American Journal of Preventive Cardiology 13 (2023) 100456

Contents lists available at ScienceDirect

American Journal of Preventive Cardiology

Commentary

Advanced subclinical atherosclerosis: A novel category within the cardiovascular risk

A R T I C L E I N F O A B S T R A C T

Keywords Traditionally, guidelines divide patients into primary and secondary prevention for atherosclerotic cardiovas-
Cardiovascular disease cular disease (ASCVD) risk management. However, the modern understanding of the biological progression of
Primary prevention atherosclerosis is inconsistent with this binary approach. Therefore, a new approach demonstrating both
Subclinical atherosclerosis
atherosclerosis and ASCVD risk as a continuum is needed to give clinicians a framework for better matching risk
Coronary artery calcium
and intensity of therapy. Advances in coronary imaging have most clearly brought this problem into view, as for
Risk assessment
Education example coronary artery calcium (CAC) scoring has shown that some individuals in the primary prevention have
equal or higher ASCVD risk as certain subgroups in secondary prevention. This article introduces “advanced
subclinical atherosclerosis” as a new and distinct clinical group that sits between the traditional groups of pri-
mary and secondary prevention. Importantly, this article also introduces a new graphic to visualize this inter-
mediate population that is explicitly based on plaque burden. The aim of the graphic is both to educate and to
allow for better identification of a patient’s cardiovascular risk and guide more effective risk-based management.

Cardiovascular diseases (CVD) remain the leading cause of disease ischemic event occurs [10–12]. Many studies have shown that the ma-
burden in the world, with the age-standardized rate of CVD rising in jority of coronary events happen in patients not previously considered
some high-income countries [1]. Although the medical and surgical high risk, who do not have known obstructive coronary artery disease,
management of patients after an ischemic event has improved and/or whose functional tests remain normal [12–14]. A review con-
immensely, population-wide prevention of ischemic events lags behind. ducted across 1,475 patients who experienced a myocardial infarction at
This is due in part to our limited ability to both identify patients at high age ≤50 years, found that more than 50% were considered low risk
risk and to deliver aggressive disease management. For example, we still immediately before the event [12,14].
largely rely on the assessment of traditional risk factors using The use of noninvasive imaging techniques (coronary artery calcium
population-based risk calculators such as the atherosclerotic cardio- [CAC] score and coronary computed tomography angiography [CCTA])
vascular disease (ASCVD) Risk Estimator [2] and SCORE 2 [3]. Outputs can refine the risk category that is defined by traditional algorithms
from risk calculators may overestimate or underestimate the risk asso- alone [15]. Use of the CAC score is based on the understanding that
ciated with certain groups of patients, including those older patients calcifications of the coronary arteries are not a passive process but
without risk factors and young adults with a family history of CVD [4] or pathognomonic of evolving coronary atherosclerosis. Coronary calcifi-
younger patients with metabolic syndrome en route to type 2 diabetes cation is nearly universal in all patients with documented coronary ar-
[5]. Furthermore, results from disease risk calculators are often difficult tery disease and its development is closely related to early aging
for end users to understand [6] and therefore to act upon. (starting typically at >30–40 years of age [4]), vascular injury, inflam-
There is growing evidence that an increased risk of CVD is present mation and repair, and cardiovascular risk factors such as metabolic
long before an acute ischemic event, and not infrequently before tradi- syndrome, dyslipidemia, tobacco use, hypertension, chronic kidney
tional risk factors are even detected [7]. As an example, impaired disease, high C-reactive protein levels, and high lipoprotein(a) [16].
glucose tolerance is associated with a 20–30% increased risk of devel- Several large observational studies and reviews have shown that CAC
oping CVD [8] in the absence of overt type 2 diabetes. This increase in score predicts future cardiovascular events and can be used to accurately
risk is apparent with higher glycated hemoglobin (HbA1c) in people classify patients into low-risk and high-risk categories [17,18]. Major
within the so-called normoglycemic range [9]. This raises the questions: guidelines recommend the use of CAC scoring and a recent paper pro-
are current approaches to identifying high-risk patients flawed? What vides guidance on determining the appropriate age to initiate clinical
are we missing? CAC testing [19].
The pathophysiology of atherosclerotic disease is complex and pro- However, as part of the total plaque volume comprises nondetectable
gressive in nature. It develops silently throughout different vascular noncalcified tissue, the CAC score may underestimate total coronary
territories long before a stenosis reaches functional relevance or an atherosclerotic plaque burden in select individuals, particularly younger

https://doi.org/10.1016/j.ajpc.2022.100456
Received 19 July 2022; Received in revised form 19 December 2022; Accepted 23 December 2022
Available online 24 December 2022
2666-6677/© 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Commentary American Journal of Preventive Cardiology 13 (2023) 100456

people. Furthermore, the relationship of coronary calcification with patients to maintain, Lp(a) is largely genetically determined, and target
significant stenosis is variable, as obstructive plaques can occur at sites blood pressure, low-density lipoprotein (LDL) cholesterol levels, and
with limited calcium and extensive calcific deposits can be observed HbA1c are not achieved in the majority of patients [27,28], despite the
without stenosis [15]. As imaging for early heart disease improves, new existence of numerous algorithms and treatment pathways that are
studies are painting an even clearer picture of subclinical atheroscle- designed to simplify the treatment choices. However, the impact of a
rosis. For example, while a recent general population-based study of high CAC score has been shown to positively impact the initiation and
asymptomatic adults reported a tight association between total athero- maintenance of preventive treatments and lifestyle changes for up to 10
sclerosis detected by CCTA and increasing CAC score – all people with a years [17,29].
CAC score >400 had atherosclerosis and 45.7% had significant stenosis Graphics can play a vital role in communicating healthcare messages
on CCTA [20] – importantly, 5.5% of those with a CAC score of 0 had by linking cause and effect in complex conditions in a way that is easier
atherosclerosis and 0.4% had significant stenosis, and 10% of to understand than text. Visual representations can increase attention to
intermediate-risk patients with a CAC score of 0 had coronary athero- and recall of information when compared with text alone and may
sclerosis by CCTA. Equally remarkable is that 58% of the population had generate an emotional response that could then be related to health
absolutely no plaque that could be detected by either CAC score or CCTA behaviors [30]. We reviewed the graphics developed so far describing
[20]. Another large community-based study of asymptomatic in- the cardiovascular risk continuum and believe that there is a gap in the
dividuals noted that 16% of those with a CAC score of 0 had some plaque current educational literature [31–35]. Our international author group
and over 2% had high-risk plaque features [21]. However, 51% of this could not find a single graphic that fully encapsulates what we see as the
primary prevention population had absolutely no plaque despite sub- atherosclerotic cardiovascular risk continuum across a person’s lifespan.
optimal risk factor levels. A systematic review and meta-analysis of 19 Here, we introduce a new conceptual graphic to describe the many
studies noted that 45% of patients who presented for work-up of acute interlinked and progressive pathophysiological processes involved in
chest pain had a CAC score of 0. In this review, the negative predictive atherosclerosis over its natural history (Fig. 1). This graphic illustrates
values for a CAC score of 0 ruling out obstructive coronary artery disease the continuum of atherosclerosis (spanning primary and secondary
(CAD) were 97% and 98% for stable and acute chest pain, respectively prevention) and how patients at different points along this continuum
[22]. may be at greater risk of an ischemic event than is apparent from
These studies documented marked heterogeneity of plaque burden traditional assessment of their risk factors. Although other authors have
have prompted many clinicians to challenge the reliance on traditional provided graphical representations of a disease continuum, these focus
risk factors and the current clinical dichotomy of primary and secondary on stenosis and the ischemic event as the terminal event in the process.
prevention. There is growing recognition of an intermediate population, This new graphic is among the first to clearly show that cardiovascular
a group of patients between those who are currently considered the risk progression is not strictly linear, in that some patients develop little
primary prevention population and those who have suffered an ischemic or no atherosclerosis, while others can, and do, have sudden ischemic
event, the secondary prevention population. In this article, we posit that events even though they may be asymptomatic with nonobstructive
this intermediate population is best described as those with “advanced disease. The graphic communicates how their risk post-event is directly
subclinical atherosclerosis.” This highly descriptive term is commonly influenced by the ongoing progression of underlying atherosclerosis in
understandable for patients and points to a new and distinct, yet highly other vessels. It also attempts to explain why some patients who receive
prevalent, patient population. We believe that other terms such as successful revascularization and aggressive treatment have a lower risk
“primary and a half prevention” [23] blend traditional concepts and fail of a subsequent event than patients who have not yet had an event but
to concretely describe a new population or concept. Naming this pop- have a high plaque burden (i.e. can be lower risk than the advanced
ulation is critically important; if clinical guidelines or clinical trials are subclinical atherosclerosis population), while some patients continue to
to target such a population, it needs a descriptive name that can be progress to a “very high risk” status.
clearly defined. A clear distinction between the primary prevention Early in life (even in childhood), a combination of risk factors im-
population and those with advanced subclinical atherosclerosis may also pacts the vascular endothelium to create a toxic milieu. This promotes
help to drive engagement in lifestyle changes that would prevent people the development and progression of atherosclerosis. During the primary
from moving into this higher-risk population. prevention phase, there is an opportunity to halt or reverse some of these
In order to effectively control the rise of CVD, there is an increasing processes with changes in diet and lifestyle or with targeted control of
need to identify this intermediate group of patients with advanced risk factors such as hypertension, high LDL cholesterol, or hyperglyce-
subclinical atherosclerosis and to manage their condition appropriately. mia [39,40]. As the atherosclerosis progresses, which can take decades
This is even more important as our therapies for reducing CVD risk have of an adult patient’s life, the accumulation of lipid (the yellow areas in
improved. Our most intensive preventive treatments are rarely consid- the graphic) and calcium (white areas) in plaque increases. In our
ered for patients with extensive but nonobstructive coronary artery model, plaque burden is the fundamental measure of disease risk [36].
disease [13,24]. Even though the most recent European Society of Thereafter, an ischemic event may be caused by plaque rupture, erosion
Cardiology/European Atherosclerosis Society guideline begins to or progressive plaque stenosis. The graphic reflects and visualizes our
incorporate this philosophy, the definition of high-risk populations and increasing understanding that the majority of ischemic events do not
attendant recommendations are generally restricted to those in whom take place in occluded vessels and that the global burden of athero-
aggressive statin treatment is recommended [25]. Future recommen- sclerotic plaque is the best indicator of risk of an event rather than a
dations should be based on the notion that event rates can be similar in single target lesion or stenosis.
high-risk primary and stable secondary prevention patients, and that our The graphic is a tool that physicians can use when counseling pa-
most effective treatments should not be reserved for secondary pre- tients. Integrating available measures of subclinical atherosclerosis in
vention alone [26]. risk assessment, rather than categorizing patients strictly by the primary
Two important changes can be implemented to overcome the bar- or secondary prevention categories, may enable patients to understand
riers to achieving better identification of patients with subclinical where they are along the cardiovascular risk continuum. Furthermore, it
atherosclerosis and providing appropriate management. The first in- can be used as part of the clinician–patient risk discussion, during which
volves increasing the efficiency of patient identification, and the second the physician can illustrate the impact that their risk status may have on
involves motivating physicians and patients to engage in the most their future health and how lifestyle changes and preventive therapies
appropriate management of risk factors and the use of preventive might alter this trajectory. This strategy would better represent those
medication outside of the traditional binary framework of primary/ patients who are at high risk of an event and highlight the need for more
primordial and secondary prevention. Lifestyle changes are difficult for aggressive consideration of preventive measures. We strongly suggest

2
Commentary American Journal of Preventive Cardiology 13 (2023) 100456

Fig. 1. Conceptual graphic of the cardiovascular risk continuum, incorporating advanced subclinical atherosclerosis. The graphic may serve as a useful visual aid for
physicians when discussing cardiovascular risk with patients and recognizes non-linear patterns of risk not reflected in traditional risk assessment algo-
rithms [36–38].

renewed efforts for lifestyle modification and aggressive goal-based Conceptualization, Data curation, Formal analysis, Writing – original
lowering of relevant risk factors in those people with advanced sub- draft, Writing – review & editing. Zhongwei Shi: Conceptualization,
clinical atherosclerosis who have not achieved optimal control of blood Data curation, Formal analysis, Writing – original draft, Writing – re-
pressure, LDL cholesterol, or HbA1c, along with consideration for their view & editing. Dirk Sibbing: Conceptualization, Data curation, Formal
treatment with low dose aspirin and/or emerging cardiometabolic analysis, Writing – original draft, Writing – review & editing.
therapies.
We believe that the simple visualization of the underlying and pro-
gressive processes involved in subclinical atherosclerosis presented here Declaration of Competing Interest
will encourage both clinicians and patients to think about risk in a
different way. The graphic can be used to emphasize the importance of The authors declare that they have no known competing financial
lifestyle and early risk modification, while uniquely drawing attention to interests or personal relationships that could have appeared to influence
advancing subclinical atherosclerosis, paving the way for a new para- the work reported in this paper.
digm of management and thereby reducing the risk of an ischemic event.

Funding References

[1] Roth GA, Mensah GA, Johnson CO, et al. GBD-NHLBI-JACC global burden of car-
No funding was provided for the development of this manuscript diovascular diseases writing group. Global burden of cardiovascular diseases and
risk factors, 1990-2019: update from the GBD 2019 study. J Am Coll Cardiol 2020;
76(25):2982–3021. Erratum in: J Am Coll Cardiol 2021;77(15):1958–9.
Disclosures statement [2] American College of Cardiology. ASCVD Risk Estimator Plus. Available at: http://
tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate/ (accessed 24 June
All authors are part of a Bayer AG global advisory board that convene 2022).
[3] European Association of Preventive Cardiology. HeartScore. Available at: www.
to discuss risk assessment and preventive pharmacotherapy in primary heartscore.org (accessed 24 June 2022).
and secondary prevention. MB and FS declare an investigator-initiated [4] Javaid A, Dardari ZA, Mitchell JD, et al. Distribution of coronary artery calcium by
grant funding from Bayer AG. The remaining authors declare that they age, sex and race among patients Q1 30-45 years old. J Am Coll Cardiol 2022;79
(19):1873–86.
have no other conflicts of interest. [5] Santilli F, Zaccardi F, Liani R, et al. In vivo thromboxane-dependent platelet acti-
vation is persistently enhanced in subjects with impaired glucose tolerance. Dia-
betes Metab Res Rev 2020;36(2):e3232.
CRediT authorship contribution statement
[6] Damman OC, Bogaerts NMM, van den Haak MJ, Timmermans DRM. How lay
people understand and make sense of personalized disease risk information. Health
Michael J. Blaha: Conceptualization, Data curation, Formal anal- Expect 2017;20(5):973–83.
ysis, Writing – original draft, Writing – review & editing. Magdy [7] Sinning C, Makarova N, Völzke H, et al. Association of glycated hemoglobin A1c
levels with cardiovascular outcomes in the general population: results from the
Abdelhamid: Conceptualization, Data curation, Formal analysis, BiomarCaRE (Biomarker for Cardiovascular Risk Assessment in Europe) con-
Writing – original draft, Writing – review & editing. Francesca Santilli: sortium. Cardiovasc Diabetol 2021;20(1):223.

3
Commentary American Journal of Preventive Cardiology 13 (2023) 100456

[8] Schlesinger S, Neuenschwander M, Barbaresko J, et al. Prediabetes and risk of [28] Kotseva K, De Backer G, De Bacquer D, et al. Lifestyle and impact on cardiovascular
mortality, diabetes-related complications and comorbidities: umbrella review of risk factor control in coronary patients across 27 countries: results from the Eu-
meta-analyses of prospective studies. Diabetologia 2022;65(2):275–85. ropean Society of Cardiology ESC-EORP EUROASPIRE V registry. Eur J Prev Car-
[9] Khaw KT, Wareham N, Luben R, et al. Glycated haemoglobin, diabetes, and mor- diol 2019;26(8):824–35.
tality in men in Norfolk cohort of European prospective investigation of cancer and [29] Yano Y, O’Donnell C, Kuller L, et al. Association of coronary artery calcium score vs
Nutrition (EPIC-Norfolk). BMJ 2001;322(7277):15–8. age with cardiovascular risk in older adults: an analysis of pooled population-based
[10] Esper RJ, Nordaby RA, Vilariño JO, et al. Endothelial dysfunction: a comprehen- studies. JAMA Cardiol 2017;2(9):986–94.
sive appraisal. Cardiovasc Diabetol 2006;5:4. [30] Houts PS, Doak CC, Doak LG, et al. The role of pictures in improving health
[11] Toth PP. Subclinical atherosclerosis: what it is, what it means and what we can do communication: a review of research on attention, comprehension, recall, and
about it. Int J Clin Pract 2008;62:1246–54. adherence. Patient Educ Couns 2006;61(2):173–90.
[12] Ahmadi A, Argulian E, Leipsic J, et al. From subclinical atherosclerosis to plaque [31] Blaha MJ. Personalizing treatment: between primary and secondary prevention.
progression and acute coronary events: JACC state-of-the-art review. J Am Coll Am J Cardiol 2016;118(6):4A–12A. Suppl.
Cardiol 2019;74(12):1608–17. [32] de Lemos JA. Navar AM. A life-course approach to cardiovascular disease pre-
[13] Dzaye O, Razavi AC, Blaha MJ, Mortensen MB. Evaluation of coronary stenosis vention. Nat Med 2022;28(6):1133–4.
versus plaque burden for atherosclerotic cardiovascular disease risk assessment [33] Mortensen MB, Cainzos-Achirica M, Steffensen FH, et al. Association of coronary
and management. Curr Opin Cardiol 2021;36(6):769–75. plaque with low-density lipoprotein cholesterol levels and rates of cardiovascular
[14] Singh A, Collins BL, Gupta A, et al. Cardiovascular risk and statin eligibility of disease events among symptomatic adults. JAMA Netw Open 2022;5(2):e2148139.
young adults after an MI: partners YOUNG-MI Registry. J Am Coll Cardiol 2018;71 [34] Raitakari O, Pahkala K, Magnussen CG. Prevention of atherosclerosis from child-
(3):292–302. hood. Nat Rev Cardiol 2022;19:543–54.
[15] Nucifora G, Bax JJ, van Werkhoven JM, et al. Coronary artery calcium scoring in [35] Jacobs Jr DR, Woo JG, Sinaiko AR, et al. Childhood cardiovascular risk factors and
cardiovascular risk assessment. Cardiovasc Ther 2011;29(6):e43–53. adult cardiovascular events. N Engl J Med. 2022;386(20):1877–88.
[16] Mohan J, Bhatti K, Tawney A, et al. Coronary artery calcification [Updated 2021 [36] Mortensen MB, Dzaye O, Steffensen FH, et al. Impact of plaque burden versus
Sep 24]. StatPearls. Treasure Island (FL): StatPearls Publishing; 2022 [Internet] stenosis on ischemic events in patients with coronary atherosclerosis. J Am Coll
Available at, https://www.ncbi.nlm.nih.gov/books/NBK519037/. Cardiol 2020;76(24):2803–13.
[17] Greenland P, Blaha MJ, Budoff MJ, et al. Coronary calcium score and cardiovas- [37] Douglas PS, Hoffmann U, Patel MR, et al. Outcomes of anatomical versus func-
cular risk. J Am Coll Cardiol 2018;72:434–47. tional testing for coronary artery disease. N Engl J Med 2015;372(14):1291–300.
[18] Greenland P, Lloyd-Jones DM. Role of coronary artery calcium testing for risk [38] Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of
assessment in primary prevention of atherosclerotic cardiovascular disease: a re- coronary atherosclerosis. N Engl J Med 2011;364:226–35.
view. JAMA Cardiol 2022;7(2):219–24. [39] Volpe M, Gallo G, Modena MG, et al. Updated recommendations on cardiovascular
[19] Dzaye O, Razavi AC, Dardari ZA, et al. Modeling the recommended age for initi- prevention in 2022: an executive document of the Italian Society of Cardiovascular
ating coronary artery calcium testing among at-risk young adults. J Am Coll Car- Prevention. High Blood Press Cardiovasc Prev. 2022;29(2):91–102.
diol 2021;78(16):1573–83. [40] Villines TC, Rodriguez Lozano P. Transitioning from stenosis to plaque burden in
[20] Bergström G, Persson M, Adiels M, et al. Prevalence of subclinical coronary artery the cardiac CT era: the changing risk paradigm. J Am Coll Cardiol 2020;76(24):
atherosclerosis in the general population. Circulation 2021;144(12):916–29. 2814–6.
[21] Nasir K, Cainzos-Achirica M, Valero-Elizondo J, et al. coronary atherosclerosis in
an asymptomatic U.S. population: Miami heart study at Baptist health south
Florida. JACC Cardiovasc Imaging 2022. https://doi.org/10.1016/j. Michael J. Blahaa,*, Magdy Abdelhamidb, Francesca Santillic,
jcmg.2022.03.010. Zhongwei Shid, Dirk Sibbinge
[22] Agha AM, Pacor J, Grandhi GR, et al. The prognostic value of CAC zero among a
Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular
individuals presenting with chest pain: a meta-analysis. JACC Cardiovasc Imaging
2022. https://doi.org/10.1016/j.jcmg.2022.03.031.
Disease, Blalock 524D1, 600 N. Wolfe Street, Baltimore, MD 21287, USA
b
[23] Celermajer DS. Primary and a half prevention: can we identify asymptomatic Department of Cardiovascular Medicine, Faculty of Medicine, Kasr Al
subjects with high vascular risk? J Am Coll Cardiol 2005;45(12):1994–6. Ainy, Cairo University, Egypt
[24] Gatto L, Prati F. Subclinical atherosclerosis: how and when to treat it? Eur Heart J c
Suppl 2020;22(E):E87–90. Suppl.
Department of Medicine and Aging and Center for Advanced Studies and
[25] Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular Technology, University of Chieti, Chieti, Italy
d
disease prevention in clinical practice: developed by the Task Force for cardio- Ruijin Hospital, Shanghai Jiao Tong University School of Medicine,
vascular disease prevention in clinical practice with representatives of the Euro-
Shanghai, China
pean Society of Cardiology and 12 medical societies With the special contribution e
of the European Association of Preventive Cardiology (EAPC). Eur Heart J 2021;42 Ludwig-Maximilians University (LMU), Germany and Privatklinik
(34):3227–37. Lauterbacher Mühle am Ostersee, Munich, Seeshaupt, Germany
[26] Feldman DI, Michos ED, Stone NJ, et al. Same evidence, varying viewpoints: three
questions illustrating important differences between United States and European
*
cholesterol guideline recommendations. Am J Prev Cardiol 2020;4:100117. Corresponding author.
[27] Davies MJ, D’Alessio DA, Fradkin J, et al. A consensus report by the American E-mail address: mblaha1@jhmi.edu (M.J. Blaha).
Diabetes Association (ADA) and the European Association for the Study of Diabetes
(EASD). Diabetes Care 2018;41(12):2669–701. 2018.