk factors for
2 Pluse 2023;11:1–8
DOI: 10.1159/000530616
hypertension, hypercholesterolemia, and diabetes melli-
tus [7–9].
There are many discrepancies in the reported useful-
ness 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
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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 thick-
ness and plaque in the carotid artery, aorta, and femoral
artery using ultrasonography [17]. This analysis is useful
for evaluating and classifying or reclassifying cardiovas-
cular 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 stim-
ulation in the coronary or peripheral arteries. As the
endothelium plays a key role for the onset, development,
and clinical course of atherosclerosis, endothelial func-
tion testing offers a reliable biomarker of the presence and
level of progression of atherosclerosis [19]. Flow-
mediated dilatation of the brachial artery using ultra-
sound 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
Park/Avolio

Fig. 1. 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.
the resistance to blood flow within blood vessels. Fur-
thermore, blood hyperviscosity is closely associated with
macrovascular and microvascular complications of athe-
rosclerosis [22]. Thus, the measurement of whole blood
viscosity is likely to serve as a marker of endothelial
functions related to vascular injury.
Among the methods for measuring arteriosclerosis
(arterial stiffening), regional pulse wave velocity
(PWV) and local distensibility or compliance are com-
monly 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 buffer-
ing 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
Clinical Assessment of Arteriosclerosis and
Atherosclerosis
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measured noninvasively with ultrasound-based techni-
ques, 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 periph-
eral (brachial) arterial pressure. Arterial-ventricular cou-
pling can also be measured [25], although this method is
not often applied in clinical practice. All methods have
their strengths and limitations (Table 1).
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, dia-
betes mellitus, and hypercholesterolemia produce individ-
ual variations in vascular aging based on their presence and
management, leading to substantial differences in the
Pluse 2023;11:1–8 3
DOI: 10.1159/000530616
Table 1. Strengths and limitation of vascular function tests

Strength Limitation

Arteriosclerosis
Pulse wave Accepted as the gold standard of cardiovascular Only provides the average PWV and does not provide the
velocity risk stratification and therapeutic efficacy location of the arterial abnormalities
Cut-off value of high-risk and normal versus Coarse approximations of the distance by external
abnormal measurement, especially in tortuous arteries or in the
Reproducible and inexpensive presence of abdominal obesity
Pulse wave Recognition of forward and reflected arterial Difficulty in location accuracy
analysis wave and heart load Influenced by heart rate and vasoactive drugs
Estimation of central systolic pressure Operator dependency
Local More precise evaluation of a short segment of Difficulty in accurate assessment of pulse pressure at the
distensibility/ artery sites
compliance Probably early diagnostic tool to detect local Affected by many factors such as age and sex
biomechanical properties
Atherosclerosis

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Endothelial Well accepted as a marker of atherosclerosis Technically challenging in measurement of endothelial
function Early detection of cardiovascular disease function test
test Easy to track changes the effectiveness of Weak fixed cutoff values between normal and
treatments cardiovascular risk
Lack of standardized protocols
Ultrasound-based Well accepted predictable tool of cardiovascular Highly operator dependent in ultrasound quality
wall thickness/ risk and events Limited resolution and false positives and negatives
plaque Numerous outcome studies
Blood viscosity A key determinant to regulate vascular Insufficient clinical data
resistance No standard method to measure blood viscosity
Inflammatory Well-established concept in atherosclerotic Considerable within-individual variability
markers disease process and atherosclerotic Lack of specificity
cardiovascular disease Poor predictive value
Large body of clinical outcome studies Lack of consensus on optimal cut-off values
Simple with repeatability

levels of vascular damage between individuals. Early vas-
cular aging (EVA) refers to more severe vascular damage
than what is expected of one’s chronologic age, whereas
supernormal vascular aging (SUPERNOVA) is the oppo-
site 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 progres-
sion 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 pres-
sure further, aggravating atherosclerosis and arterioscle-
rosis in medium-to-large arteries, which, in turn,
aggravates the vascular damage, forming a positive feed-
back 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, respec-
tively – 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 quanti-
tatively 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

4 Pluse 2023;11:1–8 Park/Avolio

DOI: 10.1159/000530616
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, arterioscle-
rosis 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 arteriosclero-
sis and atherosclerosis will allow for quantitative and
accurate assessment of accelerated vascular aging, ena-
bling 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 endo-
thelial 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 macro-
vascular 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, hypercho-
lesterolemia, smoking, obesity, and family history) accel-
erate 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 atheroscle-
rosis 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 in-
crease 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
Clinical Assessment of Arteriosclerosis and
Atherosclerosis
on their blood pressure measured at the clinic warrants
certain considerations. First, the patient should be exam-
ined 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 con-
trol [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 med-
ication with subsequent follow-up monitoring. Third, the
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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 (CO-
VID-19) induces systemic inflammation and damages the
immune system, further hastening the onset of athero-
sclerosis 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 progres-
sion of atherosclerosis. Nevertheless, there may be cases
of a notable progression of arteriosclerosis without high
levels of traditional CVD risk factors such as hyper-
tension, hypercholesterolemia, and hyperglycemia. To
interpret these cases and determine which clinical ap-
proaches 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
Pluse 2023;11:1–8 5
DOI: 10.1159/000530616
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 contrac-
tion to undergo early reflection to the central aorta, which
causes central systolic hypertension. An increase in cen-
tral systolic pressure leads to cardiac overload on one axis,
causing a typical cardiovascular atherosclerotic continu-
um that underlies left ventricular hypertrophy, myocar-
dial 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]. Fur-
thermore, 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 hyper-
tensive 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 pa-
tients, lowering the heart rate could help reduce age-related
arteriosclerosis [43]. In patients with hypertension being
treated with an antihypertensive drug, increases in arterio-
sclerosis 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 approx-
imately 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 Euro-
pean 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
6 Pluse 2023;11:1–8
DOI: 10.1159/000530616
between clinical values of baPWV or CAVI and various
risk factors as well as their ability to predict cardiovas-
cular events [56]. In South Korea, mass screening of
subclinical atherosclerosis and arteriosclerosis is cur-
rently underway, and PWV measurement in atheroscle-
rosis 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 dis-
playing 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
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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 arte-
riosclerosis 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 dysfunc-
tion 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.
Park/Avolio
 Fourth, although controlling blood pressure, glucose, Acknowledgments
and cholesterol is important following pharmacologic or
non-pharmacological treatment of a significant CVD risk This was presented at the third webinar “2022 Highlights from
Pulse.”
factor, follow-up monitoring should be conducted to
determine whether the improvements to the traditional
CVD risk factors contributed to improved arterial func-
Conflict of Interest Statement
tion and structure. In addition, the contribution of actual
prevention of hard cardiovascular disease should be The authors have no conflicts of interest to declare.
determined. If no change to arterial function and struc-
ture was induced despite improvements to CVD risk
factors, including blood pressure, glucose, and cholester- Funding Sources
ol, or if further deterioration has been observed, a scru-
pulous effort should be made to identify other causes. The authors received no financial support for the research,
Finally, aging research is being conducted using various authorship, and/or publication of this article.
animal models [62]. In animals such as the naked mole-rat,
the longest-living rodent, healthy cardiovascular structure,

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and function are maintained even at an age corresponding Author Contributions
to 92 human years. Although this may be beyond the scope Jeong Bae Park contributes the writing of all parts of this review.
of this review, these animals may offer insights into the Alberto Avolio contributes to the comments to the revision of the
prevention of age-induced vascular stiffness in humans. manuscript.

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