International Journal of Cardiovascular ResearchISSN: 2324-8602

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Research Article, Int J Cardiovasc Res Vol: 4 Issue: 4

Statin Therapy is Associated with Reduction of Epicardial Adipose Tissues and Coronary Plaque Volumes with Vulnerable Composition, Measured by Computed Tomography Angiography

Naser Ahmadi*, Vahid Nabavi, Jennifer Malpeso, Fereshteh Hajsadeghi, Hussain Ismaeel and Matthew Budoff
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center,Torrance, California, USA
Corresponding author : Naser Ahmadi, MD
David Geffen School of Medicine,UCLA, 1124 W. Carson Street, RB3, Torrance, CA, 90503, USA
Tel: +310-803-0443
E-mail: [email protected]
Received: January 30, 2015 Accepted: April 27, 2015 Published: April 29, 2015
Citation: Ahmadi N, Nabavi V, Malpeso J, Hajsadeghi F, Ismaeel H, et al. (2015) Statin Therapy is Associated with Reduction of Epicardial Adipose Tissues
and Coronary Plaque Volumes with Vulnerable Composition, Measured by Computed Tomography Angiography. J Cardiovasc Res 4:4. doi:10.4172/2324-8602.1000216

Abstract

 Statin Therapy is Associated with Reduction of Epicardial Adipose Tissues and Coronary Plaque Volumes with Vulnerable Composition, Measured by Computed Tomography Angiography

Background: Increased coronary plaque volume and epicardialadipose-tissue (EAT) are independently predicting major-adversecardiovascular-events. This study evaluates the changes in EAT, total and composition-specific plaque-volume measured noninvasively by computed-tomography-angiography (CTA) in subjects with and without statin-therapy. Methods: This is a study of 106 consecutive-subjects (age 67 ± 9years, 80.7% men) who underwent serial clinically-indicated CTAs with median-interval of 1.2-year. Clinical and demographicfindings of 31 with statin-therapy and 75 without statin-therapy were evaluated. Changes in indexed total and composition-specific plaque-volume of target-segment with luminal-stenosis <50% as well as EAT, adipose-tissue inside pericardial-sac, were measured quantitatively. Results: At baseline, there was no significant difference in EAT, total and composition-specific plaque-volumes among subjects with and without statin-therapy (p>0.05). At follow-up, there were significant absolute-decrease in total plaque-volume (-38.2%) and EAT (-18.4%) in individuals with statin-therapy as compared to those without statin-therapy (p=0.0001). Similarly, significant decrease in non-calcified and mixed plaque-volume as well as lack of progression of calcified plaque-volume in statin-therapy group was noted (p<0.05). Risk adjusted median-decrease in total, mixed, calcified, non-calcified plaque-volumes, and EAT were 56%, 12%, 43%,144% and 76% more in statin-therapy as compared to those with diet-therapy (p<0.05). Furthermore, a significant directcorrelation between decrease in LDL-C and reduction in noncalcified plaque-volume (r2=0.64,p=0.0001) and decrease in EAT and non-calcified plaque-volume was noted (r2=0.69,p=0.0001). Conclusions: Statin therapy is associated with concomitant decreases in LDL-C, EAT and coronary plaque volumes especially non-calcified and mixed coronary plaques, which the latter suggesting plaque stabilization. This highlights that CTA can accurately and quantitatively measure the changes in EAT and coronary plaque volumes over time and monitor response to therapies.

Keywords: Coronary plaque volume; Computed tomography angiography; Statin-therapy; Plaque composition; Epicardial adipose tissue

Keywords

Coronary plaque volume; Computed tomography angiography; Statin-therapy; Plaque composition; Epicardial adipose tissue

Introduction

Coronary plaque volume and its progression over time as well as epicardial adipose tissue (EAT) are independent predictors of cardiovascular mortality [1,2]. EAT is associated with the pathogenesis of coronary plaque formation as well as plaque vulnerability through a paracrine effect [3,4].
The current coronary artery disease (CAD) treatment guidelines, e.g. the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III), identify low density-lipoprotein (LDL)-cholesterol as the primary target for prevention of CAD [5]. Numerous large-scale, multicenter, randomized, primary and secondary prevention clinical trials reported the clinical benefit of lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) [6]. A part of the clinical benefit of statins is believed to be mediated through causing coronary plaque stabilization and regression. However, non-invasive monitoring of plaque progression, EAT and their relation remains a challenge and its clinical utilization is still unclear [1,7].
Cardiovascular computed tomography angiography (CTA) is an emerging noninvasive technology able to identify and prognosticate CAD and its outcome [8]. CTA with its excellent negative predictive value and incremental value in predicting cardiovascular events is an invaluable tool in assessing symptomatic patients with an intermediate likelihood of CAD [9]. CTA’s ability to visualize the characteristics and morphology of coronary plaques as well as EAT is promising [4]. Serial IVUS, while safely and accurately assess changes in the nature and severity of coronary atheroma with time is an invasive procedure requiring hospitalization, presence of cardiac catheterization laboratory and expensive equipment’s [10]. Similarly, histopathology studies of EAT is invasive, expensive and not practical in clinical setting [11]. Recent studies have shown that CTA can accurately and reliably evaluate the burden of atherosclerosis, plaque morphology and volume as well as EAT; with results comparable to those of intravascular ultrasound (IVUS) and histopathology, respectively [4].
This study evaluates the change in total plaque volumes and composition-specific plaque-volumes as well as EAT, measured by computed tomography angiography (CTA) in subjects with and without statin therapy.

Methods

This nonrandomized case-control study included 106 consecutive subjects (aged 67 ± 9 years, 80.7% men) with non-obstructive CAD (luminal stenosis of 1% to 49%), who were referred to CTA laboratory for evaluation of chest pain and suspected coronary artery disease (CAD). None of subjects were on lipid lowering therapy at baseline. Of all studied subjects, 31 received atorvastatin 40 mg/day plus dietary intervention and 75 declined any form of lipid-lowering pharmacotherapy and received dietary intervention alone. Serial clinically indicated CTA -for evaluation of chest pain- was performed at baseline and subsequently after a median duration of 1.2 years. The changes in plaque volumes of discrete non-obstructive lesion (1-49% stenosis by CTA) that were not in tandem or diffuse as well as EAT over were studied. Subjects with established cardiovascular disease, stroke, diabetic retinopathy, Raynaud’s syndrome, active infection, cancer, immunosuppression, systemic inflammation, advanced renal or liver disease, CTA measured left ventricular ejection fraction <50%, creatinine >1.4 mg/dl, and triglyceride >400 mg/dl were excluded. The study protocol and consent form were approved by the Institutional Review Board Committee, Board of Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center, Torrance, California.
Cardiac CTA: Beta blockers were administered for pulses greater than 65 bpm. A test IV bolus of 15 ml of contrast agent was followed by 20 ml of normal saline flush at a rate of 4.5 ml/s. Using a dualhead power injector (Stellant, Medrad, Indianola, PA), a prospective ECG gated cardiac CT angiography (mSv:3.8 ± 1.5) was performed with a tri-phasic consecutive injection sequence beginning with 50 ml nonionic IV contrast material (Iopamidol 370; Bracco Diagnostics, Plainsboro, NJ) injected at a rate of 5.0 ml followed by 50 ml of a mixture of 60% contrast and normal saline and ended with a 50- ml flush of normal saline. Contrast was injected through an 18- to 20-gauge angiocatheter in an antecubital vein. Mean heart rate during the scan was 56 ± 3 bpm.
Data acquisition
A snapshot pulse acquisitions axial ECG-Triggering mode with prospective gating using the 64- Multi-detector Computed Tomography (MDCT) lightspeed VCT scanner (General Electric Healthcare Technologies, Milwaukee, WI) was used for all patients. Imaging was started 1 inch above the left main ostium and continued to 1 inch below the bottom of the heart. The following imaging and reconstruction parameters were applied: data acquisition collimation 0.625 mm×64=4 cm; 120 kVp; 220–670 mAs; pitch 0.18–0.24 (depending on heart rate); rotation time 0.35 s; slice width 0.625 mm; matrix 512×512 and pixel size 0.39 mm2. ECG-triggered dose modulation with padding was applied in each case with 400–600 mA in 70–80% R-R interval.
Coronary Plaque Measurement: Coronary vessels were reviewed (Vitrea 5.2, Vital Images, Minnetonka, Minnesota) and volume renderings and curved multi-planar reformations were done. Starting and terminating points of each target segment containing the study lesion were carefully selected (Figure 1). Within each segment, we determined contrast resolution, geometric and compositional parameters. Percentage of atheroma volume was calculated using the following equation: (total vessel area – total lumen area)/total vessel area. All values were indexed for lesion length to give the vascular volume index, lumen volume index, and plaque volume index [12] Compositional parameters included the volume and percentage of 3 components: calcified, mixed and non-calcified atherosclerotic plaques. Between the outer vessel wall boundary and the luminal boundary, voxels were classified as calcified with attenuation values 130 HU (Hounsfield units) or greater, and non-calcified with attenuation values of -100 to 129 HU, and mixed plaque with combination of calcified and non-calcified components. Total volume and percentage of each of the 3 plaque were measured in each target segment using automated software (Figure 1). We have previously evaluated and published inter-rater reliability for this approach [12- 14]. Two skilled cardiologists blinded to the clinical data assessed the coronary arteries separately. The coronary arteries were divided into 1) left main coronary artery (LM), left anterior descending artery (LAD) and diagonal branches; 2) left circumflex (LCX) and obtuse marginal branches; group 3) right coronary artery (RCA), acute marginal branches, posterior descending artery (PDA) and posterolateral branch (PLB). Left or right dominance was determined [15].
Figure 1: Characteristic of mixed coronary plaque volume with calcified and non-calcified components in the proximal left anterior descending coronary artery at baseline and 1 year follow up.
Epicardial Adipose Tissue (EAT) Measurement: Two experienced computed tomography readers, blinded to each other, patient characteristics, and treatment status, measured EAT. EAT, adipose tissue inside the pericardial sac, was measured in axial images starting 15 mm above the superior extent of the left main coronary artery to the bottom of the heart. Volume Analysis software (GE Healthcare, Waukesha, WI) was used to discern EAT on the basis of a corresponding HU threshold of -190 to -30 HU (mean, -120 HU) [4]. EAT was measured by a semiautomatic segmentation technique in each slice with the above display settings. The reader was required to manually trace the EAT. The EAT volume is the sum of all voxels (cubic centimeters) containing adipose tissue from 15 mm above the left main coronary artery ostium to bottom of the heart.

Statistical Analysis

Mean ± SD and proportions were used to summarize the characteristics of the study group. Continuous variables were compared by t test, and categorical variables were compared by the chi squares test. Logistic regression analyses were employed to assess the relationship of change in EAT, total and composition-specific plaque volume in subjects with and without statin therapy, before and after adjustment for age, gender, family history of premature coronary heart disease, hypertension, hypercholesterolemia, diabetes mellitus, baseline coronary plaque volumes, EAT and lipid profiles. All statistical analyses were performed with STATA 12.2 (www.stata. com, College Station, Texas) and SPSS version 20.0 (www.spss.com, SPSS Institute Inc., Chicago, IL). The level of significance was set at p<0.05 (two-tailed).

Results

Table 1 shows that there were no significant differences between the groups in terms of age, gender, diabetes mellitus and body mass index at baseline. Hypertension, hypercholesterolemia and family history of premature CHD were more prevalent in atorvastatin group as compared to diet therapy group (P<0.05).
Table 1: Demographic Characteristics of Subjects with and without Statin Therapy. (Note: aSelf-reported diagnosis of hypertension, prescribed medication for hypertension, or current blood pressure >140 mmHg systolic or >90 mmHg diastolic (>130/80 mmHg if diabetic). b Self-reported diagnosis of high cholesterol, prescribed medication for high cholesterol, or current total cholesterol >200 mg/ dl. c Self-reported diagnosis of diabetes (type 1 or 2) or prescribed medication for diabetes or two fasting blood sugar with a month interval >126 mg/dl. d First degree relative; female <65 years, male <55 years.
Table 2 demonstrates the baseline and annual change in lipid profile and composition-specific plaque volumes. There were no significant differences between groups in low density lipoprotein cholesterol, EAT, total, calcified, mixed and non-calcified plaque volumes at baseline (P>0.05). At 1-year, decreases in total, mixed and non-calcified plaque volumes were significantly higher in atorvastatin as compared to diet therapy (p<0.05) (Figure 2). Furthermore, there was a trend with decrease in progression of calcified plaque volume with Atorvastatin as compared to diet therapy (p=0.1). In addition, levels of EAT, LDL-C, triglyceride and total cholesterol were significantly lower in Atorvastatin (p<0.05). Similarly, levels of HDL-C was significantly higher with Atorvastatin (p<0.05) (Table 2). There was a significant direct correlation between decrease in LDL-C and reduction in non-calcified plaque volume (r2=0.64, p=0.0001), also there was a significant decrease in EAT and non-calcified plaquevolume (r2=0.69, p=0.0001) after adjustment for risk factors and changes in LDL-C. Similar association between decrease in EAT and CAC non-progression (annual CAC increase<15%) was noted (r2=0.45, p=0.0001).
Figure 2: Statin therapy is associated with significant decrease in noncalcified and mixed coronary plaque volumes as well as lack of progression of calcified plaque volumes.
Table 2: Baseline and Absolute Change at Follow up in Lipid profile, Total and Composition-specific Coronary Plaque Volumes in Subjects with and without Statin therapy.
Table 3 reveals that after adjustment for risk factors including age, gender, family history of premature coronary heart disease, hypertension, hypercholesterolemia, diabetes mellitus, baseline coronary plaque volumes, EAT and lipid profiles, the likelihood ratio of decreased total plaque volume was 56% higher in atrovastatin as compared to diet therapy group (P<0.05). Similarly the likelihood ratio of decreased non-calcified, mixed and calcified plaques as well as EAT were 2.44, 1.12, 1.43 and 1.76 in atorvastatin group as compared to diet therapy group, respectively. (p<0.05). Finally, the likelihood ratio of simultaneous decreased non-calcified plaque volume (<median) and decreased EAT (<median) was 6.68 (95%CI 3.4 -11.8, p=0.0001) in atorvastatin group as compared to diet therapy group.
Table 3: Baseline and Absolute Change at Follow up in Lipid profile, Total and Composition-specific Coronary Plaque Volumes in Subjects with and without Statin therapy.
Figure 3 shows that there is significant absolute annual decrease in total plaque volume with atorvastatin, but not in diet group, in both genders which was more prominent in females (p<0.05).
Figure 3: Statin therapy is associated with significant decrease in total coronary plaque volumes in both genders which is more robust in females.
Figure 4 reveals that higher rate of decrease in non-calcified plaque volume in response to atorvastatin was noted in women as compared to men, especially in volume of non-calcified plaque.
Figure 4: Absolute annual change in non-calcified coronary plaque volumes in subjects with and without statin therapies across genders.

Discussion

The present study demonstrated that: 1) Statin therapy was associated with significant decrease in CTA measured coronary plaque volumes and EAT, which were more robust in women, 2) The effect of statins was mainly on mixed and non-calcified coronary plaques, and 3) There is a direct association between decreases in noncalcified plaque volume, decreases in EAT and decreases in LDL-C in response to statin therapy.
Vulnerable Plaque and Statin Therapy: Non-obstructive coronary plaques are much more prevalent than severely obstructive plaques. Most acute coronary syndromes (ACS) are caused by the rupture of mild to moderate plaques that did not significantly compromise the coronary lumen before the event [16]. We recently reported that the presence of non-calcified and mixed coronary plaques independently provided incremental value in predicting all-cause mortality in symptomatic subjects with non-obstructive CAD [17]. Plaque regression and stabilization are expected to be the key mechanisms underlying the clinical benefit of lipid-lowering therapy with statins [18]. Otagiri et al analyzed the change in volume and tissue characteristics of non-obstructive plaques measured by IVUS in response to rosuvastatin in 20 subjects with acute coronary syndrome (ACS). From baseline to 6-month follow up, the low-density lipoprotein-cholesterol levels decreased significantly from 117 ± 34 mg/dl to 73 ± 19 mg/dl (P<0.001) after statin therapy. Similarly, plaque burden significantly reduced from 98.4 ± 42.1 mm3/10 mmto 80.2 ± 35.8 mm3/10 mm (P<0.001) and in the lipid volume from 44.1± 29.6 mm3/10 mm to 28.6 ± 17.8 mm3/10 mm (P<0.001). With respect to the % lipid volume, the reduction rate at follow-up showed a significant correlation with its baseline value (r=-0.498, P=0.024) [19]. A comparable reduction in plaque volume in response of different statins has been reported [20,21]. The current study reconfirms previous studies; demonstrating that there is a significant correlation between decrease in LDL-C and a reduction in plaque and lipid volume in response to statin therapy [20].
EAT and Statin Therapy: EAT is a metabolically active organ which plays a pathogenetic role in the development and progression of coronary atherosclerosis, also is associated with plaque vulnerability characteristics such as low-density cores, positive remodeling, and spotty calcification [22]. EAT has paracrine and vasocrine signaling effects on coronaries and myocardium [11]. Adipokines and proinflammatory cytokines – secreted from EAT- directly interact with vasa vasora, vascular smooth muscle cells, endothelium and cellular components of the plaque. Furthermore, these cytokines migrate alongside the vasa vasorum into its lumen and are transported downstream to react with cells in the media and the intima around plaques [11]. Alexopoulos et al. in their sub-study of the BELLES trial on 420 patients - 194 on atorvastatin and 226 on pravastatinreported that EAT, but not coronary artery calcium, reduced with intensive statin therapy in post-menopausal women [23]. There are in line with animal studies that demonstrated statin therapy reduced white adipose tissue activity, facilitate weight reduction, and ameliorate insulin resistance [24]. The findings of the current study confirms previous studies that salutary effects in response to statin therapy have been associated with evidence of concomitant removal of oxidized phospholipids from the vessel wall and the stabilization of atherosclerosis, as well as reduction in low-density lipoprotein particles, also provides evidence of strong correlation between decreases in EAT and regression in coronary plaque volumes especially in mixed and non-calcified coronary plaques [23,25].
Clinical Implications: A direct relationship was observed between the burden of coronary atherosclerosis, its progression, and adverse cardiovascular events [7]. Recent studies comparing quantitatively CTA-measured tissue components of plaque to histopathology have shown that CTA density values correspond well with plaque histology and also can detect non-calcified, mixed and calcified plaque [26] with excellent accuracy, inter- and intra-observer agreement [27]. EAT is measured on the same scans with no extra radiation exposure, time, and cost for the patient with very good reproducibility and accuracy [4]. The current study reconfirmed previous studies [26,28] that serial CTA follow-up studies can non-invasively and accurately measures quantitative changes in total and composition-specific coronary plaque volumes as well as EAT over time, at very low radiation dose in the community based setting [29]. Furthermore, our study demonstrated a direct association between decrease in LDL-C with decrease in EAT as well as non-calcified plaque volumes in response to statin therapy which latter observation suggests plaque stabilization [25,30] .

Limitation

This study has several limitations. This is a nonrandomized casecontrol study of consecutive patients with non-obstructive CAD who underwent CTA with relatively small sample size. However, the findings of the current study revealed a significant decrease in total and composition-specific coronary plaque volumes in response to statin therapy after adjustment for risk factors. Given the established clinical benefit of lipid-lowering therapy, it would have been unethical to withhold treatment from the control group or to use a crossover design. We therefore relied on patients who could not tolerate or had declined lipid-lowering therapy for our control group, raising the possibility of selection bias. Nevertheless, the treatment and control groups in our study were very comparable with respect to age, gender, EAT, total and composition-specific plaque-volumes and prevalence of diabetes mellitus at baseline. Finally, over the short duration of this study, it was not possible to assess the significance of these changes with respect to event-driven, hard clinical endpoints. Nevertheless, such changes seen in the lipid profile have been previously established to translate into substantial decreases in clinical events with drugs in this class.

Conclusions

Statin therapy is associated with significant decrease in LDL-C, EAT and coronary plaque volumes especially non-calcified and mixed coronary plaques in at risk individuals without known CAD. The salutary effects in response to statin therapy have been associated with evidence of concomitant decrease in LDL-C and EAT and the stabilization of coronary atherosclerosis measured by reduction of coronary plaque volumes with vulnerable composition. This highlights that CTA can accurately and quantitatively measure the changes in EAT and coronary plaque volumes in response to therapies over time and play a pivotal role in follow up management of high risk individuals for CAD.

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