Studying aims
Perceive learn how to use your entire vary of coronary artery calcium scores (from 0 to >1000) to information shared decision-making and allocate heart problems prevention therapies.
Establish the significance of detection of coronary artery calcium on non-cardiac CT chest scans and the potential function of synthetic intelligence algorithms for automated coronary artery calcium detection.
Describe the proof for measurement of coronary atherosclerotic burden as a superior predictor for heart problems occasions in contrast with coronary stenosis.
Look at the increasing function of coronary artery calcium in randomised scientific trials.
Introduction
Coronary artery calcium (CAC), carried out utilizing a standardised non-contrast ECG-gated cardiac CT protocol, is a direct measurement of a person’s coronary atherosclerotic burden. In 1990, Arthur Agatston and Warren Janowitz developed the primary scoring protocol during which every calcified coronary lesion (outlined as contiguous voxels ≥130 Hounsfield items) receives a density weighting issue from 1 to 4 based mostly on the height density. The world of every lesion is then multiplied by the density weighting issue with the scores of every lesion then summed to calculate the entire Agatston rating. Utilizing the Agatston rating, CAC is usually categorised as excellent (0) or gentle (1–99), reasonable (100–299), and excessive (300–999), or extreme (≥1000) (determine 1). Utilizing this standardised protocol, CAC scoring has a radiation publicity of roughly 1 millisievert, whereas the common annual background radiation dose for individuals residing within the USA is roughly 3 millisievert.
Instance of (A) no, (B) gentle, (C) reasonable and (D) excessive coronary artery calcium (CAC) with corresponding CAC-Diagnostic Reporting System class.
A person’s burden of CAC is strongly related to their brief, intermediate and long-term threat of heart problems (CVD).1 This graded affiliation between greater CAC scores and better threat of CVD is powerful and constant throughout age, intercourse and race/ethnicity. A novel attribute of CAC scoring is that the absence of CAC (CAC=0) is a typical discovering and really strongly related to a low long-term threat for CVD. That is true even amongst individuals who’re estimated to have a excessive CVD threat based mostly on conventional threat elements. Subsequently, amongst sufferers labeled as elevated threat based mostly on conventional threat elements, CAC=0 can serve to ‘de-risk’ these sufferers by offering a extra correct estimate of their arterial or organic age.2 Moreover, CAC=0 is a marker of not solely wholesome arterial ageing and low CVD threat, however can be related to a low charge of incident most cancers and all-cause mortality.3
CAC and conventional threat elements
Atherosclerosis and CVD are complicated multifactorial processes, that are hardly ever brought on by any single threat issue. Generally used CVD threat prediction fashions solely use the measurement of CVD threat elements at a single time limit and don’t take note of a person’s dietary and train habits. Moreover, whereas some genetic alleles and genetic ailments have been recognized, these solely present a small pattern of a person’s general genetic make-up, and the scientific utility of polygenic threat scores stays unsure. Subsequently, whereas conventional CVD threat scores work moderately nicely on a inhabitants degree, they work much less nicely to estimate a person’s CVD threat. In distinction, CAC scoring successfully integrates a person’s lifetime optimistic and adverse threat issue exposures together with their genetic susceptibility and/or resilience to supply an individualised quantification of CVD threat.4
Accordingly, CAC is a superior predictor of CVD occasions and particular person CVD threat in contrast with commonplace scientific measurement of conventional threat elements and novel threat elements reminiscent of high-sensitivity C reactive protein, carotid intimal medial thickness and ankle-brachial index.5 It additionally outperforms American Faculty of Cardiology (ACC)/American Coronary heart Affiliation (AHA)-identified risk-enhancing elements, even amongst people with ≥3 risk-enhancing elements.6 Certainly, even amongst sufferers with familial hypercholesterolaemia (FH), extreme hypercholesterolaemia or an elevated lipoprotein(a) (Lp(a)), CAC gives higher threat stratification.7 8 Amongst middle-aged individuals with FH and elevated Lp(a), the prevalence of CAC=0 is roughly 40% and it’s robustly related to a low CVD threat over at the very least an intermediate follow-up time interval.9
CAC to information main prevention therapies
CAC additionally gives a major enchancment in CVD threat stratification past a person’s estimated 10-year atherosclerotic CVD (ASCVD) threat. Roughly 40% of individuals with an intermediate or excessive 10-year estimated ASCVD threat have CAC=0 and a low 10-year noticed ASCVD occasion charge.10 11 Conversely, amongst sufferers with a low 10-year ASCVD threat estimate who’ve CAC >0, the danger of ASCVD is considerably greater and identifies individuals who might profit from main prevention therapies.
Primarily based on these knowledge, the 2018 AHA/ACC Ldl cholesterol Remedy Guideline and 2019 ACC/AHA Main Prevention Guideline present a IIa suggestion to carry out CAC scoring to enhance ASCVD threat stratification amongst borderline to intermediate-risk sufferers (5%–<20% 10-year threat) to help within the shared determination on whether or not to withhold, postpone or provoke statin remedy. These tips advocate that for sufferers with CAC 1–99, at the very least moderate-intensity statin remedy needs to be thought-about, whereas sufferers with CAC ≥100, reasonable to high-intensity statin remedy needs to be began (determine 2). The 2022 ACC Knowledgeable Consensus Resolution Pathway (ECDP) Guideline additional expands upon the function of CAC scoring and recommends consideration of ezetimibe remedy for sufferers with CAC ≥100 whose low-density lipoprotein ldl cholesterol (LDL-C) is ≥70 mg/dL.12
![Figure 2](https://heart.bmj.com/content/heartjnl/109/22/1714/F2.medium.gif)
Indications to contemplate performing coronary artery calcium (CAC) scoring and recommended therapy algorithm. ASCVD, atherosclerotic heart problems; CAD, coronary artery illness; GLP-1, glucagon-like peptide 1; LDL-C, low-density lipoprotein ldl cholesterol; PCSK9, proprotein convertase subtilisin/kexin sort 9.
Quite a few different worldwide tips together with these from Canada, Europe and the UK have comparable suggestions to contemplate CAC scoring amongst individuals ≥40 years outdated who’re asymptomatic and at intermediate threat. Nevertheless, within the 2021 European Society of Cardiology CVD Prevention Guideline, CAC scoring has a IIb suggestion in contrast with the 2019 ACC/AHA Prevention Guideline during which CAC scoring has a IIa suggestion. These tips usually agree on using CAC=0 to establish low-risk sufferers in whom statin remedy could also be withheld after which usually agree that when CAC ≥100, initiation of statin remedy needs to be thought-about. There may be much less consensus amongst these worldwide tips about whether or not CAC scoring needs to be used to allocate aspirin remedy or antihypertensive drugs. Conversely, whereas tips from China and Japan recognise CAC scoring for threat evaluation, these tips emphasise conventional threat elements for allocation of prevention therapies.
It’s also now recognised that main prevention sufferers with very excessive CAC scores have an analogous CVD threat in contrast with sufferers with a previous CVD occasion. In an evaluation of sufferers with out identified CVD from the Multi-Ethnic Examine of Atherosclerosis (MESA), a CAC rating of roughly 900 had a significant antagonistic cardiovascular occasion (MACE) charge that corresponded to the MACE charge for sufferers within the Additional Cardiovascular Outcomes Analysis with PCSK9 Inhibition in Topics with Elevated Danger (FOURIER) trial.13 Primarily based on this proof, the 2022 ACC ECDP recommends consideration of PCSK9 inhibitors amongst sufferers with CAC ≥1000 whose LDL-C stays ≥70 mg/dL on statins and/or ezetimibe.
Antiplatelet remedy with low-dose aspirin is not routinely really helpful amongst main prevention sufferers, as quite a lot of trials have proven that the danger of bleeding outweighs the potential CVD threat discount. Nevertheless, individuals with a CAC rating ≥100 have an elevated CVD threat commensurate with profit from low-dose aspirin remedy and amongst sufferers with a CAC rating of ≥100, low-dose aspirin remedy could also be thought-about.11
Whereas sufferers with CAC=0 have a low long-term threat of CVD and roughly 40% have wholesome arterial ageing with persistent CAC=0 10 years later, detecting CAC early when there’s a low burden of atherosclerosis represents the optimum time to start out main prevention therapies.14 15 Accordingly, figuring out the most effective strategies to establish sufferers probably to transform to CAC >0 and the optimum time for repeat CAC scoring has vital scientific implications for detection of atherosclerosis at an early stage.16 Dzaye et al demonstrated {that a} greater estimated 10-year CVD threat was related to elevated probability of conversion from CAC=0 to CAC >0, however even over 10-year follow-up, the vast majority of sufferers with incident CAC >0 transformed to a CAC rating between 1 and 99. Utilizing these knowledge in an effort to have a 25% yield of conversion to CAC >0 (ie, one out of 4 sufferers scanned), approximate rescan intervals of 5–7 years for low-risk sufferers, 3–5 years for intermediate threat and three years for high-risk sufferers with diabetes may be thought-about.17
There may be an rising consciousness that CAC scoring needs to be thought-about amongst appropriately chosen individuals <40 years outdated, particularly amongst males who sometimes develop CAC about 10 years sooner than girls, because the presence of any quantity of CAC in a teenager is untimely and related to a considerably elevated lifetime threat of CVD. This was highlighted in a latest pooled evaluation utilizing knowledge from members 30–45 years outdated from the MESA, Coronary Artery Danger Growth in Younger Adults (CARDIA) and the Walter Reed Examine during which there was a prevalence of CAC >0 of 26% amongst white males, 16% amongst black males, 10% amongst white girls and seven% amongst black girls (determine 3).18 Accordingly, it’s particularly vital to calculate age, intercourse and race/ethnicity CAC percentiles amongst youthful individuals, which helps to quantify their long-term diploma of elevated threat, which has the potential to be underestimated if solely absolutely the Agatston rating is used. If ≥75% percentile, the ACC/AHA Ldl cholesterol Remedy and Main Prevention Pointers, together with the 2022 ACC ECDP Guideline, advocate initiation of statin remedy.12 Sufferers probably to have CAC >0 and in whom CAC scoring could also be thought-about earlier than the age of 40 years outdated are these with an elevated threat issue burden or a robust household historical past of untimely CVD.14 16 Basically, amongst individuals <40 years outdated with any particular person conventional threat issue (eg, hypertension, hyperlipidaemia, smoking), there’s an roughly 5%–10% likelihood of CAC >0 for males and <5% likelihood for ladies (determine 4).
![Figure 3](https://heart.bmj.com/content/heartjnl/109/22/1714/F3.medium.gif)
Instance of prevalence of coronary artery calcium (CAC) amongst black males <45 years outdated (tailored from Javaid et al
18 and cac-tools.com).
![Figure 4](https://heart.bmj.com/content/heartjnl/109/22/1714/F4.medium.gif)
Predicted likelihood of CAC >0 by age and intercourse (tailored from Dzaye et al
17). CAC, coronary artery calcium; CHD, coronary coronary heart illness; HLD, hyperlipidaemia; HTN, hypertension.
Entry to CAC scoring
A main benefit of CAC scoring is the standardised protocol, which is easy to carry out and doesn’t require using specialised scanners, intravenous distinction or imaging technicians/readers with extremely specialised coaching in performing cardiac CT. Accordingly, CAC scoring may be carried out at practically any centre that provides CT scanning, which significantly will increase entry to performing CAC scoring. Whereas CAC scoring shouldn’t be routinely lined by insurance coverage corporations, extra are starting to supply protection and even with out insurance coverage protection, the worth is usually $75–$100. Moreover, CAC scoring is strongly related to elevated CVD threat throughout race/ethnicity, which addresses a significant limitation of the Pooled Cohort Equations and will help to extra precisely allocate prevention therapies.
CAC on non-cardiac CT
There are numerous non-cardiac indications to carry out a CT chest scan, of which roughly 80 million are carried out yearly within the USA in contrast with roughly 2 million cardiac CT scans. Vital data on a affected person’s atherosclerotic burden may be obtained from these research, and non-cardiac CTs of the chest have minimal distinction in quantitative or visible categorisation based mostly on the presence/absence of CAC or as gentle, reasonable or extreme CAC.19 These CAC scores from non-cardiac CT additionally show comparable associations with CVD threat. Subsequently, reporting a affected person’s CAC burden from non-cardiac CT chest is really helpful by the Society of Cardiovascular CT (SCCT).20 The SCCT recommends utilizing the CAC Diagnostic Reporting System (CAC-DRS), which is a rating that mixes absolutely the CAC burden with the variety of coronary arteries which have CAC. For the CAC-DRS, the burden of CAC may be measured by both formal Agatston CAC scoring (A) or visible categorisation (V, for instance, gentle, reasonable, extreme) evaluation from non-cardiac CT together with the variety of coronary arteries with CAC. CAC-DRS is easy to attain and an rising CAC-DRS has a graded relationship with greater CVD threat.21 Specifically, there’s an particularly excessive utility for measuring CAC amongst sufferers present process CT of the chest for lung most cancers screening in whom there was a forty five% prevalence of CAC ≥100 and the SCCT recommends reporting CAC for non-cardiac CT of the chest for sufferers present process most cancers staging or surveillance.22 23
Synthetic intelligence (AI) algorithms may be particularly useful for figuring out and reporting CAC on non-cardiac CT scans and are quickly being adopted in scientific apply. Using AI algorithms can improve the velocity, effectivity and accuracy of CAC scoring in an effort to scale back limitations to measurement and reporting of CAC on non-cardiac CT scans.24 At present, quite a lot of corporations are pursuing Meals and Drug Administration approval for reporting CAC based mostly on AI algorithms, and the NOTIFY-1 Examine which used an AI algorithm to establish and rating CAC from non-cardiac CT demonstrated the scientific promise of this method. Within the intervention arm, main care clinicians had been notified of sufferers with prevalence CAC and supplied with the 2018 AHA/ACC Ldl cholesterol Remedy Guideline IIa suggestion to start out statin remedy. On the 6-month follow-up, 51% of sufferers with CAC had been prescribed statin remedy vs 7% in the usual of care group.
CAC versus coronary CT angiography
The ACC/AHA tips primarily advocate CAC scoring for asymptomatic, borderline to intermediate-risk main prevention sufferers. The concentrate on asymptomatic sufferers is partially as a result of luminal stenosis and non-calcified plaque can’t be measured by non-contrast CT imaging. Nevertheless, the 2021 AHA/ACC Chest Ache Guideline is the primary nationwide US guideline to advocate consideration of CAC scoring in symptomatic sufferers, which relies on the very low ASCVD occasion charge for sufferers with CAC=0. It gives a IIa suggestion for using CAC scoring amongst low-risk sufferers with secure chest ache and no identified CAD to exclude calcified plaque and establish sufferers with a low probability of obstructive coronary artery illness (CAD). Including help to the utility of CAC scoring amongst symptomatic sufferers, a meta-analysis of 19 research during which 79 903 members with chest ache had CAC scoring and coronary CT angiography discovered that 58% of sufferers with acute chest ache had CAC=0. Amongst these with CAC=0 and acute chest ache, solely 13% had non-calcified plaque amongst whom 9% had non-obstructive plaque and 4% had obstructive plaque. On this group of symptomatic sufferers with acute chest ache, there was a adverse predictive worth of 98% for sufferers with CAC=0 (desk 1). Moreover, the danger of CVD amongst individuals with CAC=0 was comparable throughout age teams with a 1.4% threat over 4-year follow-up for youthful sufferers in contrast with 1.8% for older sufferers.
Atherosclerotic burden and predictive worth for coronary artery calcium (CAC) amongst symptomatic sufferers with acute chest ache
Whereas luminal stenosis can’t be measured from a CAC scan, solely a small share of asymptomatic people with CAC >400 have obstructive CAD and it’s now recognised that measurement of obstructive luminal stenosis (eg, ≥70%) is greatest used to find out if affected person signs are attributable to angina, whereas coronary plaque burden is the optimum measurement for CVD threat prediction. There are two principal causes for this statement. First, weak or high-risk plaques, whereas related to an elevated threat of plaque rupture, are unusual in contrast with non-high-risk plaques and subsequently solely present at most a minimal improve in CVD threat.25 Moreover, the entire variety of plaques or burden of atherosclerosis is extra informative, as a result of the larger the variety of plaques, the upper the danger that anyone of those plaques might rupture resulting in myocardial infarction. Accordingly, whereas the Agatston rating doesn’t straight report the variety of plaques, the next rating is strongly correlated with an elevated variety of plaques and elevated atherosclerotic burden. This was highlighted in an evaluation of 23 759 people with symptomatic chest ache during which CAC scoring and coronary CT angiography had been carried out. When the presence or absence of obstructive CAD was examined by CAC group, these with obstructive CAD didn’t have the next CVD threat in contrast with individuals in the identical CAC class with non-obstructive CAD.26 Second, quite a lot of research have proven that different measures of coronary plaque phenotype don’t have any clinically vital enchancment in CVD threat prediction past CAC scoring. This absence of added worth for coronary CT angiography past CAC scoring was demonstrated within the Coronary CT Angiography Analysis for Scientific Outcomes an Worldwide Multicenter (CONFIRM) registry the place amongst 1226 asymptomatic people, the incorporation of coronary CT angiography confirmed no added prognostic profit past a mannequin that included CAC scoring.
Enhancing upon the Agatston rating
The Agatston rating is easy to calculate and strongly related to CVD threat. Nevertheless, an abundance of knowledge past a person’s CAC burden, reminiscent of the next variety of coronary arteries with CAC and larger variety of plaques, is related to elevated threat and may be extracted from these scans to additional refine CVD threat. As a result of the CAC rating relies on a peak density weighting issue of every plaque, plaques with the next density contribute a bigger quantity to the rating than a equally sized plaque with a decrease peak density. Nevertheless, elevated density is indicative of a extra secure plaque and research have demonstrated an inverse relationship between plaque density and CVD threat prediction.27 Equally, a main pathophysiological good thing about statin remedy is plaque stabilisation that happens through a discount in quantity of weak low-attenuation plaques and elevated development of high-density calcified plaques.
Past calcified plaque, extracoronary calcification may support in CVD threat prediction. Measurement of ascending and descending thoracic aorta calcification has a graded relationship of CVD inside CAC teams.28 Cross-sectionally, greater aortic valve calcium (AVC) scores are strongly correlated with elevated aortic valve gradients and the American Society of Echocardiography/European Affiliation of Cardiovascular Imaging advocate AVC scoring as a tiebreaker within the prognosis of extreme aortic stenosis.29 Latest work from our group has additionally demonstrated that AVC has a particularly robust affiliation with the long-term threat for extreme aortic stenosis.
Future instructions
It’s now more and more recognised that whereas conventional threat elements work moderately nicely for CVD threat prediction on a inhabitants degree, they work much less nicely on the person degree and that direct measurement of atherosclerosis by CAC considerably improves identification of excessive and low-risk people. Accordingly, individuals with very excessive CAC scores have CVD occasion charges just like sufferers with a previous CVD occasion. Subsequently, use of CAC scoring to enrol high-risk people probably to learn from novel therapy methods or therapies is starting to emerge in scientific trials.
Thus far, there has not been a randomised scientific trial analyzing the efficacy of statin remedy allotted based mostly on CAC rating. Nevertheless, the Danish Cardiovascular Screening trial (DANCAVAS) invited 46 611 community-dwelling people to a complete CVD screening protocol that included CAC scoring.30 Within the screening group, 10 471 males (63%) underwent CVD screening and people with an above median CAC rating based mostly on their age had been really helpful to start out low-dose aspirin and moderate-intensity statin remedy. The general main final result of CVD mortality didn’t attain statistical significance between screening teams, however people <70 years outdated had an 11% discount in whole mortality (HR 0.89 (95% CI 0.83 to 0.96)) and a 7% discount within the threat for MACE (HR 0.93 (95% CI 0.89 to 0.97)). Whereas a number of screening exams had been carried out as a part of this trial, the noticed CVD threat discount was most strongly attributable to aspirin and statin remedy, which was guided by the outcomes of CAC testing. A ten-year follow-up is deliberate for this trial and whether or not the extra 5 years of follow-up impacts the general and CVD outcomes is an eagerly anticipated discovering.
With the intention to extra straight tackle the utility of CAC scoring for allocation of main prevention methods, the Coronary Calcium (CorCal) Examine is a practical open-label randomised trial at the moment below enrolment and carried out by Intermountain Well being (Utah, USA) (desk 2). On this examine, half of the anticipated 9000 members will obtain a CAC scan and be randomised to statin remedy based mostly on ACC/AHA tips, whereas the management group will obtain commonplace threat evaluation based mostly on the Pooled Cohort Equations. As well as, the Pragmatic Analysis of Occasions and Advantages of Lipid-lowering in Older Adults (PREVENTABLE) trial is at the moment underway to check the efficacy of statin remedy amongst people ≥75 years outdated for CVD threat discount. As part of this trial, roughly half of the members can have blinded baseline CAC scoring carried out. Whereas the intervention won’t be randomised based mostly on CAC scoring, outcomes from this trial will present vital data on the utility of statin allocation by CAC rating for CVD threat discount in older individuals. The biggest of those trials is the Dutch Danger or Profit in Screening for Heart problems (ROBINSCA) trial, which has enrolled 43 447 middle-aged women and men who’ve been randomised for screening based mostly on conventional threat elements and CAC. Enrolment has been accomplished for this trial in 2021 and the first final result outcomes for CAD morbidity and mortality at 5 years follow-up are anticipated to be the primary obtainable of those ongoing CAC trials.
Randomised cardiovascular final result trials evaluating coronary artery calcium (CAC) in main prevention
Conclusions
There may be an abundance of proof demonstrating that CAC scoring considerably improves CVD threat prediction among the many general inhabitants, in sufferers labeled as excessive threat by conventional threat elements, and in these with a genetic predisposition to CVD. The ACC/AHA tips now advocate CAC scoring as the popular methodology for CVD threat prediction and for allocation of statin remedy past conventional threat elements (class IIa). Throughout the final yr, ACC/AHA tips have now expanded indications for CAC scoring amongst sufferers with low-risk chest ache and for allocation of non-statin therapies together with ezetimibe and PCSK9 inhibitors. Moreover, we anticipate an elevated use of CAC scoring to establish high-risk people for scientific trials analyzing CVD preventive therapies. This will even probably embrace using AI algorithms to establish sufferers at elevated threat based mostly on clinically carried out non-cardiac CT chest scans. Future research incorporating further measures reminiscent of calcium density and extracoronary calcification will even result in additional enchancment in CVD threat stratification, personalisation of CVD threat prediction and improved allocation of prevention therapies based mostly on a person’s burden of coronary atherosclerosis.
Key messages
Coronary artery calcium is a direct measure of atherosclerotic burden.
Coronary artery calcium is a greater predictor of a person’s heart problems (CVD) threat in contrast with conventional threat elements.
Main tips now advocate using coronary artery calcium to find out allocation of a number of prevention therapies together with using aspirin, statin and non-statin drugs.
Non-contrast non-cardiac CT chest scan experiences ought to embrace quantification of coronary artery calcium.
Quantification of atherosclerotic burden by coronary artery calcium is a superior predictor of CVD threat in contrast with coronary stenosis.
The Agatston rating, a larger variety of plaques, variety of coronary arteries with coronary artery calcium and plaque quantity are related to an elevated threat of CVD, whereas greater peak density is related to a decrease threat of atherosclerotic CVD.
Coronary artery calcium is more and more being utilized in randomised scientific trials to establish high-risk people probably to learn from novel therapy therapies or methods.
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Ethics statements
Affected person consent for publication
Ethics approval
Not relevant.