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Long-term Statin Therapy is Associated with Severe Coronary Artery Calcification

Kyari Sumayin Ngamdu, Dhairyasheel S. Ghosalkar, Hojune E. Chung, Jared L. Christensen, Cadence Lee, Celia A. Butler, Tiffany Ho, Alice Chu, Jacob R. Heath, Muhammad Baig, Wen-Chih Wu, Gaurav Choudhary, Alan R. Morrison

Abstract
Atherosclerosis and consequent risk of cardiovascular events or mortality can be accurately assessed by quantifying coronary artery calcium score (CACS) derived from computed tomography. HMG-CoA-reductase inhibitors (statins) are the primary pharmacotherapy used to reduce cardiovascular events, yet there is growing data that support statin use may increase coronary calcification. We set out to determine the likelihood of severe CACS in the context of chronic statin therapy.

Introduction
Coronary artery disease (CAD) due to calcific atherosclerosis is a major cause of morbidity and mortality worldwide. Measures of increased atherosclerotic plaque calcification have been predictive of coronary artery disease burden, cardiovascular events, and all-cause mortality. Moreover, an increasing rate of progression of the calcification in the coronary vasculature has been associated with worsening prognosis and increased adverse events. 

More recently, there has been evidence supporting the association between increased density of calcification in atherosclerotic plaques and more stable disease. Pharmacotherapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has been successful at reducing the risk of cardiovascular events such that statins have become the current standard of care in patients at moderate to elevated cardiovascular risk

Materials and methods
The Providence Veterans Affairs Medical Center (PVAMC) Institutional Review Board (IRB) approved this study and granted a Health Insurance Portability and Accountability Act (HIPAA) authorization waiver and waiver of consent. This study complies with the Declaration of Helsinki, and all patient data were managed in full compliance of the HIPAA regulations. This study was a retrospective analysis of medical records, and all patient data were fully anonymized for analysis. For the purpose of reproducing the results or replicating the study, the anonymized minimal dataset can be accessed as a (S1 File).

Results
We evaluated a total of 1,181 individuals who underwent clinically indicated LCSCT for significant smoking history at PVAMC between October 1, 2013, and July 31, 2014, and met the inclusion/exclusion criteria (Fig 1, Table 1). The mean age of this population was 64.7 (SD: 7.2) years. Indicative of the northeast U.S. veteran population, the vast majority of these patients were Caucasian (94%) and male (95.5%). The mean BMI of the population was 28.9 (SD: 6.1) kg/m2.

Discussion:
Coronary artery calcification is a marker of the overall burden of atherosclerosis and is associated with worsening cardiovascular events and all-cause mortality. However, recent studies indicate that the ultrastructural composition of calcium within plaque may confer features of reduced risk and consequent plaque stability in some instances. Statins have been tremendously successful at reducing the risk of cardiovascular events in patients, and this risk reduction has been demonstrated to be out of proportion to the lipid-lowering effect, suggesting alternative mechanisms may help to stabilize coronary plaque. While there continues to be some disagreement over whether statins can influence the calcium composition of atherosclerotic plaque, growing clinical data support that statins may increase atherosclerotic calcification.

Conclusions
In conclusion, long-term duration of time on statin therapy is associated with likelihood of having severe CACS in patients who have sufficient smoking history to qualify for lung cancer screening. These findings highlight an important complexity to the relationship between statin therapy and CACS, indicating that risk from CACS should be interpreted not just in the context of traditional cardiovascular risk factors and serial CACS progression, but also in the context of plaque-altering treatment. The use of CACS to interpret cardiovascular event risk may require adjustment in the context of chronic statin therapy.

Citation: Ngamdu KS, Ghosalkar DS, Chung HE, Christensen JL, Lee C, Butler CA, et al. (2023) Long-term statin therapy is associated with severe coronary artery calcification. PLoS ONE 18(7): e0289111. https://doi.org/10.1371/journal.pone.0289111

Editor: Xinlin Zhang, Nanjing Drum Tower Hospital: Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, CHINA

Received: August 23, 2022; Accepted: July 11, 2023; Published: July 27, 2023

Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Data Availability: The data can be found in the fully anonymized minimal data set provided as a supplemental file.

Funding: Research reported in this publication was supported by National Heart, Lung, and Blood Institute of the National Institutes of Health under award numbers R01HL139795 (A.R.M.), R01HL163005 (A.R.M), and R01HL148727 (G.C.). This work was also supported by National Institute of General Medical Sciences of the National Institutes of Health under Institutional Development Award number P20GM103652 (G.C. & A.R.M.). This work was also supported by VA VHA BLR&D IK2BX002527(A.R.M.), VA VHA CSR&D 1I01CX002231 (A.R.M), and VA VHA CSR&D 1I01CX001892 (G.C.). The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the US government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.