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Coronary artery calcium paradox and physical activity
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  1. Gaurav S Gulsin1,2,
  2. Alastair James Moss1
  1. 1 Department of Cardiovascular Science, University of Leicester, Leicester, UK
  2. 2 Department of Radiology, University of British Columbia and St. Paul's Hospital, Vancouver, British Columbia, Canada
  1. Correspondence to Dr Alastair James Moss, Department of Cardiovascular Science, University of Leicester and NIHR Leicester Biomedical Research Centre, Leicester LE3 9QP, UK; ajm136{at}leicester.ac.uk

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Reducing the risk of plaque rupture events in individuals without a prior myocardial infarction is an imprecise science. To help clarify whether there is evidence of coronary artery disease and avoid ‘medicalisation’ of otherwise healthy individuals, international guidelines recommend incorporating the measurement of coronary artery calcium alongside risk prediction models.1 Coronary artery calcium serves as a surrogate marker of advanced calcified atherosclerosis and can be calculated from a non-contrast ECG-gated CT scan where a score of 1–99 Agatston units represents subclinical atherosclerosis, and a score of 100 or more Agatston units is considered an appropriate threshold for initiating medical therapy.1 At ≥100 Agatston units, the burden of advanced calcified atherosclerosis justifies statin implementation and this has been validated in a real-world cohort study of 16 996 subjects with a 10-year number needed to treat to prevent one cardiovascular event of 12.2 Many clinicians have advocated the benefits of coronary artery calcium in redefining the cardiovascular risk assessment of healthy individuals, as there is a strong link between high burdens of coronary artery calcium, accelerated progression of calcified plaque and the risk of future myocardial infarction. However, if the burden of calcified plaque is an accurate barometer of cardiovascular risk, one would expect an intervention which reduces an individual’s cardiovascular risk to attenuate progression of calcified plaque. And herein lies the coronary artery calcium paradox; both invasive and non-invasive imaging studies have consistently demonstrated that high-intensity statin therapy, an established modifier of cardiovascular risk, accelerates the deposition of calcified plaque.3 4 Is this paradoxical response of accelerated calcified plaque progression only observed in response to statin therapy?

Sung and colleagues address whether the progression of coronary artery calcium is associated with different levels of physical activity in healthy individuals.5 In a large cohort derived from two South Korean hospitals, 25 485 subjects underwent serial measurement of coronary artery calcium obtained over a median duration of 3 years and assessment of physical activity using the International Physical Activity Questionnaire Short Form. Physical activity was graded by the investigators as: inactive (n=11 920, 47%); moderately active (n=9683, 38%); or health-enhancing physically active (n=3882, 15%), equivalent to running 6.5 km/day. Interestingly, the group performing the higher medically recommended levels of physical activity had the highest baseline burden of advanced calcified plaque (coronary artery calcium score ≥100 Agatston units: inactive 2.8%, moderately active 3.5%, health-enhancing physically active 5.0%) which may be potentially attributable to an older demographic with higher rates of hypertension, diabetes and statin use. While it is unclear what the rationale was for undertaking health-enhancing physical activity in this cohort, it is likely that some participants with subclinical disease were doing so following medical guidance to improve control of established risk factors. Reassuringly in those with a coronary artery calcium score of zero (a low-risk group from a cardiovascular disease prevention perspective), medically recommended levels of physical activity did not accelerate the rate of coronary artery calcium progression modelled at 5 years (adjusted difference in mean coronary artery calcium score 0.32 Agatston units, 95% CI −0.15 to 0.81). However, in those who already had subclinical or more advanced atherosclerosis, health-enhancing physical activity significantly increased the burden of calcified plaque (adjusted difference in mean coronary artery calcium score 15.02 Agatston units, 95% CI 0.56 to 29.49). Does this really mean that vigorous exercise in those with established coronary artery disease paradoxically accelerates plaque progression? This study fuels a wider discussion of some of the key limitations regarding the use of the coronary artery calcium scan to monitor coronary artery disease progression.

First, the amount of calcification measured at baseline is a key determinant of the rate of progression. As illustrated in the Heinz Nixdorf Recall study, the trajectory of plaque calcification has a strong relationship with the baseline coronary artery calcium scan.6 In asymptomatic 40 year-olds, a coronary artery calcium score ≥100 Agatston units is considered a high burden of disease and one would expect to observe exponential growth in calcification over 5 years. In contrast, a coronary artery calcium score of zero would rarely change over the same time frame leading some investigators to label this as a ‘warranty period’ conferring coronary vascular stability. These small differences in coronary artery calcium scores at baseline become amplified over a 5-year follow-up period. Hence, the results of the study performed by Sung et al are in keeping with the main observation of the Heinz Nixdorf Recall study; progression is almost inevitable following the onset of calcification and the rate of progression appears to be only marginally influenced by the control of traditional risk factors.6

Second, an accelerated rate calcified plaque progression does not equate to an accelerated rate of total atherosclerotic plaque progression. In this regard, the Progression of Atherosclerotic Plaque Determined by Computed Tomography Angiography Imaging study (NCT02803411) has provided valuable insight into the temporal changes in plaque composition using contrast-enhanced coronary CT angiography. In a cohort of 1255 patients recruited from seven countries, including South Korea, interval scans performed over a median of 3.4 years demonstrated a small increase in calcified plaque volume per annum in statin-taking compared with statin-naïve patients (progression of calcified plaque volume per annum 1.27±1.54 mm3 vs 0.98±1.27 mm3).4 However, the overall trend was towards slower rates of total plaque progression in those taking statins and this was driven by lower rates of non-calcified plaque accumulation (progression of non-calcified plaque volume per annum 0.49±2.39 mm3 vs 1.06±2.42 mm3).4 These changes are small in line with the chronic nature of atherosclerotic coronary artery disease. More advanced molecular imaging techniques have shown that metabolically active plaques undergo phenotypic transformation from a non-calcified phenotype towards a more calcified plaque.7 It is within necrotic cores of non-calcified plaques, identified on coronary CT angiography as low-attenuation regions, where the propensity of plaques to rupture is greatest.8 As such, the calcification pathways upregulated in non-calcified plaques are thought to be a protective mechanism in response to chronic inflammation. By ‘walling off’ necrotic cores, calcification may indicate a transition towards a more stable metabolic phenotype.

Do these findings mean that we should stop using coronary artery calcium scores to assess coronary artery disease? Sung and colleagues have produced a timely manuscript that highlights the complexity of interpreting coronary artery calcium scores in patients who have implemented recommendations on physical activity or commenced on statin therapy. While proponents would argue that it is an effective tool to screen for subclinical atherosclerosis in asymptomatic individuals, clinicians should be cautious regarding the overuse of this test in otherwise healthy individuals. The coronary artery calcium paradox should not result in paradoxical care for our patients.

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Footnotes

  • Contributors GSG and AJM conceived and wrote the manuscript.

  • Funding The British Heart Foundation provides funding support for GSG (FS/16/47/32190, PG/07/068/2334) and AJM (AA/18/3/34220).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Commissioned; internally peer reviewed.

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