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ISSUE NO. 4

Obesity and Atherosclerosis

Obesity is associated with an increased risk of coronary heart disease, in part due to its strong association with atherogenic dyslipidemia, which is characterized by high low-density lipoprotein (LDL) cholesterol and the presence of high triglycerides and low high-density lipoprotein (HDL) cholesterol.¹ There has been substantial research focused on the link between obesity and atherosclerosis.¹ It has been shown that both obesity and atherosclerotic heart disease have similar pathophysiological pathways involving inflammatory processes.^2,3 With the escalating prevalence of obesity, early detection of atherosclerosis is becoming increasingly important for risk stratification and clinical intervention.

PREVALENCE OF OBESITY AND ATHEROSCLEROSIS

Obesity has reached epidemic proportions globally, with more than 1 billion adults overweight, and at least 300 million of them clinically obese.⁴ The increase in the prevalence of obesity has led to an increase in the prevalence of metabolic syndrome, which is a cluster of obesity-related risk factors including abdominal obesity, insulin resistance, elevated blood pressure, atherogenic dyslipidemia (elevated triglycerides and low HDL cholesterol), proinflammatory state (elevated C-reactive protein), and prothrombotic state.⁵ Metabolic syndrome directly leads to the development of atherosclerotic cardiovascular disease.^5,6

In the United States, atherosclerosis is the leading cause of illness and death.^7,8 In 2005, it was estimated that 16 million people in the United States alone had atherosclerotic heart disease.⁸ As a result, there has been substantial research focused on the causal link between obesity and atherosclerosis.¹

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NEWSLETTERS

OBESITY AND ATHEROSCLEROSIS

Prevalence of Obesity and Atherosclerosis

Pathophysiology of Atherosclerosis

Detection of Atherosclerosis in Obese Patients

Conclusions

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PATHOPHYSIOLOGY OF ATHEROSCLEROSIS

Atherosclerosis was once thought to be a lipid-storage disease,⁹ but it is now recognized as a subacute inflammatory condition of the vessel wall, characterized by infiltration of macrophages and T cells, which interact with one another and with cells of the arterial wall.⁹ It is likely that inflammation induced by obesity accelerates atherosclerosis.⁹

Adipose tissue from obese individuals is a source of proinflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), leptin, plasminogen activator inhibitor (PAI), angiotensinogen, resistin, and C-reactive protein (CRP).¹⁰ These proinflammatory mediators exert effects on the vasculature, which promotes the various stages of atherogenesis, including endothelial dysfunction, plaque initiation, plaque progression, and plaque rupture.¹⁰ Nitric oxide and adiponectin typically offer protection against these proinflammatory mediators; however, their concentrations are decreased in obese individuals.¹⁰

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DETECTION OF ATHEROSCLEROSIS IN OBESE PATIENTS

The presence of coronary artery calcification is a marker for underlying atherosclerosis.¹¹ Cardiac computed tomography (CT) with electron beam CT (EBCT) or multidetector CT (MDCT) can be used to detect and quantify calcified atherosclerotic plaque in the coronary arteries. A coronary artery calcium (CAC) score is computed based on the amount of calcification detected, and has been shown to be an accurate predictor of the degree of narrowing of the coronary arteries and the likelihood of a future coronary event.¹² CAC scoring by cardiac CT is appropriate for patients with multiple risk factors, but no clinical evidence of CAD. It provides diagnostic assessment and risk stratification of patients with suspected CAD.¹³

Radionuclide myocardial perfusion imaging (MPI) is another widely used modality for detecting atherosclerosis. MPI shows the distribution of blood flow in the myocardium by imaging the uptake of an intravenously administered radionuclide.¹⁴ Abnormal uptake of the radionuclide shows up on the scan as a "cold spot," which indicates reduced myocardial blood flow due to ischemia or scar.¹⁴

Perfusion defects can be characterized by their type, location, extent, and severity.¹⁵ The most commonly used modality for MPI is single-photon emission computed tomography (SPECT), which can be performed at rest, during cardiovascular exercise stress, or during pharmacologic stress. Positron emission tomography (PET) is another imaging technology capable of assessing myocardial perfusion at rest and during pharmacologic stress; however, the short half-lives of PET radiotracers make exercise stress testing difficult.

While CAC is a sensitive marker for overall atherosclerosis burden, it is less useful for detecting clinically significant stenosis. MPI detects stenotic lesions but may miss lesions that do not limit blood flow.¹⁶ Therefore, it is feasible that these two modalities can be used together to provide incremental diagnostic information.

Studies have shown a relationship between the extent of calcification measured by CAC score and the presence of myocardial ischemia measured by MPI.¹³ Therefore, one strategy for integrating MPI and CAC scoring might be to initiate MPI for further testing of patients who have a high CAC score. As shown in figure 1, the initial assessment involves estimation of the 10-year risk of developing myocardial infarction (MI) or cardiac death based on measures such as the Framingham risk score, as recommended by standard Adult Treatment Program (ATP) III guidelines, with the addition of family history of early CAD and assessment of the metabolic syndrome.¹⁷ For patients with a CAC score of >400, referral for stress imaging may be beneficial because the 10-year risk of myocardial infarction or cardiac death is generally substantial, even in asymptomatic patients.^13,17

CONCLUSIONS

Obesity represents a major risk factor for atherosclerosis, in which systemic obesity-related inflammation is believed to be the main culprit.^2,3 The increasing prevalence of obesity underscores the need for early detection of atherosclerosis, which is a risk factor for major coronary events.⁵ Cardiac CT has become a widely used method for early detection of CAC.¹³ Referral for SPECT or PET MPI may also be appropriate to further enhance diagnostic assessment and risk stratification.^13,17

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REFERENCES

1.	Bamba V, Rader DJ. Obesity and atherogenic dyslipidemia. Gastroenterology. 2007;132:2181-2190.
2.	Rocha VZ, Libby P. Obesity, inflammation, and atherosclerosis. Nat Rev Cardiol. 2009;6:399-409.
3.	Berg AH, Scherer PE. Adipose tissue, inflammation, and cardiovascular disease. Circ Res. 2005;96:939-949.
4.	World Health Organization. Obesity and overweight. http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/. Accessed August 30, 2010.
5.	Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III): final report. Circulation. 2002;106:3143-3421.
6.	Grundy SM, Brewer HB, Cleeman JI, et al. Definition of metabolic syndrome. Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433-438.
7.	Kavey R-EW, Daniels S, Lauer RM, Atkine DL, Hayman LL, Taubert K. American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation. 2003;107:1562-1566.
8.	Merck Manual Home Edition. Atherosclerosis. http://merck.com/mmhe/sec03/ch032/ch032a.html. Accessed August 30, 2010.
9.	Wang Z, Nakayama T. Inflammation, a link between obesity and cardiovascular disease. Mediators of Inflammation. 2010.
10.	Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S. Adipokines: molecular links between obesity and atherosclerosis. Am J Physiol Heart Circ Physiol. 2005;288:H2031-H2041.
11.	Lembcke A. Coronary artery calcifications: a critical assessment of imaging techniques. Blood Purif. 2007;25:115-119.
12.	Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with coronary calcification. J Am Coll Cardiol. 2007;49:1860-1870.
13.	Berman DS, Wong ND, Gransar H, et al. Relationship between stress-induced myocardial ischemia and atherosclerosis measured by coronary calcium tomography. J Am Coll Cardiol. 2004;44:923-930.
14.	Strauss HW, Miller DD, Wittry MD, et al. Procedure guideline for myocardial perfusion imaging 3.3. 2008. http://interactive.snm.org/docs/155.pdf. Accessed October 2008.
15.	Berman DS, Hachamovitch R, Shaw LJ, Hayes SW, Germano G. Nuclear cardiology. In: Fuster V, Hurst JW, O'Rourke RA, et al, eds. Hurst's the Heart. 12th Ed. New York, NY: McGraw-Hill; 2007:544-576.
16.	Ramakrishna G, Miller TD, Breen JF, Araoz PA, Hodge DO, Gibbons RJ. Relationship and prognostic value of coronary artery calcification by electron beam computed tomography to stress-induced ischemia by single photon emission computed tomography. Am Heart J. 2007;153:807-814.
17.	Berman DS, Hachamovitch R, Shaw LJ, et al. Roles of nuclear cardiology, cardiac computed tomography, and cardiac magnetic resonance: noninvasive risk stratification and a conceptual framework for the selection of noninvasive imaging tests in patients with known or suspected coronary artery disease. J Nucl Med. 2006;47:1107-1118.

CONSULTANT DISCLOSURE

Len Fromer, MD from the University of California, Los Angeles and the David Geffen School of Medicine at UCLA is the consultant for this CardioWatch series. Dr Fromer is a speaker and consultant for Astellas Pharma US, Inc.

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