Epicardial adipose tissue (EAT) has been recognized as a sensitive marker of cardiometabolic risk. Recent evidence suggests efficacy of long-term statin therapy in reducing EAT in patients with coronary artery disease. Whether short-term statin therapy is associated with changes in the volume of EAT is currently unknown. A cohort of patients with atrial fibrillation who underwent pulmonary vein isolation were randomized to receive either 80 mg/day of atorvastatin (n = 38, 32 men, age 56 ± 11 years) or placebo (n = 41, 33 men, age 56 ± 10 years) for a 3-month period. EAT volume was assessed by cardiac computed tomography at baseline and at follow-up. Patients randomized to statin treatment exhibited a modest but significant decrease in median EAT volume (baseline vs follow-up: 92.3 cm 3 [62.0 to 133.3] vs 86.9 cm 3 [64.1 to 124.8], p <0.05), whereas median EAT remained unchanged in the placebo group (81.9 cm 3 [55.5 to 110.9] vs 81.3 cm 3 [57.1 to 110.5], p = NS). Changes in median systemic inflammatory markers and lipid profile were also seen with statin treatment: C-reactive protein (2.4 mg/L [0.7 to 3.7] vs 1.1 mg/L [0.5 to 2.7], p <0.05), total cholesterol (186 mg/dL [162.5 to 201] vs 123 mg/dL [99 to 162.5], p <0.001), and low-density lipoprotein cholesterol (116 mg/dL [96.5 to 132.5] vs 56 [40.5 to 81] mg/dL, p <0.001) diminished, whereas median body mass index did not change (27.8 kg/m 2 [25 to 30] versus 27.6 kg/m 2 [25.7 to 30.5], p = NS). No variations occurred in the placebo group. In conclusion, short-term intensive statin therapy significantly reduced the volume of EAT in patients with atrial fibrillation.
Epicardial adipose tissue (EAT) is a locally active endocrine organ covering 80% of the heart surface and is located between the myocardium and visceral pericardium. Because of its anatomical proximity and same microcirculation, epicardial tissue has been proposed to locally influence adjacent myocardium. Statins improve cardiometabolic status in subjects with cardiovascular risk factors and in patients with overt cardiovascular diseases. Recent evidence suggests efficacy of long-term statin therapy in reducing EAT in patients with coronary artery disease. Whether the volume of EAT changes in patients with atrial fibrillation (AF) treated with statins for a short time period is not known. Therefore, using a randomized, double-blind, placebo-controlled study design, we examined changes in EAT volume before and after 3 months of statin treatment.
Methods
We reviewed computed tomographic (CT) images of patients included in a clinical trial investigating the effects of intensive statin treatment on AF recurrence in patients who underwent pulmonary vein isolation (PVI, NCT00579098). The original prospective study was conducted at the Mayo Clinic from January 2008 to December 2009 and showed no difference between patients treated with statin compared with those in the placebo arm in terms of AF recurrence after PVI. Eligible patients were subjects aged ≥18 years with a clinical indication for a left atrial ablation procedure for AF. The definition and classification of AF used in this study were based on published guidelines from the American College of Cardiology-American Heart Association and the European Society of Cardiology. Patients with known malignancy, inflammatory diseases, surgery, trauma, or myocardial infarction in the previous month, those with contraindications to statin therapy, elevated liver enzymes >2-fold than the upper limit of normal, those using statin, niacin, or fibrates at the time of randomization, and those with an indication for statin therapy per published guidelines were excluded. One hundred twenty-five patients (98 men; aged 57 ± 10 years) were enrolled in the study and randomized in a 1:1 ratio to receive either atorvastatin (80 mg/day) or placebo starting on the first postoperative day and continuing for 3 months after the ablation procedure. Randomization was completed using a simple randomization schedule generated by SAS Statistical Software (SAS Institute, Cary, North Carolina). Only the statistician and pharmacist had access to the randomization schedule until the study was completed. Informed written consent was obtained from each patient, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Mayo Clinic Institutional Review Board.
All subjects underwent standard transthoracic echocardiography on the day before the ablation procedure. Measurements were performed according to the recommendations of the American Society of Echocardiography. Medical history and anthropometric measures were collected before intervention. Presence of hypertension, coronary artery disease, diabetes, and obstructive sleep apnea were determined by the presence of clinical diagnosis based on medical records. The CHA 2 DS 2 -VASc was calculated assigning 2 points to patients ≥75 years or those with a previous stroke or transient ischemic attack. A single point is assigned for each of female gender, heart failure, hypertension, age 65 to 74 years, diabetes, and vascular disease (myocardial infarction, aortic plaque, peripheral artery disease). Fasting venous blood samples for C-reactive protein (CRP), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were taken before initiation of the therapy and at the 3-month follow-up visit.
To identify the pulmonary vein stenosis, all subjects underwent a CT or magnetic resonance imaging scan within 30 days before the intervention and 3 months after the procedure. For the purpose of the current analysis, we reviewed all CT scans of adequate quality to measure EAT. Patients who underwent magnetic resonance imaging (n = 13) and those with incomplete CT data were excluded (n = 33). Cardiac CT angiography was acquired using a 64-slice CT (Sensation; Siemens Medical Solutions, Erlangen, Germany). Electrocardiogram-referenced scans were obtained after intravenous administration of contrast material (Omnipaque 350, GE Healthcare, Buckinghamshire, United Kingdom). Acquisitions were conducted on the entire heart area in the head-to-feet direction. Scan parameters were as follows: collimation 64 × 0.625 mm, gantry rotation time of 0.5 seconds, tube voltage of 120 kV, and tube current of 850 mA. Because pulmonary vein assessment was the primary clinical goal, 1.5-mm-thick images were reconstructed.
Epicardial fat quantification was conducted by a dedicated off-line workstation (Aquarius 3D Workstation; TeraRecon Inc., San Mateo, California). Image reconstructions were performed at 75% of the RR interval. The superior heart limit slice was selected at the split of pulmonary artery. The inferior heart boundary was set as the most inferior slice of the myocardium. Epicardial fat was defined as the entire adipose tissue outside the myocardium enclosed by the visceral pericardium. All epicardial fat measurements were performed by an experienced reader blinded to the randomization status. Pericardial contours were generated by spine interpolation through several controls that were placed manually. When necessary, the reader made manual adjustments through the scan volumes to account for interpolating errors. Fat voxels were identified using threshold attenuation values of −250 to −30 HU. The intraclass correlation coefficient for intrarater reliability was 0.99 (95% confidence interval 0.99 to 1.0), whereas intraclass correlation coefficient for inter-rater reliability was 0.98 (95% confidence interval 0.98 to 0.99), thus indicating excellent reproducibility of EAT measurements. Consistent with the protocol followed for assessing EAT on the entire cohort, readers were blinded to the study participant trial arm and to the results of the previous measures.
Normally distributed data are expressed as mean (SD), whereas median and interquartile ranges are provided for skewed variables. Categorical variables are presented as percentages. Wilcoxon rank-sum tests and Fisher’s exact tests were used to compare the baseline characteristics of continuous and categorical measures between the study arms (atorvastatin vs placebo), respectively. Changes from pre- to post-treatment in EAT, lipid profile, CRP, and body mass index (BMI) within each treatment group were tested by means of Wilcoxon signed rank tests. Between-group comparisons on delta values were performed with Wilcoxon rank-sum tests. To examine the relation between baseline EAT and clinical and laboratory parameters, univariate and multivariate regression analyses were run. Log transformation was applied to improve normality when needed, and the variance inflation factor was calculated to detect multicollinearity. The significance level was set at <0.05 for all tests. The JMP 9.0.3 (SAS Institute, Cary, North Carolina) statistical package was used for data management and analysis.
Results
Of the 79 patients included in this study, 38 received atorvastatin and 41 placebo. As summarized in Tables 1 and 2 , there were no significant differences in baseline characteristics between the study groups. As for the entire study cohort, atorvastatin treatment did not reduce 3-month AF recurrences in the population subset included in this study (log-rank test for group difference in the survival curves, p = 0.677). Patients randomized to atorvastatin exhibited a significant reduction in median EAT volume after 3 months of therapy (delta −4.6 cm 3 [−8.9 to 1.3] cm 3 , p <0.05, absolute values are provided in Table 2 ). Expected decreases in median CRP (delta −0.4 mg/L [−1.8 to 0.2] mg/L, p <0.05), total cholesterol (delta −61 mg/dL [−77 to −32], p <0.001), and LDL cholesterol (delta −55 mg/dL [−63 to −37], p <0.001) levels were also observed, whereas BMI, HDL cholesterol, and triglycerides did not change appreciably. In the placebo group, total cholesterol (delta 14 mg/dL [−5 to 29], p <0.01) and triglycerides (delta 24 mg/dL [−13 to 50], p <0.05) increased significantly, whereas EAT and other measures remained unchanged. The between-group comparison of EAT volume changes is shown in Figure 1 . In comparison with patients with paroxysmal AF, those with persistent AF had significantly higher baseline median EAT volume (100.4 cm 3 [75.1 to 131.3] vs 81.8 cm 3 [57 to 108.2], p <0.05).
| Characteristic | Atorvastatin (n=38) | Placebo (n=41) |
|---|---|---|
| Age (years) | 56 ± 11 | 56 ± 10 |
| Men | 32 (84 %) | 33 (81 %) |
| Hypertension | 12 (32 %) | 8 (20 %) |
| Coronary artery disease | 0 | 0 |
| Diabetes mellitus | 1 (3 %) | 0 |
| Obstructive sleep apnea | 10 (26 %) | 6 (15 %) |
| Current smokers | 4 (11 %) | 2 (5 %) |
| Left ventricle ejection fraction (%) | 0.57 ± 0.11 | 0.60 ± 0.07 |
| History of atrial fibrillation (years) | 5.4 ± 4.9 | 4.8 ± 4.2 |
| Left atrium volume index (cc/m 2 ) | 39 (29-43) | 36 (30-41) |
| Paroxysmal atrial fibrillation | 25 (66 %) | 35 (85 %) |
| CHA2DS2-VASc | 1 (0-1.25) | 0 (0-1) |
| Characteristic | Atorvastatin (n=38) | Placebo (n=41) | ||
|---|---|---|---|---|
| Baseline | Follow-up | Baseline | Follow-up | |
| Body mass index (kg/m 2 ) | 28 (26-32) | 27 (27-32) | 28 (25-30) | 28 (26-31) |
| C-reactive protein (mg/L) | 2.4 (0.7-3.7) | 1.1 (0.5-2.7) ∗ | 1.3 (0.7-2.1) | 1.3 (0.5-2.6) |
| Total Cholesterol (mg/dL) | 186 (163-201) | 123 (99-163) ‡ | 190 (173-210) | 204 (183-223) † |
| Low-density lipoprotein Cholesterol (mg/dL) | 116 (97-133) | 56 (41-81) ‡ | 122 (107-133) | 123 (110-146) |
| High-density lipoprotein Cholesterol (mg/dL) | 45 (37-54) | 48 (37-59) | 47 (38-56) | 46 (39-60) |
| Triglycerides (mg/dL) | 101 (74-150) | 83 (68-122) | 116 (74-144) | 118 (99-175) ∗ |
| Epicardial adipose tissue (cm 3 ) | 92 (62-133) | 87 (64-125) ∗ | 82 (56-111) | 81 (57-111) |
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