JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
12, 2019
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VOL. 74, NO.
ª 2019 PUBLISHED BY ELSEVIER ON BEHALF OF THE
AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
JACC FOCUS SEMINAR: HISTORICAL AND CONCEPTUAL CHANGES OF
CORONARY ARTERY DISEASE (1980–2020)
JACC STATE-OF-THE-ART REVIEW
From Subclinical Atherosclerosis to
Plaque Progression and Acute
Coronary Events
JACC State-of-the-Art Review
Amir Ahmadi, MD,a,b Edgar Argulian, MD,a Jonathon Leipsic, MD,b David E. Newby, MD,c Jagat Narula, MD, PHDa
ABSTRACT
It has been believed that most acute coronary events result from the rupture of mildly stenotic plaques, based on studies
in which angiographic information was available from many months to years before the event. However, serial studies in
which angiographic data were available from the past as also within 1 to 3 months of myocardial infarction have clarified
that nonobstructive lesions progressively enlarged relatively rapidly before the acute event occurred. Noninvasive
computed tomography angiography imaging data have confirmed that lesions that did not progress voluminously over
time rarely led to events, regardless of the extent of luminal stenosis or baseline high-risk plaque morphology. Therefore,
plaque progression could be proposed as a necessary step between early, uncomplicated atherosclerosis and plaque
rupture. On the other hand, it has been convincingly demonstrated that intensive lipid-lowering therapy (to a low-density
lipoprotein cholesterol level of <70 mg/dl) halts plaque progression. Given the current ability to noninvasively detect the
presence of early atherosclerosis, the importance of plaque progression in the pathogenesis of myocardial infarction, and
the efficacy of maximum lipid-lowering therapy, it has been suggested that plaque progression is a modifiable step in the
evolution of atherosclerotic plaque. A personalized approach based on the detection of early atherosclerosis can trigger
the necessary treatment to prevent plaque progression and hence plaque instability. Therefore, this approach can
redefine the traditional paradigm of primary and secondary prevention based on population-derived risk estimates and
can potentially improve long-term outcomes. (J Am Coll Cardiol 2019;74:1608–17) © 2019 Published by Elsevier on
behalf of the American College of Cardiology Foundation.
A dvances in cardiovascular imaging modal-
ities in recent years have provided valuable
insights into the development and evolution
of atherosclerotic coronary artery disease (CAD).
have allowed detection of early and subclinical
atherosclerotic lesions, as well as examination of the
natural history of these lesions as it relates to plaque
progression and plaque instability. In the current re-
Atherosclerosis is a progressive disease process that view, we describe plaque progression as an essential
has a long latent phase of clinically unapparent le- intermediary step linking early uncomplicated sub-
sions. The acute or chronic manifestations of athero- clinical atherosclerotic lesions to plaque rupture un-
sclerotic cardiovascular disease usually represent derlying an acute event. We also propose that the
late stages of the disease and higher disease burden. assessment of subclinical disease might help refine
Various invasive and noninvasive imaging modalities the traditional paradigm of primary and secondary
From the aIcahn School of Medicine at Mount Sinai Hospital, New York, New York; bSt. Paul’s Hospital, University of British
Columbia, Vancouver, British Columbia, Canada; and the cBritish Heart Foundation Centre for Cardiovascular Science, University
of Edinburgh, Edinburgh, Scotland. Dr. Leipsic has served as a consultant for and holds stock options in Circle CVI and HeartFlow;
and has received research support from GE Healthcare. All other authors have reported that they have no relationships relevant to
the contents of this paper to disclose. Stephan Achenbach, MD, served as Guest Associate Editor for this paper.
Manuscript received March 3, 2019; revised manuscript received July 30, 2019, accepted August 1, 2019.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2019.08.012
JACC VOL. 74, NO. 12, 2019
SEPTEMBER 24, 2019:1608–17
HIGHLIGHTS
 The majority of coronary artery events
occur as a result of plaque rupture.
 Plaque progression is a necessary but
modifiable step between subclinical
atherosclerosis and plaque rupture.
 Subclinical atherosclerosis can be
conveniently detected with noninvasive
imaging.
 Intensive lipid-lowering therapy can halt
plaque progression and should reduce
events.
prevention of atherosclerotic cardiovascular disease
(Central Illustration).
IS PLAQUE PROGRESSION A NECESSARY
STEP BEFORE PLAQUE RUPTURE?
For many decades, it has been accepted that most
acute coronary events arise from the rupture of
mildly stenotic plaques (1). This belief has been based
on angiographic studies that measured the degree of
luminal narrowing in culprit plaques months to years
before the occurrence of myocardial infarction (MI)
(2–5). However, in studies of patients with acute ST-
segment elevation MI (STEMI) who underwent
either successful fibrinolysis or thrombectomy, the
average culprit lesion lumen diameter stenosis
excluding the thrombus has been reported to be more
than 60% (6,7). Similarly, a postmortem study of pa-
tients who died suddenly reported that 70% of
ruptured plaques exhibited more than 75% cross-
sectional vascular area narrowing (8). The discrep-
ancy between studies that demonstrated that mild
plaques were responsible for MI and the post-MI
angiography or postmortem studies showing that
the lesions responsible for the acute event were not
insignificant in size was resolved by studies that had
serial coronary angiograms available for evaluation.
These studies uniformly demonstrated plaque pro-
gression as the step between nonobstructive sub-
clinical atherosclerosis and the acute coronary event.
In these studies, initially a nonobstructive plaque
evolved over the ensuing weeks to months before it
ruptured and resulted in an acute event.
In the PROSPECT (Providing Regional Observations
to Study Predictors of Events in the Coronary Tree)
study of patients with acute coronary syndrome (9),
intravascular ultrasound (IVUS)–verified nonculprit
high-risk lesions, which were frequently mild on
Ahmadi et al. 1609
Plaque Progression Before Plaque Rupture
initial angiographic assessment, doubled in ABBREVIATIONS
AND ACRONYMS
size during the period between the baseline
measurement (32
21%) and the time of the
CAD = coronary artery disease
event (65
16%; p < 0.001). The PROSPECT
CT = computed tomography
study demonstrated that interim plaque
CTA = computed tomographic
enlargement quadrupled the likelihood of an
angiography
event. Similarly, in the Dynamic Registry of
IVUS = intravascular
the National Heart, Lung, and Blood Institute ultrasound
(10), the mean diameter stenosis of the non-
LDL = low-density lipoprotein
culprit lesion progressed from a baseline
MI = myocardial infarction
value of 42
21% to 84
14% at the time of
NNT = number needed to treat
the subsequent event. Studies in patients
STEMI = ST-segment elevation
with STEMI (11,12) wherein serial angio-
myocardial infarction
graphic evaluations were available also
described plaque progression as a step before MI. The
average diameter stenosis of lesions that eventually
led to STEMI (11) increased from 37
21% more than
3 months before the acute event to 59
32% at the
time of STEMI (11,12) (Figure 1). In a prospective Jap-
anese study, patients were evaluated by 4 serial
invasive coronary angiograms in 1 year. A subset of
patients in this study demonstrated a rapid increase
in the extent of luminal stenosis between 2 angio-
grams (i.e., plaque progression); >70% of this group
sustained an acute coronary event. Those with a
gradual increase in luminal stenosis across all 4 an-
giograms developed stable anginal symptoms; the
remaining patients with no change in luminal steno-
sis had an uneventful course. All 3 patient groups had
similar nonobstructive disease at baseline and were
treated similarly with time-appropriate medical
therapy; statins were not used universally at that
time. This study offers an illustrative example of the
importance and necessity of rapid plaque progression
in increasing the likelihood of plaque rupture and
MI (13).
Although it is well established that plaques with
high-risk features are responsible for most MI, not all
plaques with such features lead to an acute event. In
the postmortem study discussed previously (8), one
of the major differences between the disrupted pla-
ques and high-risk plaques (with similar histological
features as plaque rupture except for intact fibrous
caps) was the larger size of the ruptured plaques. This
pathologically suggested that a high-risk plaque must
evolve to possess a larger plaque burden and necrotic
core volume before plaque rupture. Subsequently, a
clinical study that employed coronary computed
tomographic angiography (CTA) in patients with
established or suspected CAD confirmed these find-
ings (14). This study evaluated 1,059 patients; 5% of
the patients had 2 high-risk CTA plaque features
(positive remodeling and large necrotic cores), and
1610 Ahmadi et al. JACC VOL. 74, NO. 12, 2019

Plaque Progression Before Plaque Rupture SEPTEMBER 24, 2019:1608–17

C E NT R A L I LL U ST R A T I ON Prevention Based on Detection of Subclinical Atherosclerosis Should Result in Reduced

Coronary Events

Ahmadi, A. et al. J Am Coll Cardiol. 2019;74(12):1608–17.

Until the later stages of obstructive disease or plaque rupture, coronary artery disease (CAD) remains clinically silent. On their way to developing obstructive disease or
a first event, patients are not only asymptomatic but usually also have a normal functional test. Therefore, it is not possible to distinguish normal coronary arteries
from those with subclinical atherosclerosis. To obviate obstructive CAD and a coronary event, we practice primary prevention based on various risk factor matrices
developed from epidemiological studies. Although the number needed to treat for lipid-lowering therapy in primary prevention to prevent an event is very high, it
often leads to overtreatment or undertreatment. Because of this ambiguity, the commitment to initiate and maintain therapy, both for physicians and for patients,
has not been encouraging. On the other hand, once there is obvious obstructive disease or after the first coronary event, the commitment to intensive lipid-lowering
therapy (secondary prevention) and the number needed to treat become more acceptable. With the advances in imaging technology, it has become possible to detect
subclinical atherosclerosis. Because plaque progression is a necessary and modifiable step between subclinical atherosclerosis and an acute coronary event, halting
plaque progression is proposed as a clinical indication for intensive lipid-lowering therapy. Subclinical atherosclerosis can be detected by cost-effective strategies
such as coronary calcium score, carotid and abdominal ultrasound, or computed tomographic angiography. With triage of patients into subclinical or no atherosclerosis
groups, the latter could be advised to undertake risk factor modification so as to prevent development of atherosclerosis. For the former group, intensive lipid-lowering
therapy would begin at detection of subclinical atherosclerosis to halt plaque progression to prevent the first event, rather than waiting for the first coronary event. It
should all be about treating the disease, not the risk of the disease.

22% of these patients with high-risk plaques devel- necrotic core volume (20
3 mm 3 vs. 1
1 mm 3) than
oped acute events in 2 years. The eventful lesions had lesions with high-risk plaque features that did not
a larger remodeling index (127
4 vs. 113
2), total develop MI. In a serial CTA study in 423 patients with
plaque volume (135
14 mm 3 vs. 58
6 mm 3), and stable CAD (15), high-risk plaques with progression
JACC VOL. 74, NO. 12, 2019 Ahmadi et al. 1611
SEPTEMBER 24, 2019:1608–17 Plaque Progression Before Plaque Rupture

F I G U R E 1 Is Plaque Progression a Necessary Step Before Plaque Rupture?

Average Luminal Stenosis ≤3

90 Months Prior to Average Luminal Stenosis Post to MI = 66% ± 15.5%
MI = 68% ± 17.2%
78.2% ±
14%
80
71% ±
12%
66% ± 65.4% ±
70 12% 61% ± 16.3%

3 Months Prior to MI
59.6% ± 18%
31.5%
60
% Luminal Stenosis

Average Luminal Stenosis >3 Months Prior to MI = 35.6% ± 17.4%

50 44% ± 44% ±
25% 15%

Time of MI
36.5% ±
40 32.3% ± 20.6%
30% ± 34% 30% ±
20.6%
15% 18%
30

20

10

0
41 Months 40 Months 23 Months 23 Months 24 Months 18 Months 10 Months <3 Months <1 Week Post STEMI, Post STEMI, Post Acute Postmortem:
Prior to MI Prior to MI Prior to MI Prior to MI Prior to MI Prior to MI Prior to MI Prior to MI Prior to MI Post Post Coronary Plaque
Successful Successful Syndrome Rupture was
Thrombectomy Fibrinolysis the Cause of
Death

PROSPECT Dacanay Little et al Hacket et al Zaman et al Ambrose Ojio et al Zaman et al Ojio et al Manoharan Chan et al PROSPECT Narula et al
Study (2011) et al (1994) (1988) (1989) (2012) et al (1987) (2000) (2012) (2000) et al (2009) (2010) Study (2011) (2013)

106 Lesions/ 106 Lesions/

74 Patients 32 Patients 29 Patients 10 Patients 34 Patients 15 Patients 20 Patients 7 Patients 20 Patients 102 Patients 203 Patients 102 Patients
74 Patients

This figure illustrates the average luminal stenosis of culprit lesions that resulted in myocardial infarction (MI) in various studies organized relative to the time lapse
between invasive coronary angiography and the MI. The bars are color coded to demonstrate different groups of studies as follows: red bars represent studies in which
the luminal stenosis of culprit lesions led to MI months to years after the angiography; yellow bars demonstrate studies in which the extent of luminal stenosis imposed
by culprit lesions led to MI, measured after MI, either after thrombectomy or thrombolysis or in the postmortem setting. Both red and yellow bars represent studies
that had 1-time angiography measurements available. The concept that most MIs resulted from the rupture of mild plaques emerged from 4 studies, represented here
in the red bars, that showed angiographically mild lesions at baseline (2–5). There were a total of 86 patients in these 4 studies; the average luminal stenosis by culprit
lesions responsible for MI was 41
21%. These measurements were undertaken 26 months (range, 18 to 41 months) before MI. On the other hand, the studies that
investigated culprit lesions after MI showed the obstructive lesions that were responsible for MI had an average luminal stenosis of 66
16% (yellow bars) (6–8). In
this figure, only post-MI data with successful fibrinolysis or thrombectomy or postmortem data are included, to ensure measurements were not significantly affected
by presence of thrombus. The paired color bars (blue, black, and purple) represent invasive coronary angiography studies with serial measurement. These studies solve
the mystery. The PROSPECT study (9) (blue bars) demonstrated progression of lesion from 32
21% at 41 months before the event to 65
16% at the fateful time. In
one study by Zaman et al. (11) in which 2 pre-MI angiography measurements were available (black bars), the culprit lesions were demonstrated to be 37
21% stenotic
24 months before MI but 60
32% stenotic <3 months before the event. In another similar study (purple bars) by Ojio et al. (12), the average luminal stenosis
caused by culprit lesions 10 months before MI was 30
18%, with 71
12% stenotic within a week before MI. Culprit lesions likely go through a period of rapid
progression a few weeks to months before MI, and this plaque progression is a necessary step that links subclinical atherosclerosis to a coronary event. Adapted with
permission from Ahmadi et al. (16).

over time carried a 28-fold higher likelihood of an
acute coronary event, whereas plaques that did not
demonstrate progression in the interval between the
2 CTA studies remained free from acute events.
From these observations, it seems prudent to
suggest that plaque progression is an important step
between early atherosclerosis and MI (16). This
observation could have substantial clinical implica-
tions and could offer us a unique opportunity to
modify cardiovascular outcomes. Given that plaque
progression is a necessary step between early
atherosclerosis and the cardiovascular event, identi-
fying atherosclerosis
progression can help reduce the likelihood of plaque
rupture and MI.
WHAT IS PLAQUE PROGRESSION?
With invasive coronary angiography as the historical
reference standard for assessing CAD and outlining
management, lesion progression and regression have
usually been perceived as the change in the degree of
angiographic luminal stenosis. However, because
plaque rupture is deemed to be the underlying cause
of most MIs, high-risk plaque pathology is the deter-
and restricting plaque minant of acute events. Therefore, a focus on the
1612 Ahmadi et al. JACC VOL. 74, NO. 12, 2019

Plaque Progression Before Plaque Rupture SEPTEMBER 24, 2019:1608–17

F I G U R E 2 What Is Plaque Progression and Regression?

In routine clinical practice, plaque progression and regression are defined by changes in luminal stenosis by an invasive coronary angiogram (A). However, with advances
in invasive and noninvasive imaging, one could consider the change in the overall plaque volume and its morphology in defining progression and regression, especially
because it is primarily the plaque morphology that determines the fate of a lesion (B). An increase in necrotic core volume with significant positive remodeling and
fibrous cap thinning, regardless of a change in the luminal stenosis, is demonstrated in B(i). This could be considered as plaque progression. A decrease in necrotic core
volume with a resultant increase in the fibrous cap thickness with or without calcification, regardless of a change in the luminal stenosis, is demonstrated in B(ii);
a mild increase in luminal stenosis can take place because of negative remodeling. This represents plaque stabilization or lesion regression.

increasing extent of luminal stenosis seems unjusti-
fied. IVUS and CTA interrogation have established
that the presence of a thin fibrous cap, necrotic core
volume, and positive remodeling are strong pre-
dictors of cardiovascular events and plaque rupture
(14,17). Traditionally, the presence or absence of high-
risk plaque features has been described in a binary
fashion or categorized according to the presence of
none, 1, 2, or 3 of such plaque characteristics (18,19).
CTA studies have now demonstrated that high-risk
plaque features are better described in quantitative
terms, because these features are interrelated, and
their quantitative measures influence their prog-
nostic contribution to ischemia and future events
(20,21). Among various high-risk features, the volume
of necrotic core, defined by low-attenuation plaque
on CTA, has special importance. An increase in
necrotic core volume contributes to fibrous cap
attenuation (8), positive remodeling, and impaired
vasodilatory ability and renders the plaque prone to
rupture. The restricted vasodilatory potential could
lead to ischemia, independent of the degree of
luminal stenosis (20–22).
With this in mind, progression and regression
should be related to an increase or decrease in risk of
rupture as opposed to an increase or decrease in
percent luminal stenosis (which has no direct rela-
tionship to events). For example, an increase in
necrotic core volume with positive remodeling and
fibrous cap thinning, regardless of change in luminal
stenosis, could be considered plaque progression.
Similarly, a decrease in necrotic core volume with a
resultant increase in the fibrous cap thickness and
calcification of the cap, even in the presence of a mild
increase in luminal stenosis caused by negative
remodeling, could be considered plaque regression
(Figure 2).
IS PLAQUE PROGRESSION MODIFIABLE?
The clinical benefits of lipid-lowering therapy with
statins are well known. Several imaging studies using
different modalities have uniformly demonstrated
that intensive treatment with statins reduces total
plaque burden by decreasing necrotic core volume, as
well as increasing the fibrous cap thickness (23,24).
These changes in plaque morphology decrease the
odds of plaque rupture despite the fact that the
luminal stenosis or degree of calcification might
remain unchanged or occasionally even worsen. This
JACC VOL. 74, NO. 12, 2019 Ahmadi et al. 1613
SEPTEMBER 24, 2019:1608–17 Plaque Progression Before Plaque Rupture

F I G U R E 3 Is Plaque Progression Modifiable?

A IVUS Data B Coronary Angiography Data

2.5 0.05 PLAC-1-P

LCAS-P REGRESS-P
Change in Percent Atheroma Volume %-IVUS

0.04 CCAIT-P
2 PLAC-1-S

Angiographic MLD Decrease (mm/Year)

REVERSAL- Prava 40 mg
1.5 0.03
MARS-P MASS-P
1 0.02 RS-
S CCAIT-S
MA
REGRESS-S
0.5 REVERSAL- Atorva 80 mg 0.01 MAAS-S
LCAS-S
0 0
40 60 80 100 120 140 40 60 80 100 120 140 160 180
–0.5
ASTEROID- PRECISE- Atorva Alone- SAP
–1 Rosuva 40 mg SATURN- Atorva 80 mg
SATURN- Rosuva 40 mg

–1.5

–2

–2.5
Achieved LDL (mg/dI) Achieved LDL (mg/dI)

Atherosclerotic plaque progression or regression is directly related to low-density lipoprotein (LDL) levels and intensive lipid-lowering therapy. This graph presents 2
regression lines, adapted from Ahmadi et al. (28), demonstrating the relationship of plaque progression to the LDL level. (A) The blue regression line (r2 ¼ 0.926),
adapted from Tsujita et al. (29), represents intravascular ultrasound (IVUS) studies demonstrating the effect of statin therapy and LDL level on plaque progression,
measured by change in percent atheroma volume; the plaque regression occurred with LDL levels of below 80 mg/dl. (B) The red regression line (r2 ¼ 0.61), adapted
from O’Keefe et al. (30), shows that invasive coronary angiography–verified lesions do not progress when LDL is <70 mg/dl. ASTEROID ¼ A Study to Evaluate the
Effect of Rosuvastatin on Intravascular Ultrasound–Derived Coronary Atheroma Burden; Atorva ¼ atorvastatin; CCAIT ¼ Canadian Coronary Atherosclerosis Inter-
vention Trial; LCAS ¼ Lipoprotein and Coronary Atherosclerosis Study; MAAS ¼ Multicentre Anti-Atheroma Study; MARS ¼ Monitored Atherosclerosis Regression Study;
MLD ¼ mean luminal diameter; P ¼ placebo; PLAC ¼ Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study; Prava ¼ pravastatin; PRECISE ¼ Impact of
Dual Lipid-Lowering Strategy With Ezetimibe and Atorvastatin on Coronary Plaque Regression in Patients With Percutaneous Coronary Intervention; RE-GRESS
¼ Regression Growth Evaluation Statin Study; REVERSAL ¼ Reversal of Atherosclerosis with Aggressive Lipid Lowering; Rosuva ¼ rosuvastatin; S ¼ statin;
SATURN ¼ Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin.

is particularly the case with the plaque calcification (Progression of Atherosclerotic Plaque Determined by
that has been shown to increase with statin treatment Computed Tomographic Angiography Imaging), 2,252
(25). Therefore, lipid-lowering therapy is able to halt patients without known CAD underwent clinically
progression, which is defined as evolution of high- indicated serial CTA to evaluate 1 or more cardiac
risk plaque features, and not necessarily an increase symptoms. Upon follow-up, there was a slow pro-
in the degree of luminal stenosis. gression and stabilization of the plaque with statin
CTA is well placed for noninvasive plaque charac- therapy, including a significant reduction in plaque
terization and can identify phenotypic alterations in growth, defined as an increment in annualized percent
plaque characteristics when serial studies are per- atheroma volume above the median of the study
formed. In a study of 116 consecutive patients, 234 population (hazard ratio: 0.796; 95% confidence in-
vessels were examined with serial CTA. Baseline levels terval: 0.687 to 0.925; p ¼ 0.003). As expected, a
of low-density lipoprotein (LDL) were >70 mg/dl, reduction occurred for the noncalcified plaque com-
with a mean LDL cholesterol level of 98 mg/dl. ponents, including low-attenuation plaque volume
Favorable changes in plaque composition were (hazard ratio: 0.644; 95% confidence interval: 0.522 to
observed, including a decrease in total, noncalcified, 0.798; p < 0.001). A subsequent analysis of the same
and low-density noncalcified plaque volumes among study demonstrated that statins were associated with
patients who achieved a >10% reduction in LDL level. slower progression of overall coronary atherosclerosis
Conversely, plaque characteristics worsened in pa- volume, a substantial reduction in number of high-risk
tients who did not achieve a 10% LDL reduction (26). In plaque features, and increased plaque calcification,
a multinational observation registry, the PARADIGM all suggestive of plaque stabilization. This study
1614 Ahmadi et al.
Plaque Progression Before Plaque Rupture
demonstrated that statins did not affect the percent
luminal stenosis and only induced phenotypic plaque
transformation (27).
An integrated analysis of various invasive coronary
angiography and IVUS studies has demonstrated that
only intensive lipid-lowering therapy is able to halt
plaque progression. Plaque progression can be pre-
vented when LDL levels are lowered to 70 to 80 mg/dl,
but regression in plaque volume requires that LDL
levels be even lower (Figure 3) (28–30). In a serial study
of positron emission tomography–computed tomog-
raphy (CT) imaging, reduction in carotid inflammation
was only observed with statin therapy; inflammation
actually increased in the dietary modification–only
group (31). Similarly, with magnetic resonance imag-
ing, plaque-to-myocardium signal intensity ratio on
noncontrast T1 mapping decreased by 19% with statin
therapy compared with an increase to the same extent
in the untreated group (32). Serial intracoronary
angioscopy and near-infrared spectroscopy studies
have demonstrated that the intensity of the lipid core
burden of obstructive nonculprit lesions decreased
only after significant LDL reduction, and not in a group
with lenient LDL targets (33,34). A prospective serial
CTA study evaluating the effect of statin therapy on
plaque progression with an LDL target of <70 mg/dl
demonstrated a 70% greater reduction in the rate of
plaque progression compared with a modest LDL
target (35). In the GLAGOV (Effect of Evolocumab on
Progression of Coronary Disease in Statin-Treated
Patients) study (36), serial IVUS was performed in
968 patients undergoing clinically indicated coronary
angiography randomized to receive either high-
intensity statin treatment or a proprotein convertase
subtilisin-kexin type 9 (PCSK9) inhibitor on top of
statin therapy; patients achieved average LDL levels of
93 and 37 mg/dl in the 2 arms, respectively. The PCSK9
inhibitor arm showed percent and total atheroma
volume reduction, which supports the importance of
intensive LDL-lowering therapy in halting plaque
progression or initiating plaque regression.
Furthermore, the PESA (Progression of Early Sub-
clinical Atherosclerosis) study (37) demonstrated that
almost 50% of 4,184 asymptomatic individuals had
atherosclerosis despite being considered low risk
based on traditional risk factor models. Importantly,
no evidence of atherosclerosis was observed among
subjects with LDL <60 mg/dl, alluding this to be the
minimum LDL level that is needed for the develop-
ment of atherosclerosis. Interestingly, this level is
very similar to LDL target levels in the plaque pro-
gression studies that have shown plaque stabilization
and regression (Figure 3). Therefore, the PESA study
JACC VOL. 74, NO. 12, 2019
SEPTEMBER 24, 2019:1608–17
indirectly suggests that low LDL levels in people with
established atherosclerosis might minimize or halt
plaque progression.
The evidence presented here has been consistent
in showing that the goal of halting plaque progres-
sion—stabilization of plaque morphology and
reducing events—can be achieved by intensive lipid-
lowering therapy targeting LDL levels of 70 mg/dl or
less. More lenient lipid-lowering goals may not be
successful in achieving the same outcome. Although
understandable for secondary prevention, could this
be extrapolated to primary prevention, at least when
subclinical atherosclerosis has been detected by any
imaging strategy? It would be interesting to evaluate
prospectively a strategy of detection of subclinical
atherosclerosis in its early stages, arresting the like-
lihood of progression of atherosclerosis and poten-
tially eliminating major adverse cardiac events. The
upcoming SCOT-HEART 2 (Computed Tomography
Coronary Angiography for the Prevention of Myocar-
dial Infarction) trial will be helpful in answering this
question because it will compare treatment based on
identification of subclinical atherosclerosis by coro-
nary CTA with that based on standard risk factor
scores.
STOP PLAQUE PROGRESSION TO
REDUCE ACUTE CORONARY EVENTS?
On the basis of the foregoing discussion, we could
surmise that most acute coronary events result from
plaque rupture, the rupture occurs secondary to pla-
que progression, and plaque progression is modifi-
able. It is also reasonable to agree that with intensive
lipid-lowering therapy, plaque progression can be
arrested and regression achieved. Therefore, lipid-
lowering therapy should be started upon detection
of subclinical atherosclerosis to reduce acute coro-
nary events.
In standard clinical practice, we divide the life span
of a patient into 2 distinct phases: before and after the
first symptomatic coronary events, wherein primary
and secondary prevention strategies, respectively,
are applicable (Central Illustration). For secondary
prevention, all guidelines recommend that intensive
statin treatment be initiated regardless of baseline
LDL levels.
For primary prevention, on the other hand, there is
strong reliance on population research–driven risk
estimate calculators to decide whether a patient will
or will not benefit from lipid-lowering therapy. Even
if a decision is made to start therapy, the goal of and
the pathophysiology of what is being treated seem to
JACC VOL. 74, NO. 12, 2019
SEPTEMBER 24, 2019:1608–17
be arbitrary at best, because the focus is on the LDL
being in a certain range rather than on its impact on
plaque development and progression. The limitation
of this approach is best exemplified by the fact that
more than 50% of young patients with their first
coronary event were considered low risk immediately
before the event (38). The current practice of using
the first coronary event as the defining point for
committing the patient to intensive lipid-lowering
therapy historically has been adopted for 3 reasons.
First, the results of secondary prevention trials using
statin therapy have been significantly more robust
than primary prevention trials; second, both patients
and physicians have been overly concerned about the
side effects of statins; and third and most important,
the diagnosis of CAD has traditionally relied on
symptoms and functional tests of ischemia focused
on detection of obstructive and flow-limiting coro-
nary artery lesions, and not on the detection of sub-
clinical atherosclerosis (Central Illustration).
There are several limitations of the traditional
definitions of primary and secondary prevention. Not
uncommonly, acute coronary syndrome and sudden
cardiac death are the first manifestations of athero-
sclerotic cardiovascular disease, signifying failure of
the primary prevention strategy. A history of angina
or prior revascularization is present only in a minority
of patients with acute MI (39). Moreover, during
intermediate-term follow-up (mean of 26 months) of
patients enrolled in the PROMISE study, the majority
of adverse cardiac events (78%) occurred in non-
ischemic patients in the functionally tested arm of
patients. This highlights that the notion of defining
primary prevention by the absence of a historical
coronary event or even functionally obstructive CAD
has limited overall prognostic value compared with
detection of atherosclerosis. An incident acute car-
diovascular event portends a major change in the
outcome trajectory both in the short and long term.
The increase in risk after a first event can be the direct
consequence of the event itself (such as myocardial
muscle loss and scar formation) but can also be
attributable to the accumulation of significant
atherosclerotic burden by the time of the first event
(40). Therefore, detection of atherosclerosis should
define the spectrum of primary and secondary
prevention.
CAD is a chronic disease with a long latent period,
and it develops in a pathophysiologically predictable
manner from subclinical plaque to an acute adverse
coronary event. The era of a broad clinical estimate of
the risk of an event can be supplanted by the era of
atherosclerosis imaging. Subclinical atherosclerosis
can be detected using readily available imaging
Ahmadi et al. 1615
Plaque Progression Before Plaque Rupture
techniques such as CT calcium score, coronary CTA,
and carotid and infrarenal vascular ultrasound
(41–43). It is therefore proposed that the existing
paradigm of separating primary and secondary pre-
vention be revisited. There is abundant emerging
evidence that the presence of atherosclerosis detec-
ted by even a noncontrast CT examination is superior
to risk factor–based models for predicting cardiovas-
cular events (44,45).
Detection of subclinical atherosclerosis could
allow a shift from the traditional before-the-event
primary prevention to primary prevention in sub-
jects with subclinical atherosclerosis. A recent study
of more than 9,000 patients reported that there was
no benefit with statin treatment in primary preven-
tion when calcium score was zero, but the number
needed to treat (NNT) was only 12 when there was
evidence of subclinical atherosclerosis with a cal-
cium score >100 (46). Such imaging-based NNT was
superior to the NNT of >300 for traditionally defined
primary prevention and an NNT >500 for primary
prevention with a calcium score of 0 (47). The rele-
vance of the coronary artery calcium score has now
been incorporated into the American College of
Cardiology/American Heart Association recommen-
dations, defining a welcome shift in the approach to
coronary disease. Although there is no randomized
study that might have directly compared the effects
of therapy guided by a risk estimate score and that
guided by the presence of subclinical atheroscle-
rosis, the recently published SCOT-HEART (Scottish
Computed Tomography of the Heart) 5-year outcome
study is a teaser of what a trial like that would find.
The 5-year follow-up of the SCOT-HEART study
demonstrated a 41% greater likelihood of MI in
symptomatic patients evaluated by CTA and func-
tional testing than by functional testing alone. In
both the CTA and functional testing arms, 25% of
patients were referred to coronary angiography and
the rest were deemed to not have obstructive CAD
requiring revascularization. The rate of revasculari-
zation was greater in the first year for CTA because
of more frequent diagnosis of CAD. However, by 5
years, there was no difference between the 2 groups
because the standard-of-care arm underwent more
invasive angiography and coronary revascularization
after 1 year as the disease progressed. Interestingly,
event reduction emerged predominantly in patients
from either arm of the study who were deemed not
to have significant disease based on functional and
CT testing and who did not report typical angina
symptoms and were not referred to the cardiac
catheterization laboratory for further investigation.
In the CTA arm, patients were more likely to be
1616 Ahmadi et al. JACC VOL. 74, NO. 12, 2019

Plaque Progression Before Plaque Rupture SEPTEMBER 24, 2019:1608–17

treated with aspirin, statins,
converting enzyme inhibitors based on the pres-
ence of atherosclerosis, whereas in the standard-of-
care arm the decision to treat was made on the ba-
sis of a risk estimate calculator, and treatment was
restricted to statins only (hazard ratio: 0.45). Out-
comes were significantly superior in the CTA arm. In
this study, the superior outcome was based on the
difference in strategy for starting treatment, which
highlights the difference between atherosclerosis-
based and risk estimate–based treatment strategies
(48).
If we phenotyped our patients by the absence or
presence of atherosclerosis, whereas the former
would be advised to undertake risk factor modifica-
tion to preclude the development of atherosclerosis,
the latter would receive maximum lipid-lowering
therapy because of the imaging evidence of subclini-
cal disease, rather than treatment prompted by the
first coronary event. The rationale for an early ther-
apeutic intervention is to stall the necessary but
modifiable step of plaque progression that could
eventually transform subclinical atherosclerosis into
a coronary event. Therefore, it is proposed that
manipulation of the eventful natural course of coro-
nary disease could be made possible by the early
and angiotensin- detection of subclinical atherosclerosis on an indi-
vidual basis and restriction of its progression by
timely intervention with lipid-lowering regimens.
The phenotyping approach could constitute an
important step toward a proactive approach in car-
diovascular health promotion and cardiovascular
disease prevention (Central Illustration).
CONCLUSIONS
Evolving strategies for the imaging of atherosclerosis
suggest the feasibility of a personalized approach to
atherosclerotic cardiovascular disease beyond the use
of traditional risk factors. It offers to treat the disease
rather than the likelihood of disease. We propose that
plaque progression is a necessary but modifiable step
in the natural history of the disease, and the early
detection of uncomplicated subclinical atheroscle-
rosis provides a window of opportunity for effective
intervention to halt plaque progression and therefore
to reduce events.
ADDRESS FOR CORRESPONDENCE: Dr. Jagat Narula,
Mount Sinai Heart, One Gustave L. Levy Place; Box 1030,
New York, New York 10029. E-mail: narula@mountsinai.
org.

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KEY WORDS acute coronary syndrome,
cardiovascular health, CT angiography,
primary prevention, secondary prevention,
statin therapy