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Introduction
Introduction
Aortic distensibility is closely related to the bioelastic
function of the aorta and serves as a pathogenic marker
in cardiovascular diseases. The thoracic aorta plays an
important role in the cardiovascular system. Arterial distensibility, as a
measure of vascular function, can serve as a marker of coronary heart
disease risk in humans (Shehata et al., 2015).
Carotid to femoral pulse wave velocity (PWV) is the gold standard

biomarker used for non-invasive measurement of arterial stiffness.
Moreover, it is highly reproducible, widely applied, and an independent
predictor of primary coronary events (Hayashi et al., 2015). PWV in the
arterial tree has been commonly used in clinical medicine. This is based
on the idea that the propagation of pressure wave is faster in a stiffer tube
than in a softer one. In the cardiovascular system, the velocity is obtained
from the measurements of temporal blood pressure waves at two sites
along the arterial tree. As this measurement can be done noninvasively
and easily, this method has been clinically used for several decades
(Hayashi et al., 2015).
1
Introduction
A coronary artery calcium score (CACs) examination is a non-

invasive examination of the coronary arteries in which the amount of
calcium in the coronary arteries is determined using cardiac computed
tomography (Greenland et al., 2018).
With the exception of patients with renal failure, who may also have
medial calcification, coronary calcium is exclusively the result of
coronary atherosclerosis. The amount of calcium in the arteries roughly
correlates with extent of any atherosclerotic plaque that is present in the
coronary arteries (Montalescot et al., 2013).
According to the European Guidelines on cardiovascular disease

prevention in clinical practice (2016 version), the CACS can be
considered for cardiovascular risk assessment in asymptomatic adults
who are at a moderate risk (Mlynarska et al., 2019). The coronary artery
calcium score, which is calculated in cardiac computed tomography, can
support a cardiovascular risk evaluation, and therefore, it can support
clinical decisions. Interestingly, Japanese researchers confirmed that an
elevated CACS that is determined using coronary computed tomography
angiography is an independent predictor of mid- to long-term
cardiovascular mortality and morbidity in patients that are suspected of
having coronary artery disease (CAD) (Yamamoto et al., 2018).
2
Aim of Work
Aim of work
To evaluate whether impaired aortic distensibility index (ADI) and
Aortic stiffness measured by Cardiac CT is correlating with the severity of
coronary artery disease and coronary calcium scoring in at-risk individuals
assessed by Coronary Computed Tomography Angiography (CCTA).
3
Review of literature: Chapter 1 Aortic Distensibility and Aortic stiffness
Chapter 1: Aortic Distensibility and

Aortic stiffness
 Aortic structure and functions
Recognized as a conduit for distributing blood, abnormalities of the functional

properties of the aorta are increasingly realized as important contributors to
cardiovascular (CV) disease. The aorta performs several important functions: First,
the aorta transmits and distributes blood from the heart to medium-sized conduits
that supply the periphery. Second, the aorta acts as an expandable reservoir that
buffers the pulsatile force from left ventricular contraction (Nichols et al., 2011).
The Windkessel principle, first outlined in the late 1800s, models the aorta as
an elastic reservoir absorbing the systolic blood flow from left ventricular
contraction and then releasing this blood by elastic recoil during diastole providing
more constant (rather than pulsatile) blood flow to the periphery (Westerhof et al.,
2009). Figure 1
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Figure 1. Windkessel effect of Aorta (Westerhof et al., 2010)
In addition, a healthy aorta limits the augmentation phenomenon from the

reflective pressure wavefronts that return toward the heart from the medium sized
conduits that supply the periphery (O’Rourke and Nichols, 2005).
As the pressure wavefront from ventricular contraction propagates down the

vasculature tree, reflections of these wavefronts return from the periphery and
amplify the systolic pressure within the aorta that thereby increases left ventricular
afterload. This mechanical interplay between the left ventricle and the arterial tree is
termed ventricular arterial coupling with the aorta playing an integral role in this
relationship (Sunagawa et al., 1983).
In healthy normal individuals, under a wide range of vascular loading

conditions, the aorta allows for optimized work efficiency in conjunction with the
left ventricle (De Tombe et al., 1993).
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However, alterations in the vessel wall and loss of these properties that occur
with aging and disease processes can reduce circulatory efficiency (O’Rourke and
Hashimoto, 2007).
Optimal function of the aorta is related to the structure and composition of 3

regions of the wall of the aorta (Figure 2): the intima, media, and adventitia (Gasser
et al., 2006).
Figure 2. Cross-Sectional Diagram of the Aortic Vessel With the Components of the 3 Layers in a
Healthy Young Individual (20 Years of Age) and in an Elderly Individual (70 Years of Age)
Demonstrating the Effects of Arterial Aging (Whitlock and Hundley, 2015)
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 Arterial distensibility and Arterial Stiffness
Vascular dysfunction has been shown to be an independent predictor of

adverse cardiovascular events (Epstein et al., 1992, 1990; Griendling et al., 1997).
Impaired vascular function is associated with coronary artery disease (Bogren

et al., 1989), hypertension (Laurent et al., 1994), diabetes (Eren et al., 2004;
Lehmann et al., 1992a), and hypercholesterolemia (Dart et al., 1991; Lehmann
et al., 1992b; Oliver and Webb, 2003).
Arterial distensibility, a measure of vascular function, can serve as a marker

of coronary heart disease risk in humans (Bank et al., 1996; Sudhir et al., 1995), In
addition animal studies suggest that reduced arterial distensibility is an early sign of
atherosclerotic change (Hironaka et al., 1997). Previous studies revealed an inverse
relationship between aortic distensibility and cardiovascular risk factors and may
predict outcome (Cruickshank et al., 2002; Kingwell et al., 2002; Tentolouris et
al., 2003).
The aorta maintains low left ventricular after-load, promotes optimal

subendocardial coronary blood flow (Belz, 1995), and transforms pulsatile into more
luminar blood flow. Impaired aortic distensibility leads to higher left ventricular
systolic pressures, diminished subendocardial blood supply (Belz, 1995) and may
ultimately contribute to left ventricular dysfunction (Kelly et al., 1992; Ohtsuka et
al., 1994).
There has been a tremendous interest in the role of arterial stiffness in the
pathophysiology of cardiovascular diseases (CVD) over the past two decades. In this
regard, around 100 articles were published on the topic of arterial stiffness in 1998.
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This number increased to about 500 articles in 2008 and over the past 5 years, more
than 1000 articles are published per year in this area.
There is a well-known correlation between arterial stiffness and morbidity and

mortality from hypertension, especially in relation to age-related progression of
arterial stiffness. However, the recent surge in interest is in large part due to
population level data suggesting that arterial stiffness as an independent risk factor
for CVD and hypertension (Niiranen et al., 2016; Padilla et al., 2016; Safar, 2018;
Smulyan et al., 2016; Townsend et al., 2015)
This may also be due to the ability to measure carotid-femoral pulse wave
velocity (cfPWV) with relative ease and the widespread acceptance of using this
technique to correlate risk for CVD (“Determinants of pulse wave velocity in
healthy people and in the presence of cardiovascular risk factors: ‘establishing
normal and reference values,’” 2010).
The remaining question has been whether there are specific pharmacological
and non-pharmacological interventions that can mitigate the CVD risk from arterial
stiffening (Briet and Schiffrin, 2013; Laurent et al., 2011; Padilla et al., 2016;
TANAKA and SAFAR, 2005).
8
 History and Evolution of Arterial Stiffness

Measurement
In 1733, the English philosopher Stephen Hales inserted a flexible tube into
the carotid artery of a horse and measured the rise in the column of blood. In doing
so, he earned the credit for measuring the first recorded arterial blood pressure
(Avolio et al., 2010).
The inconvenience of this method prompted future physicians and/or

researchers to develop non-invasive techniques to measure the arterial pulse and
blood pressure. Marey in 1863 and Mahomed in 1872 devised cupped external
devices that would measure pulse waves over arteries (Avolio et al., 2010; Booth,
1977). These sphygmographs used transducers and levers to trace the arterial wave
on a rotating drum (Avolio et al., 2010). In 1896, Riva-Rocci developed the brachial
cuff that allowed for the evaluation of systolic arterial pressure by palpation (Avolio
et al., 2010; Booth, 1977).
Korotkoff identified the auscultatory changes that occurred with the release
of the brachial cuff thus allowing for the identification of both systolic and diastolic
pressures (Avolio et al., 2010; Booth, 1977). This combination formed the basis of
the sphygmomanometer that has remained essentially unchanged to this day.
Sphygmograph and sphygmomanometers indirectly measure stiffness through pulse
pressure although measurement of pulse pressure cannot be used to diagnose
underlying disease such as diabetes or atherosclerosis (O’Rourke et al., 2001;
Wilkinson et al., 2001).
This method of measuring blood pressure, however, does not take into account
the waveform that is transmitted with each heartbeat. The sharp rise at the start of
the wave corresponds to the opening of the aortic valve in systole. Upon reaching its
9
peak, it begins to decline at the start of diastole. The closure of the aortic valve soon
after diastole begins produces the dicrotic notch (Esper and Pinsky, 2014).
Figure 3. Central pulse pressure waveform. Systolic and diastolic pressures are the peak and
trough of the waveform. (Nelson et al., 2010)
The shape of the wave is dependent on the distance from the ventricle and the
elasticity of the vessel and it has been demonstrated that brachial pressures are
differentially lowered compared to the central pressures. For this reason, the
measurement of brachial cuff pressures as a determinant of arterial blood pressures
and prediction of clinical risk was under scrutiny (Avolio et al., 2010).
Not only do arteries serve as a conduit for blood flow to tissues and organs,
they also have a dampening effect, transforming the cyclic blood flow in the aorta
into the capillary flow and dampened arterial pressures experienced in the
microcirculation. The elasticity of arterial segments expanding in systole and
10
recoiling in diastole determine their ability to maintain flow while serving as a buffer
to central pressure (Boutouyrie et al., 2014).
Figure 4. Physiologic Properties of the Aorta as a Reservoir and Conductive System: The Windkessel
Principle The aorta is regionally heterogeneous and not a simple conduit for blood distribution. The
viscoelastic properties of the proximal aorta absorb the energy of left ventricular ejection and dampen
pulsatile flow
When ventricular contraction occurs, the arterial pressure wave that is

generated in the aorta is propagated forward through all the arteries in the body.
Upon reaching organs and tissues, this pressure wave is reflected back towards the
aorta-reflected pressure wave. As a result, measurement of wave forms with systole
is bidirectional from the proximal aorta towards peripheral vessels and back.
This produces the dicrotic notch seen on wave forms. Increasing arterial
stiffness modifies wave reflection timing and causes the loss in the notch. It also
11
diminishes the stiffness gradient resulting in pressure overload to smaller arterial

segments, the microcirculation, and its resultant complications.
Pulse wave velocity (PWV) remains the most widely used technique for
assessing arterial stiffness (Boutouyrie et al., 2014).
As arteries harden with age (the most widely recognized risk factor for
stiffness), there is a loss in the elasticity of the arteries caused by the replacement of
elastic elastin fibers with less elastic collagen. These changes are associated with the
reorganization of cellular elements within the vessel wall. The end result is a vessel
less capable of expanding to transmit the wave generated in systole at the opening
of the aortic valve at the root of the aorta. Increased aortic stiffness in turn means
that the reflected wave that is transmitted back from the end organs centrally is
transmitted earlier. This phenomenon is seen in hypertensives, likely a function of
the longer lifespan of our species. Given the fact that different organs experience
different degrees of arterial pressure, consistent with the distance from the aorta and
the anatomy of the vascular tree, records of these waveforms vary from vessel to
vessel.
In order to identify the transit time of the wave, two sites are usually required.
While it can be measured on any artery or between arterial sites, carotid-femoral
pulse wave velocity is the gold standard for measuring arterial stiffness (Obeid et
al., 2017; Townsend et al., 2015).
It involves the application of an air-filled diaphragm to the carotid and femoral

arteries. Using techniques first developed in ophthalmic tonometry, pressure to the
vessel minimizes motion artifacts that would interfere with measurements. Sensors
pick up the changes occurring with pulsations. The cut off for carotid-femoral pulse
wave velocity is 10 m/s (Van Bortel et al., 2012).
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Pulse wave velocity has been shown to provide a better predictive value than
blood pressure for end organ damage. Indeed, arterial stiffness was shown to be
superior to blood pressure in predicting hypertension-associated cognitive decline
(Hajjar et al., 2016; Weber et al., 2012).
The association with adverse cardiovascular outcomes makes it a useful tool,

both for predicting outcomes and treating risk factors (Ferruzzi et al., 2018; Safar,
2018).
Pulse wave velocity can be measured using commercially available devices at

several anatomical sites including carotid-radial and femoral-tibial arterial segments
as well as brachial-ankle or single-point pulse wave velocity measurements (Teren
et al., 2016).
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 Mechanisms Underlying Arterial Stiffness
I. Aging
While aging-associated arterial stiffness is well recognized, there have been a

number of mechanisms identified that contribute to the development of arterial
stiffness (Figure 5) (Lyle and Raaz, 2017).
However the role of hormones/regulatory peptides and their receptors,

proinflammatory cytokines/chemokines, as well as calcium deposition within the
vasculature is an active area of investigation.
Figure 5. Mechanisms underlying arterial stiffness
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II. The Renin-Angiotensin-Aldosterone System
The renin-angiotensin-aldosterone system (RAAS) is thought to be activated

in conditions of metabolic syndrome and obesity in addition to their well- recognized
roles in hypertension and diabetes (Cabandugama et al., 2017; DeMarco et al.,
2014).
Data has shown that several animal models and a subset of human subjects
are characterized by elevations of both plasma and tissue RAAS. Increased local
RAAS activation is thought to contribute to a major proportion of the prevailing
vascular stiffness. There are several components in RAAS-mediated activation of
stiffness (Aroor et al., 2013).
Angiotensin II (Ang II) is perhaps the most well-known of the peptide

hormones with a major role in mediating vascular remodeling in cardiovascular
disease (Aroor et al., 2013; Barhoumi et al., 2011; Briet and Schiffrin, 2013;
Cabandugama et al., 2017; Zieman et al., 2005).
Pathologically increased or abnormal Ang II Type 1 receptor (AT1R)

signaling under conditions of RAAS activation (mentioned above) leads to
activation of many pro-growth/mitotic pathways including activation of ERK,
mTOR/S6K, and PKC that leads to smooth muscle hypertrophy and endothelial
dysfunction (reduced bioavailable NO) (Zieman et al., 2005).
In addition, Ang II activation leads to secretion of pro inflammatory cytokines

such as IL1β, IFNγ, IL17, and MCP1 and suppression of anti-inflammatory
cytokines such as IL10, IL4, and IL13, via activation of macrophages (M1
15
polarization), T cells, and B-cells and suppression of T regulatory cells (Barhoumi

et al., 2011).
Furthermore, Ang II is a well-known stimulator of oxidative stress via

activation of NADPH oxidase and mitochondria ROS production, together leading
to reduction of bioavailable NO by nitrosylation into 3-nitrotyrosine (Nguyen Dinh
Cat et al., 2013; Zieman et al., 2005).
There is also some role for central regulation of vascular tone via increased
brain Ang II and activation of the sympathetic system. Taken together, Ang II is a
powerful mediator of vascular stiffness especially in conditions of diabetes, obesity,
and hypertension (Hamlyn et al., 2014).
Novel Mechanisms in RAAS-Regulation of Arterial Stiffness
1. Mineralocorticoid Receptor Signaling
Enhanced mineralocorticoid (MR) signaling independently (via cortisol) in

the setting of metabolic syndrome/obesity has been shown to increased vascular
stiffness (McCurley et al., 2013; Tirosh et al., 2010).
Blockade of the mineralocorticoid receptor with low-dose (this dose did not
block the principle cell action of MR in the kidney) spironolactone has been shown
to prevent a Western diet-induced (high fat, high refined sugars, WD) increase in
arterial stiffness (DeMarco et al., 2015).
This beneficial effect of MR blockade was demonstrated by improvements in

aortic and femoral artery PWVs. Furthermore, endothelial MR-deficient mice were
protected from WD-induced increases in arterial stiffness both by aPWV and
measurement of endothelial cortical stiffness by atomic force microscopy, strongly
16
suggesting that the endothelial MR activation is the mechanism for WD-induced

increase in arterial stiffness in this model.
2. Endothelial Sodium Channel
There has been much interest into the mechanisms behind MR-dependent
arterial stiffness. Studies performed in WD-fed female mice showed that activation
of the MR was correlated with an increase in endothelial sodium channel (EnNaC)
activity on endothelial cells and this was associated with endothelial dysfunction and
vascular stiffening (Jia et al., 2016).
Reducing EnNaC activity using very low-dose Amiloride (a dose that does
not block ENac activity in the kidney) produced a significant reduction in endothelial
and aortic stiffness, suggesting that endothelial MR-EnNaC activation may play a
major role in WD-induced increase in vascular stiffness (Martinez-Lemus et al.,
2017).
III. Insulin Resistance
Insulin resistance and endothelial dysfunction have been postulated as likely

contributors to the accelerated incidence of arterial stiffness that has been seen with
the obesity pandemic (Jia et al., 2015).
Insulin affects the vasculature through metabolic signaling via its receptor, as
well as growth factor/mitotic signaling. Regulation of endothelial function by insulin
metabolic signaling (PI3K-Akt-eNOS) is critical for normal endothelial function and
vascular stiffness. This insulin metabolic signaling is inhibited/suppressed by Ang
II and aldosterone in vascular endothelial cells and vascular smooth muscle cells by
several mechanisms including alteration of PI3K downstream activation,
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Akt/eNOS/S6K1 phosphorylation, and diversion of insulin metabolic pathway to the

mitotic pathway (ERK activation). Insulin metabolic signaling stimulates production
of the vasodilator NO (Brillante et al., 2009).
This is in contrast to the action of growth factor signaling pathways that leads
to the production of the vasoconstrictor ET–1. ET–1, along with Ang II and
aldosterone, is a major contributor to vascular stiffness (Zieman et al., 2005).
IV. Uric Acid
Recently, a lot of interest has been generated by the potential for using
allopurinol in mitigating the increase in arterial stiffness mediated by the WD
(Canepa et al., 2017; Mehta et al., 2015). WD-feeding led to increase in plasma as
well as tissue uric acid levels and tissue xanthine oxidase levels in association with
increase in arterial stiffness, oxidative stress, and kidney injury/proteinuria (Aroor
et al., 2017).
Suppression of XO as well as reduction in uric acid levels was correlated with

improvements in arterial stiffness by both PWV and endothelial cortical stiffness
measurements. Furthermore, both inflammation and oxidative stress were improved
by allopurinol along with the kidney injury suggesting that vascular kidney injury
could be mediated by XO/uric acid pathway and targeting vascular stiffness may be
a novel therapy in conditions of metabolic kidney injury. Interestingly, WD-feeding
led to an increase in EnNaC expression levels in the vasculature that was improved
by allopurinol suggesting an interaction between the uric acid and MR-EnNaC
pathways(Aroor et al., 2017).
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V. The Role of Adipose Tissue
Adipokines are hormones produced by adipocytes and are associated with

inflammation and cardiovascular complications seen in hypertension. The
mechanisms of obesity-related hypertension include, among others, aldosterone
excess and inflammatory adipokines, which have demonstrated a significant role in
the pathogenesis of metabolic syndrome and RH (de Faria et al., 2014).
1. Adiponectin
The most abundant of the plasma proteins produced by adipocytesplays an

anti-inflammatory, antiproliferative, anti-atherogenic role and has insulin-
sensitizing properties (Achari and Jain, 2017; Sabbatini et al., 2015;
Yiannikouris et al., 2010).
Hypoadiponectinemia is noted in obesity, insulin resistance, type 2 diabetes,

coronary artery disease, and hypertension (Su et al., 2011). In settings where there
is already vascular endothelial injury, low levels of the adiponectin and the low-
grade inflammation are believed to contribute to aortic stiffness in hypertensive
patients (Ebrahimi-Mamaeghani et al., 2015).
Several studies are providing increasing data as to its correlation in healthy

volunteers and in other conditions like diabetes mellitus and CKD. Its impact on
arterial stiffness requires additional research (El Khoudary et al., 2012; Kim et al.,
2017).
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2. Leptin
Leptin is a 16 kDa peptide hormone mainly produced by white adipose tissue.

High leptin levels are implicated in metabolic, inflammatory, and homeostatic
factors associated with obesity, hypertension, and cardiovascular disease (Sabbatini
et al., 2015; Söderberg et al., 2009).
Leptin binds to CNS receptors to produce sympathetic outflow to the kidneys

(Xue et al., 2016). It also acts as a stimulant of the renin-angiotensin-aldosterone
system, leading to volume expansion and hypertension. Leptin is a promoter of
vascular smooth muscle proliferation and reduces nitric oxide and aortic mechanical
function with a resultant increase in arterial stiffness (Noblet et al., 2016).
3. Resistin
Resistin is a 12.5 kDa peptide hormone mainly produced in macrophages

which suggests a role in inflammatory responses (Jamaluddin et al., 2012; JUNG
et al., 2006). It is known to impair glucose tolerance hence its name (Resistance to
Insulin) (Steppan et al., 2001).
Overexpression of resistin is associated with atherosclerosis, endothelial

dysfunction, inflammatory markers, triglyceridemia, and elevated LDL and systolic
and diastolic blood pressure in human models (Jamaluddin et al., 2012). Increased
expression of vascular adhesion molecules and cytokines and the promotion of
smooth muscle proliferation form the basis of resistin’s role in hypertension (JUNG
et al., 2006).
Despite the aforementioned associations, establishing causality is difficult for

any one adipokine due to the complex interactions between them.
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VI. Inflammatory Markers
A series of inflammatory biomarkers have been shown to be associated with

increased arterial stiffness and resistant hypertension (Barbaro et al., 2015).
Interleukin-6, interleukin-1, tumor necrosis factor, and high-sensitivity CRP

are positively related with pulse wave velocity in hypertensive patients (Mozos et
al., 2017).
The inflammatory responses contribute to structural and functional changes

in arterial walls and may contribute to arterial stiffness. Based on a series conducted
in Japan, in middle-aged men without hypertension at study baseline, long-term
active inflammation appears to be associated with a longitudinal increase of arterial
stiffness (Tomiyama et al., 2017).
This was in turn associated with elevated biomarkers of chronic inflammation,

increased arterial stiffness, and longitudinal elevation of blood pressure to the
hypertensive range (Tomiyama et al., 2017).
VII. Vascular Calcification
Ectopic arterial calcium deposition may take place either in the intima or
media of blood vessels (Pikilidou et al., 2015).
Vascular calcification whether it be medial or intimal results in arterial

stiffening. Calcium deposition in arterial walls may be the result of a shift in
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functionality of bone marrow-derived circulating stem cells with a calcifying

potential—the osteoprogenitor cells. Once deposited in the vascular wall, they can
then become mineralized (Pikilidou et al., 2015).
Medial calcification—elastocalcinosis or Mokenberg’s disease—involves

apoptotic cell death of vascular smooth muscle cells, macrophages, lipids, and
calcification stimulatory proteins and mechanisms that increase the extracellular
calcium and phosphate concentration. Intimal calcification results from lipid-rich
fibrous cap of the atheroma and is the net result of factors either favoring or
inhibiting calcification. In favor of calcification are apoptotic cell death of VSMC,
macrophages, and calcification stimulatory proteins, while those opposing
calcification include phagocytosis, calcification inhibitory proteins, and a potential
contribution of osteoclast macrophages (Obeid et al., 2017).
The process of arterial calcification largely affects arterial stiffness and its
resultant morbidity and mortality (Aoki et al., 2009).
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 Novel Diagnostic Methods for Measuring Aortic

Distensibility Index (ADI) and Arterial Stiffness
 Aortic Distensibilty index
Aortic distensibility (AD), or the degree to which the aorta can contract and expand,
is a property of the vessel wall itself. It is defined as the maximum change in
area/(minimum area × pulse pressure). AD can be measured at any point along the
aorta, and previous studies have confirmed changes in distensibility in both the
ascending and descending aorta (Ganten et al., 2007, 2008). AD has been shown to
be inversely proportional to disease severity and presence of cardiovascular risk
factors (Malayeri et al., 2008). It is markedly decreased in patients with known
coronary artery disease (CAD) and is inversely proportional to the amount of CAD
as determined by the degree of stenosis on invasive coronary angiography
(Giannattasio et al., 2007; Stefanadis et al., 1990). AD using ultrasound on
medium-caliber vessels, specifically the carotid artery, is feasible due to its
superficial location (Giannattasio et al., 2001).
 Pulse Wave Velocity (PWV)
PWV is the most validated method to noninvasively quantify arterial stiffness.

It is considered the gold standard index of AS, given its simplicity, accuracy,
reproducibility, and strong prediction of adverse outcomes (Asmar et al., 1995;
Chin et al., 2012; Lehmann et al., 1993).
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 How to Measure Arterial Stiffness?
Pulse wave velocity testing remains the gold standard for non-invasive
measurement of central arterial stiffness. To increase its ease of use and availability,
several approaches are being tested. Single-point PWV utilizes oscillometric
measures (David et al., 2014).
A number of devices have been developed with varying degrees of variability

and reproducibility for the measurement of PWV by commercial companies such as
Arteriograph, Complior, and SphygmoCor (Baulmann et al., 2008).
Doppler probes positioned at the substernal notch and close to the umbilicus
can be used to measure aPWV. Taking into consideration, the curvatures and
bifurcations that occur throughout the vascular tree, carotid-femoral pulse wave
velocity has been accepted as the standard. Interestingly, an MRI can detect both
distention and/or flow and allows for precise measurements of true path length
(Townsend et al., 2015).
For several reasons including modesty (carotid femoral PWV requires

exposure of the groin), it has been difficult to convert PWV into clinical practice. In
addition, the equipment needed for these measurements was often large and
cumbersome. Recently, newer techniques are being developed including the brachial
ankle pulse wave velocity that is often used in Asian countries. Moreover, it avoids
exposing the groin of the subject (Zhang et al., 2014).
A novel approach to carotid-femoral pulse wave velocity assessment was

developed utilizing leg cuff-based detection of femoral pulses that eliminated the
need for sequentially placed tonometry involving the carotid and femoral pulse. This
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removed the need to perform signal gating and reduced the time requirement for a
single measurement. The results obtained, however, varied from those of traditional
tonometry due to the increase in transit time and the distance accrued from additional
femoral segment. An algorithm that corrected for these parameters, when applied,
supported the cuff-based technology to provide similar pulse wave velocity values
as the tonometry-based approach (Butlin et al., 2013).
Another attempt at measuring arterial stiffness has utilized the arterial

compliance probe with dual magnetic plethysmograph (MPG) transducers for local
pulse wave velocity (PWV) measurement (P.M. et al., 2017).
In a study utilizing a bathroom scale, Campo et al. were able to estimate

carotid-femoral PWV with acceptable accuracy and precision (Campo et al., 2017).
In spite of the differences between their method and standard tonometry, they
were able to show good correlation between pulse transit times between the two
devices. Cardiovascular magnetic resonance has been validated as a non-invasive
means of assessing arterial compliance and aortic stiffness. This measure of arterial
stiffness has been found to be associated with non-fatal cardiac events but not with
cardiovascular death or non-fatal extracardiac vascular events (Maroules et al.,
2014).
Ultrasound has also been used as a diagnostic tool to estimate of carotid

intima-media thickness and measurement of PWV in high-risk pediatric patients.
Ambulatory blood pressure monitoring was also seen as a promising option for high-
risk pediatric patients (Skrzypczyk and Pańczyk-Tomaszewska, 2017).
New devices are being evaluated to measure arterial stiffness that improve the
ease of measurement. One such device made with highly sensitive graphene-based
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skin-like sensor that senses pulse waves is comfortable and easy to use (Yang et al.,
2017).
Other parameters are being evaluated as surrogates for arterial stiffness

beyond the carotid femoral PWV. The stiffness parameter is an index of arterial
stiffness that unlike PWV is not influenced by blood pressure. This parameter was
recently applied to develop a new arterial stiffness index called the cardio-ankle
vascular index (CAVI). Several studies have shown to have a high value in
arteriosclerotic diseases (Saiki et al., 2016).
PWV can be determined by measuring the pulse transit time from the pressure
waveforms at the 2 sites along a vascular segment. The distance (L) is divided by
the wave foot-to-foot time (ΔT) it takes for that forward wave to reach the end
measuring point (PWV) (Figure 6).
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Figure 6. Non-invasive Determination of PWV Between the Carotid Artery and the Terminal Aorta.
Femoral artery is the terminal aorta. The measured distance is L. If ΔT represents the time delay between
the feet of the 2 waves, pulse wave velocity (PWV)= L/ ΔT. Distensibility might be then deduced from the
Bramwell-Hill formula. Automatic PWV measurements are currently widely used. Reprinted with
permission from Safar M. Atherosclerosis, large arteries and cardiovascular risk. In: Safar ME, Frohlich
E, editors. Advances in Cardiology. Basel; Karger AG, 2007:1–18.
Pulse wave velocity is inversely related to vascular compliance. Hence, a

stiffer vessel will conduct the pulse wave faster than a more distensible and
compliant vessel.
PWV is a regional functional measurement of arterial stiffness over a certain

arterial length, whereas strain, com-pliance, and distensibility are local markers of
arterial elasticity. Local AS has been characterized—to allow com-parisons between
indexes—as the inverse relation of aortic distensibility (AD) (Asmar et al., 1995;
Nelson et al., 2009) as demonstrated by the Bram-well–Hill equation and expressed
in meters/second:
Redheuil et al. (Redheuil et al., 2010) showed that local aortic elastic
properties measured by magnetic resonance imaging (MRI) were markedly
decreased before the fifth decade of life, whereas concomitant increase in aortic arch
PWV (increased AS) was seen demonstrating that inverse relationship.
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Other investigators (3,4) have proposed that aortic compliance and

distensibility are the absolute and relative changes for pressure steps, respectively.
Aortic distensibility is the relative cross-sectional diameter (or area) change for a
given pressure step at fixed vessel length. The frequently used formula that expresses
this relationship is:
Where Aomax= maximal aortic lumen and Aomin= minimal aortic lumen.
As with any quantification technique, care must be taken to consider the

methodology being used when comparing results between patient groups and among
different studies (Table 1).
Table 1. Non-invasive Methods to Assess Aortic Stiffness. CMR= cardiac magnetic resonance;
PWV= pulse wave velocity.
28
1. Measurements of AD and PWV by Cardiac CTA
Distensibility can be expressed as follows (Ganten et al., 2005):
Where SA is the maximal systolic area, DA is the minimal diastolic area, SBP is
systolic blood pressure, and DBP is diastolic blood pressure.
The principle of aortic distensibility measurement is illustrated in Figure 8.

The window level and width of 300 and 800 HU was used. True CSA and diameter
of ascending aorta (AAo) was measured both manually and with the automated
software. The CSA and diameter of AAo were measurements 15 mm above the
ostium of left main coronary artery (Mao et al., 2003).
Maximum AAo diameter and CSA was observed at end-systolic phase, 35%
of R–R interval in individuals with a heart rate ≥ 60 bpm. AAo diameter and CSA
decreased linearly from end-systole to end-diastole phases from 35 to 95% of R–R
interval; which the minimum AAo diameter and CSA was observed at the end-
diastolic (95% of R–R interval) phase.
We can also measure Aortic Stiffness form Aortic distensibility by measuring

Pulse wave velocity (PWV) as PWV and distensibility are inversely related to one
another by the Bramwell-Hill equation (Bramwell JC. Hill, 1922):
29
Figure 7. Changes in the volume of ascending aorta (AAo) at the end systolic and end diastolic phase,
35% and 95% of R–R interval respectively, 15 mm above LM ostium using axial and coronal views. Using
axial image, AAo image 15 mm above LM ostium was assessed (C), then perpendicular diameter and
volume of AAo was measured using coronal and oblique views (B) at end systole and diastole, respectively
30
2. Measurement of AS by applanation tonometry and

oscillometric method
The applanation tonometry principle for arteries followed directly from the
ocular application, given the propensity for a circular arterial segment to be flattened
by an external force. An excellent in-depth review of this technique can be found
elsewhere (Nelson et al., 2010). With 2 different sites (carotid and femoral artery,
for example), the oscillometric method measures noninvasively the pulse transit time
from the pressure waveforms at the 2 sites and infers the velocity in the “conduit”
(Figure 8).
Figure 8. Measurement of Aortic Stiffness by Carotid-Femoral Oscillometric Signal. (A) Neckpad

placement; (B) thigh cuff placement; (C) aortic path length measurement; (D) pulse wave velocity (PWV)
analysis is displayed on the computer screen. Reproduced with permission from Skidmore Medical, Ltd.,
Bristol, United Kingdom
31
Asmar et al. (Asmar et al., 1995) calculated PWV with the oscillometric
method in more than 400 individuals with excellent intra- and inter-observer
reproducibility and good correlation between the automatic and manual approaches
(Asmar et al., 1995).
Normal values in the typical adult of middle-age are 4 m/s in the ascending
aorta, 5 m/s in the abdominal aorta and carotids, 7 m/s in the brachial artery, and 8
m/s in the iliac arteries (Zambanini et al., 2005).
Ideally, the transit time should be coupled to a precise and reproducible

measurement of true vascular lumen length. An important limitation to this method
is that, because no vascular imaging is performed, the vascular length travelled by
the pulse wave (i.e., the carotid to femoral distance) has to be approximated from a
body surface measurement. Rigid measurements with calipers are monodimensional
and do not take into account the 3-dimensional morphology of the aorta, carotid and
femoral arteries (particularly in the anteroposterior direction) or the potential
tortuosity associated with older arteries. This is also true for flexible tape measures,
and it is a major argument in favour of making such distance measurements on a
comprehensive aortic imaging dataset, such as those available with MRI. Direct
intravascular distance measurements will always be much better than indirect
external approximations.
Carotid-femoral pulse wave velocity (CFPWV) is con-sidered to be a global

estimate of arterial PWV through the entire aorta. However, we should note that this
PWV is measured between 2 peripheral sites, with flow in the carotid and femoral
arteries being in opposite directions, whereas the ascending aorta—a prime location
of aortic stiffening—is not directly accounted for in this approach.
32
Another important caveat to this method is the amplification phenomenon.

This phenomenon occurs because the pressure wave is progressively amplified due
to increased wave reflections in smaller, less elastic, and more muscular distal
arteries. Thus, it is inaccurate to use brachial pulse pressure as a surrogate for aortic
or carotid pulse pressure, particularly in young subjects (Laurent et al., 2006).
33
3. Measurement of AS and distensibility by echocardiography
Pulse wave velocity can also be assessed noninvasively by echocardiography

with pulse wave Doppler. Although this method has not been as commonly used, it
seems to have good correlation (r = 0.83) with the applanation tonometry (Jiang et
al., 2008). Furthermore, pulse wave Doppler allows quantification of regional PWV,
which could be advantageous as a future research tool (Baguet et al., 2003). The
main advantage of ultrasound techniques is their wide availability, and the main
limitation is the incomplete visualization of the aortic arch.
Aortic stiffness has also been evaluated with advanced echocardiography

techniques such as tissue Doppler and strain imaging in different populations
(Mahfouz Badran and Elnoamany, 2006; Vitarelli et al., 2010). These techniques
are important research tools, with future clinical applications remaining to be found.
Furthermore, assessment of AD by transthoracic and transoesophageal

echocardiography has a high degree of accuracy when compared with invasive
measurements, in different populations (Stefanadis et al., 1990). On transthoracic
echocardiography, M mode measurements are obtained at 3 cm above the aortic
valve on parasternal long-axis view (Figure 9) (Gedikli et al., 2007).
34
Figure 9. Measurements of Aortic Diameters Shown on the M-Mode Tracing. Measurements of aortic
diameters shown on the M-mode tracing obtained at a level 3 cm above the aortic cusps.
Ao= aorta; D= diastolic aortic diameter; S= systolic aortic diameter.
On transesophageal echocardiography, measurements are done at the level of

pulmonary artery bifurcation (2 to 3 cm above the aortic valve) and in the descending
thoracic aorta just distal to the branching site of the left subclavian artery (Vitarelli
et al., 2008). The following formula, described by Stefanadis et al. (Stefanadis et
al., 1990), is then applied:
35
Pulse pressure amplification might confound these estimations when using brachial
pulse pressure, especially in young individuals.
36
4. Measurement of AS by MRI
Unlike CFPWV, which is an average measure of overall arterial stiffness,

MRI enables the detection of more subtle changes in regional stiffness. Magnetic
resonance imaging has several advantages over ultrasound in that full 3-dimensional
visualization of the vessel is possible, enabling the imaging plane to be placed
perpendicular to the vessel in a reproducible location. This is an obvious advantage
for the measurement of distensibility measured in MRI as a change in 2-dimensional
vessel perimeter or area instead of 1-dimensional vessel diameter. Furthermore,
velocity data can be acquired simultaneously within 1 acquisition plane in 2 aortic
locations, and the path length (distance between the 2 aortic locations) can be
measured precisely.
To assess AD by MRI, steady-state free precession cine imaging with

electrocardiographic gating can be used to measure the changes in cross-sectional
aortic area after aortic contouring, with a temporal resolution of 40 ms.
Alternatively, the modulus images of a similarly placed cine gradient echo phase
contrast velocity acquisition can be used for aortic contouring and area
measurements (Herment et al., 2010). The mini-mum and maximum ascending
aortic cross-sectional areas should be measured and AD calculated as the following:
where ΔP is the pulse pressure in mm Hg (Malayeri et al., 2008).
Grotenhuis et al. (Grotenhuis et al., 2007) obtained AD measurements by

MRI in patients with bicuspid aortic valves and showed significantly reduced aortic
37
elasticity throughout the entire thoracic aorta when compared with control subjects
(Figure 10).
Figure 10. Distensibility Measurement of the Aortic Root with Cardiac MRI (A and B) Taken in the oblique
coronal plane, these images show the slice positioning of the acquisition planes at minimal and maximal
aortic flow for distensibility measurements, respectively, thus correcting for through-plane motion of the
aortic root during contraction. Note the difference in position of the aortic root in both images, because of
cardiac motion. (C and D) Corresponding area measurements in the double oblique transverse orientation.
MRI= magnetic resonance imaging. Reproduced with permission from Grotenhuis et al. (Grotenhuis et
al., 2007).
Moreover, it is favourable to use central aortic pressures instead of brachial

pressures to calculate distensibility to minimize the amplification phenomenon. Velocity-
38
encoded MRI with phase contrast sequences allows accurate assessment of the blood flow
velocity with a sufficient temporal and spatial resolution to study the propagation of the
aortic systolic flow wave. Velocity-encoded MRI, when compared directly with invasive
hemodynamic measurements, had excellent correlation and reproducibility. A recent
article by Redheuil et al. (Redheuil et al., 2010) compared several of these non-invasive
techniques used for the assessment of the elastic properties of the aorta and reported aortic
distensibilities with MRI with central pres-sures. Ascending aorta distensibility correlated
strongly with aortic arch MRI-derived PWV (r = 0.73, p = 0.0001), and both indexes were
more strongly and specifically related to aging than applanation tonometry-derived indexes
(CFPWV, augmentation index) or carotid distensibility (Redheuil et al., 2010).
Figure 11. Central pulse pressure waveform. Systolic and diastolic pressures are the peak and trough of
the waveform. Augmentation pressure is the additional pressure added to the forward wave by the reflected
wave. Augmentation index is the ratio between augmentation pressure and central pulse pressure. The
dicrotic notch represents closure of the aortic valve and is used to calculate ejection duration. Time to wave
reflection is calculated at the point of rise in the initial ejection wave to the onset of the reflected wave. The
reflected wave in this central pressure waveform results in augmentation of systolic flow (Nelson et al.,
2010).
39
 Load-Bearing Components
The main load-bearing components in large conduit arteries are elastin and
collagen, with a much lower contribution by smooth muscle in the muscular arteries.
Due to the anatomical arrangement of the elastin and collagen fibres, elastin engages
at low distension (hence at low pressure) and collagen at higher distension (and
pressure) (WOLINSKY and GLAGOV, 1964).
However, although the lamella unit is proposed as being the fundamental

structural element of elastin in the media of the artery wall, there is significant
variation in human arteries compared to other species (Wolinsky and Glagov, 1969;
WOLINSKY and GLAGOV, 1967).
In addition, there is substantial variation in the isotropic properties (Dobrin

and Mrkvicka, 1992) and the contribution to wall stiffness of elastin and collagen
along the aortic trunk (Lillie et al., 2012, 2010).
The adaptation seen with a change in function is evident as the design of load-
bearing components is optimized to minimize the amount of collagen recruitment,
and thus stiffness, as it is a necessary function in diving mammals (Gosline and
Shadwick, 1996).
40
 Arterial Stiffness Dependence on Distending Pressure
An inherent feature of the mechanical properties of arteries is that the wall

becomes stiffer with distending pressure (Cox, 1975).
This is due to the increased amount of recruitment of stiffer collagen fibres

with increasing distension. That is, the relationship of stress (pressure) and strain
(diameter) is non-linear, with concavity toward the distension axis, such that there
is diminishing distension with increasing force.
This property is essential for the efficient mechanical operation of arteries as

conduits for blood, such that, with the maintaining of residual stress, the vessels do
not collapse and so always ensure patency for blood flow. That is, the wall tension
(T) as balanced by the transmural pressure (P) and radius (r) (T = P · r, as determined
by Laplace's law) has a single operating point on the pressure-diameter curve.
Indeed, the non-linear elastic behaviour of arteries has been described as a

fundamental evolutionary property of the arterial design for all vertebrates and
invertebrates with closed circulatory systems (Shadwick, 1999).
41
 Haemodynamic Effects of Arterial Stiffness
Arterial stiffness is a major determinant of vascular impedance, hence

affecting the relationship between arterial pressure and flow (Nichols et al., 2011).
For elastic conduits, the wave velocity is related to the stiffness of the wall, so
changes in stiffness will modulate the pressure-flow relationships. This is then
expressed as changes in the frequency spectrum of arterial impedance(Nichols et al.,
2011).
 Effects on Blood Storage (Compliance): Determinant of Pulse

Pressure
In a closed circulatory system, blood is stored in distensible compartments,

with the venous system being responsible for buffering slow and relatively large
changes in volume. However, the arteries, with the residual wall stress and elastic
walls, are also able to buffer rapid changes in blood volume, such as occur during a
single cardiac cycle.
Hence, the value of the elastic modulus of the artery wall is such that there is
sufficient recoil so that the volume taken up during systole is returned during
diastole, hence buffering the pressure due to pulsatile ejection. Thus, increases in
arterial stiffness will generate higher pulse pressure (PP) for similar stroke volumes
(SV).
Since the SV is the volume taken up by arterial distension and that flowing
through the peripheral resistance (R), the ratio SV/PP is related to the total arterial
compliance (C). In terms of arterial design, arterial stiffness is matched to obtain a
value of C so as to optimize blood volume in the arterial compartment.
42
For example, for maximal damping of PP, a large value of C would be required
for a given SV, that is, a highly distensible system. However, this would store large
volumes with a slow time constant (RC) for recoil, and so would result in an
inefficient circulation because of high inertia due to the large blood mass to be
displaced. These concepts are quantified in terms of the lumped parameter
Windkessel (RC) model of the arterial system and extended to a three-element model
by the addition of the characteristic impedance (Zc) (Westerhof et al., 2009). The
model has been recently used to compute the intrinsic reservoir pressure due to the
increase in aortic volume associated with cardiac ejection (Wang et al., 2003).
Effects of Wave Propagation: Pulse Wave Velocity – Surrogate

Measure of Arterial Stiffness. Although the Windkessel model is adequate for
lumped parameter estimation, it does not account for the finite time travel of the
arterial pulse (Westerhof et al., 2009).
This requires a spatially distributed system which is described in terms of

wave propagation characteristics. Arterial stiffness affects PWV through the
constitutive relation of wall stiffness, vessel geometry and blood density (Moens-
Korteweg equation). In the large conduit arteries, the small ratio of wall thickness in
relation to diameter (h/D) makes changes in the material stiffness of the artery highly
correlated with measured PWV. This is manifest by the similar non-linear
dependency of PWV on distending pressure.
Hence, the measurement of pulse propagation time over a known distance to

compute PWV has been found to be a robust surrogate of arterial stiffness, in the
absence of any confounding arterial malformation such as significant stenosis
(Chirinos, 2012).
43
 Arterial stiffness treatments
Given that cfPWV is the most validated index of AS, trials with various
interventions have been designed to investigate the effects on this surrogate index
and hopefully to improve the CVD outcomes. Herein, we reviewed several meta-
analyses discussing the effects of medications and body weight loss on AS and
abbreviated the treatments as “ABCDE,” which stands for Antihypertensive
agents, Body weight loss, Cholesterol lowering agents, and DM and ESRD/CKD
treatments.
1. Antihypertensive medications
Antihypertensive medication could passively reduce AS through BP-

dependent mechanism and improve AS by exerting its pleiotropic effects on vascular
wall modification (Mahmud and Feely, 2002; Ong et al., 2011).
According to an observational cohort study that took approximately 5.4 years,

sustained cfPWV reduction can be obtained by routine clinical practice of
antihypertensive medications (Ait-Oufella et al., 2010).
Angiotensin receptor blocker (ARB) and angiotensin-converting enzyme

inhibitor (ACEi), which block the renin–angiotensin system (RAS), can improve BP
and vascular elasticity and reduce AS better than calcium-channel blockers (CCB),
beta-blockers, and diuretics independent of BP changes (Ong et al., 2011).
Mallareddy et al. showed that ACEi can reduce cfPWV, with average absolute
and relative values of −1.15 m/s and −9.74%, respectively, in patients with HTN
(Mallareddy et al., 2006). However, in a longitudinal study by London et al., ACEi
44
(perindopril), as well as CCB (nitrendipine), induced a similar reduction in cfPWV

(London et al., 1994).
Asmar et al. found that the combination therapy of indapamide and

perindopril results in a similar reduction of aortic PWV to atenolol, indicating that
diuretics have a rather neutral effect on AS beyond brachial artery BP reduction
(Asmar et al., 2001). Another meta-analysis showed that treatment with ACEi
results in a pooled mean cfPWV change of −1.69 m/s compared with placebo
independent of BP reduction, but not superior to ARB, CCB, beta-blocker, and
diuretics (Shahin et al., 2012).
According to Peng et al., ARB exhibited better effects on cfPWV than placebo
with regard to AS, with a significant overall cfPWV reduction of −0.425 m/s but not
superior to CCB, diuretics, ACEi, or beta-blocker (Peng et al., 2015). Moreover,
Wenquan et al. found that beta-blocker exerted better effects than placebo on PWV
(−1.15 m/s; 95% CI, −1.561 to −0.669), but is less favorable than ACEi or ARB on
all indices except heart rate (Niu and Qi, 2016).
Taken together, AS could be controlled by most antihypertensive

medications; RAS-blocking agents displayed effects not inferior to others; diuretics
could serve as a monotherapy or as an add-on agent to decrease BP, with neutral
effects on AS; and these BP-independent changes are amplified with long-term
treatments. Therefore, an optimal antihypertensive agent to lower BP and improve
AS should be selected individually.
45
2. Body weight loss
Weight loss reduces cfPWV by mitigating vascular remodeling and

inflammation (Petersen et al., 2015). Petersen et al. conducted a meta-analysis,
which included studies on patients with energy-restricted diet with or without
exercise, antiobesity agents, and bariatric surgery followed up for 8–52 weeks;
through diet and lifestyle intervention, the cfPWV improved by an average weight
loss of 8% of the initial body weight (Van Doornum et al., 2004).
3. Statin as a cholesterol-lowering agent
HMG-CoA reductase inhibitors (statins) are the most potent agents in

reducing low-density lipoprotein cholesterol and in improving CV events including
AS, possibly through the pleiotropic effects, such as anti-inflammation (Van
Doornum et al., 2004). D'elia et al. recently reported that statin therapy had
significant and favorable effects, with −0.68% reduction in cfPWV independent of
the changes of BP, lipid profiles, and statin types (D’elia et al., 2018).
In patients with CKD, statin can induce an insignificant 41% slower rate of
PWV increment compared with placebo-treated patients, possibly because of the
distinct arteriosclerosis of vascular walls (Fassett et al., 2010).
As mentioned, AS plays an important role in predicting future CV events, and

each 1 m/s increment in PWV increases 15% of CV and all-cause mortality risks;
hence, a nearly 7% reduction of PWV by statin treatment might substantially reduce
CV events, but this consideration remains questionable in patients with CKD/ESRD
(Vlachopoulos et al., 2010).
46
4. DM treatments
Considering that DM is associated with AS occurrence according to

multifactorial factors, interventions for AS improvement include targeting BP and
glucose by administering RAS-blocking and oral hypoglycemic agents, respectively
(Agarwal et al., 2010; Karalliedde et al., 2008; Nakamura et al., 2004).
Newly developed antidiabetic agents such as dipeptidyl peptidase-4 inhibitor

(DDP-4i), glucagon-like peptide-1 receptor agonist (GLP-1 RA), and sodium-
glucose cotransporter-2 inhibitors (SGLT-2i) not only lower the glucose level but
also exhibit effects on the vascular wall (Batzias et al., 2018; Norhammar et al.,
2019; Solini et al., 2017).
Batzias et al. conducted a meta-analysis and reported that both DDP-4i and
GLP-1 RA can induce a significant reduction in PWV, possibly related to their
glucose-lowering effects (Batzias et al., 2018). In addition to the beneficial effects
on CVD (Norhammar et al., 2019),
Solini et al. reported that patients with DM who use dapagliflozin, which is
an SGLT-2i, manifest PWV reduction, independent of BP level decrease, through
the possible mechanism of mitigating the oxidative stress (Solini et al., 2017).
However, the conclusion that the new antidiabetic agents can improve AS, should
be interpreted with caution, given the modest quality of evidence along with
significant heterogeneity between studies and the existing controversy on their use
in advanced CKD.
47
Review of literature: Chapter 2 Coronary Artery Calcium Score and Coronary Artery Disease
Chapter 2: Coronary Artery Calcium

Score and Coronary Artery Disease
 Initial changes in the arterial wall in
atherosclerosis
 Dysfunctional endothelium and lipoprotein infiltration and
retention
The vascular endothelium is a semi- permeable barrier that controls the

diffusion of plasma molecules and regulates vascular tone, inflammation, and
haemostasis (Krüger-Genge et al., 2019).
The endothelial antithrombotic properties are maintained through the

continuous release of NO and PGI2, and by the expression of transmembrane
proteins, including thrombomodulin and heparin- like molecules (Figure 12).
Figure 12 illustrates the complexity of events that drive the atherosclerotic process. The first step in
atherosclerosis is the internalization of lipids in the intima that induces the endothelial secretion of
48
chemotactic substances and the expression of adhesion receptors that favour monocyte recruitment,
adhesion, and transmigration into the arterial wall. Once there, macrophages accumulate lipids,
leading to foam cell formation. Foam cells aggravate the atherogenic process by releasing growth
factors, cytokines, metalloproteinases, and reactive oxygen species, all of which perpetuate and amplify
the vascular remodelling process and activate VSMC migration. On the other hand, continuous
exposure of risk factors damages the endothelium, which loses its antithrombotic features (green
circles), which, in conjunction with endothelial dysfunction/ disruption, induces platelet activation.
Activated platelets, through the release of chemokines, cytokines, and a number of immunomodulatory
ligands, mediate the inflammatory response. Indeed, activated platelets have a large arsenal of
mediators that interact with both leucocytes and endothelial cells, promoting atherogenesis progression
and further complications. Finally, EVs derived from platelets, leucocytes, macrophages, and
endothelial cells are suggested to contribute to all stages of atherosclerosis development by promoting
endothelial activation, inflammation, VSMC migration, and eventual thrombus formation through TF.
CD40L, CD40 ligand; CXCL- 2, chemokine (C- X- C motif) ligand 2; EV, extracellular vesicle; IL,
interleukin; KLF, Kruppel- like factor; LDL, low- density lipoprotein; LFA- 1, lymphocyte- associated
antigen- 1; MCP- 1, monocyte chemoattractant protein- 1; M- CSF, macrophage colony- stimulating
factor; mLDL, modified LDL; MMP, matrix metalloproteinase; NO, nitric oxide; PGI2, prostacyclin;
PSGL- 1, P- selectin glycoprotein ligand- 1; ROS, reactive oxygen species; TF, tissue factor; TNF- α,
tumour necrosis alpha; VCAM, vascular cell adhesion molecule.
The endothelial transcription factors Kruppel- like factor 2 and 4 (KLF4)

have been shown to contribute to maintaining the antithrombotic endothelial
surface by inducing endothelial nitric oxide synthase (eNOS) and
thrombomodulin expression. Besides, the endothelium blocks coagulation by the
expression of tissue factor pathway inhibitor (TFPi) and the activation of tissue
plasminogen activator (tPA) which enhances spontaneous fibrinolysis.
Endothelial- derived NO also exerts other vasoprotective effects such as vascular
relaxation (in concurrence with endothelium- derived hyperpolarizing factor),
endothelial regeneration, and inhibition of inflammatory cell recruitment and
transmigration (Goto and Kitazono, 2019).
49
Indeed, NO modulates leucocyte trafficking by blocking the expression of

nuclear factor (NF) κB- regulated cytokines/ chemokines and vascular adhesion
molecules. Endothelial NO is produced through enzymatic conversion of L-
arginine to L- citrulline by eNOS. However, continuous exposure of the
endothelial layer to cardiovascular risk factors (e.g. hyperlipidaemia,
hypertension, smoking, obesity, insulin resistance, or inflammation, among
others) leads to endothelial cell dysfunction and eNOS impairment. We
demonstrated that atherogenic concentrations of native unmodified LDL and low
concentrations of minimally modified LDL (mmLDL) suffice to decrease NO
bioavailability, either via a reduction of eNOS activity or via a decrease in mRNA
and protein eNOS expression (Bonnefont-Rousselot, 2016).
Furthermore, oxidized LDL (oxLDL) has also been shown to impair

acetylcholine- induced eNOS activation. Hence, increased plasma levels of LDL
particles damage the endothelium, enhancing vascular permeability and
favouring circulating LDL entry into the arterial wall. In fact, arterial deposition
of cholesterol has been shown to be directly proportional to the concentration of
circulating plasma lipoproteins. Subendothelial retention and modification of
LDL particles and subsequent accumulation of LDL- derived lipids in the intima
are the central pathogenic event that promotes atherosclerotic lesion formation
(Linton et al., 2019) .
LDL transports cholesterol and other lipids in the circulation where it is in

native non- oxidized form, because plasma antioxidant molecules protect against
oxidation. However, once these apolipoprotein- B- rich particles have entered the
intimal space, they become modified and retained by ECM components of the
intima such as proteoglycans. Chondroitin sulfate proteoglycans, such as
versican, a main structural proteoglycans of the ECM, can strongly interact with,
retain, and aggregate LDLs. The length and number of proteoglycan- related
50
glycosaminoglycan chains, as well as their degree of sulfation, determine their

capacity to retain LDL particles within the arterial intima (Kang et al., 2019).
Once sequestered in this intimal microenvironment, lipoprotein–

proteoglycan complexes are susceptible to modifications (aggregation/ fusion,
enzymatic cleavage, and hydrolysis) and oxidative changes. During the initial
stages of in vitro LDL oxidation, oxidative modifications of LDL lipids can occur
in the absence of changes, or little change, in apolipoprotein- B. Such modified
LDLs are called mmLDLs, which retain the affinity to the LDL receptor, have a
negative charge, activate anti- apoptotic signalling, and enhance chemokine and
cytokine release (Lee et al., 2021).
This results in the recruitment of inflammatory cells which promote

continued LDL oxidation, thereby affecting the LDL apolipoprotein- B
component (oxLDL). oxLDLs lose their recognition by the LDL receptor and
shift to a recognition by pattern recognition receptors [toll- like receptors (TLRs)
and scavenger receptors In this regard, oxLDLs have been shown to induce
inflammasome activation through TLR stimulation. Inflammasomes are
intracellular complexes able to convert pro- IL1β and pro- IL18 into their mature
forms, thereby contributing to a proinflammatory innate immune response.
Among the various inflammasome complexes, inflammasome NLRP3 is
associated with the pathogenesis of multiple inflammatory diseases. As such,
recent studies have evidenced the presence of NLRP3 in the cytoplasm of
macrophages and foam cells and have identified the microRNAs (miRNAs) that
modulate NLRP3 activation (Shi et al., 2015).
Moreover, NLRP3 has been correlated with the severity and prognosis of
coronary atherosclerosis in ACS patients (Song et al., 2019). oxLDL also
enhances the endothelial expression of adhesion molecules [vascular cell
adhesion molecule 1 (VCAM- 1), intercellular adhesion molecule 1 (ICAM- 1),
51
and selectin] and monocyte chemoattractant protein 1 (MCP- 1) expression,

favouring the recruitment and influx of monocytes through interendothelial gaps
into the subendothelial region. Transmigration of monocytes preferably occurs in
areas where the basal lamina is enriched with modified LDL particles
(Huhtaniemi and Martini, 2018).
Systemic and local risk factors for plaque complications and event
presentation. ACS may be caused by plaque rupture or erosion. Rupture of
vulnerable plaques is responsible for approximately 75% of coronary thrombi,
leading to MI or death, and around 90% of thrombosed carotid plaques, causing
ischaemic stroke (Dziedzic et al., 2018).
Much less is known about non- rupture- related thrombosis, among which
the so- called erosion- prone plaque dominates. However, endothelial cell
erosion/ disruption is not a necessary prerequisite for functionally relevant
interactions of platelets with vascular endothelial cells. For instance, platelets
may be activated by local haemodynamics in the atherosclerotic vessels. Indeed,
high shear stress induces the exposure of platelet receptors and the triggering of
the aggregation cascade (Hamilos et al., 2018). GRP78, an endoplasmic reticulum
chaperone, is exposed on the resting platelet membrane and is translocated to the
cytosol, after shearinduced platelet activation, to allow platelet aggregation (ESC
Textb. Intensive Acute Cardiovasc. Care, 2021).
On the other hand, chronic exposure to systemic risk factors also induces
platelet interaction with the intact, but dysfunctional, endothelial layer, because
of impairment of antithrombotic/ thrombolytic properties, in addition to the
exposure of platelet adhesion molecules, such as fibronectin, ICAM- 1, P-
selectin, E- selectin, integrin αvβ3, and von Willebrand factor (vWF), on their
surface. However, all these stimuli induce limited platelet deposition that most
likely intervenes in the progression of atherosclerosis, rather than in the ultimate
52
thrombotic complications. In contrast, both endothelial erosion and/ or

atherosclerotic plaque rupture expose the components of the vascular matrix
(mainly collagen types I and III, vWF, fibronectin, laminin, fibulin, and
thrombospondin) to the bloodstream, which triggers extensive platelet adhesion,
activation, and aggregation. In addition, TF may also enter in contact with the
blood flow, triggering thrombin generation, which converts fibrinogen to fibrin
and potently activates platelets, eventually leading to thrombus mass formation
(ESC Textb. Intensive Acute Cardiovasc. Care, 2021).
53
 Atherosclerotic plaque burden and plaque

imaging
Over the past few years, the great advances in imaging techniques have
allowed the visualization and characterization of atheromatous plaques, as well
as the monitoring of their progression or regression (Mayer et al., 2020).
As per the invasive imaging modalities most widely employed,

intravascular ultrasound virtual histology (IVUS- VH) enables the assessment of
plaque morphology and composition, although optical coherence tomography
(OCT), because of its higher resolution, allows a more detailed assessment of
vulnerable plaque morphology, such as the presence of macrophages,
neovascularization, and microcalcifications, as well as a better estimation of
fibrous cap thickness. Regarding non- invasive- based approaches, coronary
computed tomography angiography (CCTA) facilitates the assessment of
coronary atherosclerosis and provides 3D pictures of the arterial tree; however its
radiation hazard has limited its use. MRI, in contrast, is safe and effectively
assesses plaque morphology on the carotid artery, but its reliability is questioned
in the coronary tree. Finally, molecular imaging using PET detects inflammation
and metabolic processes within atherosclerotic lesions (Vilahur et al., 2018).
Arteriosclerosis is diagnosed through various tests including
 Coronary Angiography
Coronary angiography, also called cardiac catheterization, is a minimally

invasive study that is considered the gold standard for diagnosing coronary artery
disease. This test is performed under local anesthesia and involves injecting X-
ray dye or contrast medium into the coronary arteries via tubes called catheters.
An X-ray camera films the blood flow to show the location and severity of artery
54
narrowing. This test can show if the blood vessels in your heart have narrowed,
your heart is pumping normally and blood is flowing correctly and your heart
valves are functioning properly. It also can identify any heart abnormalities you
may have been born with or congenital abnormalities.
 Echocardiogram (ECHO)
This non-invasive test translates sound waves from your chest into pictures
of your heart. It provides information about how the heart is pumping, how blood
flows in the heart and blood vessels, how large the heart is and how the valves
are working.
 Electrocardiogram (ECG or EKG)
The electrocardiogram records the heart's electrical activity. Small patches

called electrodes are placed on your chest, arms and legs, and are connected by
wires to the ECG machine. Your heart's electrical impulses are translated into a
wavy line on a strip of paper, enabling doctors to determine the pattern of
electrical current flow in the heart and to diagnose arrhythmias and heart damage.
 Stress Echocardiogram
Stress tests are performed to see how the heart performs under physical
stress. The heart can be stressed with exercise on a treadmill or in a few instances,
a bicycle. If you can't exercise on a treadmill or bicycle, medications can be used
to cause the heart rate to increase, simulating normal reactions of the heart to
exercise. During the stress test, you will wear ECG electrodes and wires while
exercising so that the electrical signals of your heart can be recorded at the same
time.
 Stress Thallium Test
55
Stress thallium tests have two components — a treadmill stress test and
heart scan after injection of a radionuclide material, such as thallium, which
allows doctors to see the coronary arteries and the shape and function of the heart.
It has been used in this manner safely for many years to demonstrate the amount
of blood the heart is getting under various conditions — rest and stress.
56
 Aims of non-invasive coronary imaging
In evaluating the clinical role of non-invasive imaging, it is important to

distinguish between patients based on the presence or absence of symptoms likely
to be related to myocardial ischaemia. The former group comprises individuals
with suspected stable angina pectoris or possible acute coronary syndromes.
Here, the diagnostic objective is to identify or to exclude the presence of
obstructive plaque causing sufficient luminal compromise that myocardial blood
flow may be in-sufficient to meet metabolic demand. In contrast, coronary
imaging in the asymptomatic population is largely targeted at estimating the risk
of future events through the identification of atherosclerotic burden including
non-obstructive disease and high-risk plaque (Figure 13).
Figure 13. Complementary roles of non-invasive coronary imaging. The use of non-invasive coronary
imaging can be considered in three contexts, each with specific objectives that may inform the choice
of imaging modality. (A) Computed tomography angiography provides accurate assessment of coronary
stenosis that can guide management of patients with suspected stable angina and rule out Type 1
myocardial infarction in patients with potential acute coronary syndrome. (B) Coronary artery calcium
57
scanning is able to reliably quantify overall atherosclerotic burden and improve risk stratification in
asymptomatic individuals. (C)T1-weighted magnetic resonance coronary angiography can identify
features of atherosclerotic instabil-ity including intracoronary thrombus and intraplaque haemorrhage
and may be of value in suspected acute coronary syndrome or asymptomatic risk stratification. (D)
Positron emission tomography can employ specific tracers designed to target markers of plaque
vulnerability that may improve prognostic assessment or act as a surrogate of therapeutic response in
asymptomatic patients.
The four most developed non-invasive coronary imaging modalities

include computed tomography coronary artery calcium (CAC) scoring, CCTA,
MRCA, and positron PET—usually employed in combination with either
computed tomography or magnetic resonance imaging (Table 2).
Table 2. Comparison of non-invasive coronary imaging modalities
58
 Lifestyle and therapeutic implications in

atherothrombosis
Atherosclerosis prevention is mainly focused on the management of so-

called ‘cardiovascular risk factors’. Indeed, abundant studies have reported on the
effect of healthy lifestyle habits, such as exercise, body weight, a Mediterranean
diet, light to moderate alcohol consumption, smoking, and stress, not only on
limiting the atherosclerosis progression, but also on reducing blood
thrombogenicity (Dominguez et al., 2021).
As for the mechanisms behind the benefits afforded by healthy dietary

habits, systems biology studies, by combining several ‘- omics’ disciplines
(mainly genomics/ transcriptomics, proteomics, and metabolomics), have
demonstrated the key role of bioactive food components in preventing CVD by
decreasing low- grade inflammation and oxidation, leucocyte activation, platelet
aggregation, or microparticle shedding (Badimon et al., 2018, 2017).
At a pharmacological level, there are several lipid- lowering agents

available to prevent hyperlipidaemia and atherosclerosis and a wide
armamentarium of antiplatelet and anticoagulant drugs to prevent and/ or treat
thrombosis- related complications. Yet, despite implementation of these
therapeutic strategies and the progressive reduction in morbidity and mortality
due to CVD, treatment goals are still unmet, since 20% of MI patients suffer from
a recurrent event. Efforts are currently focused on reducing this residual
cardiovascular risk either by combined targeting of different pathological
pathways or by developing and testing new drugs (Chan and Weitz, 2019;
McFadyen et al., 2018; Székely et al., 2019).
Atherosclerosis is the build-up of plaque in arteries that can constrict and

impede blood flow. Coronary atherosclerosis, also known as coronary artery
59
disease (CAD), refers to the building up of plaque in the main arteries supplying
the heart muscle, leading to decreased blood flow. This plaque calcifies and
ruptures over a period leading to thrombotic consequences (POLETTO et al.,
2018).
CAD is one of the significant cardiovascular disorders that affect people

all over the world. In both developed and developing countries, CAD is
responsible for one-third of mortality among persons over 35, with the percentage
in Western countries nearing 50 percent (Malakar et al., 2019).
Although there is an equal susceptibility of CAD in men and women,

women tend to have a better risk profile at a younger age and vice-versa in old
age (Cherukuri et al., 2021).
Pre-test probability (PTP) of obstructive CAD has been determined for

several decades based on symptom presentation and recognized cardiovascular
(CV) risk factors such as hypertension, hyperlipidemia, family history, and
smoking. Many people have major adverse cardiac events (MACEs) despite
being categorized as low risk based on traditional risk factors. These risk factor
assessment scores only predict 65-80 percent of future cardiac events
(Aengevaeren et al., 2020).
CAD is a complex illness, and early diagnosis of high-risk patients is

critical since specific interventions can reduce clinical events and death
significantly (Brown et al., 2022). Coronary artery calcium (CAC) has been used
as a diagnostic marker of atherosclerosis since the 1940s (Yeboah et al., 2012).
Janowitz et al. proposed a technique for measuring the amount of arterial

calcification based on a specific score that measured the densities and extent of
calcium in coronary arteries using Computed tomography (CT), which became
known as the Agatston score, in 1991(Berman et al., 2016).
60
A CAC score examination is a non-invasive examination of the coronary

arteries in which the amount of calcium in the coronary arteries is determined
using cardiac CT. Coronary calcium is exclusively the outcome of coronary
atherosclerosis, with the exception of individuals with renal insufficiency, who
may also develop medial calcification (Greenland et al., 2018).
The quantity of calcium in the vessels is generally proportional to the

amount of atheroma in the coronary vessels. The CAC score, which is determined
using cardiac computed tomography, can assist in cardiovascular risk assessment
and, as a result, clinical decision-making. According to the European Guidelines
on heart disease prevention in clinical practice, the CAC score can be used to
predict heart disease risk in asymptomatic adults at intermediate risk (“2013 ESC
guidelines on the management of stable coronary artery disease,” 2013;
Blankstein et al., 2017; Greenland et al., 2018).
61
 Pathophysiology of CAD
Coronary artery disease is typically caused by atheromatous constriction

of the vessel and subsequent blockage. From young adulthood onwards, early
atheromatous plaque (derived from the Greek word; Athera - porridge and Oma -
lump) is evident. A mature plaque comprises two components that are
macrophages and smooth muscle cells, each of which belongs to a particular cell
lineage (Grech, 2003).
The necrotic "foam cells" - monocyte-derived macrophages that move into

the intima and absorb lipids - are the primary source of the lipid core. Smooth
muscle cells migrate in the vascular wall from the media into the intima, where
they multiply and change their phenotype to create a fibrous capsule around the
lipid core, forming the connective tissue matrix (Grech, 2003).
Calcification of the coronary arteries occurs in tandem with the progression

of severe atherosclerosis. Calcification usually begins as micro-nodules (0.5 to
15.0 μm) and later progress to larger calcium particles which form sheets like
deposition (>3mm) in the arteries. These changes appear to take place
concurrently with plaque evolution (Figure 14) (Mori et al., 2018).
Coronary artery stenosis of more than 50% or a reduction in the cross-

sectional area by 80% usually leads to angina on exertion. Intimal damage causes
thrombus development by causing denudation of the thrombogenic matrix or lipid
pool. Occlusion is more complete in acute myocardial infarction than unstable
angina, where arterial occlusion is frequently partial. Acute coronary events
usually occur when a plaque ruptures and triggers the formation of a
thrombus (Grech, 2003).
62
Figure 14 Coronary artery calcification. CT - computed tomography, ACS - acute coronary

syndrome, HF - heart failure
Various factors have a role in the onset and advancement of calcification,

which vary depending on the stage of plaque and the surrounding environment.
Although it is usually associated with aging, various factors, including numerous
associated risk factors that can accelerate the calcification in atheromatous
plaques like environmental, genetic, family history, and lifestyle accounting for
early CAD. Following are the associated risk factors (Figure 15) (Hajar, 2017).
63
Figure 15 Risk factors associated with the development of CAD. HTG - hypertriglyceridemia, CAD
- coronary artery disease
Here are inferences from studies stating the influence of risk factors on
CAC: females experience a 10 to 15-year delay in the development of
atherosclerosis compared to males, which is largely due to estrogen's preventative
effects throughout the premenopausal years. Hyperlipidemia has both direct and
indirect effects on vascular calcification (Tintut et al., 2004; Williams et al.,
1990).
Diabetes mellitus with abnormal glucose metabolism can directly promote

vascular cell calcification, and insulin can inhibit it (Chen et al., 2006; Wang et
al., 2007).
And adipose tissue-derived factors regulate vascular calcification;

adiponectin slows calcification, and leptin accelerates the process of
vascular calcification (Luo et al., 2009; Parhami et al., 2001).
64
 Coronary artery calcium (CAC)
CAC is a highly accurate marker of coronary artery disease. Based on

single-center and multicenter clinical and population-based studies with short-
term and long-term outcomes, CAC scoring has emerged as a readily accessible,
reliable, and efficacious means of assessing the risk of major cardiac events,
especially in asymptomatic people planning for primary prevention interventions
such as aspirin and statins. In asymptomatic groups with a wide range of baseline
risk, CAC testing is cost-effective (Greenland et al., 2018).
Vascular calcification was formerly thought to be an inevitable, natural

aging process. With medical advancements, atheroma calcification is now
recognized as an active pathological process. Ectopic bone growth is a common
feature of atherosclerosis, causes calcification of the coronary arteries (Tintut et
al., 2004).
The process is influenced by developmental, inflammatory, and metabolic

variables. Master transcription factors including Msx2, Runx2, Osterix, and Sox9
and influential osteogenic differentiation factors like bone morphogenetic
proteins (BMPs) two and four have been linked to vascular calcification. Matrix
Gla protein is a BMP inhibitor that is abundant in calcified human arteries. The
expression of both anti and pro-osteogenic elements in CAC demonstrates how
tightly this process is controlled (Tyson et al., 2003).
Many oxidative stress mediators are linked to calcification. Lipid oxidation

produces pro-osteogenic mediators such as minimally altered low-density
lipoprotein (LDL) and oxidized phospholipids (Bear et al., 2008).
65
Inflammation is induced by apolipoproteins and oxidized phospholipids in

the vasculature, which is required for the development of vascular calcification
and atherosclerosis (Li et al., 2010; Tintut et al., 2002).
Radiography, computed tomography (CT), and intravascular imaging can

all be used to identify these calcification sheets and fragments (Grech, 2003).
The CAC score is calculated using 3 mm CT slices with no overlapping or

gaps, limited to the cardiac region, acquired prospectively in synchrony with the
electrocardiogram at a predetermined moment in the R-R interval, usually in the
mid/late diastole, and without the use of intravenous contrast medium (Budoff et
al., 2006; Nasir and Clouse, 2012).
Calcification is defined as areas of at least 1 mm of hyper attenuation with

> 130 Hounsfield units (HU) or fewer than three consecutive pixels (Agatston et
al., 1990).
CAC may be detected using a variety of imaging modalities. However,

non-contrast, electrocardiographic gated - multidetector computed tomography
(MDCT) and electron beam computed tomography (EBCT) are the most
commonly used in outpatient settings. The CAC score was first investigated using
EBCT, and much of the scholarly literature at the time was based on this method
(Budoff et al., 2006).
Later MDCT has become the modality of choice for CAC evaluation. As a
result, electron beam computed tomography is now almost non-existent (Budoff
et al., 2006).
There are various methods for the assessment of CAC scores. The Agatston
method, calcium volume determination, and calcium mass score are the three
basic approaches for calculating the CAC score (Nasir and Clouse, 2012; Yoon
et al., 1997).
66
The first two are the most extensively used, notably the Agatston
technique, which is cited in most population databases and articles and is,
therefore, the most widely employed in clinical practice. Calcium density and
calcium content measurements are more consistent (Azevedo et al., 2012).
 The Agatston Method
The Agatston method uses the weighted sum of lesions with a density above 130
HU. It multiplies the area of calcium by a factor related to maximum plaque
attenuation (130-199 HU, factor 1; 200-299 HU, factor 2; 300-399 HU, factor 3;
and 400 HU, factor 4) (McCollough et al., 2007; Sarwar et al., 2009).
 Calcium Volume Score
This method is the most reliable and repeatable (McCollough et al., 2007)
. It is calculated by multiplying the number of calcified voxels by the volume of
each voxel, considering all voxels with an attenuation more significant than 130
HU. However, depending on the position of the plaque in the axial slice acquired,
this method is particularly sensitive to partial volume (especially in plaques with
high attenuation) and subject to variability between tests (McCollough et al.,
2007; Sarwar et al., 2009).
 Relative Calcium Mass Score
The relative calcium mass score is calculated by multiplying the calcified

plaque's mean attenuation by the plaque volume in each image, reducing the
variation caused by partial volume. A correction factor based on water attenuation
is used to calculate the absolute calcium mass score (McCollough et al., 2007;
Sarwar et al., 2009).
67
The Agatston CAC score can be interpreted and classified by adjusting

values for patient age, gender, and ethnicity and calculating distribution
percentiles in the general population using several population databases (Table 3)
Table 3. Agatston coronary artery calcium scoring. CAC – coronary artery calcium
CAC
score
Risk analysis Clinical correlation
(Agatston
method)
0 Absent/ No risk Low risk of future cardiovascular events.
Minimal atherosclerosis may be present with a
1-10 Minimal
low risk of future cardiovascular events.
There is likely mild to minimum coronary artery
11-100 Mild stenosis. A mild risk of coronary artery disease
exists.
Reasonable amount of plaque can be confirmed.
101-400 Moderate Has a moderately increased risk of future
cardiovascular events.
A high coronary calcium score corelated with a
>400 High significant risk of having a cardiovascular event
(such as myocardial ischemia) in near future.
 Coronary artery calcium score and coronary vascular

disease
Asymptomatic individuals with no associated risk factors and a calcium
score of zero are highly unlikely to have any significant luminal obstruction or
atheromatous plaque. They are also at very low risk of any cardiovascular events
within the next two to five years (Neves et al., 2017).
Positive (non-zero) CAC scores, on the other hand, indicate the existence
of coronary atherosclerotic plaque, and rising values are linked to increased
coronary heart disease (CHD) risk (Figure 16) (Bild et al., 2005a).
68
Figure 16. Coronary artery calcium scoring and coronary vascular disease. CAC -
coronary artery calcium
The Multi-Ethnic Study of Atherosclerosis (MESA) started in 2000 with a

prospective multi-center cohort sample of 6,814 men and women aged 45 to 84.
Approximately 38% of the recruited participants were white, 28% were African
American, 22% were Hispanic, and 12% were Asian. MESA used EBCT
scanners in three locations and MDCT systems in three locations (McClelland et
al., 2006).
For both EBCT and MDCT, CAC distributions were similar. CAC was
shown to differ by ethnicity, with whites having a higher incidence than the other
three ethnic groups (McClelland et al., 2006).
Risk factor differences did not entirely explain variations in CAC

distributions between ethnicities, indicating that other variables must account for
69
part of the variation in CAC distributions. MESA offered estimated curves for the
50th, 75th, and 90th percentiles of calcium throughout age, allowing users to see
briefly what an approximate percentile signifies for a certain patient (McClelland
et al., 2006).
Similarly, Framingham Heart Study (FHS) in 2005 incorporated a CAC

assessment by MDCT to the Framingham Offspring and Third Generation
cohorts' examinations. Although the FHS only includes white men and women,
the CAC >0 and CAC >100 distributions were remarkably comparable to those
previously reported from MESA. A new analysis of CAC data looked at whether
information on the distribution of CAC and coronary dominance, as found by
MDCT, helped predict incident CHD in addition to the standard Agatston score.
After multivariable adjustment, the study concluded that the number of coronary
arteries with CAC and CAC presence in the proximal dominant coronary artery
were substantially linked with major CV events over a median follow-up of seven
years (Ferencik et al., 2017).
Also, the Coronary Artery Risk Development in Young Adults (CARDIA)

research, the first prospective cohort to collect data on CAC among 2,831 patients
aged 32 to 46, assessed CAC throughout follow-up. CAC >0 is not rare in this
age group, according to CARDIA, especially when a risk factor is present. CAC
highly predicted risk beyond established risk variables in these young people over
a 10-year follow-up (Carr et al., 2017).
Dennis et al. conducted a prospective study in 263 patients (women aged

30-65 years and men aged 30-62 years) with chest pain and low-to-moderate risk
of coronary artery disease. They performed a traditional emergency department
(ED) chest pain evaluation as well as a CT CAC scan. 133 (51%) had a CAC
score of zero. The absence of CAC was highly linked to the chance of
experiencing noncardiac chest discomfort. Only one (1%) of the 133 patients with
70
a CAC score of 0 developed cardiac chest discomfort. On the other hand, 30

(97%) of the 31 patients with cardiac chest discomfort revealed evidence of CAC
on CT. According to the findings, CT CAC assessment is an effective supplement
in evaluating people at low-to-intermediate risk and concluded that in this cohort,
cardiac chest discomfort is highly unlikely due to the lack of or mild CAC
(Laudon et al., 2010).
Dekker et al. conducted a single-center observational cohort study of 1265

patients in the Netherlands from 2014-2016. Only individuals who had a coronary
angiography (CAG) within 90 days before or after myocardial perfusion imaging
(MPI) were included in this study. The final cohort consisted of 150 patients after
excluding those who had previously undergone coronary artery bypass grafting
(CABG) or percutaneous coronary intervention (PCI), as well as five individuals
who had incomplete MPI data. CAC scores combined with MPI increase
obstructive coronary artery disease diagnosis in people who have never had a
revascularization procedure (Dekker et al., 2020).
Table 4 lists the included studies of all different designs conducted between
2005 - 2019 that link the relationship between CAC score and CAD in
asymptomatic individuals.
71
Table 4: Summary of studies of different designs conducted between 2005-2019 that link the
relationship between CAC score and CAD in asymptomatic individual. MESA- Multi-Ethnic
Study of Atherosclerosis, CARDIA - Coronary Artery Risk Development in Young Adults, FSH
- Framingham Heart Study, CAC - coronary artery calcium, CAD - coronary artery disease,
CHD - coronary heart disease, CVD - coronary vascular disease, MPI - myocardial perfusion
imaging
References Study Design Sample Age of the Percentage Conclusion
Year population participants with CAC >0
at baseline
examination
MESA (Bild 2005 Prospective 6,814 45-84, mean Men: 52%– Beyond known risk factors,
et al., 2005a) multicenter age: 62.2 ± 70%, CAC reliably predicted
cohort 10.2 women: cardiovascular risk in all four
35%–45% ethnic groups, with similar
strength in all four ethnic
groups.
Dennis et 2010 Prospective 263 30-62, mean 49% On a five-year follow-up 1%
al. (Carr et study age: 46 of the 133 patients with a
al., 2017) CAC score of 0 developed
cardiac chest discomfort. The
absence of CAC suggests an
excellent long-term
prognosis.
CARDIA 2017 Prospective 5115 32-56, mean After surveillance for 30
(Ferencik et Community age 40.3 years, it concluded that a
al., 2017) based CAC score of 100 or above
study was linked to a higher risk of
mortality. Adults under the
age of 50 who have any CAC
found on a computed
tomographic scan, even with
extremely low scores, are at
an increased risk of clinical
CHD, CVD, and mortality.
FHS Study 2017 Observational 3,238 Men >35, Men: 40.5%, The presence and extent of
(McClelland cohort study women >40, women: coronary artery calcium
et al., 2006) mean age 20.6% (CAC) are associated with
49 ± 10.9 increased risk for
cardiovascular events.
Dekker 2019 Observational 1265 Mean age 94% CAC scores combined with
(Laudon et cohort study 67.6 MPI increase the
al., 2010) diagnosis of obstructive
coronary artery disease in
people who have never had a
revascularization
procedure.
Coronary artery calcium (CAC) monitoring has become a popular

subclinical approach for predicting cardiovascular disease in asymptomatic
people. The predictive value of CAC scanning in symptomatic people is less
established. It has no predictive value in already symptomatic people and is
associated with additional cost and radiation burden. Pursnani et al. conducted a
72
prospective study in the United States in 2015 with 473 elderly population of age
group 54±8 years, 53% men concluded that CAC score does not provide
additional value beyond coronary computed tomography angiography (CCTA)
for acute coronary syndrome (ACS) diagnosis in emergency department patients
with acute chest pain. CAC=0 does not rule out ACS, and a high CAC score does
not rule out CCTA interpretation in most patients (Pursnani et al., 2015).
Chang et al. performed a prospective observational cohort study in the

emergency department of the Hospital of the University of Pennsylvania with a
total of 1049 patients of medical age 48.1, 55% female, 63% African American
concluded that coronary angiography calcium scores alone could not risk
stratifying patients in the emergency department who may be suffering from acute
coronary syndromes. The addition of the coronary angiography calcium score to
coronary computed tomography angiography did not improve prognostic value.
These studies helped in concluding that CAC score has no significance in
symptomatic patients (Chang et al., 2011).
73
Review of literature: Chapter 3 Correlation between Aortic Distensibility, Aortic stiffness and CAD
Chapter 3: Correlation between Aortic

Distensibility, Aortic stiffness and coronary
artery disease (CAD)
Studies have linked increased arterial stiffness with abnormal collagen
turnover and increased metalloproteinase (MMP) activity. More specifically,
transforming growth factor b1 and MMP-9 are part of one complex pathway in the
regulation of collagen turnover (Ikonomidis et al., 2012).
This pathway, through altered collagen turnover within the cardiovascular

system, results in arterial and myocardial stiffness and perivascular fibrosis and
endothelial dysfunction, leading to coronary microcirculatory impairment
(Ikonomidis et al., 2008). The net effect of this pathway is vascular stiffness and
impaired LV diastolic function (Ikonomidis et al., 2008; Leung et al., 2006),
especially when combined with myocardial ischemia in patients with CAD.
A recent study has shown a close link between MMP-9 and C-reactive protein
(CRP) levels with increasing PWV in patients with CAD (Ikonomidis et al., 2012).
The role of inflammation in the determination of vascular stiffness in CAD is further
supported by the association of PWV with circulating lipoprotein-associated
phospholipase A2 (LP-PLA2) in patients with angiographically documented CAD
(Ikonomidis et al., 2014a), arterial compliance with interleukin (IL)-1b blood levels
in patients with CAD and rheumatoid arthritis (Ikonomidis et al., 2014b), and AIx
with increased titers of antibodies against Chlamydia pneumoniae (Pitiriga et al.,
2006) in patients with CAD (Figure 17).
74
Figure 17. The figure represents a simplified schematic that attempts to describe a potential
pathophysiologic framework linking impaired cardiac function, on the one hand, and arterial stiffness and
impaired coronary flow reserve, on the other, having as a common link the transforming growth factor b1-
mediated imbalance between collagen synthesis and degradation.
 Risk for CAD
 Pulse wave velocity
Kobayashi et al. suggest that the combi-nation of baPWV (Colin device)

predicts athero-sclerotic burden either alone or in combination with carotid intima-
media thickness (cIMT) and flow-mediated dilatation in a high-risk population of
75
older adults with high prevalence of cardiovascular disease (Kobayashi et al.,

2004).
A close relation between CAVI (oscillometric device, Fukuda Denshi Co.

Ltd., Tokyo, Japan) and CAC or stenosis has been reported in asymptomatic patients
(Park et al., 2013). After adjustment for potential confounders, including age, sex,
hypertension, diabetes mellitus, and dyslipidaemia, a predefined cut-off value of
CAVI ≥8 was associated with advanced CAC (CAC ≥300) and significant coronary
stenosis (stenosis ≥50%) in 549 asymptomatic Korean individuals.
Previous studies from the Rotterdam registry have shown in 2835 individuals
during a mean follow-up period of 4.1 years that the hazard ratios and corresponding
95% confidence intervals (CIs) of CAD for patients in the second and third tertiles
of the aortic PWV (aPWV) (Complior, Artech Medical) compared with patients in
the reference category were 1.72 (0.91–3.24) and 2.45 (1.29–4.66), respectively,
after adjustment for age, sex, mean arterial pressure, heart rate, cIMT, ankle-arm
index, and PP. Carotid distensibility as measured in this study was not independently
associated with cardiovascular disease (Mattace-Raso et al., 2006).
Moreover, in a recent meta-analysis of 17635 participants, the pooled age-

and sex-adjusted hazard ratios per 1-SD change in loge aPWV were 1.35 (95% CI,
1.22–1.50; P < 0.001) for incidence of CAD (Ben-Shlomo et al., 2014; Fukuda et
al., 2006; Mattace-Raso et al., 2006). In untreated hypertensive patients,
microvascular damage measured as microalbuminuria was closely related to PWV
(oscillometric device) (Mulè et al., 2004).
Increased arterial stiffness plays an important role in the prediction of

cardiovascular risk in metabolic syndrome. Its age-related deterioration is associated
with the number of risk factors involved in metabolic syndrome causing increased
76
SBP and decreased DBP, abnormalities that characterize elderly hypertensive

patients (Safar et al., 2013). Increased PWV (Sphygmocor) was associated with the
presence of peripheral arterial disease (PAD) with a mean value of 11 m/s in PAD
versus 9.8 m/s in normal controls (Catalano et al., 2013).
Figure 18. Insults Leading to Structural Changes in the Aorta and its Functioning Several processes
can alter the homeostasis of aortic elastic properties leading to increased stiffness and decreased
compliance. LV left ventricular
 Augmentation index
In 465 consecutive, symptomatic men undergoing coronary angiography for

the assessment of suspected CAD, AIx (applanation tonometry Millar Instruments)
has been associated with the presence of coronary atherosclerosis, particularly in
patients younger than 60 years, with an unadjusted odds ratio between AIx quartiles
77
I and IV of 8.25 (P < 0.01) and a multiple-adjusted odds ratio between these quartiles
of 16.81 (P < 0.05) (Weber et al., 2004). AIx (Sphygmocor, radial tonometry) was
also independently associated with a lower ankle-brachial index as a marker of PAD
in patients with CAD (Lekakis et al., 2006).
 Therapeutic implicatios
Several interventions may lead to improved arterial stiffness. Weight

reduction and exercise training have been shown to lead to improvement in aortic
distensibility (Ikonomidis et al., 2007), PWV, and AIx, particularly in patients with
CAD (Oliveira et al., 2014). Smoking cessation improves PWV, Aix, and central
BP (Takami and Saito, 2011) with a significant linear relationship between duration
of smoking cessation and improvement in PWV [tonometry system (HEM-9000AI;
Omron Healthcare, Kyoto, Japan) and AIx] (Jatoi et al., 2007).
Treatment with statins has also been associated with lower values of AIx,
central aortic pressures (Lekakis et al., 2006), and PWV (Liu et al., 2013) in
patients with CAD. Inhibition of IL-1 activity has been shown to improve aortic
compliance in patients with CAD and rheumatoid arthritis (Ikonomidis et al.,
2014b).
The Conduit Artery Function Evaluation (CAFE) study has shown that
treatment with calcium channel blockers improved prognosis in hypertensive
patients compared with b-blockers because of a greater effect on central BP
(Sphygmocor) and despite a similar effect on the reduction of peripheral BP
(Williams et al., 2006). Moreover, the lower risk of stroke in hypertensive patients
under calcium channel blockers compared with b-blockers in the same study cohort
78
may also be attributed to a greater effect on central BP in addition to reduction of

systolic BP variability (Rothwell et al., 2010).
Treatment with angiotensin-converting enzyme inhibitors has been associated

with a modest reduction in PWV in patients with CAD, beyond the expected degree
only from the BP lowering effect (Mitchell et al., 2007). However, studies in
patients with CAD examining whether improvement in aortic wall properties may
lead to improvement in outcome are lacking
79
Review of literature: Chapter 4 Correlation between coronary calcium and aortic distensibility and stiffness
Chapter 4: Correlation between coronary

calcium scoring and aortic distensibility
and stiffness
Coronary artery calcium is a highly specific feature of coronary
atherosclerosis that has been explored in several large studies and has emerged as
one of the most predictive single cardiovascular risk markers. The Multi-Ethnic
Study of Atherosclerosis (MESA) (Bild et al., 2005b) was a large, prospective,
multi-institutional study with more than 6800 participants of varying ethnicity, in
which CACS scores were found to reliably predict cardiovascular risk in all included
ethnic groups, independent of traditional cardiovascular risk factors.
Coronary artery calcium (CAC) is a marker of overall atherosclerotic burden

and correlates well with the total plaque burden, the presence of obstructive coronary
artery disease (CAD) and future cardiovascular events in both genders across
ethnicities (Brown et al., 2008; Budoff et al., 2009; Detrano et al., 2008). Systemic
vascular dysfunction measured through reactive hyperemia procedure is strongly
correlated with increasing Framingham risk score (FRS) and CAC independent of
age, sex, and traditional cardiac risk factors and is superior to FRS for the prediction
of significant CAC (Ahmadi et al., 2008).
La Monte et al. (LaMonte et al., 2005) conducted a study of 10,746 adults

aged 22–96 years, with no known coronary disease history, and found that CACS
was a significant predictor of both hard events (coronary heart disease, death,
nonfatal myocardial infarction) and all events (hard events plus coronary
revascularization) in asymptomatic persons (LaMonte et al., 2005).
80
In 111 individuals, PWV (Sphygmocor) was moderately associated with

epicardial and pericardial adi-pose tissue thickness but increased proportionally with
the severity of coronary artery calcification (CAC) score from 0 to 400þ (Choi et
al., 2013), suggesting the predictive role of PWV for the diagnosis of CAD. Indeed,
PWV (model BP-203RPE, Colin, oscillometric method) is closely linked to the
presence of angiographically documented CAD (Tsuchikura et al., 2010).
Endothelial dysfunction, defined as the inability of the artery to sufficiently

dilate in response to an appropriate stimulus, is an early predictor of cardiovascular
disease (Heitzer et al., 2001). Endothelial dysfunction precedes atherosclerotic
lesions and may contribute to the development of those lesions and clinical
complications. Earlier smaller studies have shown inconsistent results regarding the
association between low RHI and coronary atherosclerosis (Li et al., 2012;
Matsuzawa et al., 2013; Woo et al., 2014).
Arterial stiffness is a hallmark of vascular aging (Nilsson, 2008), and studies

have shown an association between arterial stiffness with factors such as coronary
artery disease and arterial hypertension (Liao and Farmer, 2014).
A previous study was conducted as an interim analysis of a sub-population of

the BIG3 study and is, to our knowledge, the largest to evaluate the relationship of
coronary calcification with endothelial function and arterial stiffness using CACS,
RHI, and AI measurements, respectively (Torngren et al., 2020). The mean age of
the study population was 62 years, balanced with respect to sex, and enriched in
smokers, but otherwise without selection criteria. Different cut-offs for categorizing
severity of CACS have been used, and no standard has been established. The authors
classified CACS according to the commonly used 0, 1–400, and >400 Agatston units
(Handy et al., 2016; Iwasaki and Matsumoto, 2016; Mlynarska et al., 2019).
81
Increased CACS was associated with increases in age, systolic blood pressure,
and serum creatinine as well as showing higher prevalence in males, diabetics,
previous smokers, and those with previous myocardial infarction. However, for RHI,
only diabetes showed a clinically relevant association. This differs from some
previous reports (Li et al., 2012; Matsuzawa et al., 2013; Woo et al., 2014), and
may reflect the healthy, relatively young BIG3 study population.
A high AI was associated with older age, higher systolic blood pressure and
was more common in females, those with history of myocardial infarction, and
smokers. These are factors that have previously been associated with arterial
stiffness (Liao and Farmer, 2014; Nilsson, 2008).
For groups of increasing CACS, a decrease in endothelial function was found

that remained significant after adjustment for age, smoking, sex, p-cholesterol,
systolic blood pressure and BMI. This indicates that there is a relationship between
endothelial dysfunction and coronary calcium even after adjustment for background
demographics. The difference in endothelial function was only apparent at high
levels of CACS (>400), indicating that relatively well-established atherosclerosis is
needed to see endothelial dysfunction. For groups of increasing CACS, significant
increases in arterial stiffness were found. However, the association was not
significant after adjustment for age, smoking and sex, suggesting that these common
risk factors drive development of both coronary calcium and arterial stiffness.
The authors performed exploratory subgroups analyses. When patients with

previous heart attack were excluded, results consistent with the overall analyses were
found for the relationship between RHI and AI with CACS, indicating that the results
are also valid for a population without previous heart attacks. For the groups of never
smokers or the combination of never smokers and previous smokers, the results were
82
also similar to the total population. However, for the group of smokers, the
association between RHI and CACS was lost. This could be explained by smoking
disturbing the association between CACS and RHI, but it could also be explained by
insufficient power in a small subgroup. In the group of smokers, no significant
relationship between CACS and AI could be seen, but the numerical trends were
similar. For CACS and AI, it is most likely that the loss of significance could be
explained by insufficient power in a small subgroup.
These findings indicate that physiological assessment of endothelial function

and arterial stiffness could be tools to identify vulnerable patients at risk of
developing coronary artery calcium and subsequent cardiovascular events. One
possibility is that endothelial dysfunction leads to arterial stiffness, which, in turn,
progresses to coronary calcification, but no causal relationship could be shown in
this study.
All the three diagnostic methods evaluated in the current study are available
in the clinic where RHI and AI are easier to use and without radiation. Although all
three have shown to have prognostic information regarding cardiovascular events
(Greenland et al., 2004; LaMonte et al., 2005; Rubinshtein et al., 2010), CACS
is the best validated of the methods. A possible clinical scenario could be to use RHI
and AI as a first screening, and if they indicate vascular disease, CACS could be
performed to add one more prognostic indicator. The ongoing longitudinal follow-
up of the subjects in BIG3 will provide insights into the prognostic value of
endothelial function and arterial stiffness measurements.
An association between non-invasively determined markers of endothelial

dysfunction and arterial stiffness with coronary arterial calcium scores has been
found, indicating that they may reflect similar mechanisms for development of
83
cardiovascular disease. Long-term clinical follow-up in BIG3 may establish whether

coronary calcification, endothelial dysfunction, and arterial stiffness can predict
different cardiovascular events or if they confer the same prognostic information.
84
Patients and methods
 Patient selection:
This current cross sectional study included all consecutive patients

with suspected CAD who referred for non-invasive Coronary Computed
Tomography Angiography (CCTA) in Alazhar university hospitals during the period
from April 2021 to March 2022.
During the study there were 220 patients, but we excluded 40 patients due to
some technical difficulties during measurements and only a 180 patients were
included.
An informed consent was taken from all patients and the study was approved
by ethics committees in Alazhar Faculty of Medicine and Alazhar Cardiology
Department.
 Inclusion Criteria:
The study included all Patients with suspected CAD referred for non-invasive
coronary Computed Tomography Angiography (CCTA). This criterion include all
of the followings:
 All patient with low to intermediate PTP based on age, sex, and symptoms
according to "2019 ESC Guideline on the diagnosis and management of
Chronic Coronary Syndrome" (Figure 19)
85
 Atypical chest pain, chest tightness, epigastric pain/ burning, and

jaw/shoulder pain.
 Patient with Dyspnea, worsening/reduced effort tolerance, new ECG

abnormalities, and unequivocal stress tests.
Figure 19: 2019 ESC Guideline on the diagnosis and management of

Chronic Coronary Syndrome
 Exclusion criteria:
The study excluded any subject with any one of the following characteristics:
 History of allergy to contrast media.
 Renal dysfunction (estimated glomerular filtration rate eGFR <30

mL/min/1.73 m2 or creatinine > 1.8 mg/dl).
 Patients with a history of open-heart surgery, CABG, history of coronary

artery stenting by percutaneous coronary intervention (PCI), post valve
86
replacement, pericardial effusion, and those with pacing leads also were
excluded from the study.
 Patients with markedly irregular heart rhythm like AF and frequent Extra-
systoles.
 Patients have difficulties in performing CT, like inadequate breath holding

and heart failure.
 Patients diagnosed as having acute coronary syndrome (elevated cardiac

biomarkers and/or dynamic ECG changes).
 Patients with high probability CAD.
87
 Methods:
All patients were subjected to:
A. Full history taking include the following data:

1. Age.
2. Sex.
3. Family history of premature CAD (first degree relatives).
4. Smoking.
5. Hypertension.
6. Diabetes mellitus.
B. Short clinical examination including:
1. Blood pressure measurement
2. Heart Rate.
C. Standard ECG including the following data:
1. Rhythm.
2. Rate.
3. Ischemic changes.
D. Routine laboratory investigations including:
1. Hemoglobin (Hb)
2. Serum creatinine.
3. Complete Lipid profile: Which included the serum assay of:
 Total Cholesterol
 Triglycerides (TG)
 LDL Cholesterol
 HDL Cholesterol
88
Multi-slice CT angiography:
A. Imaging Technique
1. Imaging Machine:
All CT scans were performed on SIEMENS dual source 128- slice CT
scanner (figure 20) with the following characteristics:
 Acquisition 128 (2 X 64)
 Rotation speed 0.28 sec
 Generator power 200 KW (2 X 100 KW)
 KV Steps 70, 80, 100, 120, 140 KV
 Max. scan speed 458 mm/s with flash spiral
 Table load up to 307 Kg/676 Ib.
 Scan range 16 cm
 Gantry opening 78 cm.
Figure 20: SIEMENS SOMATOM Definition Flash dual 128-slice CT scanner.
89
2. Patient preparation and protocol:

The CT coronary angiography was performed to all patients utilizing a dual
source scanner (SIEMENS SOMATOM Definition Flash) using dual X-ray
sources which make better visualization of the coronary tree at relatively high
heart rates. The following protocol was followed:
All coronary arteries were evaluated at different phases of the cardiac cycle
by acquisition of thin slice sections (0.5 mm).
The heart rate of all patients was determined one hour before examination.
If the heart rate is > 75 bpm, the patient was given beta-blocker agent orally
(metoprolol 50 -100 mg) one hour before the study or postponed the study
to another day with medications to control the heart rate.
Five milligram sublingual dose of nitroglycerin was administered just
before the scan.
All scans were preceded by non-contrast enhanced scan for coronary
calcium score.
We did not proceed to coronary CTA in the presence of extensive coronary
calcium on one coronary arteries or total calcium score more than 800
Agatston score.
All included patients received intravenous nonionic iso-osmolar contrast
medium (using the test bolus technique) a bolus of 10 ml of the contrast
agent injected intravenously at a rate of 5 -5.5 ml/s, followed by injecting
50 ml saline.
Then angiography done by injecting 70 ml of the same contrast agent at a
rate of 5 -5.5 ml/s, followed by injecting 50 ml saline.
All studies begin with scout or Topogram (similar to chest x-ray) which
used:
90
 To fix the acquisition limits of the study (define region of interest

for imaging).
 Taken from tracheal bifurcation to the diaphragm in a
single breath-hold in the cranio-caudal direction.
3. Test bolus:
 Injection of 10 ml Iopromide 370 mg/mL followed by 50 ml saline at a
rate of 5 -5.5 ml/s and then acquisition of sequence of images at the level
of the Aorta and Pulmonary arteries every two seconds.
 Calculation of the actual delay time from start of injection till maximum
intensity of dye in the ascending Aorta.
4. CT angiography:
After accurate calculation of delay time and checking
the ECG trigger, images acquisition is done after injection of 70 ml
Iopromide 370 at flow rate 5 -5.5 ml/s followed by 50 ml saline at
the same flow rate using power dual automatic injector.
5. Image reconstruction:
The CT scanning was performed with the following mode:
retrospective ECG-gated acquisition spiral mode.
 A three dimensional workstation was used to reconstruct axial images

retrospectively at an optimal window. The image data sets were analyzed
by means of Multi planar reformatted images (axial, coronal, and sagittal
views), curved Multi-planar reformatted images (cMPR), thin-slice
maximum- intensity projection images (thin MIP), and volume-rendered
image (VRI).
91
 Two-dimensional reconstructions (curved Multi planar reformation) of the

coronary arteries were performed on several planes to assess patency of
the vessels. These 2- dimensional images show the vessel's wall and lumen
and all the surrounding tissue. They are reconstructed on at least two
orthogonal planes, and continuity of contrast material throughout the
vessel serves as an indication of patency.
 All reconstruction were done by following workstations : Vitrea, Horos,
and RadiAnt DICOM Viewer
B. Measurement of plaque burden and degree of coronary

arteries stenosis and coronary arteries calcium score (CAC
score) :
Coronary segments were visually scored for the presence of coronary

plaque according to following scores:-
1. Segment-involvement score (SIS):
The coronary artery tree was classified into 16 segments (Figure

21) according to American Heart Association classification
[1]proximal, [2] mid, [3] distal right coronary artery; [4] posterior
descending artery;
[5] left main artery;
[6] proximal, [7] mid, [8] distal left anterior descending artery;
[9] first, [10] second diagonal branch;
[11] proximal, [13] mid, [15] distal left circumflex artery; [12] first,
[14] second obtuse marginal branch; [16] posterolateral ventricular
branch (Min et al., 2007)
92
Figure 21: Coronary Artery Segments According to the AHA.
2. Segment-stenosis score (SSS):
SSS was calculated as a measurement of total coronary plaque

burden. Each segment was given a score from 0 to 3 according to the degree
of lumen stenosis. (Min et al., 2007).
[0] for normal, [1] for mild (<50%), [2] for moderate (50% to 69%), [3] for
severe (≥70%).
Patient were classified into four groups according to the degree of

stenosis as following (Table 5):
93
Table 5 : classification of patients according to degree of coronary Artery stenosis
Groups Group 1 Group 2 Group 3 Group 4
CTA-Diagnosed coronary artery Stenosis < 50 % Stenosis 50 – 70 % Stenosis > 70%

Normal
disease
Coronaries
Mild Moderate Severe
(Degree of Stenosis)
3. Coronary Artery Calcium Scoring (CAC score):
In this test, which did not use X-ray contrast, pictures were taken
of the heart to look for the presence of calcium deposits in the coronary
arteries. The amount of calcium deposits were measured by
"Agatston score" as showen in Table (6) (Wexler et al., 1996).
94
Table 6: Relationship between CT coronary calcium score, plaque

burden and probability of significant CAD.
Ca Presence of Plaque Probability of

Score (Plaque burden) significant CAD
0 No evidence of plaque Very low (generally < 5% likelihood)
1-10 Minimal evidence of plaque Very unlikely (generally < 5% likelihood)
Mild or minimal coronary artery stenosis

11-100 Mild evidence of plaque
likely
Non-obstructive CAD highly likely,

101-400 Moderate evidence of plaque
although obstructive disease possible
High likelihood (> 90%) of at least one

Over 400 Extensive evidence of plaque
significant coronary stenosis
Patient were classified into four groups according to the degree of coronary
arteries calcium scoring (CAC score) as following (Table 7):
Table 7 : classification of patients according to degree of Coronary Artery

Calcium (CAC) score
Groups Group 1 Group 2 Group 3 Group 4
Coronary artery calcium

0 1 - 99 100 - 400 > 400
CAC score
95
C. Measurement of Aortic Distensibility Index (ADI) and
Aortic Stiffness
1) Aortic distensibility
Aortic distensibility is the degree to which the aorta can expand such that a
stiff vessel has low distensibility. Distensibility can be expressed as follows (Ganten
et al., 2005):-
Where SA is the maximal systolic area, DA is the minimal diastolic area, SBP
is systolic blood pressure, and DBP is diastolic blood pressure.
True cross sectional area (CSA) and diameter of ascending aorta (AAo) was
measured both manually and with the automated software.
The cross sectional area (CSA) and diameter of AAo were measured 15 mm
above the ostium of left main coronary artery (LMCA) as shown in figure 22 (Mao
et al.,2003)
96
Figure 22. Measurement of area of the ascending aorta (AAo) at the maximum
systole and diastole (as determined automatically by the machine) 15 mm above
LM ostium using axial and coronal views.
Maximum AAo area and diamter were measured at both maximal systole (30
– 40 % of R–R interval) and maximum diastole (65 – 95% of R-R interval.
The determination of best (maximum) systole or diastole was done

automatically by the machine.
The above equation for calculating the Distensibility was done through excel
sheet by adding this equation in master sheet to be calculated automatically.
97
2) Pulse wave velocity (PWV) and Aortic Stiffness
In this study, we measured Aortic Stiffness form Aortic distensibility by

measuring Pulse wave velocity (PWV) as PWV and distensibility are inversely
related to one another by the Bramwell-Hill equation (Bramwell et al., 1922):
The above equation for calculating the Pulse wave velocity (PWV) was done
through excel sheet by adding this equation in master sheet to be calculated
automatically.
 Ststitical analysis
Data collected throughout history, basic clinical examination, laboratory

investigations and outcome measures coded, entered and analyzed using Microsoft
Excel software. Data were then imported into Statistical Package for the Social
Sciences (SPSS version 25.0) software for analysis. According to the type of data,
qualitative data were represented as number and percentage, quantitative continuous
data were represented as mean ± SD or median (Range).
The following tests were used to test differences for significance; difference
and association of qualitative variables was assessed by Chi square test (X 2) or
Fisher’s exact test while differences between quantitative independent groups by t
test. P value was set at <0.05 for significant results & <0.001 for high significant
result. Analysis of variance (ANOVA) test: was used to test the statistical
significance for difference in the values of the means of more than two groups for
each numeric parameter.
98
 Data Analysis:
Each of the parameters mentioned above were analyzed for all studied groups
using the following measures:
Mean: the mean is the measure used for central tendency and for the
comparison of the parameter in the groups under study.
Standard deviation (SD): the standard deviation was used as a measure of data
dispersion around the mean. It indicates the extent of variability of data and the
reliability of the mean.
The X2–Test: the test is used to detect significance in two groups of non-
numeric data or observations. It was used mainly for detection of significance
between the numbers of cases in each group that showed a certain finding regarding
study criteria.
Student T–Test: the student T–Test was used to test the statistical significance
for difference in the values of the means of the two groups for each numeric
parameter.
Analysis of variance (ANOVA) test: was used to test the statistical

significance for difference in the values of the means of more than two groups for
each numeric parameter.
P-Value: The P-value stands for the probability of a certain value to be a certain
group. It is derived from student T-Test or X2 Test using special lookup tables.
Significance is determined by the value of the P- value. A level less than 0.05 means
a statistically significant difference between the two groups, a level less than 0.001
is highly significant, while P value >0.05 was considered a non-significant result.
99
Results
Results
180 patients were enrolled in this study. Patients were classified into groups
according to their CAC score and according to severity of CTA-Diagnosed coronary
artery disease (Table 5. & Table 7. Patients and methods)
The mean age of the included patients was 53.3 ± 10.6 [Min: 23 - Max: 83].
Of them 101 patients (56%) were men while 79 patients (44%) were women.
DM was present in 43 patients (24%), HTN in 76 (42%), and Dyslipidemia in
103 (57%). 55 patients (31%) were smokers, and 32 (18%) had a positive family
history.
The mean SBP (mmHg) was 119.7 ± 9.8. [Min: 90 - Max: 150], mean DBP
(mmHg) was 81.9 ± 10 [Min: 60 - Max: 110], and mean HR (bpm) was 60.1 ± 6.8
[Min: 45 - Max: 75]).
The ECG Rhythm showed Normal sinus rhythm in 178 (99%), while 1 patient
(0.6%) had Atrial Fibrillation, and 1 patient (0.6%) had Premature ventricular
complex (PVC).
100
Results
Table 8. Demographics and clinical examination findings (n= 180)

N= 180
Sex
Female 79 (43.9%)
Male 101 (56.1%)
Age
Mean (SD) 53.3 (10.6)
Range 23.0 - 83.0
Diabetes Mellitus
No 137 (76.1%)
Yes 43 (23.9%)
Hypertension
No 104 (57.8%)
Yes 76 (42.2%)
Dyslipidemia
No 77 (42.8%)
Yes 103 (57.2%)
Smoking
No 125 (69.4%)
Yes 55 (30.6%)
Family History
No 148 (82.2%)
Yes 32 (17.8%)
Systolic blood pressure (mmHg)
Mean (SD) 119.7 (9.8)
Range 90.0 - 150.0
Diastolic blood pressure (mmHg)
Mean (SD) 81.9 (10.0)
Range 60.0 - 110.0
Heart rate (bpm)
Mean (SD) 60.1 (6.8)
Range 45.0 - 75.0
ECG Rhythm
Atrial Fibrillation 1 (0.6%)
Normal sinus rhythm 178 (98.9%)
Premature ventricular complex 1 (0.6%)
101
Results
The mean level of hemoglobin was 14.0 ± 1.2 g/dl (range, 10.0 g/dl, 17.0 g/dl),
and the mean serum Creatinine level was 1.0 mg/dl (SD=0.2) [Min: 0.6 - Max: 1.8].
We observed that the mean of total cholesterol was 187.8 mg/dl (SD=48.8)
with range from 97.0 to 304.0 mg/dl, while the mean triglyceride level was 179.8 ±
54.2 mg/dl [Min: 82.0 - Max: 324.0]. Regarding LDL, the mean LDL level was
109.3 mg/dl (SD=32.9) with range from 25.0 to 240.0 mg/dl. While HDL mean level
was 50.2 mg/dl (SD=9.3) with range from 27.0 to 70.0 mg/dl.
Table 9. Laboratory Investigations among the included patients (n= 180)

N= 180
Hemoglobin concentration (g/dl)
Mean (SD) 14.0 (1.2)
Range 10.0 - 17.0
Serum Creatinine (mg/dl)
Mean (SD) 1.0 (0.2)
Range 0.6 - 1.8
Total Cholesterol (mg/dl)
Mean (SD) 187.8 (48.8)
Range 97.0 - 304.0
Triglyceride (mg/dl)
Mean (SD) 179.8 (54.2)
Range 82.0 - 324.0
Low density Lipoprotein (mg/dl)
Mean (SD) 109.3 (32.9)
Range 25.0 - 240.0
High density Lipoprotein (mg/dl)
Mean (SD) 50.2 (9.3)
Range 27.0 - 70.0
102
Results
Coronary plaque features
Concerning the coronary plaque features of our included patients. 6 patients
(3.3%) had the calcific plaque of the left main coronary artery (LM), while the mixed
type was found in 4 patients (2.2%).
Of the left anterior descending artery (LAD), 42 patients (23.3%) presented
with the calcific plaques while 26 patients (14.4%) were having mixed plaque and
14 patients (7.8%) with soft plaque.
19 Patients (10.6%) were having calcific plaques of left circumflex artries
(LCX), 14 patients (7.8%) presented with mixed plaques, and 2 patients (1.1%) with
soft plaques.
On the other hand, the calcific type of right coronary artery (RCA) was found
in 25 patients (13.9%), 11 patients (6.1%) with mixed plaques, and 5 patients (2.8%)
with soft plaques.
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Results
Table 10. Coronary Plaque features among the included patients (n= 180)
Left Main Coronary Artery (LM)
NO 170 (94.4%)
Calcific 6 (3.3%)
Mixed 4 (2.2%)
Left Anterior Descending Artery (LAD)
Mixed 26 (14.4%)
No 98 (54.4%)
Calcific 42 (23.3%)
Soft 14 (7.8%)
Ramus Intermedius Artery
Patients with no Ramus 151 (83.9%)
No 21 (11.7%)
Calcific 8 (4.4%)
Diagonal Artery (branch of LAD)
No 164 (91.1%)
Calcific 8 (4.4%)
Mixed 5 (2.8%)
Soft 3 (1.7%)
Left Circumflex Artery (LCX)
No 145 (80.6%)
Calcific 19 (10.6%)
Mixed 14 (7.8%)
Soft 2 (1.1%)
Obtuse Marginal Artery (branch of LCX)
No 173 (96.1%)
Calcific 4 (2.2%)
Mixed 2 (1.1%)
Soft 1 (0.6%)
Right Coronary Artery (RCA)
No 139 (77.2%)
Calcific 25 (13.9%)
Mixed 11 (6.1%)
Soft 5 (2.8%)
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Results
Degree of the coronary stenosis
We assessed different degrees of coronary artery stenosis in the included
patients. 52 patients (13.9%) had significant coronary stenosis (> 70 %), 18 patients
(10.0%) had moderate coronary stenosis, and 30 patients (16.7%) had mild coronary
stenosis, while the rest 107 patients (59.4%) had no coronary stenosis.
Left main coronary artery (LM) was found to be moderately stenosed in 1
patient (0.6%) and mildly stenosed in 5 patients (2.8%).
Regarding the left anterior descending (LAD) artery, significant stenosis was
found in 18 patients (10.0%), 17 patients (9.4%) had moderate coronary stenosis,
and 29 patients (16.1%) had mild coronary stenosis, and 3 patients (1.7%) were non-
evaluable cases.
In Left Circumflex Artery (LCX), we found 5 patients (2.8%) had significant
stenosis, 6 patients (3.3%) had moderate stenosis, and 9 patients (5.0%) had mild
stenosis.
Right Coronary Artery (RCA) was found to be significantly stenosed in 7
patient (3.9%), moderately stenosed in 9 patients (5.0%), and mildly srenosed in 13
patients (7.2%).
105
Results
Table 11. CT Coronary Angiography (vessels involved and degree of stenosis) among the
included patients (n= 180)
0= no coronary stenosis 174 (96.7%)
1= mild coronary stenosis (< 50 %) 5 (2.8%)
2= moderate coronary stenosis (50 - 70 %) 1 (0.6%)
3= significant coronary stenosis (> 70 %) OR subtotal OR total stenosis 18 (10.0%)
Non Evaluable 3 (1.7%)
Ramus Intermedius Artery
No Ramus 154 (85.6%)
Non Evaluable 1 (0.6%)
Diagonal Artery (branch of LAD)
No Diagonal 1 (0.6%)
Obtuse Marginal Artery (branch of LCX)
Number of Involved Vessels
106
Results
Multivessel 37 (20.6%)
NO 107 (59.4%)
Single 36 (20.0%)
Degree of stenosis
107
Results
Coronary Artery Calcium Scoring (CAC score)
Our study's total mean CAC score was 78.4 (SD=154.2). The included
patients were classified into four groups according to the CAC score, whereas group
1 included 102 patients (56.7%) with a CAC score of 0, group 2 included 37 patients
(20.6%) with a CAC score ranging from 1 to 99, group 3 included 31 patients
(17.2%) with a CAC score ranging from 100 to 400, and group 4 included 10
patients (5.6%) with a CAC score of more than 400.
Table 12. Calcium Scoring among the included patients (n= 180)

Mean (SD) 3.2 (16.0)
Range 0.0 - 120.5
Mean (SD) 42.7 (77.0)
Range 0.0 - 356.7
Mean (SD) 13.0 (40.3)
Range 0.0 - 280.0
Mean (SD) 19.5 (63.4)
Range 0.0 - 497.7
TOTAL
Mean (SD) 78.4 (154.2)
Range 0.0 - 756.0
Calcium Scoring Groups
Group 1: CAC score= 0 102 (56.7%)
Group 2: CAC score= 1 - 99 37 (20.6%)
Group 3: CAC score= 100 - 400 31 (17.2%)
Group 4: CAC score= > 400 10 (5.6%)
108
Results
Aortic Distensibility Index (ADI) and Pulse Wave Velocity
(PWV)
Aortic distensibility index (ADI) was measured in all included patients. The
mean systole of Ascending Aorta cross-sectional area was 9.9 (SD=1.8) with a range
from 5.8 to 15.6, while the mean diastole of ascending aorta cross-sectional area was
7.3 (SD=1.4) with a range from 4.0 to 12.1. The mean aortic distensibility index and
pulse wave velocity were 9.4 (SD= 1.3) [Min: 5.7 - Max: 12.1] and 1.2 (SD=0.1)
[Min: 1.0 - Max: 1.5].
Table 13. Aortic distensibility and aortic stiffness measurements among the included
patients (n= 180)
Aortic Distensibility Index (ADI) Measurement
Ascending Aorta cross-sectional area (Systole)
Mean (SD) 9.9 (1.8)
Range 5.8 - 15.6
Ascending Aorta cross-sectional area (Diastole)
Mean (SD) 7.3 (1.4)
Range 4.0 - 12.1
Pulse pressure
Mean (SD) 37.8 (5.6)
Range 25.0 - 55.0
Aortic Distensibility Index
Mean (SD) 9.4 (1.3)
Range 5.7 - 12.1
Aortic Stiffness: Pulse Wave Velocity (PWV)
Mean (SD) 1.2 (0.1)
Range 1.0 - 1.5
109
Results
Table 14. Aortic Distensibility Index and Pulse Wave Velocity among the included patients
stratified based on the CT coronary calcium score (n= 180)
Group 1 Group 2 Group 3 Group 4 Total
p value
(N=102) (N=37) (N=31) (N=10) (N=180)
Mean (SD) 10.2 (0.6) 9.1 (0.8) 7.9 (0.7) 6.7 (1.3) 9.4 (1.3) < 0.0011
Range 8.2 - 12.1 7.3 - 11.1 6.9 - 10.0 5.7 - 10.1 5.7 - 12.1
Mean (SD) 1.1 (0.0) 1.2 (0.1) 1.3 (0.1) 1.4 (0.1) 1.2 (0.1) < 0.0011
Range 1.0 - 1.2 1.1 - 1.3 1.1 - 1.4 1.1 - 1.5 1.0 - 1.5
Group 1: CAC score= 0; group 2: CAC score= 1-99, group 3: CAC score= 100 – 400, and group
4: CAC score= > 400.
This table shows that the overall mean aortic distensibility index was 9.4 (SD=
1.3). It was significantly higher among the normal group 10.2 (SD= 0.6) than
patients with stenosis (P< 0.001). The overall mean pulse wave velocity was 1.4
(SD= 0.1). It was significantly higher among patients with severe stenosis 1.3 (SD=
0.1), (P< 0.001).
Figure 23. Aortic Distensibility Index and Pulse Wave Velocity among the included patients
110
Results
Table 15. Aortic Distensibility Index and Pulse Wave Velocity among the included patients
stratified based on the degree of stenosis (n= 180)
Normal Mild Moderate Severe Total
Coronaries (Stenosis (Stenosis (Stenosis (N=180)
p value
(N=107) < 50 %) 50 – 70 %) > 70%)
(N=30) (N=18) (N=25)
1
Mean (SD) 10.2 (0.7) 8.7 (1.3) 8.5 (0.8) 7.7 (1.2) 9.4 (1.3) < 0.001
Range 7.8 - 12.1 5.9 - 11.1 7.2 - 10.2 5.7 - 10.2 5.7 - 12.1
Mean (SD) 1.1 (0.0) 1.2 (0.1) 1.2 (0.1) 1.3 (0.1) 1.2 (0.1) < 0.0011
Range 1.0 - 1.3 1.1 - 1.5 1.1 - 1.3 1.1 - 1.5 1.0 - 1.5
1. Linear Model ANOVA; 2. Pearson's Chi-squared test
This table shows that the overall mean aortic distensibility index was 9.4 (SD=
1.3). It was significantly higher among the normal group 10.2 (SD= 0.7) than
patients with stenosis (P< 0.001). The overall mean pulse wave velocity was 1.2
(0.1). It was significantly higher among patients with severe stenosis 1.3 (SD= 0.1),
(P< 0.001).
Figure 24. Aortic Distensibility Index and Pulse Wave Velocity among the included patients
111
Results
There was a statistically significant negative correlation between calcium
scoring and the ADI (Pearson's r= -0.771, p< .001).
Table 16. The correlation between calcium scoring and ADI
ADI
Ca Score Pearson's r -0.771
p-value < .001
95% CI Upper -0.705
95% CI Lower -0.825
Spearman's rho -0.793
p-value < .001
N 180
Figure 25. The correlation between calcium scoring and ADI
112
Results
At the sametime there was a statistically significant positive correlation
between calcium scoring and PWV (Pearson's r=0.817, p< .001).
Table 17. The correlation between calcium scoring and PWV
PWV
Ca Score Pearson's r 0.817
p-value < .001
95% CI Upper 0.861
95% CI Lower 0.762
Spearman's rho 0.793
p-value < .001
N 180
Figure 26. The correlation between calcium scoring and PWV
113
Results
Degree of stenosis also shows consistent result like calcium scoring as
there was a statistically significant negative correlation between ADI and the
Degree of stenosis (Pearson's r=-0.707, p< .001).
Table 18. The correlation between ADI and Degree of stenosis
Degree of stenosis
ADI Pearson's r -0.707
p-value < .001
95% CI Upper -0.625
95% CI Lower -0.773
p-value < .001
N 180
Figure 27. The correlation between ADI and Degree of stenosis

114
Results
Likewise there was a statistically significant positive correlation between
PWV and the Degree of stenosis (Pearson's r=0.697, p< .001).
Table 19. The correlation between PWV and the Degree of stenosis
Degree of stenosis
PWV Pearson's r 0.697
p-value < .001
95% CI Upper 0.765
95% CI Lower 0.613
p-value < .001
N 180
Figure 28. The correlation between PWV and the Degree of stenosis
115
Results
Patients Characterestics in the four groups stratified based on
the CT coronary calcium score

The demographic data among the included patients stratified based on the CT
coronary calcium score showed in Table.20..
Important findings to note are:
16 patients (51.6%) from all 43 diabetic patients were in group 3 [CAC score=
100 to 400].
27 patients (26.5%) form all 76 hypertensive patients were in group 1 [CAC
score= 0].
In addition, 40 patients (39.2%) form all 103 dyslipidemic patients were in
group 1 [CAC score= 0].
There was a significant difference between the studied groups in terms of age,
DM, HTN, dyslipidemia, and smoking (all P < 0.05).
116
Results
Table 20. Demographic data among the included patients stratified based on the CT
coronary calcium score (n= 180)
Group 1 Group 2 Group 3 Group 4 Total (N=180)

p value
(N=102) (N=37) (N=31) (N=10)
Age
Mean(SD) 49.1 (9.0) 57.5 (9.8) 59.5 (9.2) 61.3 (13.9) 53.3 (10.6) < 0.0011
Range 23.0 - 73.0 39.0 - 83.0 44.0 - 74.0 41.0 - 77.0 23.0 - 83.0
Sex
Female 45.0 (44.1%) 18.0 (48.6%) 11.0 (35.5%) 5.0 (50.0%) 79.0 (43.9%) 0.7092
Male 57.0 (55.9%) 19.0 (51.4%) 20.0 (64.5%) 5.0 (50.0%) 101.0 (56.1%)
DM
No 91.0 (89.2%) 30.0 (81.1%) 15.0 (48.4%) 1.0 (10.0%) 137.0 (76.1%) < 0.0012
Yes 11.0 (10.8%) 7.0 (18.9%) 16.0 (51.6%) 9.0 (90.0%) 43.0 (23.9%)
HTN
No 75.0 (73.5%) 18.0 (48.6%) 9.0 (29.0%) 2.0 (20.0%) 104.0 (57.8%) < 0.0012
Yes 27.0 (26.5%) 19.0 (51.4%) 22.0 (71.0%) 8.0 (80.0%) 76.0 (42.2%)
Dyslipidemia
No 62.0 (60.8%) 8.0 (21.6%) 6.0 (19.4%) 1.0 (10.0%) 77.0 (42.8%) < 0.0012
Yes 40.0 (39.2%) 29.0 (78.4%) 25.0 (80.6%) 9.0 (90.0%) 103.0 (57.2%)
Smoking
No 80.0 (78.4%) 21.0 (56.8%) 18.0 (58.1%) 6.0 (60.0%) 125.0 (69.4%) 0.0292
Yes 22.0 (21.6%) 16.0 (43.2%) 13.0 (41.9%) 4.0 (40.0%) 55.0 (30.6%)
Family history
No 84.0 (82.4%) 28.0 (75.7%) 27.0 (87.1%) 9.0 (90.0%) 148.0 (82.2%) 0.5722
Yes 18.0 (17.6%) 9.0 (24.3%) 4.0 (12.9%) 1.0 (10.0%) 32.0 (17.8%)
Group 1: CAC score= 0; group 2: CAC score= 1-99, group 3: CAC score= 100 – 400, and group 4:
CAC score= > 400. 1. Linear Model ANOVA; 2. Pearson's Chi-squared test
117
Results
The overall mean SBP, DBP, and HR were 119.7 (9.8), 81.9 (10.0), and 60.1
(6.8). The mean SBP and DBP were significantly higher in group 4 patients (132.5
(SD= 10.6) and 94.0 (SD= 8.1)). There were statistically significant differences
between the studied groups in terms of SBP and DBP (P < 0.001).
Table 21 . Clinical examination findings among the included patients stratified based on
the CT coronary calcium score (n= 180)

p value
(N=102) (N=37) (N=31) (N=10) (N=180)
SBP (mmHg)
132.5
Mean (SD) 117.2 (8.4) 120.9 (9.6) 122.4 (10.2) 119.7 (9.8)
(10.6) < 0.0011
100.0 - 100.0 - 115.0 -
Range 90.0 - 145.0 90.0 - 150.0
140.0 140.0 150.0
DBP (mmHg)
Mean (SD) 79.9 (8.4) 81.9 (10.8) 84.4 (11.5) 94.0 (8.1) 81.9 (10.0)
< 0.0011
80.0 -
Range 60.0 - 100.0 60.0 - 110.0 60.0 - 105.0 60.0 - 110.0
110.0
HR (bpm)
Mean (SD) 59.5 (6.6) 60.7 (7.3) 61.5 (6.3) 60.0 (8.5) 60.1 (6.8) 0.5161
Range 45.0 - 74.0 46.0 - 75.0 47.0 - 71.0 46.0 - 72.0 45.0 - 75.0
Rhythm
Atrial
0.0 (0.0%) 0.0 (0.0%) 1.0 (3.2%) 0.0 (0.0%) 1.0 (0.6%)
Fibrillation
Normal sinus 102.0 30.0 10.0 178.0
36.0 (97.3%) 0.1912
rhythm (100.0%) (96.8%) (100.0%) (98.9%)
Premature
ventricular 0.0 (0.0%) 1.0 (2.7%) 0.0 (0.0%) 0.0 (0.0%) 1.0 (0.6%)
complex
Group 1: CAC score= 0; group 2: CAC score= 1-99, group 3: CAC score= 100 – 400, and group 4:
CAC score= > 400. 1. Linear Model ANOVA; 2. Pearson's Chi-squared test
118
Results
Figure 29. Clinical examination findings among the included patients stratified based on the
CT coronary calcium score (n= 180)
119
Results
We observed statistically significant differences between the studied groups
in terms of Hb. (g/dl), serum creatinine (mg/dl), total cholesterol (mg/dl), TG
(mg/dl), LDL (mg/dl), and HDL (mg/dl).
Table 22. Laboratory Investigations among the included patients stratified based on the CT
p value
(N=102) (N=37) (N=31) (N=10) (N=180)
Hb. (g/dl)
Mean (SD) 14.3 (1.1) 13.8 (1.4) 13.6 (1.1) 13.6 (1.3) 14.0 (1.2)
0.0061
10.0 - 11.0 - 11.7 - 10.0 -
Range 10.0 - 17.0
16.2 16.0 16.1 17.0
S. Creatinine (mg/dl)
Mean (SD) 1.0 (0.2) 1.0 (0.2) 1.1 (0.2) 1.2 (0.2) 1.0 (0.2) < 0.0011
Range 0.6 - 1.8 0.7 - 1.4 0.6 - 1.5 0.8 - 1.5 0.6 - 1.8
T. Cholesterol (mg/dl)
174.3 196.3 210.4 223.8 187.8
Mean (SD)
(41.8) (51.1) (50.7) (56.6) (48.8) < 0.0011
97.0 - 114.0 - 110.0 - 114.0 - 97.0 -
Range
281.0 300.0 304.0 301.0 304.0
TG (mg/dl)
157.9 196.2 217.1 226.3 179.8
Mean (SD)
(43.1) (52.3) (55.4) (51.9) (54.2) < 0.0011
82.0 - 112.0 - 97.0 - 134.0 - 82.0 -
Range
305.0 300.0 324.0 300.0 324.0
LDL (mg/dl)
116.6 128.5 141.4 109.3
Mean (SD) 97.6 (26.0)
(32.2) (38.7) (26.3) (32.9) < 0.0011
56.0 - 25.0 - 51.0 - 89.0 - 25.0 -
Range
189.0 180.0 240.0 180.0 240.0
HDL (mg/dl)
Mean (SD) 52.1 (9.0) 49.7 (9.2) 46.5 (9.3) 43.5 (7.1) 50.2 (9.3)
0.0021
32.0 - 33.0 - 35.0 - 27.0 -
Range 27.0 - 70.0
68.0 61.0 56.0 70.0
Group 1: CAC score= 0; group 2: CAC score= 1-99, group 3: CAC score= 100 – 400, and
group 4: CAC score= > 400. 1. Linear Model ANOVA; 2. Pearson's Chi-squared test
120
Results
Figure 30. Laboratory Investigations among the included patients stratified based on the CT
121
Results
Patients Characterestics in the four groups stratified based on
the degree of stenosis
The demographic data among the included patients stratified based on the
degree of stenosis showed in Table 23.
Of important findings are:
15 patients (60.0%) from all diabetic patients (n=43) were in group 4 (severe
stenosis > 70%).
17 patinets ((56.7%)) from all hypertensive patients (n=76) were in group 2
(Mild Stenosis < 50 %)
47 patients (43.9%) from all Dyslipidemic patients (n=103) had normal
coronaries (group 1).
There was a significant difference between the studied groups in terms of age,
DM, HTN, dyslipidemia, and Smoking (all P<0.05).
122
Results
Table 23. Demographic data among the included patients stratified based on the degree of
stenosis (n= 180)
Normal
(Stenosis (Stenosis (Stenosis Total
Coronaries p value
< 50 %) 50 – 70 %) > 70%) (N=180)
(N=107)
(N=30) (N=18) (N=25)
Age
53.3
Mean (SD) 50.8 (9.9) 58.9 (9.8) 56.7 (11.7) 55.0 (10.9)
(10.6) < 0.0011
23.0 -
Range 23.0 - 83.0 39.0 - 77.0 31.0 - 73.0 41.0 - 77.0
83.0
Sex
16.0 7.0 79.0
Female 50.0 (46.7%) 6.0 (33.3%)
(53.3%) (28.0%) (43.9%) 0.1862
14.0 12.0 18.0 101.0
Male 57.0 (53.3%)
(46.7%) (66.7%) (72.0%) (56.1%)
Diabetes Mellitus
19.0 13.0 10.0 137.0
No 95.0 (88.8%)
(63.3%) (72.2%) (40.0%) (76.1%) < 0.0012
11.0 15.0 43.0
Yes 12.0 (11.2%) 5.0 (27.8%)
(36.7%) (60.0%) (23.9%)
Hypertension
13.0 9.0 104.0
No 73.0 (68.2%) 9.0 (50.0%)
(43.3%) (36.0%) (57.8%) 0.0052
17.0 16.0 76.0
Yes 34.0 (31.8%) 9.0 (50.0%)
(56.7%) (64.0%) (42.2%)
Dyslipidemia
9.0 3.0 77.0
No 60.0 (56.1%) 5.0 (27.8%)
(30.0%) (12.0%) (42.8%) < 0.0012
21.0 13.0 22.0 103.0
Yes 47.0 (43.9%)
(70.0%) (72.2%) (88.0%) (57.2%)
Smoking
No 20.0 12.0 125.0
86.0 (80.4%) 7.0 (38.9%)
(66.7%) (48.0%) (69.4%) < 0.0012
10.0 11.0 13.0 55.0
Yes 21.0 (19.6%)
(33.3%) (61.1%) (52.0%) (30.6%)
Family history
25.0 15.0 17.0 148.0
No 91.0 (85.0%)
(83.3%) (83.3%) (68.0%) (82.2%) 0.2532
5.0 8.0 32.0
Yes 16.0 (15.0%) 3.0 (16.7%)
(16.7%) (32.0%) (17.8%)
123
Results
The overall mean SBP, DBP, and HR were 119.7 (9.8), 81.9 (10.0), and 60.1
(6.8) respectively.
The mean SBP and DBP were significantly higher in patients with severe
stenosis (p< 0.0011 and p= 0.03).
Table 24. Clinical examination findings among the included patients stratified based on the
degree of stenosis (n= 180)
Normal Mild Moderate Severe Total
Coronaries (Stenosis (Stenosis (Stenosis (N=180)
p value
(N=107) < 50 %) 50 – 70 %) > 70%)
(N=30) (N=18) (N=25)
SBP (mmHg)
121.7 124.8 119.7
Mean (SD) 117.4 (8.6) 123.1 (9.6)
(8.4) (13.1) (9.8) < 0.0011
100.0 - 100.0 - 100.0 - 90.0 -
Range 90.0 - 140.0
140.0 140.0 150.0 150.0
DBP (mmHg)
84.2 85.2 81.9
Mean (SD) 80.0 (8.1) 84.2 (10.5)
(10.8) (14.2) (10.0) 0.0291
70.0 - 60.0 - 60.0 - 60.0 -
Range 60.0 - 100.0
100.0 100.0 110.0 110.0
HR (bpm)
Mean (SD) 59.5 (6.7) 59.8 (6.7) 62.9 (6.8) 61.0 (7.3) 60.1 (6.8)
0.2301
46.0 - 45.0 -
Range 45.0 - 75.0 49.0 - 72.0 46.0 - 72.0
71.0 75.0
Rhythm
1.0
Atrial Fibrillation 0.0 (0.0%) 1.0 (3.3%) 0.0 (0.0%) 0.0 (0.0%)
(0.6%)
Normal sinus 29.0 18.0 25.0 178.0 0.4572
106.0 (99.1%)
rhythm (96.7%) (100.0%) (100.0%) (98.9%)
Premature 1.0
1.0 (0.9%) 0.0 (0.0%) 0.0 (0.0%) 0.0 (0.0%)
ventricular complex (0.6%)
124
Results
Figure 31. Clinical examination findings among the included patients stratified based on the
125
Results
The overall mean total cholesterol was 187.8 mg/dl (SD= 48.8). It was
significantly higher among the group with severe stenosis at 236.6 mg/dl (SD= 49.3)
(P< 0.001).
The overall mean Triglyceride was 179.8 mg/dl (SD=54.2). It was
significantly higher among patients with severe stenosis at 240.1 mg/dl (SD= 43.9),
(P< 0.001).
The overall mean Low-density Lipoprotein was 109.3 mg/dl (SD=32.9). It
was significantly higher among patients with severe stenosis at 141.7 mg/dl (SD=
35.8), (P< 0.001).
The overall mean High-density Lipoprotein was 50.2 mg/dl (SD=9.3). It was
significantly higher among patients with normal coronaries at 52.3 mg/dl (SD= 9.0),
(P< 0.001).
126
Results
Table 25. Laboratory Investigations among the included patients stratified based on the
Normal
(Stenosis (Stenosis (Stenosis Total
Coronaries p value
< 50 %) 50 – 70 %) > 70%) (N=180)
(N=107)
(N=30) (N=18) (N=25)
Hemoglobin concentration (g/dl)
Mean
14.2 (1.2) 13.7 (1.3) 13.7 (1.1) 14.0 (1.5) 14.0 (1.2) 0.1421
(SD)
Range 10.0 - 17.0 11.0 - 16.2 11.5 - 16.0 10.0 - 16.1 10.0 - 17.0
Serum Creatinine (mg/dl)
Mean
1.0 (0.2) 1.0 (0.2) 1.0 (0.2) 1.1 (0.2) 1.0 (0.2) 0.0101
(SD)
Range 0.6 - 1.8 0.7 - 1.5 0.8 - 1.3 0.6 - 1.5 0.6 - 1.8
Total Cholesterol (mg/dl)
Mean 187.8
176.6 (43.4) 181.6 (49.8) 197.1 (35.0) 236.6 (49.3)
(SD) (48.8) < 0.0011
131.0 - 140.0 - 97.0 -
Range 97.0 - 281.0 110.0 - 271.0
271.0 304.0 304.0
Triglyceride (mg/dl)
Mean 179.8
162.1 (44.3) 186.2 (57.8) 190.1 (52.8) 240.1 (43.9)
(SD) (54.2) < 0.0011
169.0 - 82.0 -
Range 82.0 - 305.0 97.0 - 280.0 98.0 - 324.0
311.0 324.0
Low density Lipoprotein (mg/dl)
Mean 109.3
98.9 (27.0) 117.8 (27.6) 111.5 (37.8) 141.7 (35.8)
(SD) (32.9) < 0.0011
25.0 -
Range 56.0 - 189.0 70.0 - 180.0 25.0 - 184.0 77.0 - 240.0
240.0
High density Lipoprotein (mg/dl)
Mean
52.3 (9.0) 48.8 (8.9) 46.1 (9.7) 45.5 (8.7) 50.2 (9.3) < 0.0011
(SD)
Range 27.0 - 69.0 32.0 - 70.0 34.0 - 61.0 33.0 - 66.0 27.0 - 70.0
127
Results
Figure 32. Laboratory Investigations among the included patients stratified based on the
128
Results
Correlation between ADI and PWV and different patients subgroups
Table 26. The correlation between calcium scoring and the degree of stenosis
Total Calcium Scoring

Degree of stenosis Pearson's r 0.653
p-value < .001
95% CI Upper 0.729
95% CI Lower 0.560
p-value < .001
N 180
This table shows that there is a statistically significant positive correlation
between calcium scoring and the degree of stenosis (Pearson's r= 0.653, p< .001).
Figure 33. The correlation between calcium scoring and the degree of stenosis
129
Results
Table 27. The correlation between No. of Involved Vessels and ADI
Involved Vessels
ADI Pearson's r -0.771
p-value < .001
95% CI Upper -0.704
95% CI Lower -0.824
p-value < .001
N 180
This table shows that there is a statistically significant negative correlation
between involved vessels and ADI (Pearson's r=-0.771, p< .001).
Figure 34. The correlation between No. of involved vessels and ADI
130
Results
Table 28. The correlation between No. of Involved Vessels and PWV
Involved Vessels
PWV Pearson's r 0.762
p-value < .001
95% CI Upper 0.817
95% CI Lower 0.693
p-value < .001
N 180
This table shows that there is a statistically significant positive correlation
between Involved Vessels and PWV (Pearson's r= 0.762, p< .001).
Figure 35. The correlation between No. Of Involved Vessels and PWV
131
Results
Table 29. The correlation between PWV and ADI among the diabetic patients
ADI
PWV Pearson's r -0.992
p-value < .001
95% CI Upper -0.985
95% CI Lower -0.996
p-value < .001
N 43
between PWV and ADI among diabetic patients (Pearson's r=-0.992, p< .001).
Figure 36. The correlation between PWV and ADI among the diabetic patients
132
Results
Table 30. The correlation between PWV and ADI among the hypertensive patients
ADI
p-value < .001
95% CI Upper -0.985
95% CI Lower -0.994
p-value < .001
N 76
between PWV and ADI among hypertensive patients (Pearson's r=-0.991, p< .001).
Figure 37. The correlation between PWV and ADI among the hypertensive patients
133
Results
Table 31. The correlation between PWV and ADI among patients with dyslipidemia
ADI
p-value < .001
95% CI Upper -0.986
95% CI Lower -0.994
p-value < .001
N 103
between PWV and ADI among patients with dyslipidemia (Pearson's r= -0.991,
p< .001).
Figure 38. The correlation between PWV and ADI among patients with dyslipidemia
134
Results
Table 32. The correlation between PWV and ADI among smokers
ADI
p-value < .001
95% CI Upper -0.989
95% CI Lower -0.996
p-value < .001
N 55
between PWV and ADI among smokers (Pearson's r= -0.993, p< .001).
Figure 39. The correlation between PWV and ADI among smokers
135
Selected cases
Selected cases
 Case 113
A 55 years female patient non-smoker, not known to be diabetic or

hypertensive but she is dyslipidemic. Her B.P. is 120/80 mmHg, her heart rate is 59
b/min. and her ECG shows normal sinus rhythm.
 Laboratory investigations:
Hb 12.8 g/dl, S. Creatinine 0.65 mg/dl, T. Cholesterol 251 mg/dl, TG 144
mg/dl, LDL 189 mg/dl, HDL 63 mg/dl.
 Coronary plaques: No
 Degree of stenosis : No
 Total calcium scoring: 0
 Measurement:
AAO CSA (S): 8.91, AAO CSA (D): 6.34, Pulse pressure: 40.00 mmHG
 ADI: 10.12
 Aortic Stiffness (PWV): 1.12.
Figure 40: CT Coronary Angiography of patient n. 113. (a) diastolic, (b) systolic.
136
Selected cases
 Case 118
A 77 years male non-smoker dyslipidemic patient, not known to be diabetic

or hypertensive. His blood pressure is 100/70 mmHg, his heart rate is 69 b/min. ECG
shows normal sinus rhythm.
 Coronary plaques: calcific plaques in LAD, LCX and RCA.
 Number of vessels affected: multivessel.
 Total calcium scoring: 329.5
 Degree of stenosis : mild stenosis in LAD and RCA
 Measurement:
AAO CSA (S): 9.36, AAO CSA (D): 7.72, Pulse pressure: 30.00 mmHg
 ADI: 7.06
137
Selected cases
 Case 141
A 42 years male patient smoker, diabetic and dyslipidemic, not known to be

hypertensive. His blood pressure is 130/90 mmHg, his HR is 54 b/min. ECG shows
normal sinus rhythm.
 Coronary plaques: calcific plaque in LAD, diagonal and RCA. Mixed plaque
in LCX and OM.
 Number of vessels affected: multivessel.
 Degree of stenosis: severe stenosis in LAD, LCX, and RCA with moderate
stenosis in diagonal branch and mild stenosis in OM branch.
 Total calcium scoring: 584.8
 Measurement:
AAO CSA (S): 8.43, AAO CSA (D): 6.64, Pulse pressure: 40.00 mmHg
 ADI: 6.77
138
Selected cases
 Case 158
A 67 years male patient hypertensive (on medication), non-smoker, not
known to be diabetic or dyslipidemic. His blood pressure is 120/80 mmHg, his HR
is 56 b/min., and his ECG shows normal sinus rhythm.
Hb 14.5 g/dl, S. Creatinine 0.9 mg/dl, T. Cholesterol 176 mg/dl, TG 82 mg/dl,
LDL 99 mg/dl, HDL 61 mg/dl.
 Coronary plaques: No
 Degree of stenosis : No
 Total calcium scoring: 0
 Measurement:
AAO CSA (S): 12.45, AAO CSA (D): 8.80, Pulse pressure: 40 mmHg
 ADI: 10.35
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Discussion
Discussion
A coronary artery calcium score (CACS) examination is a non-
invasive examination of the coronary arteries in which the amount of
calcium in the coronary arteries is determined using cardiac computed
tomography (Greenland et al., 2018).
With the exception of patients with renal failure, who may also have
medial calcification, coronary calcium is exclusively the result of
coronary atherosclerosis. The amount of calcium in the arteries roughly
correlates with extent of any atherosclerotic plaque that is present in the
coronary arteries (Montalescot et al., 2013).
According to the European Guidelines on cardiovascular disease

prevention in clinical practice (2016 version), the CACS can be
considered for cardiovascular risk assessment in asymptomatic adults
who are at a moderate risk (Mlynarska et al., 2019). The coronary artery
calcium score, which is calculated in cardiac computed tomography, can
support a cardiovascular risk evaluation, and therefore, it can support
clinical decisions. Interestingly, Japanese researchers confirmed that an
elevated CACS that is determined using coronary computed tomography
angiography is an independent predictor of mid- to long-term
cardiovascular mortality and morbidity in patients that are suspected of
having coronary artery disease (CAD) (Yamamoto et al., 2018).
158
Discussion
Carotid to femoral pulse wave velocity (PWV) is the gold standard

biomarker used for non-invasive measurement of arterial stiffness.
Moreover, it is highly reproducible, widely applied, and an independent
predictor of primary coronary events (Hayashi et al., 2015). PWV in the
arterial tree has been commonly used in clinical medicine. This is based
on the idea that the propagation of pressure wave is faster in a stiffer tube
than in a softer one. In the cardiovascular system, the velocity is obtained
from the measurements of temporal blood pressure waves at two sites
along the arterial tree. As this measurement can be done noninvasively
and easily, this method has been clinically used for several decades
(Hayashi et al., 2015).

in cardiovascular disease. The thoracic aorta plays an
important role in the cardiovascular system. Arterial distensibility, as a
measure of vascular function, can serve as a marker of coronary heart
disease risk in humans (Shehata et al., 2015).
The present study aimed to evaluate whether impaired Aortic

Distensibility Index (ADI) and Aortic stiffness measured by Cardiac CT
is correlating with the severity of coronary artery disease and coronary
calcium scoring in at-risk individuals (assessed by CTA). To obtain this
aim, 180 consecutive patients with suspected CAD were included.
159
Discussion
The current study demonstrate that: 1) excellent correlation between

ADI and PWV from one side and Coronary artery diseases and CAC
scoring from other side. 2) CCTA-measured ADI decreased
proportionally with the severity of CAC and degree of stenosis of
coronary arteries independent of other cardiovascular risk factor. 3) PWV
(aortic stiffness) calculated from Distensibility increased proportionally
with the severity of CAC and degree of stenosis of coronary arteries
independent of other cardiovascular risk factor. 4) Addition of ADI and
PWV to different scores that used to estimate the risk for coronary artery
disease could provide incremental value to predict CAD.
ADI in the present study was inversely correlated with the degree
of stenosis (r=-0.707, P < 0.001). In agreement with our finding, (Shehata
et al., 2015) found a significant inverse correlation between aortic
distensibility measured using both computed tomographic angiography
plus transthoracic echocardiography and severity of coronary artery
disease (percent luminal stenosis) r = –0.244, P = 0.045).
According to the present study, PWV (surrogate of Aortic stiffness)

was positively correlated with the degree of stenosis (r=0.697, P< 0.001).
Similarly, (Vallée et al., 2019) reported that measurements of aortic PWV
positively correlated with the severity of coronary heart disease
(p = 0.003). Moreover, aortic PWV index in (Yannoutsos et al., 2018)
was positively correlated with the severity of coronary heart disease
160
Discussion
judged on the 3 degrees of coronary arterial changes evaluated as less than

20%, presence of non-obstructive lesions, and presence of obstructive
lesions (P=0.001).
In the current study, there was also a significant negative
correlation between calcium scoring and the ADI (r= -0.771, P < 0.001).
Similarly, (Shehata et al., 2015) found a significant inverse correlation
between aortic distensibility measured using computed tomographic
angiography and transthoracic echocardiography and CAC scoring (r = –
0.265, P= 0.042).
Calcium scoring was found to be positively correlated with the
PWV in this study (r=0.817, P< 0.001). In concordance with our result,
(Torngren et al., 2020) found significant increases in arterial stiffness for
groups of increasing CACS. Moreover, the aorta calcium score in (Cho
et al., 2015) study was associated with mean brachial-ankle PWV
(r=0.387, P=0.001), suggesting arterial stiffening with raised aorta
calcium score.
Two groups have reported relations between aortic stiffness and
CAC in community-dwelling adult cohorts (Kullo et al., 2006); (van
Popele et al., 2006). These studies showed that greater carotid-femoral
pulse wave velocity (CFPWV) was associated with the presence and
extent of CAC. Extending these investigations, (Tsao et al., 2014)
examined the relations of other measures of pressure pulsatility and wave
161
Discussion
reflection with CAC and found that CFPWV had the strongest association
with CAC.
In our study, there was a significant negative correlation between
number of involved vessels and ADI (r=-0.771, P < 0.001). Similarly,
(Razik et al., 2021) found decreased aortic distensibility (AD) was
correlated with the complexity of CAD. They also found AD to be a good
predictor of CV events similar to ejection fraction and may therefore be
an early sign of CAD. Moreover, (Shehata et al., 2015) found a negative
correlation between number of diseased coronary arteries and ADI. Yet,
the correlation was not significant (r = –0.067, P = 0.578). Furthermore,
(Ahmadi et al., 2011) showed that aortic distensibility inversely
correlates with the severity of coronary atherosclerosis (assessed using
CACs and degree of coronary luminal stenosis using CCTA).
According to the present study, PWV inversely correlated with ADI
among diabetic patients (r=-0.992, P < 0.001), hypertensive patients (r=-
0.991, p <0 .001), patients with dyslipidemia (r= -0.991, p < 0.001), and
smokers (r= -0.993, p < 0.001). In line with our finding, (Salvi et al.,
2022) found a significant inverse correlation between carotid
distensibility and carotid–femoral PWV (r = −0.75; p < 0.001).
Increased plaque density contributes to higher CAC score and

overall cardiovascular risk prediction, which is likely due to a strong
association between CAC burden and CAD (Arnson et al., 2017).
162
Discussion
Calcium scoring in the current study was positively correlated

with the degree of stenosis (r= 0.653, P < 0.001). Severe coronary
calcification is known to be closely associated with significant coronary
obstruction. For its simplicity, the novel approaches for calcium scoring
have been attemped in the various opportunities to use CT scan, i.e. lung
screening or attenuation correction (Berman et al., 2017).
In the current study, increased CACS was associated with increase

in age, systolic and diastolic blood pressure, serum creatinine, total serum
cholesterol, triglycerides, and LDL (P < 0.0011 for all). While increased
CACS was associated with lower levels of Hb (P=0.0061) and HDL
(P=0.0021).
Similarly, LDL cholesterol was greater in the higher CAC score

groups (P=0.002) in (Serrano et al., 2019) study.
According to the present study, increased CACS was associated

with higher incidences of diabetes, hypertension and dyslipidemia (P <
0.0012 for all).
In agreement with our study, the presence of diabetes (P=0.002)

and older age (P < 0.001) was more prevalent in the CAC < 400 group in
(Serrano et al., 2019) study. However, (Serrano et al., 2019) results did
not show any differences among the CAC groups regarding dyslipidemia.
163
Discussion
According to the current study, CACS was associated with higher

incidences of smoking (P=0.0292).
This is in agreement with (Torngren et al., 2020), they reported

that increased CACS was associated with increases in age, systolic blood
pressure, and serum creatinine as well as showing higher prevalence in
diabetics, and previous smokers.
Coronary heart disease is depending on risk factors such as

dyslipidemia, age, and gender (Mancia et al., 2013).
In the current study, increased severity of stenosis was associated

with increases in age (P < 0.001), systolic (P < 0.001) and diastolic blood
pressure (P= 0.029), serum creatinine (P=0.010), total serum cholesterol
(P < 0.001), triglycerides (P < 0.001), and LDL (P < 0.001). While
increased severity of stenosis was associated with lower levels of HDL (P
< 0.001).
With aging, atherosclerotic changes occurs in the arteries resulting

in increased stiffness. There is also an increase in wall thickness due to
intimal thickening. Increased stiffness and an increase in wall thickness
occur with age, also without atherosclerotic disease, due to depletion and
fragmentation of elastin and the deposition of collagen in the media
(Bonarjee, 2018).
164
Discussion
In the current study, increased severity of stenosis was associated

with older age (P < 0.001). In agreement with our finding, large-scale
studies (AlGhatrif et al., 2013); (Meyer et al., 2016) reinforced the
observation that older age is independently related to an increase in pulse
wave velocity.
According to the present study, increased severity of stenosis was

associated with higher incidences of diabetes (P < 0.001), hypertension
(P=0.005), dyslipidemia (P < 0.001), and smoking (P < 0.001).
In concordance with our study, (Larifla et al., 2014) revealed that

diabetes and hypertension were independent predictors of coronary artery
disease severity for high risk lesions.
165
Conclusion
Conclusion
Impaired Aortic Distensibility and Aortic Stiffness are well
corrlelating with the severity of coronary artery disease (CAD) and
coronary artery calcium scoring (CACs).
Non-invasive ADI assessment is a feasible procedure to predict

atherosclerotic CAD. A low ADI value is associated with severity of
CAD, high CAC score, and number of involved vessels
This study demonstrates the following
1. Excellent correlation between ADI and PWV from one side and
Coronary artery diseases and CAC scoring from other side.
2. CCTA measured ADI decreased proportionally with the severity of
CAC and degree of stenosis of coronary arteries independent of other
cardiovascular risk factor.
3. PWV (aortic stiffness) calculated from Distensibility increased
proportionally with the severity of CAC and degree of stenosis of
coronary arteries independent of other cardiovascular risk factor.
4. Addition of ADI and PWV to different scores that used to estimate the
risk for coronary artery disease could provide incremental value to
predict CAD.
166
Recommendations
Recommendations
 ADI assessment is recommended as a feasible non-invasive
procedure to predict atherosclerotic CAD.
 More prospective studies on larger scales are required to
evaluate the correlation between ADI and arterial stiffness.
 More studies are required to compare between different imaging
modalities of measuring Aortic Distensibility and pulse wave
velocity (PWV) the surrogate of Aortic stiffness.
 More prospective therapeutic studies on larger scales are
required to evaluate the effect of different therapies on ADI and
aortic stiffness.
 Addition of ADI and PWV to different scores that used to
estimate the risk for coronary artery disease could provide
incremental value to predict CAD.
167
Summary
Summary
in cardiovascular disease. Non-invasive techniques can be used to
measure the distensibility and the stiffness of the aortic wall. Coronary
artery calcium (CAC) is a marker of overall atherosclerotic burden and
correlates well with the total plaque burden, the presence of obstructive
coronary artery disease (CAD) and future cardiovascular events in both
genders across ethnicities.
The present study aimed to evaluate whether impaired aortic

distensibility index (ADI) and Aortic stiffness measured by Cardiac CT is
correlating with the severity of coronary artery disease and coronary
calcium scoring in at-risk individuals (assessed by CTA). To obtain this
aim, 180 consecutive patients with suspected CAD were included.
From the current study, we can sum up the following findings:
 Increaseed CACS was associated with increases in age, systolic and

diastolic blood pressure, serum creatinine, total serum cholesterol,
triglycerides, and LDL (P< 0.0011 for all). While increased CACS was
associated with lower levels of Hb (P=0.0061) and HDL (P=0.0021).
168
Summary
 Increased CACS was associated with higher incidences of diabetes,

hypertension, and dyslipidemia (P< 0.0012 for all), as well as smoking
(P=0.0292).
 Increased severity of stenosis was associated with increases in age (P<
0.001), systolic (P< 0.001) and diastolic blood pressure (P= 0.029),
serum creatinine (P=0.010), total serum cholesterol (P< 0.001),
triglycerides (P< 0.001), and LDL (P< 0.001). While increased
severity of stenosis was associated with lower levels of HDL (P<
0.001).
 Increased severity of stenosis was associated with higher incidences of
diabetes (P< 0.001), hypertension (P=0.005), dyslipidemia (P< 0.001),
and smoking (P< 0.001).
 Calcium scoring was found to be positively correlated with the PWV
(r=0.817, P< .001) as well as the degree of stenosis (r= 0.653,
P< .001). And it was negatively correlated with ADI (r= -0.771,
P< .001).
 ADI in the present study was inversely correlated with the degree of
stenosis (r=-0.707, P< .001), and number of involved vessels (r=-
0.771, P< .001).
 PWV was found to be positively correlated with the number of
involved vessels (r= 0.762, P< .001), and degree of stenosis (r=0.697,
P< .001).
169
Summary
 PWV inversely correlated with ADI among diabetic patients (r=-

0.992, P< .001), hypertensive patients (r=-0.991, p< .001), patients
with dyslipidemia (r= -0.991, p< .001), and smokers (r= -0.993,
p< .001).
Taken together, Non-invasive ADI assessment is a feasible
procedure to predict atherosclerotic CAD. A low ADI value is associated
with significant obstructive CAD and high CAC score, and increased
number of involved vessels
170
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192
‫الملخص العربي‬
‫ترتبط قابلية الشريان األورطي للتمدد ارتبا ً‬
‫طا وثيقًا بمرونته الحيوية ووظيفته األساسية؛ وتعتبر قابلية‬
‫التمدد في الشريان األورطي ودرجة التصلب في جداره مؤشرا ً هاما ً في دراسة أمراض القلب واألوعية الدموية‪.‬‬
‫يمكن استخدام تقنيات غير جراحية لقياس قابلية تمدد وتصلب جدار الشريان األورطي؛ كما يمكننا‬
‫استخدام هذه التقنيات لقياس درجة الكالسيوم في الشرايين التاجية وكالهما عالمة على العبء الكلي لتصلب‬
‫الشرايين حيث يعتبر تصلب جدار الشريان االورطي مؤشر جيد للعبء الكلي لتصلب الشرايين في الجسم‪،‬‬
‫ومؤشر لوجود مرض الشريان التاجي االنسدادي وأحداث القلب واألوعية الدموية المستقبلية في كال الجنسين‬
‫عبر األعراق المختلفة‪.‬‬
‫هدفت الدراسة الحالية إلى تقييم ما إذا كان مؤشر تمدد الشريان األورطي وتصلب الشريان األورطي‬
‫والذي تم قياسه بواسطة التصوير باألشعة المقطعية متعددة المقاطع على القلب (التصوير المقطعي المحوسب‬
‫للقلب) مرتبطين مع شدة مرض الشريان التاجي ودرجة الكالسيوم في الشرايين التاجية في األفراد المعرضين‬
‫للخطر (تم تقييمهما أيضا ً عن طريق تصوير الشرايين التاجية باألشعة المقطعية متعددة المقاطع)‪.‬‬
‫لتحقيق هذا الهدف‪ ،‬تمت هذه الدراسة على ‪ 081‬مريضا ً متتاليا ً يشتبه في إصابتهم بمرض الشريان‬
‫التاجي‪.‬‬
‫من الدراسة الحالية‪ ،‬يمكننا تلخيص النتائج التالية‪:‬‬
‫‪ ‬ارتبط انخفاض مؤشر تمدد الشريان االورطي مع زيادة درجة الكالسيوم في الشرايين التاجية (ارتباط‬
‫عكسي)‪.‬‬
‫‪ ‬ارتبط انخفاض مؤشر تمدد الشريان األورطي مع شدة مرض الشريان التاجي‪ ،‬حيث وجدنا أن مؤشر تمدد‬
‫الشريان األورطي في الدراسة الحالية يرتبط عكسيا مع درجة التضيق في الشرايين التاجية وعدد الشرايين‬
‫التاجية المصابة‪.‬‬
‫‪ ‬وجدنا أن درجة الكالسيوم في الشرايين التاجية ودرجة التضيق في الشرايين التاجية مرتبطان بشكل إيجابي‬
‫مع سرعة موجة النبض (درجة تصلب الشريان األورطي)‪.‬‬
‫‪ ‬توصلت الدراسة إلى أن سرعة موجة النبض (درجة تصلب الشريان األورطي) مرتبطة بشكل إيجابي مع‬
‫عدد الشرايين التاجية المصابة‪.‬‬
‫‪1‬‬
‫‪ ‬ارتبطت زيادة الكالسيوم في الشرايين التاجية بزيادة العمر‪ ،‬وضغط الدم االنقباضي واالنبساطي‪،‬‬
‫والكرياتينين في الدم‪ ،‬والكوليسترول الكلي في الدم‪ ،‬والدهون الثالثية‪ ،‬والبروتين الدهني منخفض الكثافة‪.‬‬
‫بينما ارتبطت زيادة درجة الكالسيوم في الشرايين التاجية بانخفاض مستويات الهيموجلوبين والبروتين‬
‫الدهني عالي الكثافة‪.‬‬
‫‪ ‬ارتبطت زيادة درجة الكالسيوم في الشرايين التاجية بارتفاع معدالت اإلصابة بمرض السكري وارتفاع‬
‫ضغط الدم واضطراب شحوم (دهون) الدم‪ ،‬فضالً عن التدخين‪.‬‬
‫‪ ‬ارتبطت زيادة شدة تضيق الشرايين التاجية بزيادة العمر‪ ،‬وضغط الدم االنقباضي واالنبساطي‪ ،‬وكرياتينين‬
‫الدم‪ ،‬وكوليسترول الدم الكلي‪ ،‬والدهون الثالثية‪ ،‬والبروتين الدهني منخفض الكثافة‪ .‬بينما ارتبطت زيادة‬
‫شدة التضيق بانخفاض مستويات البروتين الدهني عالي الكثافة‪.‬‬
‫‪ ‬ارتبطت زيادة شدة تضيق الشرايين التاجية بارتفاع معدالت اإلصابة بمرض السكري وارتفاع ضغط الدم‬
‫واضطراب شحميات الدم والتدخين‪.‬‬
‫في الختام ‪ :‬يعتبر تقييم مؤشر قابلية التمدد للشريان األورطي غير التداخلي إجراءا ً جيدا ً للتنبؤ بمرض‬
‫تصلب الشرايين التاجية‪ .‬يرتبط انخفاض قيمة مؤشر التمدد للشريان األورطي بمرض الشريان التاجي االنسدادي‬
‫وارتفاع درجة الكالسيوم في الشرايين التاجية‪ ،‬وزيادة عدد الشرايين التاجية المصابة‪.‬‬
‫‪2‬‬
List of contents
Items Page
List of Abbreviations II
List of Figures v
List of Tables vii
Introduction 1
Aim of Work 3
Review of Literature 4
Chapter 1 : Aortic Distensibility and Aortic stiffness 4
Chapter 2 : Coronary Artery Calcium Score and Coronary Artery 48
Disease
Chapter 3 : Correlation between Aortic Distensibility, Aortic 74
stiffness and CAD
Chapter 4 : Correlation between coronary calcium and aortic 80
distensibility and stiffness
Patients and Methods 85
Results 100
Selected cases 136
Master sheet 140
Discussion 158
Conclusion 166
Recommendations 167
Summary 168
References 171
Arabic Summary 1
i
List of Abbreviations
Abbreviation Meaning
AAo Ascending Aorta
ACEi Angiotensin-converting enzyme inhibitor
ACS Acute coronary syndrome
AD Aortic distensibility
ADI Aortic distensibility index
Ang II Angiotensin II
ANOVA Analysis of variance
ARBs Angiotensin receptor blockers
AS Arterial Stiffness
AT1R Ang II Type 1 receptor
BMPs Bone morphogenetic proteins
BP Blood pressure
C Compliance
CABG Coronary artery bypass grafting
CAC Coronary artery calcium
CAC Coronary artery calcification
CACS Coronary artery calcium score
CAD Coronary artery disease
CAFE Conduit Artery Function Evaluation
CAG Coronary angiography
CARDIA Coronary Artery Risk Development in Young Adults
CAVI Cardio-ankle vascular index
CCB Calcium-channel blockers
CCTA Coronary computed tomography angiography
CFPWV Carotid-femoral pulse wave velocity
cfPWV Carotid‐femoral pulse wave velocity
CHD Coronary heart disease
cIMT Carotid intima-media thickness
CIs Confidence intervals
CKD Chronic kidney disease
CMR Cardiac magnetic resonance
CNS Central nervous system
CRP C-reactive protein
CSA Cross sectional area
CT Computed tomography
CV Cardiovascular
CVD Cardiovascular diseases
DBP Diastolic blood pressure
DDP-4i Dipeptidyl peptidase-4 inhibitor
ii
EBCT Electron beam computed tomography
ECG Electrocardiogram
ECHO Echocardiogram
ED Emergency department
eGFR Estimated glomerular filtration rate
EKG Electrocardiogram
EM Enhanced mineralocorticoid
EnNaC Endothelial sodium channel
eNOS Endothelial nitric oxide synthase
ESRD End-stage renal disease
FRS Framingham risk score
GLP-1 RA Glucagon-like peptide-1 receptor agonist
Hb Hemoglobin
HDL High density lipoproteins
HMG-CoA Hydroxymethylglutaryl-coenzyme A
HR Heart rate
HTN Hypertension
ICAM- 1 Intercellular adhesion molecule 1
IVUS- VH Intravascular ultrasound virtual histology
KLF4 Kruppel- like factor 2 and 4
LAD Left anterior descending artery
LCX Left circumflex artery
LDL Low density lipoprotein
LM Left marginal
LMCA Left main coronary artery
LP-PLA2 Lipoprotein-associated phospholipase A2
MCP- 1 Monocyte chemoattractant protein 1
MDCT Multidetector computed tomography
MESA Multi-Ethnic Study of Atherosclerosis
miRNAs MicroRNAs
MMP Metalloproteinase
MPG Magnetic plethysmograph
MPI Myocardial perfusion imaging
MRA Magnetic Resonance Angiography
MRI Magnetic resonance imaging
N Number
NADPH Nicotinamide adenine dinucleotide phosphate
NF Nuclear factor
NO Nitric oxide
No. Number
OCT Optical coherence tomography
oxLDL Oxidized LDL
PCI Percutanous coronary intervension
iii
PET Positron emission tomography
PP pulse pressure
PTP Pre-test probability
PVC Premature ventricular complex
PWV Pulse wave velocity
RAAS Renin-angiotensin-aldosterone system
RAS Renin angiotensin system
RCA Right Coronary Artery
SBP Systolic blood pressure
SD Standard deviation
SGLT-2i Sodiumm-glucose cotransporter-2 inhibitors
SIS Segment-involvement score
SV Stroke volumes
TFPi Tissue factor pathway inhibitor
TG Triglycerides
TLRs Toll- like receptors
tPA Tissue plasminogen activator
VCAM- 1 Vascular cell adhesion molecule 1
VRI Volume-rendered image
VSMC Vascular smooth muscle cell
WD Western diet
XO Xanthine oxidase
iv
List of figures
Figure No. Title
Figure 1 Windkessel effect of Aorta
Cross-Sectional Diagram of the Aortic Vessel With the Components of the 3 Layers
Figure 2 in a Healthy Young Individual (20 Years of Age) and in an Elderly Individual (70
Years of Age) Demonstrating the Effects of Arterial Aging
Central pulse pressure waveform. Systolic and diastolic pressures are the peak and
Figure 3 trough of the waveform.
Figure 4 Physiologic Properties of the Aorta as a Reservoir and Conductive System:
Figure 5 Mechanisms underlying arterial stiffness
Non-invasive Determination of PWV Between the Carotid Artery and the Terminal
Figure 6
Aorta. Femoral artery is the terminal aorta.
Changes in the volume of ascending aorta (AAo) at the end systolic and end diastolic
Figure 7 phase,
Figure 8 Measurement of Aortic Stiffness by Carotid-Femoral Oscillometric Signal.

Measurements of Aortic Diameters Shown on the M-Mode Tracing. Measurements
Figure 9 of aortic diameters shown on the M-mode tracing obtained at a level 3 cm above the
aortic cusps.
Figure 10 Distensibility Measurement of the Aortic Root with Cardiac MRI (A and B)
Central pulse pressure waveform. Systolic and diastolic pressures are the peak and
Figure 11 trough of the waveform.
Figure 12 Illustrates the complexity of events that drive the atherosclerotic process.
Figure 13 Complementary roles of non-invasive coronary imaging.

Coronary artery calcification. CT - computed tomography, ACS - acute coronary
Figure. 14 syndrome, HF - heart failure
Risk factors associated with the development of CAD. HTG - hypertriglyceridemia,
Figure.15
CAD - coronary artery disease
Coronary artery calcium scoring and coronary vascular disease. CAC - coronary
Figure. 16
artery calcium
The figure represents a simplified schematic that attempts to describe a potential
pathophysiologic framework linking impaired cardiac function, on the one hand, and
arterial stiffness and impaired coronary flow reserve, on the other, having as a
Figure. 17 common link the transforming growth factor b1-mediated imbalance between
collagen synthesis and degradation.
Insults Leading to Structural Changes in the Aorta and its Functioning Several
Figure 18 processes can alter the homeostasis of aortic elastic properties leading to increased
stiffness and decreased compliance. LV left ventricular
2019 ESC Guideline on the diagnosis and management of Chronic Coronary
Figure 19 Syndrome
Figure 20 SIEMENS SOMATOM Definition Flash dual 128-slice CT scanner.
Figure 21 Coronary Artery Segments According to the AHA.
v
Measurement of area of the ascending aorta (AAo) at the maximum systole and
Figure 22 diastole (as determined automatically by the machine) 15 mm above LM ostium
using axial and coronal views.
Figure 23 Aortic Distensibility Index and Pulse Wave Velocity among the included patients
Figure 24 Aortic Distensibility Index and Pulse Wave Velocity among the included patients
Figure 25 The correlation between calcium scoring and ADI
Figure 26 The correlation between calcium scoring and PWV
Figure 27 The correlation between ADI and Degree of stenosis
Figure 28 The correlation between PWV and the Degree of stenosis
Figure 29 Clinical examination findings among the included patients stratified based on the CT
Figure 30 Laboratory Investigations among the included patients stratified based on the CT
Figure 31 Clinical examination findings among the included patients stratified based on the
Figure 32 Laboratory Investigations among the included patients stratified based on the degree
of stenosis (n= 180)
Figure 33 The correlation between calcium scoring and the degree of stenosis
Figure 34 The correlation between No. of involved vessels and ADI
Figure 35 The correlation between No. Of Involved Vessels and PWV
Figure 36 The correlation between PWV and ADI among the diabetic patients
Figure 37 The correlation between PWV and ADI among the hypertensive patients
Figure 38 The correlation between PWV and ADI among patients with dyslipidemia
Figure 39 The correlation between PWV and ADI among smokers
Figure 40 CT Coronary Angiography of patient n. 113. (a) diastolic, (b) systolic.
vi
List of tables
Table No. Title
Non-invasive Methods to Assess Aortic Stiffness. CMR= cardiac magnetic resonance; PWV=
Table 1
pulse wave velocity
Table 2 Comparison of non-invasive coronary imaging modalities
Table 3 Agatston coronary artery calcium scoring. CAC – coronary artery calcium
Table 4 Summary of studies of different designs conducted between 2005-2019
Table 5 Classification of patients according to degree of coronary Artery stenosis
Relationship between CT coronary calcium score, plaque burden and probability of significant
Table 6
CAD.
Table 7 Classification of patients according to degree of Coronary Artery Calcium (CAC) score
Table 8 Demographics and clinical examination findings (n= 180)
Table 9 Laboratory Investigations among the included patients (n= 180)
Table 10 Coronary Plaque features among the included patients (n= 180)
CT Coronary Angiography (vessels involved and degree of stenosis) among the included
Table 11
patients (n= 180)
Table 12 Calcium Scoring among the included patients (n= 180)
Table 13 Aortic distensibility and aortic stiffness measurements among the included patients (n= 180)
Aortic Distensibility Index and Pulse Wave Velocity among the included patients stratified
Table 14
based on the CT coronary calcium score (n= 180)
Aortic Distensibility Index and Pulse Wave Velocity among the included patients stratified
Table 15
based on the degree of stenosis (n= 180)
Table 16 The correlation between calcium scoring and ADI
Table 17 The correlation between calcium scoring and PWV
Table 18 The correlation between ADI and Degree of stenosis
Table 19 The correlation between PWV and the Degree of stenosis
Demographic data among the included patients stratified based on the CT coronary calcium
Table 20
score (n= 180)
Clinical examination findings among the included patients stratified based on the CT coronary
Table 21
calcium score (n= 180)
Laboratory Investigations among the included patients stratified based on the CT coronary
Table 22
calcium score (n= 180)
Demographic data among the included patients stratified based on the degree of stenosis (n=
Table 23
180)
Clinical examination findings among the included patients stratified based on the degree of
Table 24
stenosis (n= 180)
Laboratory Investigations among the included patients stratified based on the degree of
Table 25
stenosis (n= 180)
Table 26 The correlation between calcium scoring and the degree of stenosis
Table 27 The correlation between No. of Involved Vessels and ADI
Table 28 The correlation between No. of Involved Vessels and PWV
Table 29 The correlation between PWV and ADI among the diabetic patients
Table 30 The correlation between PWV and ADI among the hypertensive patients
Table 31 The correlation between PWV and ADI among patients with dyslipidemia
Table 32 The correlation between PWV and ADI among smokers
vii

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Introduction

Carotid to femoral pulse wave velocity (PWV) is the gold standard

A coronary artery calcium score (CACs) examination is a non-

According to the European Guidelines on cardiovascular disease

Aortic stiffness measured by Cardiac CT is correlating with the severity of

coronary artery disease and coronary calcium scoring in at-risk individuals

assessed by Coronary Computed Tomography Angiography (CCTA).

Chapter 1: Aortic Distensibility and

Recognized as a conduit for distributing blood, abnormalities of the functional

Figure 1. Windkessel effect of Aorta (Westerhof et al., 2010)

In addition, a healthy aorta limits the augmentation phenomenon from the

As the pressure wavefront from ventricular contraction propagates down the

In healthy normal individuals, under a wide range of vascular loading

Optimal function of the aorta is related to the structure and composition of 3

 Arterial distensibility and Arterial Stiffness

Vascular dysfunction has been shown to be an independent predictor of

Impaired vascular function is associated with coronary artery disease (Bogren

Arterial distensibility, a measure of vascular function, can serve as a marker

The aorta maintains low left ventricular after-load, promotes optimal

There is a well-known correlation between arterial stiffness and morbidity and

 History and Evolution of Arterial Stiffness

The inconvenience of this method prompted future physicians and/or

When ventricular contraction occurs, the arterial pressure wave that is

diminishes the stiffness gradient resulting in pressure overload to smaller arterial

It involves the application of an air-filled diaphragm to the carotid and femoral

The association with adverse cardiovascular outcomes makes it a useful tool,

Pulse wave velocity can be measured using commercially available devices at

 Mechanisms Underlying Arterial Stiffness

While aging-associated arterial stiffness is well recognized, there have been a

However the role of hormones/regulatory peptides and their receptors,

Figure 5. Mechanisms underlying arterial stiffness

II. The Renin-Angiotensin-Aldosterone System

The renin-angiotensin-aldosterone system (RAAS) is thought to be activated

Angiotensin II (Ang II) is perhaps the most well-known of the peptide

Pathologically increased or abnormal Ang II Type 1 receptor (AT1R)

In addition, Ang II activation leads to secretion of pro inflammatory cytokines

polarization), T cells, and B-cells and suppression of T regulatory cells (Barhoumi

Furthermore, Ang II is a well-known stimulator of oxidative stress via

Novel Mechanisms in RAAS-Regulation of Arterial Stiffness

1. Mineralocorticoid Receptor Signaling

Enhanced mineralocorticoid (MR) signaling independently (via cortisol) in

This beneficial effect of MR blockade was demonstrated by improvements in

suggesting that the endothelial MR activation is the mechanism for WD-induced

2. Endothelial Sodium Channel

III. Insulin Resistance

Insulin resistance and endothelial dysfunction have been postulated as likely

Akt/eNOS/S6K1 phosphorylation, and diversion of insulin metabolic pathway to the

IV. Uric Acid

Suppression of XO as well as reduction in uric acid levels was correlated with

V. The Role of Adipose Tissue

Adipokines are hormones produced by adipocytes and are associated with

The most abundant of the plasma proteins produced by adipocytesplays an

Hypoadiponectinemia is noted in obesity, insulin resistance, type 2 diabetes,

Several studies are providing increasing data as to its correlation in healthy

Leptin is a 16 kDa peptide hormone mainly produced by white adipose tissue.

Leptin binds to CNS receptors to produce sympathetic outflow to the kidneys

Resistin is a 12.5 kDa peptide hormone mainly produced in macrophages

Overexpression of resistin is associated with atherosclerosis, endothelial

Despite the aforementioned associations, establishing causality is difficult for

VI. Inflammatory Markers

A series of inflammatory biomarkers have been shown to be associated with

Interleukin-6, interleukin-1, tumor necrosis factor, and high-sensitivity CRP

The inflammatory responses contribute to structural and functional changes