Carotid ultrasound and coronary calcium for the prediction of incident cardiac disease in asymptomatic individuals: A further step towards precision medicine especially in women?

In this issue of the journal, Gudmundsson and colleagues [[1]Gudmundsson E.F. Björnsdottir G. Sigurdsson S. Andersen K. Thorsson B. Aspelund T. Carotid plaque is strongly associated with coronary artery calcium and predicts incident coronary heart disease in a population-based cohort.Atherosclerosis. 2022; (In press)https://doi.org/10.1016/j.atherosclerosis.2022.01.018Google Scholar] report a population-based cohort study of 948 individuals (46% men, mean age of 63.1 years), free of symptomatic coronary heart disease (CHD) at baseline, who underwent both coronary artery calcium (CAC) and carotid plaque ultrasound assessment. The authors investigated the associations between carotid artery atherosclerosis and the presence and extent of CAC, as well as the ability of both markers (i.e., CAC and carotid atherosclerosis) to predict future CHD events. Furthermore, associations were assessed in relation to the predicted 10-year CHD risk with the use of a score developed by the Icelandic Heart Association (IHA). A subanalysis was performed in women versus men. Of note, carotid plaque was evaluated visually, differentiating between (i) absence of plaque, (ii) presence of minimal plaque or (iii) significant plaque. In addition, quantification analysis was performed by calculating the total plaque area (TPA in mm2). In this study, men exhibited a higher prevalence of (74.0 versus 47.1%) and larger CAC scores (56.9 versus 0; p < 0.001), larger TPA (53.8 versus 34.2mm2; p < 0.001) and higher 10-year CHD risk (12.7 versus 3.7%; p < 0.001) compared with women. Plotting CAC score categories (no CAC, CAC 1–100, CAC 101–300, and CAC>300) and carotid plaque categories (no, minimal and significant plaque), most men exhibited minimal carotid plaque and CAC 1–100 (23.5%), whereas women most frequently had no carotid plaque and no CAC (36.0%). Very few (<2%) individuals with no carotid plaques had a CAC score>100. Similarly, the presence of significant carotid plaque predicted the presence and extent of CAC, whereas the presence of minimal plaque burden was less predictive. Overall, CHD events occurred in 36 (8.2%) men and 25 (4.9%) women, respectively (p = 0.042) during a median follow-up of 6.5 years. CAC score categories were positively associated with an increasing number of future CHD events. In this regard, most cardiac events occurred in individuals with CAC score>300 and minimal or significant carotid plaque at baseline. Interestingly, 29 of 36 (81%) men with CHD events had a 10-year CHD score ≥10%, whereas this was true in only in 5 of 25 (20%) women with events. Additionally, most women who experienced events had a CAC score <300 at baseline, suggesting that both CAC and the 10-year IHA CHD score may underestimate the risk of future events in women. However, in women with a 10-year IHA CHD risk score <10%, there was a gradient of increased risk across carotid plaque categories, which was not seen in men, highlighting the potential role of carotid atherosclerosis for refining risk prediction in women. Notwithstanding all of the above, in multivariable analyses both TPA and CAC aided in the prediction of future cardiac events both in men and women. The report of Gudmundsson et al. [[1]Gudmundsson E.F. Björnsdottir G. Sigurdsson S. Andersen K. Thorsson B. Aspelund T. Carotid plaque is strongly associated with coronary artery calcium and predicts incident coronary heart disease in a population-based cohort.Atherosclerosis. 2022; (In press)https://doi.org/10.1016/j.atherosclerosis.2022.01.018Google Scholar] needs to be considered in the context of the current cardiovascular (CV) prevention risk assessment approaches. Despite continuous advances in the diagnosis, pharmacologic and invasive treatment of CHD, sudden death, acute coronary syndromes (ACS), and ischemic heart failure are still leading causes of morbidity and mortality [[2]Tsao C.W. Aday A.W. Almarzooq Z.I. Alonso A. Beaton A.Z. Bittencourt M.S. et al.American heart association council on epidemiology and prevention statistics committee and stroke statistics subcommittee.Circulation. 2022 Jan; (In press)Google Scholar]. In this regard, almost 50% of patients with a sudden cardiac event do not experience warning clinical symptoms, such as angina or dyspnea [[3]Marijon -E. Uy-Evanado A. Dumas F. Karam N. Reinier K. Teodorescu C. et al.Warning symptoms are associated with survival from sudden cardiac arrest.Ann. Intern. Med. 2016; 164: 23-29Google Scholar]. Therefore, the identification of patients who are asymptomatic but at increased CV risk is of paramount importance and may allow the early implementation of lifestyle modifications and/or pharmacological treatment to prevent future events. Current CV risk scores employ clinical parameters and biochemical markers to aide risk stratify asymptomatic individuals [[4]Authors/Task Force M. Piepoli M.F. Hoes A.W. et al.European guidelines on cardiovascular disease prevention in clinical practice: the sixth joint task force of the European society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European association for cardiovascular prevention & rehabilitation (EACPR).Atherosclerosis. 2016; 252 (2016): 207-274Google Scholar]. However, there are limitations with such risk scores, especially in relation to risk underestimation in women [[5]Sedlak T. Herscovici R. Cook-Wiens G. et al.Predicted versus observed major adverse cardiac event risk in women with evidence of ischemia and No obstructive coronary artery disease: a report from WISE (Women's Ischemia Syndrome Evaluation).J. Am. Heart Assoc. 2020; 9e013234Google Scholar]. Imaging tests for subclinical atherosclerosis may provide prognostic information beyond that given by traditional risk scores alone. CAC identified by non-contrast computed tomography is a well-established marker of atherosclerosis and a risk factor for incident CHD, improving risk stratification beyond established risk factors [[6]Budoff M.J. Shaw L.J. Liu S.T. et al.Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients.J. Am. Coll. Cardiol. 2007; 49: 1860-1870Google Scholar]. Carotid ultrasound is a non-invasive imaging tool that does not expose the patients to radiation, enables the direct identification of atherosclerotic lesions and, if required, quantification of the carotid plaque burden by TPA [[7]Sillesen H. Muntendam P. Adourian A. et al.Carotid plaque burden as a measure of subclinical atherosclerosis: comparison with other tests for subclinical arterial disease in the High Risk Plaque BioImage study.J. Am. Coll. Cardiol. Img. 2012; 5: 681-689Google Scholar]. Carotid ultrasonography (mainly the presence of carotid plaques) has been previously recognized as a clinical surrogate endpoint for CV prevention by the European Society of Cardiology (ESC) Working Group on peripheral circulation [[8]Vlachopoulos C. Xaplanteris P. Aboyans V. Brodmann M. Cífková R. Cosentino F. et al.The role of vascular biomarkers for primary and secondary prevention. A position paper from the European society of cardiology working Group on peripheral circulation: endorsed by the association for research into arterial structure and physiology (artery) society.Atherosclerosis. 2015; 241: 507-532Google Scholar]. According to the latest ESC guidelines on CV disease prevention in clinical practice, both CAC and carotid artery plaque assessment using ultrasonography can reclassify CV risk [[9]Visseren F.L.J. Mach F. Smulders Y.M. Carballo D. Koskinas K.C. Bäck M. et al.ESC national cardiac societies; ESC scientific document Group. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice.Eur. Heart J. 2021 Sep 7; 42: 3227-3337Google Scholar]. The findings presented by Gudmundsson et al. [[1]Gudmundsson E.F. Björnsdottir G. Sigurdsson S. Andersen K. Thorsson B. Aspelund T. Carotid plaque is strongly associated with coronary artery calcium and predicts incident coronary heart disease in a population-based cohort.Atherosclerosis. 2022; (In press)https://doi.org/10.1016/j.atherosclerosis.2022.01.018Google Scholar] underline the association between carotid plaque burden and CAC measured by non-contrast computed tomography (CT) scans, in line with previous reports [[10]Baber U. Mehran R. Sartori S. Schoos M.M. Sillesen H. Muntendam P. et al.Prevalence, impact, and predictive value of detecting subclinical coronary and carotid atherosclerosis in asymptomatic adults: the BioImage study.J. Am. Coll. Cardiol. 2015; 65: 1065-1074Google Scholar,[11]Gudmundsson E.F. Gudnason V. Sigurdsson S. Launer L.J. Harris T.B. Aspelund T. Coronary artery calcium distributions in older persons in the AGES-Reykjavik study.Eur. J. Epidemiol. 2012; 27: 673-687Google Scholar], as well as their complementary role for the risk stratification of asymptomatic individuals. CAC remained the strongest independent predictor for future cardiac events [[1]Gudmundsson E.F. Björnsdottir G. Sigurdsson S. Andersen K. Thorsson B. Aspelund T. Carotid plaque is strongly associated with coronary artery calcium and predicts incident coronary heart disease in a population-based cohort.Atherosclerosis. 2022; (In press)https://doi.org/10.1016/j.atherosclerosis.2022.01.018Google Scholar], as previously demonstrated in the Multi‐Ethnic Study of Atherosclerosis (MESA), which reported that CAC scores improved prediction and reclassification of CHD better than carotid ultrasound measures [[12]Gepner A.D. Young R. Delaney J.A. Budoff M.J. Polak J.F. Blaha M.J. et al.Comparison of carotid plaque score and coronary artery calcium score for predicting cardiovascular disease events: the multi‐ethnic study of atherosclerosis.J. Am. Heart Assoc.: Cardiovasc. Cerebrovasc. Disease. 2017; 6e005179Google Scholar]. A recent systematic review also concluded that CAC is superior to carotid plaque measurement for the identification of subclinical atherosclerosis and the assessment of future CV risk in low-to-intermediate risk asymptomatic individuals [[13]Azcui Aparicio R.E. Ball J. Yiallourou S. Venkataraman P. Marwick T. Carrington M.J. Imaging-guided evaluation of subclinical atherosclerosis to enhance cardiovascular risk prediction in asymptomatic low-to-intermediate risk individuals: a systematic review.Prev. Med. 2021; 153: 106819Google Scholar]. However, in the present study [[1]Gudmundsson E.F. Björnsdottir G. Sigurdsson S. Andersen K. Thorsson B. Aspelund T. Carotid plaque is strongly associated with coronary artery calcium and predicts incident coronary heart disease in a population-based cohort.Atherosclerosis. 2022; (In press)https://doi.org/10.1016/j.atherosclerosis.2022.01.018Google Scholar], CAC>100 was present in very few (<2%) individuals without carotid plaques and only 3 of 131 (2%) patients without carotid plaques experienced cardiac events. In addition, quantitative assessment of TPA allowed the prediction of cardiac events over traditional risk scores and CV risk factors [[1]Gudmundsson E.F. Björnsdottir G. Sigurdsson S. Andersen K. Thorsson B. Aspelund T. Carotid plaque is strongly associated with coronary artery calcium and predicts incident coronary heart disease in a population-based cohort.Atherosclerosis. 2022; (In press)https://doi.org/10.1016/j.atherosclerosis.2022.01.018Google Scholar]. These findings suggest that the presence of carotid plaques could be a potential gatekeeper for risk stratification by CAC or more advanced cardiac or vascular imaging. This would reduce costs and eliminate exposure to ionizing radiation and contrast media [[14]Raffort J. Lareyre F. Katsiki N. Mikhailidis D.P. Contrast-induced nephropathy in non-cardiac vascular procedures, A narrative review: Part 1.Curr. Vasc. Pharmacol. 2022; 20: 3-15Google Scholar,[15]Katsiki N. Athyros V.G. Karagiannis A. Mikhailidis D.P. Contrast-Induced nephropathy: an "All or none" phenomenon?.Angiology. 2015; 66: 508-513Google Scholar]. Of note, even in patients with asymptomatic carotid stenosis aggressive risk factor control and best medical treatment should be implemented, whereas a prophylactic carotid intervention may be considered in selected patients with high-risk features to prevent future cerebrovascular events [[16]Paraskevas K.I. Mikhailidis D.P. Antignani P.L. Baradaran H. Bokkers R.P.H. Cambria R.P. et al.Optimal management of asymptomatic carotid stenosis in 2021: the jury is still out. An international, multispecialty, expert review and position statement.J. Stroke Cerebrovasc. Dis. 2022; 31: 10618Google Scholar]. Finally, the findings of the present study [[1]Gudmundsson E.F. Björnsdottir G. Sigurdsson S. Andersen K. Thorsson B. Aspelund T. Carotid plaque is strongly associated with coronary artery calcium and predicts incident coronary heart disease in a population-based cohort.Atherosclerosis. 2022; (In press)https://doi.org/10.1016/j.atherosclerosis.2022.01.018Google Scholar] underscore the weakness of traditional CHD models for the estimation of cardiac events, especially in women. Indeed, most cardiac events in women occurred in those classified as having low risk, in whom there was a gradual risk increase across carotid plaque categories. Hence, it would appear that carotid ultrasound may be particularly useful for risk stratification of women. Since women are less likely to undergo interventional cardiac procedures compared with men and generally have a worse outcome after suffering a CHD event [[17]Calabrò P. Niccoli G. Gragnano F. Grove E.L. Vergallo R. Mikhailidis D.P. et al.Working Group of Interventional Cardiology of the Italian Society of Cardiology. Are we ready for a gender-specific approach in interventional cardiology?.Int. J. Cardiol. 2019; 286: 226-233Google Scholar], a gender-specific approach may be required not only for risk refinement, but also for CHD diagnosis and interventional approaches in the era of precision medicine (Fig. 1). Some limitations need to be considered when interpreting the results of the present study. Some technical aspects in the assessment of carotid plaque as well as CAC could have increased the prognostic value of these measurements. Parameters such as calcium localization, density, texture and other radiomic features were recently recognized beyond CAC scoring as additional markers for increased CV risk [[18]Eslami P. Parmar C. Foldyna B. Scholtz J.E. Ivanov A. Zeleznik R. et al.Radiomics of coronary artery calcium in the framingham heart study.Radiol. Cardiothorac. Imag. 2020; 2e190119Google Scholar]. As far as carotid ultrasound, 3-dimensional (3D) imaging, scanning both carotid arteries from the clavicle to the jaw, rather than focusing on the carotid bifurcation alone, [[7]Sillesen H. Muntendam P. Adourian A. et al.Carotid plaque burden as a measure of subclinical atherosclerosis: comparison with other tests for subclinical arterial disease in the High Risk Plaque BioImage study.J. Am. Coll. Cardiol. Img. 2012; 5: 681-689Google Scholar] or the additional assessment of plaque burden in the femoral bifurcation, [[19]Korosoglou G. Maylar N. Looking to the femoral rather than the carotid bifurcation to predict obstructive coronary artery disease?.Int. J. Cardiovasc. Imag. 2021; 37: 2975-2977Google Scholar] may have provided incremental value for the prediction of incident CHD. Biochemical markers such as cardiac troponins, which are established markers of CV risk, recently reported to add complementary prognostic information to CAC in asymptomatic individuals, [[20]Sandoval Y. Bielinski S.J. Daniels L.B. Blaha M.J. Michos E.D. DeFilippis A.P. et al.Atherosclerotic cardiovascular disease risk stratification based on measurements of troponin and coronary artery calcium.J. Am. Coll. Cardiol. 2020 Jul 28; 76: 357-370Google Scholar] were not available in the present study. In addition, analysis of outcomes was limited to coronary events, whereas endpoints such as stroke and limb events were not reported. Such endpoints may have helped to identify individuals at high-risk to develop polyvascular disease with cerebrovascular and limb complications (Fig. 1). Finally, beyond CAC, coronary computed tomography angiography (CCTA) imaging may be added in the future to more precisely risk stratify asymptomatic individuals. The ongoing SCOT-Heart 2 trial will likely clarify some of these issues (ClinicalTrials.gov Identifier: NCT03920176). With CCTA, markers such as pericoronary fat attenuation index, low-attenuation plaque components and other high-risk features can be assessed with a radiation exposure comparable to that of CAC, and a low (<50 mL) contrast agent volume [[21]Giusca S. Schütz M. Kronbach F. Wolf D. Nunninger P. Korosoglou G. Coronary computer tomography angiography in 2021-acquisition protocols, tips and tricks and heading beyond the possible.Diagnostics. 2021; 11: 1072Google Scholar,[22]Korosoglou G. Giusca S. Contrast agent volume in coronary computer tomography angiography—where are the limits?.Quant. Imag. Med. Surg. 2021 Oct; 11: 4511-4513Google Scholar]. Despite these limitations, the study by Gudmundsson et al. [[1]Gudmundsson E.F. Björnsdottir G. Sigurdsson S. Andersen K. Thorsson B. Aspelund T. Carotid plaque is strongly associated with coronary artery calcium and predicts incident coronary heart disease in a population-based cohort.Atherosclerosis. 2022; (In press)https://doi.org/10.1016/j.atherosclerosis.2022.01.018Google Scholar] provides evidence that carotid atherosclerosis adds incremental value to CAC for the risk stratification of asymptomatic individuals. Especially for women, carotid ultrasound findings can further improve CV risk assessment. Such imaging studies may lay the groundwork for life-style modification or tailored pharmacologic interventions in high-risk asymptomatic individuals, especially in women, whose risk may be underestimated by currently available cardiovascular risk scores. Health care systems will need to consider adapting reimbursement strategies in this context, providing incentives for the broader use of non-invasive imaging over the much more costly invasive procedures in individuals who develop cardiovascular complications. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.