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INTRODUCTION
Over the past few decades, atherosclerotic cardiovascular disease
(CVD) has become the leading cause of death worldwide. This rapid
increase in the incidence and prevalence of CVD has resulted in growing
appreciation of the need to develop and implement effective strategies
for its prevention. While increasing the population awareness about
cardiovascular risk factors (CVRFs) and the role of healthy lifestyle
in their prevention is theoretically the most effective strategy, it is
limited by the widespread negligence and unacceptably poor compliance
of the general population towards these measures. The more effective
strategy therefore would be to identify the individuals who are at high
Early Detection of
Sub-clinical
Atherosclerosis
Dr. Manish Bansal, MD, DNB, MNAMS
Consultant Cardiologist
Dr. Ravi R. Kasliwal, MD, DM, FIMSA, MNAMS
Senior Consultant Cardiologist;
Director, Cardiology & Community Outreach Program
Global Health Pvt. Ltd.
Indraprastha Apollo Hospitals, Sarita Vihar, Mathura Road, New Delhi
1515
ECAB Clinical Update: Cardiology Volume 1, Issue 1
16
risk of developing CVD and then target efforts and resources to prevent
the development of disease in them.
At present, identification of these ‘high-risk’ individuals is based
predominantly on recognition and
assessment of Framingham risk
factors and, to a smaller extent, the
newer emerging risk factors.
Although numerous studies have
demonstrated high prevalence of these risk factors in individuals with
CVD,
1,2
the relationship between the presence of these risk factors
and future development of CVD is far from being perfect, the reason
is its being influenced by several external factors such as genetic
susceptibility, number and type of concomitant risk factors, duration
of exposure and presence of yet unidentified risk modulators.
Consequently, people with one or more of CV risk factors do not
necessarily develop CVD in the long term and similarly, it is also not
uncommon to come across patients with acute myocardial infarction
who do not have any known CV risk factors. Therefore the techniques
are needed that have the potential to detect the disease directly at an
early stage irrespective of the presence or absence of the risk factors.
Such an approach would enable us to identify and treat only those
individuals who actually need it. Over the past few years, several
such non-invasive tools have been developed that provide a means to
detect and quantify atherosclerosis at an early i.e. sub-clinical stage
(Figure 1). This review will discuss the technical aspects and the role
in risk assessment of some of these techniques.
DETECTION AND ASSESSMENT OF
SUB-CLINICAL ATHEROSCLEROSIS
The various techniques that are available for detection of sub-clinical
atherosclerosis can be categorized broadly into two groups: those
that detect the disease within the coronary vasculature [e.g. coronary
calcium scoring (CCS), computed tomographic (CT) or magnetic
resonance imaging (MRI) coronary angiography] and the ones that
Early detection is an effective
strategy to prevent coronary
artery disease.
Early Detection of Sub-clinical Atherosclerosis Bansal and Kasliwal
17
detect atherosclerosis in the peripheral vessels [e.g. carotid intima-
media thickness (CIMT), brachial artery flow-mediated dilatation
(BAFMD), pulse wave velocity and analysis (PWV and PWA), etc.].
Although the former have the advantage of providing evidence of the
disease in the coronary vessels directly, they have several limitations
such as technical complexity, limited availability, cost, radiation
exposure, etc. Moreover, MRI coronary angiography is at present
under evolution and CT coronary angiography is being used
predominantly for detection of significant yet asymptomatic coronary
plaques, and not for early CV risk stratification. In contrast, the latter
techniques such as CIMT, BAFMD and PWV are easier to perform,
more widely available, less expensive and more patient-friendly. The
underlying rationale for the use of these techniques for CV risk
prediction is the fact that atherosclerosis is a diffuse disease and
involvement of one vascular bed predicts involvement of other sooner
or later—a fact proven by several clinical and autopsy studies.
3–6
The
present discussion will therefore be restricted to the potential role of
CIMT, BAFMD, PWV, PWA and CCS in cardiovascular risk prediction.
Figure 1. Process of atherogenesis and role of newer non-invasive
tools for detection of sub-clinical atherosclerosis. BAFMD: brachial
artery flow-mediated vasodilatation, CIMT: carotid intima-media thickness,
PWV: pulse wave velocity, PWA: pulse wave analysis, CCS: coronary
calcium scoring.
Risk
modulator
Endothelial
dysfunction
Traditional
risk factor
No risk
factor?
Atherosclerotic
plaque
(sub-clinical)
Clinical
cardiovascular
disease
Newer non-invasive tools (e.g.
BAFMD, CIMT, PWV, PWA, CCS)
ECAB Clinical Update: Cardiology Volume 1, Issue 1
18
CAROTID INTIMA-MEDIA THICKNESS
Methodology
Carotid IMT is measured using a linear array transducer of 5–12 MHz
frequency attached to a high-resolution ultrasound machine having
duplex B-mode scanner. The patient should be lying supine, with the
head directed away from the side of interest, and the neck extended
slightly. In this position, extra-cranial carotid vessels are scanned from
origin of the common carotid artery (CCA) till the proximal segments
of internal and external carotid arteries (ICA and ECA, respectively).
Initially the vessels are scanned in transverse section to detect any
plaques and to localize the site of maximum intimal thickening.
Subsequently, the measurements are performed on the longitudinal
image. On a longitudinal B-mode image, carotid artery wall is seen as
two echogenic lines (intima and adventitia) separated by an echolucent
zone (the media). IMT is measured as the distance between the lumen-
intima interface to the media-adventitia interface (Figure 2). Although
measurements can be obtained on both near and far wall, trailing edges
will have to be defined in case of near wall and the leading edges in
case of far wall. Since accurate localization of trailing edge is often
very difficult owing to its heavy dependence on gain settings,
7
it is
recommended that only the far wall should be used for measurement
of CIMT.
In the initial studies, CIMT measurements were usually performed
in multiple segments viz. distal 1 cm of CCA just before bifurcation,
carotid bifurcation itself and proximal 1 cm of ICA. Several studies
have however demonstrated that measurement yield and reproducibility
are highest for CCA because of its tubular shape, perpendicular
orientation relative to the skin and almost universal accessibility.
7–9
In
addition, prognostic value of IMT measurements obtained from CCA
has been comparable to the same for other segments.
10–12
Therefore,
most investigators now-a-days prefer to restrict measurements to CCA
alone. Another debatable issue is whether to measure only the maximum
thickness in a given segment or calculate the average of multiple
measurements obtained within the same segment. The latter approach
Early Detection of Sub-clinical Atherosclerosis Bansal and Kasliwal
19
is usually preferred owing to its greater reproducibility. Regardless of
the protocol followed, all measurements must be made at end-diastole.
In addition, use of automated edge detection techniques with electronic
calipers is highly recommended for reducing error in CIMT
measurements and to ensure their reproducibility. Carotid plaques,
defined as focal thickening at least 50% greater than the surrounding
wall, should be excluded from the measurement of IMT and their
dimension, location, and characteristics should be mentioned
separately.
Definition of Abnormal CIMT
It is difficult to define single cut-off value for CIMT as it is significantly
influenced by age, gender and race and also because the relationship
between CIMT and cardiovascular risk is a continuous one and no
cut-off value is there that clearly separates individuals with high and
low risk of adverse cardiovascular events. Ideally nomograms should
be developed for different age, gender and race based on large
population studies. Nonetheless for reference purpose, the approximate
age-adjusted 75th percentile values for common CIMT derived from
the Atherosclerosis Risk In Communities (ARIC) study and
Cardiovascular Health study are presented in Figure 3.
13,14
Bifurcation
ECA
ICA
CCA
Media
Adventitia
IMT
Intima
(A) (B)
Figure 2. (A) Ultrasound image showing carotid intima-media thickness;
(B) Schematic diagram showing layers of the arterial wall and segments
of carotid artery where intima-media thickness measurements are taken.
CCA: common carotid artery, ICA: internal carotid artery, IMT: intima-
media thickness, ECA: external carotid artery.
ECAB Clinical Update: Cardiology Volume 1, Issue 1
20
Reproducibility of CIMT Measurement
Good reproducibility of CIMT measurements has been demonstrated
in several small and large studies. Average absolute intra-observer
differences in common CIMT measurements have been shown to be
in the range of 0.04 mm.
15
Use of automated edge detection techniques
provides even better reproducibility.
16
Clinical Applications
Association with Risk Factors
Strong association has been demonstrated between CIMT and various
CVRFs in several cross-sectional studies.
17–22
ARIC study reported
mean CIMT to be about 0.08 mm greater in diabetics than in non-
diabetics.
17
Similarly, the Chennai Urban Population Study also showed
significantly raised mean CIMT values in diabetic patients (0.95 ±
0.31 mm) compared to non-diabetic subjects (0.74 ± 0.14 mm,
p < 0.001).
18
In a study published recently, we assessed the relationship
between metabolic syndrome, diabetes mellitus and CIMT. It was
found that patients with metabolic syndrome in absence of diabetes
mellitus had similar CIMT as patients with CVRFs without metabolic
0
0.2
0.4
0.6
0.8
1
1.2
35-45 yrs 46-55 yrs 56-65 yrs >65 yrs
Age
CIMT (mm)
Men Women
Figure 3. Approximate age and gender values for common carotid
intima-media thickness (CIMT) representing the approximate 75th
percentile value.
35–45 years 46–55 years 56–65 years >65 years
Early Detection of Sub-clinical Atherosclerosis Bansal and Kasliwal
21
syndrome. However when diabetes was added to metabolic syndrome,
CIMT values were found to be significantly elevated.
20
In addition,
there is evidence to suggest that CIMT correlates well with not only
the individual risk factors but the total risk burden as well. In a study
on 241 individuals with or without coronary artery disease (CAD), a
linear relation was demonstrated between CIMT and number of
conventional CVRFs present.
22
Prediction of Cardiovascular Risk
Presently available data from prospective studies strongly supports
the role of CIMT as a predictor of future adverse cardiac events.
Cardiovascular Health Study described relationship between CIMT
and incidence of new myocardial infarction and stroke in asymptomatic
adults >65 years of age. The risk of myocardial infarction increased
in a linear fashion with increasing IMT and the relative risk of
myocardial infarction and stroke for the quintile with highest thickness
as compared with lowest quintile was 3.87 (95% CI, 2.72–5.51).
14
In
the ARIC Study, the hazard rate ratio comparing extreme mean IMT
(>1 mm) to not extreme IMT (<1 mm) was 5.07 for women (95%
CI, 3.08–8.36) and 1.85 for men (95% CI, 1.28–2.69). Although
including major CAD risk factors reduced the strength of the
association, it remained elevated at a higher IMT.
13
Hodis et al in their
studies found that for each 0.03 mm increase per year in CIMT, the
relative risk for non-fatal myocardial infarction or coronary death was
2.2 (95% CI, 1.4–3.6) and the relative
risk for any coronary event was 3.1
(CI, 2.1–4.5) (p < 0.001).
23
Absolute
IMT was also related to the risk of
clinical coronary events. A subgroup
analysis of Rotterdam study population
has also shown an association between increase in common carotid IMT
and future cerebrovascular and CV events independent of age, sex and
history of myocardial infarction or stroke.
24
Based on the findings of
these studies, CIMT has been accepted as a tool for further refinement
of risk in patients with intermediate risk of CV events.
25
Presently available data validates
the utility of carotid intima-media
thickness as a predictor of future
adverse cardiac events.
ECAB Clinical Update: Cardiology Volume 1, Issue 1
22
As a Surrogate Marker of Presence of Disease
The role of carotid IMT as an indicator of presence of CAD has been
assessed in various studies.
22,26–30
In ARIC study that included 13870
subjects, carotid far wall IMT was
consistently greater in subjects with
clinical CVD than in disease-free
subjects.
26
Visona et al showed that
common carotid artery IMT in CAD
patients (1.45 ± 0.95 mm) was
significantly higher than in controls
(0.87 ± 0.1 mm, p < 0.005).
27
In a study on 558 consecutive patients
undergoing coronary angiography for suspected CAD, Kablak-Ziembicka
et al showed that CIMT was not only higher in patients with CAD, but
also had a significant linear trend with the number of involved coronary
arteries.
28
Similarly, in the study mentioned earlier, we also found both
average and maximum CIMT to be significantly higher in patients with
CAD as compared to those without CAD.
22
Moreover, another study
from our lab showed that CIMT was significantly higher in patients with
left main CAD as compared to those who had angiographic CAD without
involvement of left main coronary artery.
29
However, it must be
remembered that a significant overlap exists with respect to CIMT,
between patients with and without obstructive CAD and thus, no particular
value of CIMT can be taken as a definite indicator of presence of CAD at
present.
Assessment of Response to Therapy
Numerous clinical trials with lipid lowering therapy, angiotensin-
converting enzyme (ACE) inhibitors, calcium channel blockers, etc.
have shown regression of CIMT with the therapy.
31–35
In the SECURE
trial, progression rate of CIMT was 0.0127 mm/year in the placebo
group, 0.0180 mm/year in the ramipril 2.5 mg/day group and 0.0137
mm/year in the ramipril 10 mg/day group (p = 0.033).
31
Similar findings
have been reported in other studies also. The non-invasive nature and
easy applicability of CIMT make it ideally suited for assessing response
to anti-atherosclerotic therapy in clinical practice. Moreover,
There is no cut-off value of
carotid intima-media thickness
that can be taken as a
definite indicator of
coronary artery disease.
Early Detection of Sub-clinical Atherosclerosis Bansal and Kasliwal
23
demonstration of presence of raised CIMT and regression with therapy
may also help enhancing patients’ compliance to the treatment.
Carotid IMT or Carotid Plaque?
The relative significance of CIMT and non-obstructive plaques in the
context of future CV risk prediction has been a matter of considerable
debate. Since atherosclerotic changes in the vessel wall are usually
confined to the intima and the arteriosclerotic changes predominantly
involve media, combined measurement of intima and media may not
be the true marker of atherosclerosis. Currently available evidence in
literature on this issue is rather limited and conflicting. Many previous
studies have not clearly mentioned whether plaques were included in
the IMT measurement or not and therefore generalization of the results
becomes difficult. If the plaques are included in the measurement of
IMT, CIMT becomes essentially a correlate of atherosclerosis only.
However, when plaques are excluded from the CIMT measurement,
this distinction assumes significance.
Of the studies that have clearly described the measurement
protocol, some have provided evidence that carotid plaque predicts
prevalent CAD better than IMT does
11,36,37
and that CAD risk is largely
associated with the presence of non-obstructive or obstructive plaque
rather than IMT.
38,39
In contrast, other studies have suggested that
IMT rather than localized plaque may be a good marker of the total
body atherosclerotic burden and
hence a better tool for this
purpose.
40,41
It is possible that
measurement of the thickness of
intima alone may prove to be a better
marker of future CV risk than CIMT
or carotid plaque. However, currently
available techniques do not allow accurate and reproducible measurement
of intima alone. Until then, it appears reasonable to measure CIMT
separately from plaques to avoid confusion and to ensure homogeneity
among the studies.
Intima thickness alone may be a
better marker of future
cardiovascular risk than
carotid intima-media thickness or
carotid plaque thickness.
ECAB Clinical Update: Cardiology Volume 1, Issue 1
24
Limitations
Lack of availability of age- and gender-specific normal and abnormal
values of CIMT for different populations is an important factor limiting
its widespread use in routine clinical
practice. In addition, it has not yet
been defined how assessment of
CIMT affects long-term outcome in
patients with/without CVRFs. Also,
most of the data currently available
has been obtained in highly skilled
research setting. Whether similar degree
of accuracy can be reproduced in
clinical setting needs to be determined.
Finally, as already discussed, relative importance of CIMT and carotid
plaques is a matter of ongoing debate.
BRACHIAL ARTERY FLOW-MEDIATED
DILATATION
Technique
The technique of BAFMD was first developed by Celermajer.
42
It
assesses the endothelium-mediated vasodilatory response of the artery
to increased blood flow. The increase in flow is produced by induction
of ischemia in downstream blood vessels by occluding the artery
studied. There is sudden increase in flow upon relieving the occlusion
that leads to shear stress on the arterial endothelium resulting in release
of nitric oxide. Released nitric oxide then causes local vasodilatation
that peaks at around 1 minute after relieving the occlusion (Figure 4).
Ideal vessel size to get maximum vasodilatation is 2.5–5 mm and since
brachial artery size is within this range, in >90% normal individuals, it
is the vessel of choice for FMD assessment.
43
There are wide variations in the methodology followed for
estimation of BAFMD, such as duration of cuff occlusion, site of
cuff placement, etc. International Brachial Artery Reactivity Task Force
has issued guidelines to standardize the technique so that the results
Widespread clinical use of
carotid intima-media thickness
measurement as a risk assessment
tool is limited by lack of age-
and gender-specific normal and
abnormal value of
carotid intima-media thickness for
different populations.
Early Detection of Sub-clinical Atherosclerosis Bansal and Kasliwal
25
are reproducible and comparable across various studies.
44
In particular,
utmost attention needs to be given to the patient preparation since
BAFMD is easily influenced by several external factors.
45–50
The test
is to be performed in the fasting state; smoking and caffeinated
beverages are prohibited on the morning of the study, and all vasoactive
medications including nitrates, ACE inhibitors and beta-blockers should
be withheld for 24 hours before the study. Room temperature, timing
during the day and timing during the phase of menstrual cycle should
also be kept uniform.
BAFMD is performed with the patient lying in supine position. After
the patient has been lying at rest for at least 5 minutes, the brachial
artery is imaged above the elbow using a linear array transducer with
a minimum frequency of 7 MHz attached to a high quality ultrasound
system. Baseline brachial artery diameter and blood flow velocities
are recorded. The artery is then occluded completely using the
sphygmomanometer cuff, tied around the arm and inflated to at least
50 mmHg above systolic pressure. The cuff is deflated after 5 minutes.
The flow velocities are recorded again immediately after cuff deflation
(and no later than 15 seconds) and brachial artery diameter is recorded
after 1 minute of cuff deflation. Magnitude of FMD is expressed as
percentage increase in diameter during hyperemic phase (i.e. 1 minute
diameter) compared to baseline. Assessment of flow-mediated dilatation
Figure 4. Mechanism of brachial artery flow-mediated vasodilatation.
Flow
Time
0 min 5 min
Cuff deflation
Reactive hyperemia
Cuff occlusion
(arm/forearm)
No flow;
ischemia in distal vessels
Local vasodilatation
(peaks at ~1 min)
Shear stress on brachial
artery endothelium
Nitric oxide released
ECAB Clinical Update: Cardiology Volume 1, Issue 1
26
should be followed by assessment of endothelium independent
vasodilatation. For this, patient is allowed to rest for 15 minutes.
Baseline brachial artery diameter is recorded again and 400 µg of
nitroglycerin is administered
sublingually. Three minutes after
administration of nitroglycerine,
brachial artery diameter is recorded
once again and percentage increase
in diameter from baseline is
calculated.
Definition of Abnormal BAFMD
Similar to CIMT, BAFMD is also influenced greatly by age, gender
and ethnicity. In addition, it is also affected by brachial artery
diameter,
51
position of the cuff (whether tied around arm or
forearm),
52,53
duration of cuff inflation and all the other factors
mentioned above. Hence, it is even more difficult to define normal
and abnormal values for BAFMD. However, normal individuals usually
have 8% or more vasodilatation when cuff is tied around the arm and
the occlusion is maintained for >4.5 minutes.
15
Occlusion of the artery
for less than <4.5 minutes produces less vasodilatation as does the
placement of cuff around forearm.
Clinical Applications
Association with Risk Factors
Since endothelial dysfunction is the earliest event in atherogenesis, it
has potential to detect disease at a stage when no structural or clinical
manifestations of atherosclerosis have occurred.
42,54,55
Celermajer
studied 500 non-hypertensive subjects who did not have any
manifestation of atherosclerotic disease. FMD was found to have
significant correlation with hypercholesterolemia, cigarette smoking,
hypertension, male sex and family history of premature vascular
disease.
42
In a study on 198 individuals, we found BAFMD to be as
impaired in patients with diabetes mellitus without CAD as in those
with CAD but no diabetes, thereby implying CAD risk equivalence of
Brachial artery flow-mediated
dilatation assesses the
endothelium-mediated
vasodilatory response of the
artery to increased blood flow.
Early Detection of Sub-clinical Atherosclerosis Bansal and Kasliwal
27
diabetes.
56
Several other studies have also shown that endothelial
function as assessed by brachial artery FMD is impaired in presence
of individual risk factors like cigarette smoking,
45
hypertension,
57,58
hypercholesterolemia,
59,60
and hyperhomocysteinemia.
61
However in a
recently published meta-analysis, FMD was found to correlate with
Framingham risk score only in individuals in low-risk category and
not in those in medium- or high-risk categories.
62
One plausible
explanation could be that endothelial damage occurs early in the course
of atherogenesis and further increase in risk may not lead to any further
damage to endothelium. Problems inherent with meta-analysis could
also explain these results partly.
Prediction of Cardiovascular Risk
Impaired endothelial dysfunction has been shown to predict risk of
future adverse CV events in several studies, however, studies using
BAFMD as a marker of endothelial dysfunction are relatively
limited.
54,55,63,64
Gokce et al in a study on 187 patients undergoing vascular
surgery demonstrated impaired BAFMD to be an independent predictor
of CV events at 30-days’ follow-up.
63
Patti et al studied risk of restenosis
in 136 patients undergoing percutaneous coronary intervention and found
that only 4% of patients with FMD ≥7% (median value) developed in-
stent restenosis as compared to 28% of those with FMD <7%. In
addition, FMD was found to be the strongest predictor of risk of
restenosis
64
.
As a Surrogate Marker of Presence
of Disease
Numerous studies have shown that
impaired BAFMD correlates well with
the presence of angiographically
detectable CAD.
65–67
In a study on 122
consecutive patients undergoing coronary angiography for suspected
CAD, Schroeder et al showed BAFMD to be significantly impaired in
patients with any angiographically detectable disease of any severity
as compared to those without it. Sensitivity and specificity of BAFMD
Impaired brachial artery
flow-mediated dilatation correlates
well with the presence of
angiographiacally detectable
coronary artery disease.
ECAB Clinical Update: Cardiology Volume 1, Issue 1
28
≤ 4.5% for predicting any coronary artery disease were 71% and
81%, respectively.
65
We also found significantly impaired BAFMD in
patients with angiographically significant CAD and the association
was independent of conventional
CVRFs.
66
Young Finns study clearly
demonstrated significance of endo-
thelial dysfunction in development
of atherosclerosis. CIMT and
BAFMD were performed in 2109
individuals with age 24–39 years. It was found that increase in CIMT
was predominantly restricted to those subjects who had impaired
BAFMD. In contrast, individuals with normal BAFMD had normal
CIMT irrespective of number of risk factors they had. In other words,
the study provides strong evidence to support protective role of normal
BAFMD against development of atherosclerosis.
67
Assessment of Response to Therapy
BAFMD has been used extensively in evaluating influence of various
therapeutic agents on endothelial function. ACE inhibitors, angiotensin
receptor blockers, statins, dietary interventions and estrogen
replacement therapy have all been shown to produce improvement in
BAFMD in various subsets of individuals.
68–71
However, relationship
between effect of these interventions on BAFMD and improvement in
clinical outcomes is yet to be determined.
Limitations
The major limitation with BAFMD is its tendency to get easily affected
by a number of factors as mentioned above. Reproducibility of the
test is therefore compromised. In addition, it is very operator sensitive
with significant inter-observer variability. Besides these technical
factors, its specificity for presence of significant CAD appears to be
poor although sensitivity is good. Finally, as with CIMT, it is not
known how incorporation of BAFMD assessment in clinical practice
would affect long-term outcome of patients.
Clinical utility of brachial artery
flow-mediated dilatation is limited
by various factors affecting its
measurement.
Early Detection of Sub-clinical Atherosclerosis Bansal and Kasliwal
29
PULSE WAVE VELOCITY AND
PULSE WAVE ANALYSIS
Pulse wave velocity (PWV) and pulse wave analysis (PWA) are non-
invasive markers of arterial stiffness which plays an important role in
development and progression of vascular damage. Although several
pathological processes distinct to atherosclerosis affect arterial
stiffness, numerous studies have shown association between arterial
stiffness and increased risk of CV events.
72–79
Hence, measurement of
arterial stiffness has been proposed as one of the tools for assessment
of CV risk.
Pathophysiological Mechanisms Linking Arterial Stiffness
and Cardiovascular Risk
Several pathophysiological mechanisms can explain increased CV risk
in presence of arterial stiffness:
Increased arterial stiffness results in augmentation of central pulse
pressure by increasing systolic blood pressure (BP) and reducing
diastolic BP. Elevated systolic BP leads to increased cardiac
workload resulting in increased myocardial oxygen demand. On
the other hand, reduced aortic diastolic BP results in impairment
of coronary perfusion gradient thereby compromising myocardial
oxygen supply. A combination of these two factors leads to adverse
cardiac hemodynamics and thus increased risk of cardiac
complications. In addition, increased central systolic BP causes
development of left ventricular
hypertrophy,
80,81
which through
several known and unknown
mechanisms, increases CV
risk.
80
The pathological changes that are responsible for development of
peripheral arterial stiffness (alterations in normal fibrous
architecture of the vessel wall, inflammation, atherosclerosis, etc.)
also take place in coronary and cerebral vasculature and thus
result in direct damage to these vessels.
82
Increased arterial stiffness gives a
measure of risk of coronary
artery disease.
ECAB Clinical Update: Cardiology Volume 1, Issue 1
30
Increased central pulse pressure exposes the cerebral vasculature
to exaggerated fluctuations in the BP and thus leads to vascular
damage.
83
Methodological Considerations
Basic Principles in the Measurement
Pulse wave velocity: Pulse wave velocity is the velocity at which the
pressure pulse wave travels along the arterial system and is distinct
from (and faster than) the velocity of propagation of the blood. Since
the pulse wave travels at a faster speed in the stiffer arteries, higher
PWV indicates increased arterial stiffness. Measurement of PWV
requires recording of pulse waveform at two different points in the
vascular system and then calculate the difference in time that the
pulse takes to reach the second point as compared to the first point.
The distance between these two points divided by the time difference
provides the PWV within that segment (Figure 5). Of the various
segments of the arterial system, carotid-femoral PWV is considered
to be the gold standard as it, being the closest to the aorta, reflects the
aortic stiffness the best and has the maximum epidemiological evidence
base to support its use.
72–79
Different methods are available for recording the pulse waveforms
in the peripheral arteries using an applanation tonometer, a
mechanotransducer or a piezoelectric sensor which sense pressure
wave and finger photoplethysmography which records volume waves.
The recording of pulse wave can be done either simultaneously or
sequentially. When the pulse waveforms are recorded sequentially,
relative time delay between the two waveforms is calculated with the
help of ECG gating. The distance between the sampling points is either
measured manually or calculated using a nomogram based on the
height, weight and gender. Several commercial systems (Sphygmocor
®
,
Complior
®
, AT-form PWV/ABI
®
, etc) are available for automated
measurement of PWV.
Pulse wave analysis: Pulse wave analysis involves identification
and analysis of different components of the central pressure wave
Early Detection of Sub-clinical Atherosclerosis Bansal and Kasliwal
31
form. The arterial pressure waveform is a composite of the forward
pressure wave created by ventricular contraction and the wave reflected
from the periphery (mainly at branch points). In elastic vessels, because
PWV is low, reflected wave tends to arrive back at the aortic root
during diastole. In the case of stiff arteries, PWV rises and the reflected
wave arrives back at the central arteries earlier, adding to the forward
wave and augmenting the systolic pressure. This phenomenon can be
quantified through the augmentation index (AIx)—defined as the
difference between the second and first systolic peaks (P2 – P1)
expressed as a percentage of the pulse pressure (Figure 6).
The central aortic pressure waveform can be estimated either from
the common carotid waveform directly or from the radial artery
Figure 5. Non-invasive measurement of carotid-femoral pulse wave
velocity. Δt, the time delay between the arrival of pulse at common carotid
artery and at the femoral artery is calculated by recording the pressure
waveform at these two points simultaneously; ΔL, the distance between
the two measurement points is measured manually.
Pulse wave velocity = ΔL/Δt
Pulse wave velocity = ΔL/Δt
ΔL
Δt
Waveform at
common
femoral artery
Waveform at
common carotid
artery
Abdominal
aorta
Arch of aorta
ECAB Clinical Update: Cardiology Volume 1, Issue 1
32
waveform using a transfer function. At both the arteries, the pressure
waveforms are recorded using applanation tonometry. Since the radial
artery is well supported by bony tissue, applanation tonometry is easier
to perform at this point. Therefore the most widely used approach for
pulse wave analysis involves performance of radial artery tonometry
followed by calculation of the aortic pressure waveform from the
radial waveform using a transfer function (Sphygmocor
®
, AtCor,
Sydney Australia).
84–86
Technical Considerations during PWA and Measurement of PWV
Similar to BAFMD, PWV is easily influenced by several external factors
and the standardization of the measurement process is essential to
ensure accuracy of the results.
87
Smoking, eating, caffeinated
beverages should be avoided for at least 3 hours and alcohol should
be avoided for at least 10 hours before measurements. All
measurements should be performed at the same time during the day,
particularly in case of follow-up studies and room temperature should
be kept at approximately 22°C. In addition, patient’s age, gender,
height, weight, blood pressure and the position in which measurements
have been obtained (i.e., supine, sitting) should be clearly recorded.
Figure 6. Carotid pressure waveform depicting different components.
The height of the late systolic peak (P2) above the inflection (P1) defines
the augmentation pressure, and the ratio of augmentation pressure to
pulse pressure defines the augmentation index (in percent).
Systolic blood
pressure
Diastolic blood
pressure
Pulse pressure
ΔP
ED
P
2
P
1
Augmentation index (AIx) = Augmentation pressure (ΔP)/pulse pressure
Early Detection of Sub-clinical Atherosclerosis Bansal and Kasliwal
33
A detailed documentation of all concomitant medications is also essential.
Definition of Abnormal Values
Similar to CIMT and BAFMD, PWV and AIx also differ according to
the age, gender and ethnicity and therefore, it is difficult to derive
cut-off values for PWV or for AIx. However, a recent meta-analysis has
defined age-specific normal ranges for PWV which are unfortunately
limited by the lack of data regarding the gender and ethnicity.
88
Reproducibility of the Measurements
Despite several variables affecting the measurements, reproducibility
of both PWV and different components of central pressure wave form
has been reported to be good.
89,90
This could be due to the fact that
the technique is relatively simple to learn, even for the inexperienced
examiner.
Clinical Significance
Association with Cardiovascular Risk Factors
Increased arterial stiffness has been reported in association with large
number of conventional and non-conventional CVRFs such as ageing,
91
diabetes,
92,93
hypertension,
94
smoking,
95
dyslipidemia,
96
obesity,
97
metabolic syndrome,
97
etc. Of these, ageing and hypertension have
particularly marked influence on arterial compliance and hence PWV
is known to be a stronger predictor of CV risk in elderly and in hyper-
tensives compared to other patient
populations.
72,73,76,77
Prediction of Cardiovascular Risk
Aortic stiffness has been shown to
have excellent predictive value for CV
mortality, total mortality, fatal and
non-fatal coronary events, and fatal
strokes in different patient subsets including hypertensives,
72,73
diabetics,
74
elderly subjects,
76,77
patients with end-stage renal disease
75
as well as in the general population.
78,79
Moreover, in many of these
studies, the PWV was found to have independent predictive value
over conventional CVRFs either considered alone or in combination
Increased arterial stiffness is
associated with: old age,
diabetes mellitus, hypertension,
obesity, smoking and
dyslipidemia.
ECAB Clinical Update: Cardiology Volume 1, Issue 1
34
in the form of Framingham risk score. Most of these data have been
obtained using carotid-femoral PWV as marker of aortic stiffness.
In contrast, rather limited data is available regarding the predictive
accuracy of AIx or central pulse
pressure. Studies involving
hypertensives
98
and the patients with
end-stage renal disease
99,100
have
shown some favorable results. For
example, CAFÉ study showed an
association between central pulse pressure and AIx and CV outcomes.
98
In contrast, no significant advantage was demonstrated by the use of
AIx over brachial cuff pressure in the ANBP2 study.
101
Assessment of Response to Therapy
Several non-pharmacological and pharmacological treatments such
as exercise training,
102
dietary changes,
103
various antihypertensive
agents,
98,104–106
statins,
107
etc. have been shown to reduce arterial
stiffness. Of particular interest are the findings of the CAFÉ study
which showed that despite similar effects on peripheral BP, amlodipine–
perindopril combination resulted in greater reduction in central pulse
pressure as compared to the combination of atenolol and a thiazide,
and this differential effect was associated with differences in CV
outcomes in the two groups of patients.
98
In another study involving
patients with end-stage renal disease, lack of regression of PWV with
therapy was reported to be associated with increased mortality
irrespective of the reduction in peripheral BP.
108
These data provide
some evidence to suggest that measures of arterial stiffness may have
an important role to play in guiding and monitoring treatment in
hypertensive subjects; however more data is needed before these could
be applied in routine clinical practice.
Limitations
There are several limitations to the routine clinical use of assessment
of aortic stiffness for the purpose of CV risk assessment and
management of patients. The most important of these is the lack of
Aortic stiffness is highly predictive
of fatal and non-fatal accidents
and mortality in patients with
coronary artery disease.
Early Detection of Sub-clinical Atherosclerosis Bansal and Kasliwal
35
defined normal ranges for different populations. In addition, as already
mentioned, more data is needed to show incremental benefit with their
use over conventional risk assessment in improving CV outcomes
with therapy.
CORONARY ARTERY CALCIUM SCORING
Pathophysiology
Calcium is deposited in the coronary arteries only as a result of vascular
injury with consequent development of atherosclerotic process and
not through any other mechanism.
109
Therefore presence of calcium
is considered to be pathognomonic of atherosclerosis and techniques
that can detect and quantify coronary calcium are being used as non-
invasive tools to detect CAD as well as to predict CV risk.
Contrary to earlier belief, calcium deposition can take place during
any stage of atherosclerotic process although it is commoner in the
advanced plaques. Once deposited within the plaques, it stabilizes them
and thereby usually decreases vulnerability of the plaques to rupture.
However, in some cases, when there is formation of a calcific nodule
just beneath the fibrous cap, it may paradoxically render the plaque
prone to rupture and can thus result in acute coronary event. However,
this is only a minor mechanism responsible for the link between high
coronary calcium scores and the increased risk of acute coronary
events. It has been shown that people who have calcified plaque within
their coronary arteries also have a
large number of non-calcified plaques
that are prone to rupture.
110
In fact it
has been shown that total calcium
burden represents only 20% of the
atherosclerotic burden.
110
It is this presence of soft plaques that
increases the risk of acute coronary events in these patients and not
the presence of calcified plaques themselves. Thus calcified plaque
serve as a marker of increased risk and not as the underlying cause.
The prevalence of calcium within the coronary arteries increases
with age in a fashion similar to atherosclerosis.
111
The calcium is
Presence of calcium in aterial wall
is a pathognomonic sign of
atherosclerosis.
ECAB Clinical Update: Cardiology Volume 1, Issue 1
36
virtually undetectable during the second decade but almost universally
present by the eighth decade. Also, the prevalence is higher in men as
compared to women before the age of 65–70 years owing to the
differences in the severity of
atherosclerosis in them.
111,112
Techniques for Coronary
Calcium Scoring
Coronary calcium scoring (CCS) is
performed using specialized CT scanners. There are two different CT
systems that can be used for this purpose—the electron beam CT
(EBCT) and the multi-detector CT (MDCT). EBCT utilizes
electromagnetically rotated electron beams for scanning without
requiring rotation of gantry around the patient and has very fast
acquisition time (50–100 ms per slice). In contrast, MDCT utilizes
the traditional X-ray beam for imaging. The X-ray tubes are mounted
on the gantry that is mechanically rotated around the patient which
makes the scanning process slower (approximately 350–400 ms per
rotation). MDCT differs from the conventional single-slice CT by
having multiple rows of detectors that allow acquisition of multiple
slices (4, 8, 16 or 64) simultaneously thereby reducing the acquisition
time and increasing the spatial resolution. Besides these fundamental
technical differences, EBCT and MDCT differ in several respects. In
case of EBCT, ECG gating is done prospectively whereas it can be
done either prospectively or retrospectively with MDCT. Although
retrospective gating may improve reproducibility of the measurements,
it increases scanning time and radiation exposure (which is already
higher with MDCT) and is therefore, not preferred.
113
The minimum
slice thickness that can be achieved with current generation EBCT is
1.5 mm compared to 0.5 mm for MDCT. Finally, owing to the longer
acquisition time, need to control heart rate is greater with MDCT
(<65 bpm) as compared to EBCT (<110 bpm). At present, EBCT or
fast MDCT (4-level or greater) are recommended for the purpose of
CCS.
113
Calcified plaques in the
coronary arteries are always
associated with
non-calcified plaques.
Early Detection of Sub-clinical Atherosclerosis Bansal and Kasliwal
37
Irrespective of the scanner used, quantification of coronary calcium
burden can be done either using the conventional Agatston system or
the relatively newer (and potentially advantageous) ‘volume score’
method. A detailed discussion of the relative merits of the two methods
is beyond the scope of the present review. However, it is noteworthy
that most of the data presently available for CCS has been obtained
using Agatston method.
Definition of Abnormal Values
Recently published results of the Multi-Ethnic Study of Atherosclrosis
(MESA) have provided age- and gender-specific normal values for CCS
for different populations.
114
However, as per the following discussion,
most of the studies have used absolute calcium score irrespective of age
or gender to determine CV risk.
Clinical Implications
Prediction of CV Risk
The role of CCS in prediction of CV risk in asymptomatic individuals
has been assessed in a recently published meta-analysis involving 6
large, prospective studies with a total of nearly 30,000 subjects.
115
The relative risk of CVD death or MI over 3–5 years’ follow-up was
4.3 in subjects with any measurable calcium compared to those with
zero CCS and the absolute risk of events was 1.91% and 0.4% per
year, respectively. Moreover, in patients with any measurable calcium,
the risk increased with increasing
CCS. Thus the annual event rates were
0.7%, 2.1%, 4.6% and 7.1% in patients
with CCS 1–112, 100–400, 400–999
and ≥1000, respectively.
The independent predictive value
of CCS over CVRFs and Framingham risk score has also been
evaluated in these studies.
116–121
It was found that CCS provided
prognostic information which was incremental to the information
provided by the conventional CVRFs, Framingham score and some of
the newer risk factors such as high-sensitivity C-reactive protein and
Calcified plaques in
coronary arteries serve as a
marker of increasing risk of
coronary artery disease.
ECAB Clinical Update: Cardiology Volume 1, Issue 1
38
body mass index. The incremental benefit was the maximum in patients
with intermediate Framingham risk score (i.e. 10-year event rate 10–
20%) in whom CCS <100, 100–399 and ≥400 were shown to confer
0.4%, 1.3% and 2.4% risk of CV events per year, respectively. Thus,
the patients with CCS ≥400 with
otherwise intermediate Framingham
risk score had the same risk of events
as those with established CVD.
On the basis of these findings, it
is recommended that CCS can be
used in routine clinical practice to further refine the CV risk in patients
who belong to the intermediate risk group based on the Framingham
score. In such patients, a high CCS should lead to more aggressive
risk management but a low score should not be taken as evidence for
reduction in therapy. In contrast, in patients with low or high
Framingham risk, CCS does not add to the prognostic information
and is not recommended as a routine.
Assessment of Symptomatic Patients
A large number of studies have evaluated role of CCS as a non-invasive
tool to detect obstructive CAD in patients presenting with symptoms
suggestive of ischemic heart disease.
122–125
In these studies, CCS > 0
has been demonstrated to have high sensitivity (>95%) for detection
of angiographic CAD but the specificity has been very poor. However,
increasing the CCS cut-off to 80–100 yielded reasonably high diagnostic
accuracy. In a study of 1851 patients undergoing coronary angiography
for suspected CAD, a CCS of >80 resulted in 79% sensitivity and
72% specificity.
123
In another study involving 2115 consecutive
subjects, significant CAD could be predicted with 87% sensitivity
and 79% specificity using a CCS cut-off of 100.
125
The CCS has been compared with different forms of stress
testing also for detection of angiographic CAD.
126–129
Most of these
studies have shown CCS to have similar or even higher diagnostic
accuracy than stress electrocardiography, stress echocardiography
Coronary calcium scoring
provides valuable prognostic
information in patients of
coronary artery disease.
Early Detection of Sub-clinical Atherosclerosis Bansal and Kasliwal
39
or nuclear imaging for this purpose.
126–129
Although a high-CCS predicts presence of significant CAD on
angiography, it is not site-specific.
130
This discrepancy can be explained
by the effect of positive remodeling of the arterial wall which results
in enlargement of the lumen thereby reducing the luminal narrowing
and therefore makes a ‘stenotic’ lesion much less apparent on coronary
angiography. Thus the lack of site-specificity is actually a limitation
of the angiography and not of the CCS. In fact, several histopathological
and intravascular ultrasound-based studies have demonstrated excellent
correlation between amount of coronary calcium and the actual
atherosclerotic plaque volume.
110,131
Thus at present it appears that CCS has reasonably high diagnostic
accuracy for detection of obstructive CAD in symptomatic patients
and can therefore, be used as an adjunctive technique when the
information from other non-invasive testing is inconclusive or when
the likelihood of disease is small based on the clinical assessment.
However, its use as a primary imaging modality in this setting is not
recommended at present since the conventional stress testing provides
immensely valuable information regarding the exercise capacity and
cardiovascular hemodynamics which is not available from CCS.
Limitations
Despite the favorable results, CCS has certain limitations including
high cost, radiation exposure and lack
of easy availability. In addition,
similar to other tools for detection of
pre-clinical tool, it is yet to be
determined whether use of CCS for
guiding therapy results in improved
outcomes justifying the incremental cost.
CONCLUSIONS
Development of the newer non-invasive tools such as CIMT, BAFMD,
PWV, CCS, etc has enabled us to detect atherosclerotic disease at an
A high coronary calcium score
is predictive of significant
coronary artery disease but is not
site-specific.
ECAB Clinical Update: Cardiology Volume 1, Issue 1
40
early disease without necessarily relying on the presence or absence
of conventional CV risk factors. Such an approach has the advantage
of integrating the deleterious effects of all known and unknown risk
factors and thus, offers a means to most appropriately classify the
CV risk of the individuals. Among all the tools available for this purpose
at present, CIMT and CCS have the most extensive data to support
their use for clinical purposes. CCS however has the disadvantage of
radiation exposure and the cost and therefore, CIMT appears to be
the most suitable imaging technique available for assessment of CV
risk in routine clinical practice.
In patients requiring CV risk assessment, assessment of sub-clinical
atherosclerosis has the maximum utility in the subgroup deemed to be
at intermediate risk based on office-based risk factor assessment. In
these individuals, demonstration of evidence of increased atherosclerotic
burden is likely to alter the management strategy substantially (Figure 7).
In contrast, in patients considered to be at high risk of having CV events,
further documentation of presence of sub-clinical atherosclerosis is not
likely to result in more aggressive risk factor modification or treatment
and therefore, assessment of sub-clinical atherosclerosis is less
advantageous in this subgroup. Nonetheless, even in these patients,
CIMT has a role as it provides a simple, reliable and inexpensive tool
for monitoring response to the treatment. In addition, although not
yet proven, demonstration of the presence of actual disease should
intuitively help improve the patient compliance to the treatment.
CLINICAL CASE EXAMPLE: UTILITY OF
EARLY DETECTION OF SUB-CLINICAL
ATHEROSCLEROSIS
A 57-year-old gentleman who is non-diabetic, non-smoker but is a
known hypertensive presents in the out-patient clinic for advice
regarding management of his cardiovascular (CV) risk factors. He
does not have any history of CV disease but his father had died of
myocardial infarction at the age of 52 years. His blood pressure on
Early Detection of Sub-clinical Atherosclerosis Bansal and Kasliwal
41
Figure 7. Role of assessment of sub-clinical atherosclerosis in
cardiovascular risk stratification.
treatment is 130/84 mmHg. His lipid profile revealed the following
findings: total cholesterol—204 mg/dL, LDL-cholesterol—110 mg/dL
and HDL-cholesterol—41 mg/dL. His 10-year Framingham risk score
based on these findings would be 12%. What should be the appropriate
treatment strategy for him?
a. Lifestyle modification alone
b. Stress testing followed by further management according to the
stress testing findings
c. Assessment of sub-clinical atherosclerosis and aggressive risk
factor modification (including statin), if evidence of sufficient
atherosclerotic burden
d. Assessment of sub-clinical atherosclerosis and coronary
angiography in addition to aggressive risk factor modification
(including statin), if evidence of sufficient atherosclerotic burden
As per the National Cholesterol Education Program (NCEP) Adult
Treatment Panel-3 (ATP III), he has 3 risk factors and since his
Framingham risk score is 12%, he will be categorized as having
intermediate risk of CV events. The recommended target LDL-
cholesterol level for him is <130 mg/dL. As his LDL-cholesterol is
Initial Risk Assessment
Intermediate risk
10-yr risk 10–20%
High risk
10-yr risk >20%
Low risk
10-yr risk <10%
Adherence to healthy lifestyle
(primordial/primary prevention)
Non-invasive stress testing required
based on symptoms
Tests for detection of sub-clinical atherosclerosis
No evidence of
atherosclerosis
Evidence of
atherosclerosis
Further treatment
as needed
Aggressive risk factor modification
similar to secondary prevention
YesNo
ECAB Clinical Update: Cardiology Volume 1, Issue 1
42
already below the target, he will be advised to follow lifestyle
modification and to have re-evaluation done after 1 year. Is this the
most appropriate strategy for him?
In the case discussed above, the patient underwent carotid IMT
measurement and the average CIMT was found to be 1.04 mm. This
implies already established, yet sub-clinical atherosclerotic disease and
renders him at high risk of future CV events. In view of this, ideal
LDL-cholesterol goal for him should be <100 mg/dL and statin therapy
should be strongly considered in combination with lifestyle
modification.
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