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therosclerosis is a chronic inflammatory response involving lipid accumulation, smooth cell proliferation, cellular apoptosis, necrosis, fibrosis and local inflammation. It is a leading cause of death in adults. Arterial stiffness results from a degenerative process affecting the extracellular matrix of elastic arteries under the effect of age and cardiovascular risk factors (such as diabetes, hypertension, smoking and sedentary lifestyle). Cardiovascular risk factors are associated with both the atherosclerotic process and arterial stiffness; these conditions have an age-related progression and develop at similar sites of the arterial tree. Assessment of arterial stiffness has emerged as a key tissue biomarker for cardiovascular risk stratification and estimation of biological age. This review study aimed to describe the pathophysiology of arterial stiffness, indirect measurement methods and clinical implications for the management of atherosclerotic disease [1-4]
Increased aortic stiffness is an established vascular condition that occurs through the normal biological evolution. Recent evidence shows it may be associated with atherosclerotic disease when arterial beds such as aortic arch and its branches are affected at an earlier stage .
The arterial network, primarily large vessels, is a compliant system that expands and contracts in response to pressure changes  to accommodate the blood during cardiac systole and keep the blood flow at the periphery during diastole .
In addition to aging, aortic stiffening may be accelerated in the presence of several conditions including systemic arterial hypertension, insulin resistance and diabetes mellitus, smoking, atherosclerosis and chronic kidney disease [7-11].
Reduced aortic compliance has also been associated with other factors such as genetic predisposition, inflammation and infection  (Figure 1). A decrease in arterial compliance plays a role in the dysfunction and exposure of endothelial and smooth muscle cells . This is a complex process that causes the initial pathophysiological changes of vascular damage involving cellular
and other extracellular matrix elements of the vascular wall .
Arterial stiffness is associated with increased collagen turnover and metalloproteinase activity [15-17] as well as a reduction in elastin with increased collagen deposition in the arterial wall that lead to middle layer thickening and formation of the atherosclerotic plaque .
Infection and inflammatory mechanisms are also involved with increasing circulating levels of phospholipase A2 , interleukin 1b  and Chlamydia pneumoniae . Neurohormonal and inflammatory markers including renin-angiotensin-aldosterone system, C-reactive protein, platelet activation and apolipoprotein E deficiency [21,22] have also been implicated.
When the normal heart contracts during systole, it generates
a pulse wave that is transmitted along the arteries. This wave
is reflected by each bifurcation or other irregularities that it
encounters and is then reflected back to its starting point- the
In a system with preserved compliance, this wave is reflected
back to the heart during diastole resulting in a rise in coronary
perfusion pressure and a decrease in systolic blood pressure (BP)
. When aortic stiffness is increased, the pulse wave propagates
backward prematurely in the cardiac cycle during systole and
consequently leads to increased post-load, prolonged ventricular
ejection, reduced oxygen delivery to the tissues and increased
metabolic ventricular demand [24-26].
Arterial stiffness is a manifestation of the atherosclerotic
process and usually precedes the formation of obstructive
plaques. It is thus an early marker of coronary artery disease
(CAD) (Figure 2). Assessment of the arteries using non-invasive
measurements including pulse wave velocity (PWV) has allowed
to identify patients at higher cardiovascular risk. The Conduit
Artery Functional Endpoint (CAFE) sub study  of the
Anglo-Scandinavian Cardiovascular Outcomes Trial (ASCOT)
 reported that hypertensive patients with lower central
BP (measured by radial artery applanation tonometry and
PWV) showed fewer cardiovascular outcomes than those with
apparently controlled BP in peripheral measurements but with
high central BP levels.
Other authors have investigated the correlation between CAD
and aortic stiffness assessed by PWV and augmentation index
(AIx). The Framingham Heart Study assessed PWV, pulse wave
reflection (AIx, brachial pressure amplification) and central pulse
pressure in 2,232 patients and correlated these measures with
major cardiovascular outcomes including myocardial infarction,
stroke, unstable angina and heart failure. The multivariate analysis
showed that patients with higher PWV values had 48% higher risk
of cardiovascular events regardless of other risk factors associated
(p=0.002). The other aortic stiffness measurements assessed did
not show to be as valuable .
A cohort study from China (2011)  evaluated 706
asymptomatic patients for the association between aortic stiffness
measurements as assessed by ankle brachial PWV and coronary
atherosclerosis as assessed by coronary computed tomography
angiography (CCTA). The multivariate logistic regression analysis
revealed that the cut-off PWV value at 14–18 m/s had an odds
ratio (OR) of 3.16 for the association with coronary atherosclerosis
Several other studies have demonstrated the association of
different arterial stiffness measurements with CAD. Weber et al.
 evaluated a cohort of 465 Austrian men with CAD undergoing
coronary angiography and its correlation with aortic stiffness
measurements (PWV, AIx and augmentation pressure). They found
a positive associated between high AIx and CAD (OR 4.06) .
Byung-Hee Oh et al.  assessed the association of the cardioankle
vascular index (CAVI) and the presence of calcification and
coronary stenosis detected by CCTA. They reported an association
between CAVI and >50% coronary stenosis (OR 2.8; p=0.032)
To support the use of arterial stiffness measurements as
markers for primary prevention in target populations, two
studies examined these measurements in elderly patients and
patients with type 2 diabetes mellitus (DM2). Gaszner et al.
conducted a case-control study to assess PWV and AIx in two
different groups of cardiovascular patients: DM2 and CHD. After
stratification by gender and age, BP and heart rate, they found a
significant association of CAD with PWV (p<0.01) and AIx (p<0.5).
Interestingly, after they compared the results of patients with
DM2 with healthy controls, only increased PWV values remained
significant (p<0.05), which may suggest different outcomes
depending on the methodology used to assess arterial stiffness
. Similarly, in a case-control study, Po-Chang Wang et al. 
found a relationship of aortic stiffness with CAD and aging (elderly
individuals over 65 years). They assessed brachial-ankle PWV
measurements and found a significant relationship between PWV
and the presence of CAD in elderly patients (OR 1.097; p=0.026)
The use of arterial stiffness measurements as indicators
for secondary prevention as an additional risk stratification
approach has gained increasing ground in recent research. For
more effective non-invasive risk stratification of patients with
suspected or established CHD, several studies have investigated
the correlation between aortic stiffness measures and severity of
Yoshikawa et al.  demonstrated a relationship between
aortic stiffness and coronary reserve flow in patients with
CAD. They found a significant correlation of increasing PWV
measurements and number of damaged coronary vessels .
Xiong et al.  examined in a cohort of 321 patients with
suspected CAD the relationship between brachial-ankle PWV
and severity of CAD as assessed by the SYNTAX score and found a significant positive relationship with PWV and corrected measures
by the SYNTAX score (OR 4.13; p<0.001) . Moreover, Chung
et al.  evaluated the relationship between aortic stiffness and
the SYNTAX score. In their study, brachial-ankle PWV was a major
predictor of CAD (OR 1.05) and correlated with the severity of
CAD as assessed by the SYNTAX score .
To explore an association with severity of CAD, Duman et
al.  assessed arterial stiffness by measuring carotid-femoral
PWV and its relation with the extent of CAD (as assessed by
Gensini scores). There was a significant positive relationship with
the variables studied (p<0.001); and the PWV cut-off of 7.3 m/s
showed a sensitivity of 83% and a specificity of 86% for CAD
Regarding patients with coronary stenosis undergoing
angioplasty, Mahfouz et al.  reported a positive correlation
between arterial stiffness measures and intra-stent restenosis
within one year of follow-up after angioplasty . In contrast,
in a more recent retrospective observational study, Do-Sun Lim et
al. did not find any correlation between aortic stiffness measures
(aortic-ankle stiffness and AIx) and CAD among patients with
prior angioplasty . The (Table 1) summarizes the studies
assessing arterial stiffness and CAD [41-46].
In conclusion, arterial stiffness can be understood as a
pathophysiologic aging process of arteries that is strongly
correlated with known major cardiovascular risk factors. Arterial
stiffness measurements may have important clinical implications
as evidence supports their usefulness for identifying patients
at higher risk for major cardiovascular events. Recent studies
have also pointed to a relationship of these measurements and
established coronary disease, and it may thus help identifying
patients with high risk of cardiovascular events or more extensive
disease requiring more aggressive clinical management. Arterial
stiffness assessments should be interpreted carefully in view of
different measurement approaches and devices used in studies
designed to validate their usefulness in research and clinical