Adipose Tissue of Atrial Septum as a Marker of Coronary Artery Disease*

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1 CHEST Adipose Tissue of Atrial Septum as a Marker of Coronary Artery Disease* Nithima Chaowalit, MD; Virend K. Somers, MD, PhD, FCCP; Patricia A. Pellikka, MD; Charanjit S. Rihal, MD; and Francisco Lopez-Jimenez, MD, MSc Original Research CARDIOVASCULAR RESEARCH Background: Paracrine effects of epicardial adipose tissue may promote coronary atherosclerosis. Adipose tissue is the main determinant of atrial septum thickness. The association between atrial septum thickness and coronary artery disease (CAD) has never been studied. Methods: We studied 75 patients who underwent coronary angiography and echocardiography within 1 week (mean [ SD]duration, days). Atrial septum thickness, representing adipose tissue, was identified and measured with two-dimensional transthoracic echocardiography. Angiographic data were analyzed for the presence, extent, and severity of CAD, using a standardized 27-segment classification. Any CAD was defined as the presence of stenosis of any severity in at least one coronary vessel. The number of segments with a coronary artery with at least 20% stenosis (coronary artery greater even than 20 [CAGE > 20] score) was recorded. Results: The mean atrial septum thickness was cm (median, 1.42 cm; range, 0.74 to 2.55 cm). In a simple linear regression analysis, we found no significant correlation between atrial septum thickness and clinical variables (p > 0.05). However, we found a significant correlation between atrial septum thickness and any CAD (p 0.03), which persisted after controlling for age, gender, and body mass index (p 0.03). Patients in the lowest quartile of atrial septum thickness had a lower proportion of subjects with any CAD (p 0.02) and a lower median CAGE > 20 score compared to other quartiles (p 0.04). Conclusion: Adipose tissue of the atrial septum, represented by atrial septum thickness, is associated with the presence of CAD. (CHEST 2007; 132: ) Key words: atherosclerosis; coronary artery disease; echocardiography Abbreviations: CAD coronary artery disease; CAGE 20 coronary artery greater even than 20; HDL highdensity lipoprotein; LDL low-density lipoprotein The associations between excess body fat and coronary artery endothelial dysfunction, chronic systemic inflammation, or traditional cardiovascular risk factors has been described extensively. 1 4 However, the mechanisms through which excess body fat may promote atherosclerosis have not been well defined. Apart from an anatomic location of fat stores, visceral adipose tissue may act as an endocrine and paracrine organ with various biological and metabolic functions, including synthesizing and releasing atherogenic inflammatory cytokines. 2 The deposition of the adipose tissue occurs in various locations in the body, including the heart. The adipose tissue in the heart is mostly located in the subepicardial region, particularly in the areas of the epicardial coronary arteries. Subepicardial adipose tissue has been shown to be a source of several inflammatory mediators. 4 Previous studies 2 have demonstrated some intriguing findings, suggesting a potential role of subepicardial adipose tissue in the pathogenesis of epicardial coronary artery disease (CAD). Subepicardial fat is also the main determinant of atrial septum thickness. Postmortem studies 5 7 have suggested that the posterior portion of the atrial septum is essentially an extracardiac structure, produced by the infolding of the atrial roof and containing subepicardial adipose tissue. Pathologic data demonstrated that the adipose tissue of the atrial septum merged with the overlying subepicardial adipose tissue, which was also usually prominent. 6 The fossa ovalis is always free of adipose tissue. 8 CHEST / 132 / 3/ SEPTEMBER,

2 Furthermore, the atrial septum thickness, representing mostly the adipose tissue, can be accurately determined by transthoracic echocardiography. The clinical significance of a thick atrial septum has been increasingly recognized since the initial description of lipomatous hypertrophy of the atrial septum in Since then, a possible association between a thick atrial septum and obesity, 8,10,11 advanced age, 11 atrial arrhythmias, 8,11,12 obstructive symptoms, 13 and sudden death have been reported. 14 An autopsy study 8 showed more atherosclerotic CAD in patients with fatty deposition in the atrial septum. However, there are no studies assessing the possible association between atrial septum thickness and coronary disease in living humans. The present study was designed to assess the association between the adipose tissue of the atrial septum, measured by transthoracic echocardiography, and the presence, extent, and severity of CAD. Study Population Materials and Methods The study protocol was approved by the Mayo Clinic Institutional Review Board. We selected 180 consecutive patients who underwent transthoracic echocardiography and coronary angiography within 1 week. A total of 41 patients were excluded from the study, as follows: incomplete clinical data, 18 patients; inadequate echocardiographic images, 11 patients; heart transplantation, 6 patients; and pericardial effusion, 6 patients. Among the remaining 139 patients, 64 were further excluded because the subcostal echocardiographic view was neither available nor optimal for the offline measurement of atrial septum thickness. Seventy-five patients constituted the study population. Hyperlipidemia was defined as the use of a lipid-lowering agent, low-density lipoprotein (LDL) cholesterol level of 4.14 mmol/l, or a total cholesterol level of 5.7 mmol/l. The presence of diabetes mellitus was defined according to the criteria of the American Diabetes Association or from a requirement for therapy with insulin or oral hypoglycemic drugs. *From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, MN. Dr. Chaowalit was supported by a grant from Siriraj Hospital, Mahidol University, Bangkok, Thailand. Dr. Lopez-Jimenez is supported by a Scientist Development Grant from the American Heart Association. Dr. Somers is supported by National Institutes of Health grants HL-65176, HL-70602, HL-70302, HL-73211, and M01-RR The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Manuscript received November 8, 2006; revision accepted May 15, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Francisco Lopez-Jimenez, MD, MSs, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First St, Rochester, MN 55905; lopezjimenez.francisco@mayo.edu DOI: /chest Hypertension was defined as a systolic BP of 140 mm Hg, a diastolic BP of 90 mm Hg, or a requirement for antihypertensive medication. History of CAD was defined as having a history of myocardial infarction, significant coronary artery stenosis as determined by coronary angiography, or prior coronary revascularization. A family history of CAD was defined as having a first-degree male relative 55 years of age or a first-degree female relative 65 years of age with a history of myocardial infarction, coronary revascularization, or sudden cardiac death. Metabolic abnormality was defined in patients who were not receiving any lipid-lowering agents as having at least one of the following: diabetes mellitus; fasting blood glucose level of 6.1 mmol/l; high-density lipoprotein (HDL) level of 1.03 mmol/l; or triglyceride level of 1.7 mmol/l. Height (in square meters) and weight (in kilograms) were used to calculated body mass index. Obesity was defined in patients with a body mass index of 30 kg/m 2. Echocardiographic Measurements Each patient underwent transthoracic echocardiography, and the results were recorded in a computerized database. The offline measurement of the atrial septum thickness was performed by a cardiologist who was unaware of the clinical and angiographic data. The atrial septum was identified using subcostal two-dimensional images, and its thickness, representing the adipose tissue of the atrial septum, was measured perpendicularly at the thickest part at end-diastole. The average value from three cardiac cycles was used for the statistical analysis. The atrial septum was classified as thick or thin using the median thickness as a cutoff value. Coronary Angiographic Data All patients underwent diagnostic coronary angiography as clinically indicated at the discretion of the referring cardiologist. Angiographic data were analyzed for the presence, extent, and severity of CAD. Major coronary vessels were defined as the left main, left anterior descending, circumflex, and right coronary artery. The native coronary artery system was divided into 27 segments based on the previously described classification by the Coronary Artery Surgery Study investigators. 15 Significant CAD was considered if there was 50% stenosis in at least one major coronary vessel. Any CAD was defined as the presence of stenosis of any severity in at least one coronary segment. To define the overall extent of angiographically detectable CAD, including nonobstructive and obstructive lesions, the number of segments with a 20% maximum stenosis was identified as a coronary artery greater even than 20 (CAGE 20) score. Severity score, reflecting the severity of CAD, was calculated accounting for the number and location of affected segments and by the degree of stenosis using prespecified criteria of the Coronary Artery Surgery Study investigators. 15 Briefly, the coronary segments with maximum stenosis of 25%, 26 to 50%, 51 to 75%, 76 to 90%, 91 to 99%, and 100% were scored as 1, 2, 4, 8, 16, and 32 points, respectively. A weighting factor was used for the left main coronary artery ( 5), the proximal portion of the left anterior descending or circumflex artery ( 2.5), the mid-left anterior descending artery ( 1.5), or one of the smaller coronary branches ( 0.5). Statistical Analysis Data were expressed as the number of patients (%), mean SD, or median (range). A Spearman rank correlation was performed to identify the correlation between the adipose tissue 818 Original Research

3 of the atrial septum, expressed as continuous variable, and the clinical variables. Because the atrial septum thickness was not normally distributed, we used nonparametric tests, performed a logarithmic transformation, or converted the values into quartiles, when necessary. We used the Wilcoxon rank sum test to compare the atrial septum thickness between subjects with and without any CAD, and also with and without significant CAD. To compare the mean log of atrial septum thickness among quartiles of the CAGE 20 score and among quartiles of the severity score, we used the one-way analysis of variance test. The atrial septum thickness was categorized into quartiles. The proportion of patients with significant CAD or any CAD was compared among quartiles of the atrial septum thickness using an exact test for the ordered contingency table. Similarly, a Kruskal- Wallis test was used to compare the severity score and CAGE 20 score among the quartiles. We performed multivariate regression analysis models using dichotomized angiographic data as the dependent variable and atrial septum thickness as the independent variable, using age, sex, and body mass index as covariates. A p value of 0.05 indicated statistical significance. To assess the reproducibility of the echocardiographic measurement of the adipose tissue of the atrial septum, 30 patients were randomly selected for the offline analysis by two observers who were unaware of the clinical and angiographic data. The intraclass correlation coefficient was 0.96, indicating an excellent reproducibility of the echocardiographic measurement. Results Clinical Characteristics There was no statistically significant difference between the excluded patients and the study population regarding baseline characteristics and angiographic data. The clinical characteristics and laboratory data of the 75 patients are summarized in Table 1. Transthoracic echocardiography and coronary angiography were performed within a mean ( SD) period of 2 2 days (median, 1 day; range, 0 to 7 days). Table 1 Patient Characteristics* Characteristics Values Age, yr Male gender 41 (55) Body mass index, kg/m Obesity 30 (40) Hyperlipidemia 41 (55) Diabetes mellitus 21 (28) Hypertension 49 (65) Smoking 14 (19) Family history of CAD 6 (8) Metabolic abnormality 23 (32) Prior myocardial infarction 11 (15) Prior revascularization 24 (32) History of CAD 27 (36) Glucose, mmol/l Total cholesterol, mmol/l Triglycerides, mmol/l HDL, mmol/l LDL, mmol/l *Values are given as the mean SD or No. (%). Echocardiographic and Angiographic Data The mean value of the atrial septum thickness was cm (median, 1.42 cm; range, 0.74 to 2.55 cm). Significant CAD and any CAD were present in 51 patients (68%) and 68 patients (91%), respectively. Significant stenosis of the left main coronary artery was present in 5 patients (7%). Using a 27-segment coronary artery classification, all 2,025 segments were available for analysis. The mean values for severity score and CAGE 20 score were (range, 0 to 209) and (range, 0 to 14), respectively. Clinical and Angiographic Correlates of the Adipose Tissue of the Atrial Septum Clinical and angiographic characteristics of patients with a thick atrial septum, compared to those with a thin atrial septum, are demonstrated in Table 2. Except for a higher proportion of men in the group with a thick atrial septum, the groups had similar clinical characteristics, including a similar body mass index. In a simple linear regression analysis, no significant correlation was identified between the adipose tissue of the atrial septum and clinical variables (eg, age, gender, body weight, body mass index, hypertension, diabetes mellitus, hyperlipidemia, smoking, family history of CAD, prior myocardial infarction, and prior coronary revascularization) [p 0.05]. Table 3 demonstrates a significant correlation between the adipose tissue of the atrial septum measured as a continuous variable and any CAD (p 0.03) and a borderline association with the severity score of coronary atherosclerosis (p 0.066). Multivariate logistic regression analysis showed that atrial septum thickness was associated with the presence of CAD, independent of age, sex, and body mass index (p 0.05). There were similar findings when the atrial septum thickness was analyzed in quartiles. The proportion of patients with any CAD was significantly higher in patients in the highest quartile of atrial septum thickness when compared to those in the lowest quartile (p 0.02). The association persisted after controlling for age, sex, and body mass index (p 0.03). Similarly, the median CAGE 20 score was significantly associated with the adipose tissue of the atrial septum when compared among four quartiles (Table 4). There was no significant correlation between the adipose tissue of the atrial septum and other angiographic data (ie, significant CAD and severity score). Discussion The present study suggests that the adipose tissue of the atrial septum, measured by transthoracic CHEST / 132 / 3/ SEPTEMBER,

4 Table 2 Clinical Characteristics in Patients With Thick and Thin Atrial Septum* Characteristics Thick Thin p Value Age, yr Male gender Body mass index, kg/m Obesity Metabolic abnormality Hyperlipidemia Diabetes mellitus Hypertension Smoking Family history of CAD Prior myocardial infarction History of CAD Prior revascularization Glucose, mmol/l Total cholesterol, mmol/l HDL, mmol/l LDL, mmol/l *Values are given as the mean SD or %, unless otherwise indicated. echocardiography, is associated with the presence of angiographic CAD. We used a simple and reproducible measurement, namely, echocardiographic assessment of the atrial septal thickness, as a surrogate for the amount of subepicardial adiposity. In agreement with previous studies showing the significance of visceral adiposity rather than generalized obesity as a marker of cardiovascular risk, our findings further confirm the significance of visceral adiposity, in the association with the presence of angiographic CAD. Table 3 Angiographic Correlates of Echocardiographic Adipose Tissue of the Atrial Septum* Variables AS Thickness p Value Any CAD 0.02 Yes cm No cm Significant CAD 0.55 Yes cm No cm Severity score st Quartile nd Quartile rd Quartile th Quartile CAGE 20 score st Quartile nd Quartile rd Quartile th Quartile *Values are given as the mean SD, unless otherwise indicated. AS atrial septum. Wilcoxon rank sum test. Analysis of variance test. Log-transformed atrial septum thickness. The adipose tissue of the atrial septum, a true visceral adipose tissue, is a continuity of subepicardial adipose tissue into the infolding of the atrial roof. 6,7 Previous studies 4,16 18 have addressed the potential association between subepicardial adiposity and CAD. Either its association with conventional risk factors for cardiovascular disease and metabolic syndrome or the function of subepicardial adipose tissue as an endocrine or paracrine organ 2 have been reported as possible explanations. Furthermore, the direct role of subepicardial adipose tissue as a paracrine and endocrine organ may also be vital in the development of epicardial coronary atherosclerosis. Some advances 2 have shown that adipose tissue, especially visceral fat, expresses numerous genes for secretory proteins, and that several biologically active molecules secreted from adipose tissue, known as adipocytokines, may have important roles in the development of atherosclerotic disease in obese persons. Of interest, adipocytes have been reported 2 to have an endocrine function with the ability to synthesize and release various mediators with possible inflammatory properties. Furthermore, the concept of outside-to-inside cellular crosstalk has been postulated so that the inflammatory mediators outside the coronary artery, such as pericardial and adventitial inflammation, may contribute to intimal atherosclerotic lesions. 4,16,19,20 The hypothesis for the association between the subepicardial adipose tissue and CAD is promising, and it has been tested in two studies with contradictory findings. Taguchi et al 21 demonstrated that subepicardial adipose tissue measured with CT scanning was associated with angiographic CAD in lean 820 Original Research

5 Table 4 Comparison Between Quartiles of Echocardiographic Measurement of Atrial Septum Thickness and Angiographic Data* Variables 1st Quartile 2nd Quartile 3rd Quartile 4th Quartile p Value Any CAD Significant CAD CAGE 20 score 3.5 (0 8) 6 (2 14) 5 (0 14) 6 (0 12) Severity score 21 (0 116) 49 (3 161) 26 (0 209) 35 (0 166) 0.15 *Values are given as % or median (range). patients but not in obese patients, while our group 22 found no association between subepicardial adipose tissue, measured with transthoracic echocardiography, and the presence, extent, or severity of CAD. The conflicting results may be due to the fact that subepicardial adipose tissue has an uneven distribution around the heart and the two-dimensional echocardiographic assessment at any particular location of epicardium may not be a good surrogate for the total amount of the subepicardial adipose tissue. Furthermore, the biochemical and cellular compositions of the subepicardial adiposity or its location may be more important than the total amount per se in the pathophysiology of CAD. 23,24 Conversely, the atrial septum is a relatively more distinct and localized structure than the epicardium and, therefore, may be more accurately measured with echocardiography, representing a better surrogate for the total amount of the adipose tissue of the heart than measuring the adipose tissue deposited on the coronary grooves. The major strengths of this study include a comprehensive assessment of angiographic CAD, not only in the context of the presence of disease, but also the extent and severity of disease. The interpretation of the atrial septum thickness and angiographic CAD were performed separately by blinded observers to eliminate bias. Also, we were able to measure the atrial septum thickness with excellent reproducibility, despite the variability implied when multiple sonographers acquire echocardiographic data. Study Limitations The major limitation of the present study is the selection bias because all patients underwent coronary angiography as clinically indicated. This bias creates a group with a very high prevalence of advanced coronary disease and a very small proportion of subjects without any angiographic evidence of coronary disease. However, random coronary angiography of large numbers of unselected individuals, in the absence of clinical indications, would not be ethically or logistically feasible. Furthermore, the detection of CAD by coronary angiography may miss early or eccentric lesions; therefore, patients classified as being free of coronary disease may indeed have coronary atherosclerosis. A considerable number of patients were excluded from the study because of inadequate subcostal imaging, and this may also introduce selection bias. However, the clinical characteristics of the patients excluded from the analysis were similar to those included in the analysis. Our study did not show a consistent association between the atrial septum thickness and all of the angiographic measures of coronary disease, and failed to prove an association with significant coronary disease. However, the investigation of potential risk factors for CAD usually relies on associations with either clinical events or with the presence of angiographic CAD, rather than severity of CAD. The determinants of the severity of CAD, defined as the presence of a significant stenosis in a major coronary artery, are not well understood. Our definition of significant CAD may not truly represent the burden of coronary atherosclerosis. Our study showed that atrial septum thickness correlated with the presence of CAD, but not with traditional CAD risk factors, suggesting that the association between atrial septum thickness and CAD is not mediated by traditional CAD risk factors. Furthermore, body mass index was not associated with atrial septum thickness, making it unlikely that atrial septum thickness is simply a reflection of body adiposity. However, atrial septum thickness may be an indirect measure of total visceral fat. Unfortunately, we do not have data from the measurement of abdominal fat or fat distribution like waist circumference or waist/hip ratio. Therefore, the question of whether atrial septum thickness is simply a reflection of higher visceral fat needs to be clarified in future studies. Furthermore, it would be interesting to determine the relationships between atrial septum thickness and several potential disease mechanisms of CAD, such as plasma levels of insulin, intramyocellular lipid content, and adipokines including proinflammatory and antiinflammatory cytokines. Unfortunately, these variables, which may lead to the CHEST / 132 / 3/ SEPTEMBER,

6 mechanistic aspects of the relationship between atrial septum thickness and CAD, were not available in our study. There are some potential drawbacks in the measuring of the adipose tissue of the atrial septum. First, there may be considerable variations to the shape of the atrial septum. Second, the estimation of its size may vary due to the resolution of the echocardiographic image or the imaging plane. Third, other disorders such as septal cysts, tumors, or infiltrative diseases may cause a thickened atrial septum. Because these factors would bias the results toward the null hypothesis, our positive results and reproducibility suggest that limitations related to the measurement of the atrial septum or rare conditions causing a thick atrial septum may not play a significant confounding role. Conclusion The adipose tissue of the atrial septum, as measured by transthoracic echocardiography, is associated with the presence of CAD in patients who undergo two-dimensional echocardiography and coronary angiography during their clinical evaluation. References 1 Al Suwaidi J, Higano ST, Holmes DR Jr, et al. Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries. J Am Coll Cardiol 2001; 37: Funahashi T, Nakamura T, Shimomura I, et al. Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity. Intern Med 1999; 38: Das UN. Is obesity an inflammatory condition? Nutrition 2001; 17: Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003; 108: Isner JM, Swan CS II, Mikus JP, et al. Lipomatous hypertrophy of the interatrial septum: in vivo diagnosis. Circulation 1982; 66: Devine WA, Anderson RH. Lipomatous hypertrophy ( massive fatty deposits ) of the interatrial septum. Am J Forensic Med Pathol 1997; 18: Gay JD, Guileyardo JM, Townsend-Parchman JK, et al. Clinical and morphologic features of lipomatous hypertrophy ( massive fatty deposits ) of the interatrial septum. Am J Forensic Med Pathol 1996; 17: Shirani J, Roberts WC. Clinical, electrocardiographic and morphologic features of massive fatty deposits ( lipomatous hypertrophy ) in the atrial septum. J Am Coll Cardiol 1993; 22: Prior JT. Lipomatous hypertrophy of cardiac interatrial septum: a lesion resembling hibernoma, lipoblastomatosis and infiltrating lipoma. Arch Pathol 1964; 78: Burke AP, Litovsky S, Virmani R. Lipomatous hypertrophy of the atrial septum presenting as a right atrial mass. Am J Surg Pathol 1996; 20: Heyer CM, Kagel T, Lemburg SP, et al. Lipomatous hypertrophy of the interatrial septum: a prospective study of incidence, imaging findings, and clinical symptoms. Chest 2003; 124: Hutter AM Jr, Page DL. Atrial arrhythmias and lipomatous hypertrophy of the cardiac interatrial septum. Am Heart J 1971; 82: McNamara RF, Taylor AE, Panner BJ. Superior vena caval obstruction by lipomatous hypertrophy of the right atrium. Clin Cardiol 1987; 10: Schejbal V, Duflou J, Virmani R, et al. Epicardial fatty tissue of the right ventricle: morphology, morphometry and functional significance. Pneumologie 1989; 43: Vlietstra RE, Kronmal RA, Frye RL, et al. Factors affecting the extent and severity of coronary artery disease in patients enrolled in the coronary artery surgery study. Arteriosclerosis 1982; 2: Chaldakov GN, Stankulov IS, Aloe L. Subepicardial adipose tissue in human coronary atherosclerosis: another neglected phenomenon. Atherosclerosis 2001; 154: Prati F, Arbustini E, Labellarte A, et al. Eccentric atherosclerotic plaques with positive remodelling have a pericardial distribution: a permissive role of epicardial fat? A threedimensional intravascular ultrasound study of left anterior descending artery lesions. Eur Heart J 2003; 24: Scher AM. Absence of atherosclerosis in human intramyocardial coronary arteries: a neglected phenomenon. Atherosclerosis 2000; 149: Shimokawa H, Ito A, Fukumoto Y, et al. Chronic treatment with interleukin-1 induces coronary intimal lesions and vasospastic responses in pigs in vivo: the role of plateletderived growth factor. J Clin Invest 1996; 97: Miyata K, Shimokawa H, Kandabashi T, et al. Rho-kinase is involved in macrophage-mediated formation of coronary vascular lesions in pigs in vivo. Arterioscler Thromb Vasc Biol 2000; 20: Taguchi R, Takasu J, Itani Y, et al. Pericardial fat accumulation in men as a risk factor for coronary artery disease. Atherosclerosis 2001; 157: Chaowalit N, Somers VK, Pellikka PA, et al. Subepicardial adipose tissue is not associated with the presence and severity of coronary artery disease. Atherosclerosis 2006; 186: Iacobellis G, Pistilli D, Gucciardo M, et al. Adiponectin expression in human epicardial adipose tissue in vivo is lower in patients with coronary artery disease. Cytokine 2005; 29: Maeda K, Okubo K, Shimomura I, et al. Analysis of an expression profile of genes in the human adipose tissue. Gene 1997; 190: Original Research