Author + information
- Peter W.F. Wilson, MD∗ ()
- Atlanta Veterans Affairs Medical Center and Emory Clinical Cardiovascular Research Institute, Atlanta, Georgia
- ↵∗Address for correspondence:
Dr. Peter W.F. Wilson, Atlanta Veterans Affairs Medical Center and Emory Clinical Cardiovascular Research Institute, 1462 Clifton Road, Atlanta, Georgia 30322.
The paper by Diederichsen et al. (1) in this issue of iJACC investigates the determinants of change in coronary artery calcification (CAC) for approximately 1,000 Danish adults. These investigators report results from a 5-year longitudinal investigation of factors that may be associated with the initial occurrence of CAC or the progression of CAC for patients with arterial calcification at baseline evaluation. Diederichsen et al. (1) report that the development of CAC was associated with age, sex, hypertension, diabetes, dyslipidemia, and smoking. Low-density lipoprotein cholesterol was an especially important determinant for change in CAC. These investigators also analyzed the potential effects of several biomarkers, and only serum phosphate levels were shown to be associated with CAC severity.
Improving our understanding of the pathobiology of arterial calcification challenges investigators. Age, sex, race, atherogenic lipid concentrations, inflammatory biomarkers, diabetes mellitus, and chronic kidney disease have been associated with greater amounts of CAC in cross-sectional studies (2), but less is known about CAC progression over time. Adults in the 40- to 60-year age range are good candidates for the study of CAC development and progression, and the availability of computed tomography scanning with low doses of radiation to the study subjects has enabled the use of repeat scanning for longitudinal research (3).
A standard Agatston score for the coronary arteries was used to investigate change over the 5-year study interval in the study by Diederichsen et al. (1) reported in this issue of iJACC. Even among patients with some CAC at baseline, the amount of change over 5 years was modest. For patients with CAC at baseline the median scores were 36 Agatston units with a median change over 5 years of +8 units in nonprogressors and a baseline median of 31 Agatston units with a median change of +148 units in progressors. In a corresponding analysis, investigators from MESA (Multiethnic Study of Atherosclerosis) reported annual differences of +14 Agatston units for women and +21 Agatston units for men in the United States. The key factors associated with progression of CAC were older age, male sex, white race, hypertension, body mass index, diabetes mellitus, glucose level, and family history of a heart attack. Interestingly, differential effects for CAC progression were associated with race and ethnicity within MESA (4). For example, diabetes mellitus imparted greater risk for CAC progression in blacks than in whites, and the diabetes effect was weakest for Hispanics.
A longer study interval or an investigation of persons at higher risk of atherosclerotic disease with a greater risk factor burden may have yielded different results in the study by Diederichsen et al. (1). There is a possibility that risk factor interventions after the baseline could have affected the results, but that appears to be unlikely in this sample of study subjects with relatively low baseline low-density lipoprotein cholesterol levels and an overall atherosclerotic cardiovascular disease risk factor burden that was not very great.
Diederichsen et al. (1) are to be complimented for undertaking a comprehensive analysis of biomarkers associated with arterial calcification and mineral metabolism. Discouragingly, most of the calcium- and mineral-related biomarkers they studied did not identify significant associations with the development of new CAC or progression of CAC. Other investigators have suggested that alterations in calcium metabolism may be associated with CAC progression. For example, Shin et al. (5) reported that higher serum levels of calcium, phosphate, and the calcium-phosphate product were associated with greater CAC, and Young et al. (6) reported that vitamin D deficiency was associated with a greater risk of CAC in patients with type 1 diabetes mellitus. In diabetic patients, Krajnc et al. (7) reported major differences in CAC for those without nephropathy compared with patients undergoing hemodialysis. Cranenburg et al. (8) described lower levels of a vitamin K–related metabolite, uncarboxylated matrix Gla protein, in hemodialysis-treated patients with more severe CAC.
Population-based observational studies of CAC have laid down a solid understanding of the role of traditional risk factors for clinical coronary artery disease and have provided insights into the biology of CAC. Few of the investigations have been longitudinal and have researched both development and progression of CAC. Unfortunately, such studies are costly, take time, and the study interval may need to be longer than 5 years to observe appreciable changes in CAC. Both cross-sectional and longitudinal studies have focused on the development of classic CAC, but newer measures such as plaque volume and plaque density analyses hold promise to provide new insights into the biological mechanisms (9).
Investigators should consider the possibility of undertaking specialized study designs and the use of select study populations that could enrich the discovery of mechanisms underlying CAC development and progression. For example, case-control studies of persons with inflammatory conditions such as rheumatoid arthritis (10), or persons with altered calcium, vitamin D, and parathyroid hormone metabolism compared to adults with normal metabolism, could be especially fruitful. MESA investigators reported a pilot study of subjects with hyperparathyroidism with age- and sex-matched controls (11). These investigators did not identify a difference in CAC scores between subjects with elevated parathyroid hormone levels and subjects with normal function, but that sort of study design provides an example of a novel and potentially fruitful research design for CAC investigators in the future. The overall goal is to improve our understanding of CAC and its development. With greater understanding of the biology of arterial calcification, we could be in a position to develop newer interventions to treat and prevent arteriosclerotic coronary artery disease.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Dr. Wilson has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
- Diederichsen S.Z.,
- Grønhøj M.H.,
- Mickley H.,
- et al.
- den Harder A.M.,
- Wolterink J.M.,
- Willemink M.J.,
- et al.
- Kronmal R.A.,
- McClelland R.L.,
- Detrano R.,
- et al.
- Young K.A.,
- Snell-Bergeon J.K.,
- Naik R.G.,
- et al.