Inflammation, coronary plaque progression, and statin use: A secondary analysis of the Risk Stratification with Image Guidance of HMG CoA Reductase Inhibitor Therapy (RIGHT) study

Abstract Background Statin treatment is a potent lipid‐lowering therapy associated with decreased cardiovascular risk and mortality. Recent studies including the PARADIGM trial have demonstrated the impact of statins on promoting calcified coronary plaque. Hypothesis The degree of systemic inflammation impacts the amount of increase in coronary plaque calcification over 2 years of statin treatment. Methods A subgroup of 142 participants was analyzed from the Risk Stratification with Image Guidance of HMG CoA Reductase Inhibitor Therapy (RIGHT) study (NCT01212900), who were on statin treatment and underwent cardiac computed tomography angiography (CCTA) at baseline and 2‐year follow‐up. This cohort was stratified by baseline median levels of high‐sensitivity hs‐CRP and analyzed with linear regressions using Stata‐17 (StataCorp). Results In the high versus low hs‐CRP group, patients with higher baseline median hs‐CRP had increased BMI (median [IQR]; 29 [27–31] vs. 27 [24–28]; p < .001), hypertension (59% vs. 41%; p = .03), and LDL‐C levels (97 [77–113] vs. 87 [75–97] mg/dl; p = .01). After 2 years of statin treatment, the high hs‐CRP group had significant increase in dense‐calcified coronary burden versus the low hs‐CRP group (1.27 vs. 0.32 mm2 [100×]; p = .02), beyond adjustment (β = .2; p = .03). Conclusions Statin treatment over 2 years associated with a significant increase in coronary calcification in patients with higher systemic inflammation, as measured by hs‐CRP. These findings suggest that systemic inflammation plays a role in coronary calcification and further studies should be performed to better elucidate these findings.

measured by hs-CRP. These findings suggest that systemic inflammation plays a role in coronary calcification and further studies should be performed to better elucidate these findings.

K E Y W O R D S
coronary calcification, inflammation, statin treatment

| INTRODUCTION
Inflammation is vital to the progression of atherosclerosis and accounts for 20%-30% of residual risk for adverse cardiovascular events, driven in part by rupture of unstable coronary plaque. [1][2][3] Systemic inflammatory diseases are associated with elevated risk of atherosclerotic events and premature cardiovascular disease. [4][5][6][7] In particular, patients with psoriasis, a chronic inflammatory disease, have an increased development in noncalcified coronary burden (NCB), which serves as an important predictor of future cardiac events beyond traditional risk factors. 8,9 Calcified plaques, commonly referred to as dense-calcified coronary burden (DCB), are traditionally known to be more stable than NCB. 10 Recently, the PARADIGM study 11 reported that statin treatment promotes coronary artery calcification, thus conferring a lower risk of adverse cardiac events. 12 Chronic inflammatory conditions, such as psoriasis, are considered a major indication to begin statin treatment in patients at intermediate risk of heart attack or stroke by the 2018 AHA Cholesterol Guidelines. 13 Statins also reduce systemic inflammation as assessed by aortic FDG uptake on PET/CT. 14 Further, they reduce incident cardiovascular events in those with elevated high-sensitivity C-reactive protein (hs-CRP). 15 Hs-CRP is a prognostic biomarker of inflammation that predicts incident MI, stroke, and peripheral arterial disease. 16  scans at baseline and 2-year follow-up ( Figure S1).
Participants either received statin treatment using an imageguided assessment of atherosclerosis via coronary computed tomography angiography (CCTA), or statin treatment in accordance with standard clinical practice as described by the NCEP (National Cholesterol Education Program, Panel III) guidelines.
After a 2-year follow-up, the two groups were compared for differences in carotid wall thickness. These primary results are reported on Clinicaltrials.gov (NCT01212900).
Our subcohort consisted of 142 participants who completed two sets of CCTA scans, in addition to the aforementioned MRI, to assess differences in coronary plaque progression and were further stratified based on the median value of baseline hs-CRP (Table 1 and Figure S1).

| Inclusion/exclusion criteria
Exclusion criteria were ineligibility for MRI due to: previous pacemaker implantation, presence of automatic implantable cardioverterdefibrillator, metal implants, or other ferromagnetic devices, and foreign material. Other exclusion factors included contraindication or allergy to statin medications, claustrophobia, current statin treatment at or above the maximum dosage permitted by study therapy, use of fibrates, ezetimibe, niacin, or bile acid binding agents within 6 months of screening visit, and pregnancy and nursing. All participants were provided written, informed consent, and all study protocols were approved by the institutional review board of the National Institutes of Health and complied with the Declaration of Helsinki.

| Carotid artery wall volume measured by MRI
Carotid MRI was carried out using a 3-T scanner and surface carotid coils. Images were acquired cross-sectionally with a DIR fast spin-echo pulse sequence, ECG gated, with black blood and fat suppression. Slice thickness was 2.0 mm with in-plane resolution of 500-600 µm. Readers used commercially available contouring software (QPlaque, Medis Inc) and were blinded to group assignment. .00 Delta ( Delta (

| Effects of inflammation on clinical and lipid parameters
The cohort was middle-aged (mean ± SD; 65 ± 6.3 years), predomi-

| Baseline statin intensity of cohort
There were no differences in baseline low/medium/high-intensity statin use among participants when the cohort was stratified by median value of baseline hs-CRP (  (Table S1). Despite these similar levels, participants with high hs-CRP experienced significant increase in the change in DCB without significant differences in the change in NCB over the 2-year period of statin treatment (Table 1). Increased hs-CRP significantly associated with change in DCB and persisted beyond adjustment for hypertension, BMI, LDL-C, triglycerides, and statin intensity (Table 3)  scores over 2 years (deltaCAC) was not significantly associated with log(hs-CRP) or change in log(hs-CRP) ( Table 4).

| DISCUSSION AND CONCLUSION
We performed a secondary analysis of the (RIGHT) study (NCT01212900) to assess the potential differential effect of statin treatment on coronary calcification in patients stratified by pretreatment hs-CRP levels. We found that patients with higher baseline inflammation had significant increase in mean coronary calcification content, which leads them to derive more benefit from statin treatment. 19 Thus, our findings demonstrate the effectiveness of statin treatment in inducing greater coronary calcification in patients with higher baseline inflammation, but larger studies are needed to understand the basis of these findings.
Our results on calcification occurring following statin treatment are in line with the findings from the PARADIGM study (NCT02803411), which characterized the modulation of coronary artery plaque in a primary prevention cohort stratified by statin use 11 and found that statin treatment associated with slower progression of overall coronary atherosclerosis volume, reduction of high-risk plaque features, and increased plaque calcification. 11 The JUPITER study found a reduction in cardiovascular events in those with elevated hs-CRP after treatment with rosuvastatin 15 and it is possible that plaque stabilization occurred following statin treatment, but this was not evaluated in that study.
Our findings also suggest the potential contribution of inflammation in promoting microcalcification. Microcalcifications represent an early, active stage of vascular calcification correlated with an inflammatory state and directly contribute to plaque rupture. [20][21][22] We found that participants with higher baseline inflammation experienced significant increase in coronary calcification over 2 years of statin treatment, as assessed by DCB, illustrating the association between inflammation, microcalcification, and the effect of statin treatment on coronary calcification. However, CAC scores did not differ between high versus low hs-CRP groups over 2 years.
This further confirms that while the CAC score is a good measure of overall plaque burden and stable end-stage macroscopic calcification, it is not a useful measure in identifying unstable atherosclerotic plaques. 22,23 Further, our findings suggest that DCB may be a potential sensitive measure of microcalcifications; however, these results must be confirmed with 18F-sodium fluoride (18F-NaF) positron emission tomography (PET)/CT imaging, as CCTA has limited spatial resolution to detect such changes. 22,24 18 F-NaF PET/CT imaging is an imaging modality sensitive to microcalcifications that has been established as a method to better elucidate the relationship between inflammation, microcalcification, and atherosclerotic plaque activity. 22,24 While our findings provide insight into the potential effects of statins on patients with higher inflammation, we acknowledge that there are limitations to our study. As this study was observational and cross-sectional in nature, causality and directionality are difficult to establish. It is also a post-hoc analysis and is therefore subject to inherent residual confounding. Additionally, due to a small sample size, the study groups did not have the power to adjust for additional  F I G U R E 1 Central illustration of coronary calcification and inflammation. Increased coronary calcification, as measured by dense-calcified coronary burden, in the left anterior descending artery in patients with higher baseline inflammation, as measured by median high-sensitivity C-reactive protein (hs-CRP). Images were captured through CCTA and analyzed with QAngio CT (Medis). CCTA, cardiac computed tomography angiography