Choice of Imaging Modality in the Assessment of Coronary Artery Disease Risk in Extreme Obesity

The current obesity epidemic is responsible for a burdensome prediction of increased coronary artery disease (CAD) (1). Extreme obesity (EO) (class 3 obesity, BMI ≥ 40 kg/m2) occurs in 1 in 20 American adults, and this population is especially at risk of poor health outcomes and increased cost of health care (2). CAD and its risk factors including diabetes mellitus, high blood cholesterol, and high blood pressure increase across weight classes (3,4). It is therefore of utmost importance that accurate risk assessment and stratification is able to be performed in this population at risk for greater morbidity and mortality from CAD. Despite as increased risk, evaluation of CAD in the EO population presents unique challenges. Symptoms concerning for CAD, such as dyspnea and reduced exercise tolerance, occur at a high frequency in those with extreme obesity with or without the presence of significant CAD (5), and may lower the sensitivity and specificity of the history and physical exam. In a cohort of class 2 and 3 obesity, dyspnea climbing two flights of stairs occurred in 69–87% and with bathing or dressing in 12–24% of patients (5). Determining the etiology of reduced exercise tolerance in this cohort is further confounded by increased prevalence of sedentary lifestyle as well as arthritis, which occurs in 44% of those with class 3 obesity (4). Assessment of symptoms can be further complicated by the increased incidence of chest pain with exertion (5) as well as left ventricular (LV) hypertrophy and repolarization abnormalities on electrocardiogram (6). Incident obstructive sleep apnea, which occurs in 50% of the EO population (7), can masquerade as systolic heart failure with nocturia, lower extremity edema, and paroxysmal nocturnal dyspnea (8). Given these limitations to the history and physical exam, cardiovascular imaging is a vital modality to objectively and quantitatively characterize CAD risk. However, common techniques to assess CAD are often limited by body mass of individuals with extreme obesity (9). Although advances in imaging techniques have improved the accuracy and lessened the artifacts previously seen in class 1 and 2 obesity, few studies have included significant numbers of extremely obese patients (2). Better patient care and resource allocation when assessing CAD in extreme obesity require an understanding of the limitations and advantages of various imaging modalities. It is evident that the risks of CAD are elevated in the EO, but the signs and symptoms concerning for CAD may be even more common and not necessarily related to CAD; this requires a knowledgeable approach to the evaluation of CAD in EO. In advanced obesity, a multidisciplinary approach is frequently necessary to discern the etiology of possible cardiac symptoms and to make a timely diagnosis. Cardiac assessment in the extreme obese population represents well the current challenge of appropriate resource allocation and utilization of technological advances in patient care. The following is a detailed review of imaging options and the current literature to assist the physician and researcher in care of this unique patient population as well as highlight needed future investigations. A number of forms of imaging are commonly used in the evaluation of symptoms of dyspnea or chest pain in the general population. These may include echocardiography, myocardial perfusion imaging (MPI), stress echocardiography (SE), magnetic resonance imaging (MRI), and rubidium-82 positron emission tomography (Rb-PET). We discussed the advantages and disadvantages of these modalities for the EO population (Table 1). Echocardiography is a valuable tool in assessing cardiac anatomy and function. Diagnosis of depressed LV ejection fraction carries prognostic implications that alter patient management (10). In obese individuals, echocardiography has been shown to detect alterations of diastolic function in asymptomatic patients referred for bariatric surgery, patients with newly diagnosed arterial hypertension, and patients with obstructive sleep apnea (11,12,13). Some investigators have suggested a staged evaluation of obese patients prior to bariatric surgery with echocardiography performed only in those with baseline electrocardiogram abnormalities such as conduction or ST-T wave abnormalities (14). The difficulty in utilizing echocardiography in the obese patient population is the frequent problem of image quality. Patients with EO are at risk of poor image quality because chest wall thickness is the most common barrier to adequate transthoracic (TT) echocardiography imaging (15). The advent of intravenous echocardiographic contrast agents for left heart opacification has improved the quality of TT studies in a large number of patients. These agents typically contain a perfluorocarbon gas with a lipid, protein, or polymer shell. The microbubbles are the size of red blood cells and can traverse the pulmonary circulation to opacify the LV (16). Contrast agents greatly enhance the ability to interpret technically difficult echocardiograms for the assessment of regional wall motion (17). MPI. Single-photon emission computed tomography (SPECT) imaging provides assessment of myocardial perfusion and viability. In the general population, MPI is used extensively, has excellent prognostic value and has contributed to improved outcomes (18). For standard protocols, the sensitivity and specificity for the detection of CAD are 88 and 74%, respectively, for exercise and pharmacologic stress (19). Protocols that include imaging in both the supine and prone positions increase sensitivity and specificity to 92 and 86%, respectively, for both nonobese and obese population (20). In the EO population, the image quality with MPI with SPECT is better when using exercise as opposed to pharmacologic stress; however, only 25% of extremely obese patients are able to adequately exercise. Therefore, most patients require pharmacologic stress, yet optimal dosing in obesity has not been completely elucidated and remains an area of controversy (9). There are several artifacts that may interfere with the interpretation of myocardial perfusion studies, the most common being breast/soft tissue attenuation, diaphragmatic attenuation, and excess gastrointestinal activity adjacent to the heart (21). Limitations such as these contributed to significantly lower accuracy in the diagnosis of CAD in a study of 607 patients with obesity undergoing exercise thallium-201 SPECT (22). Thompson et al. reported that in 116 (mean (s.d.) BMI 31 (7) kg/m2) patients who underwent coronary angiography after Tc-99m sestamibi SPECT (76% with CAD; 48% with obesity), the specificity for the prediction of CAD by MPI with SPECT declined with increasing BMI in nonattenuation corrected image interpretation (Figure 1) (23). Specificity dropped from 85% in class 1 and 2 obesity to 67% in class 3 obesity; however, this was not statistically significant, as there were only 56 subjects between the two groups (23). Attenuation correction improved specificity in obese subjects (P = 0.03) but did not significantly affect it in the normal weight participants (23). Attenuation correction is valuable in decreasing artifacts in cardiac imaging in patients with obesity but still has limitations especially in EO. Hybrid SPECT/CT combines MPI with anatomical imaging and allows improved attenuation correction (24). Early reports support that it enhances the ability to detect CAD in patients with class 1 and 2 obesity (25,26). Specificity for significant coronary heart disease with (gray) and without (black) attenuation correction in all patients (*P = 0.02). Reprinted from ref.23 Cardiac perfusion scans communicate important prognostic value in the obese population, but further investigation is needed in EO. Elhendy et al. prospectively compared normal and abnormal perfusion scans in a high-risk obese population (mean (s.d.) BMI of 37 (7) kg/m2) followed for a mean of 5.5 (2) years. The annual total mortality rate was 1.3% compared with 4.2%, respectively, values that compare to the nonobese population (27). However, in a retrospective study of 433 patients with EO (mean (s.d.) BMI of 47 (8) kg/m2) with follow-up of 2 (1) years, the mortality rate was 3.7 and 6.5% in those with normal and abnormal perfusion scans, respectively. The high rate in those with normal scans is especially concerning, as it exceeds not only what is reported for nonobese (9) but also what is reported in lower classes of obesity (27) and suggests underdiagnosis of CAD. Several limitations exist in MPI including a lack of standardization of attenuation correction (28). SPECT imaging is limited by the 182-kg (400-lb) standard weight limit of the cantilevered table. In patients exceeding this weight, MPI using SPECT is not feasible. If total body weight does not preclude imaging with myocardial perfusion SPECT, patients should receive 99m Tc-labeled drugs rather than thallium-201, and most obese patients should have attenuation correction performed (22,23). From this review of the literature, it is clear that the MPI can detect coronary atherosclerosis in a significant percentage of patients. However, the utility of the test becomes more restricted in patients with EO due to attenuation artifact or absolute weight. In these patients, alternative stress imaging methods are often necessary. Rb-PET. PET uses positron emitting radionuclides to obtain images of myocardial perfusion and metabolism. There are several advantages of PET over SPECT that include routine measured attenuation correction, high special and contrast resolution that decreases the false-negative rate and increases sensitivity, and high temporal resolution that allows quantification of myocardial perfusion (29). Normal MPI with Rb-PET has a good prognostic value in obese patients out to four years (30). PET with CT accounts for 80% of recently installed PET units. There has been concern that this hybrid imaging modality may affect the diagnostic accuracy of MPI due to differences between PET and CT in spatial resolution and breathing patterns. Therefore, Sampson et al. studied the accuracy of hybrid PET with CT for attenuation correction in a population of 64 patients with a mean (s.d.) BMI of 31 (8) kg/m2. They found a sensitivity of 93%, specificity of 83%, and overall accuracy of 87% when using the presence of a 70% lesion on coronary angiography as the gold standard (31). The literature is limited on the specific utility of Rb-PET for evaluation in patients with EO, but these studies do suggest that it could be a promising area to investigate. Disadvantages of Rb-PET include increased cost, table weight limits (182 kg), and limited availability. MRI. MRI uses a powerful magnetic field to align the nuclear magnetization of hydrogen atoms in water in the body. Radiofrequency fields are used to alter the alignment of this magnetization, causing the hydrogen nuclei to produce a rotating magnetic field detectable by the scanner. This signal can be manipulated by additional magnetic fields to build up enough information to construct an image of the body. MRI allows for assessment of valve structure, regurgitation, myocardial perfusion and viability along with ischemia (32). Nagel et al. first described the use of high-dose dobutamine infusion for dobutamine stress magnetic resonance in patients undergoing both echocardiography and MRI. The sensitivity and specificity were higher for dobutamine stress magnetic resonance compared with dobutamine SE (DSE) (86% vs. 74% and 86% vs. 70%, respectively). Of note, 17 patients could not complete the protocol-11 due to claustrophobia, 1 due to retro-orbital metal, and 5 due to body weight exceeding weight limits (33). Hundley et al. (32) examined 153 patients with nondiagnostic DSE with dobutamine stress magnetic resonance and found a sensitivity of 83% and specificity of 83%. The major limitations of MRI include the presence of metallic implants in the patient, weight >182 kg, claustrophobia, or an inability to rest comfortably in the camera (bore diameter 60 cm). TT-SE. DSE is an established modality for CAD evaluation that has been studied in the obese and extremely obese. Advantages of DSE include its wide availability and the potential for use with both exercise and pharmacologic stress testing. In the nonobese population, a positive test with TT-DSE is associated with an annual event rate (cardiac death or myocardial infarction) of 5.4% whereas a normal DSE has an annual event rate of 1.2% over 5 years (34). In a prospective study of overweight and obese patients (n = 62, mean (s.d.) BMI 29 (1) kg/m2) who underwent coronary angiography and DSE with and without contrast, contrasted images improved sensitivity and specificity (82% vs. 70% and 78% vs. 67%, respectively for with and without contrast) (35). Retrospectively, Lerakis et al. assessed TT-DSE as a preoperative screen for CAD in a bariatric surgery population (n = 611, mean (s.d.) BMI 48 (6) kg/m2). Adequate imaging was obtained in 97%, but to achieve this, intravenous echocardiographic contrast was required in 72%. The study was inconclusive in 6.4%. Five of seven patients who had positive tests underwent coronary angiography but only one of the five had significant disease (36). Limitations of this study include a low-risk population and limited follow-up of 6 months; therefore, long-term prognostic value of this test cannot be determined from this data. The utility of TT-DSE is limited by image quality, due to obesity or structural changes of advanced pulmonary disease, and the frequent need for contrast to obtain interpretable images. Transesophageal SE. Transesophageal SE (TE-SE) was described as early as 1990 by Lambertz et al. (37). They performed simultaneous TE atrial pacing with TE echocardiography (TEE) imaging and correlative routine bicycle exercise testing in 44 participants. All participants underwent cardiac catheterization with CAD defined as >50% stenosis. For TEE, the overall sensitivity and specificity were 93 and 100%, respectively. Sensitivity increased to 100% for 2- or 3-vessel disease. This exceeded the sensitivity and specificity values for bicycle ergometry, 50 and 53%, and atrial pacing electrocardiogram, 67 and 49%, respectively (37). In 1991, Zabalgoitia et al. performed TEE-SE with atrial pacing in 36 patients with known or suspected CAD. The sensitivity was 90% and the specificity was 93% (ref. 38). This study was limited by the use of short axis images only; these results may have been improved with more extensive evaluation of wall motion in other views. Pharmacologic stress TEE was first reported using dipyridamole when Agati et al. in 1992 studied 32 patients with inadequate TTE windows. Stress testing with TEE was completed using high-dose dipyridamole with a dose of 0.84 mg/kg over 10 min. Using a definition of 70% stenosis on coronary angiography as significant CAD, dipyridamole stress TEE had a sensitivity of 92% and specificity of 100%. The sensitivity for 1-, 2-, and 3-vessel disease was 67, 100, and 100%, respectively (39). Panza et al. first reported the use of dobutamine TE-SE (TE-DSE) when they enrolled 76 patients with known or suspected CAD. The sensitivity and specificity were 89 and 100%, respectively, and the accuracy was 91% with the definition of a significant stenosis being 70% lesion on coronary angiography. Three of the 76 patients (4%) did not tolerate probe placement (40). Multiple small studies support that TE-DSE is valuable in the EO population. Madu completed a prospective study of 23 obese participants with a history of chest pain who were evaluated by TE dobutamine stress (TE-DSE). He reported TE-DSE to be an effective and safe modality for CAD evaluation in obese participants (mean (s.d.) weight 164 (8) kg). Adequate images were obtained in 87% (20/23); CAD was found in 77% (7/9) who had abnormal imaging; and over a mean (s.d.) follow-up of 18 (6) months, no events occurred in 11 participants with normal imaging (41). In another study of seven patients with EO (mean (s.d.) BMI 67.7 (15.6) kg/m2), TE-DSE was used for preoperative evaluation of bariatric surgery. Participants with a negative test had no events over a mean follow-up period of 11 months (42). Overall, the safety of TEE in obese patients is similar to that of nonobese patients (43). Current image interpretations of TE-DSE can be limited by subjectivity, and some have advocated using advances in imaging (such as color kinesis) for standardization (44). The advantages of stress TEE include good image quality in most patients even with advanced obesity, complete evaluation of wall motion, LV and right ventricular function, and evaluation of valve anatomy and function. Limitations of the technique include potential intolerance of the probe (40) and difficulty with obtaining an adequate level of sedation. In our experience, a key to successful completion of TE-DSE is the utilization of a multidisciplinary approach with involvement of anesthesiology in administering conscious sedation to ensure successful completion of the test. A positive imaging test for CAD in patients with EO often requires special consideration before further intervention. Heart catheterization in certain patients is not feasible due to absolute table weight limits and special expertise may be required for safe arterial access (45). Additionally, the EO population has increased risks of pulmonary and renal complications (46), sternal wound infections, and operative mortality with coronary artery bypass surgery (47). However, even in a case where further invasive intervention may not be pursued establishing a diagnosis of CAD is relevant, as aggressive medical management improves outcomes (48). The EO population has an increased risk of CAD and a complex presentation due to altered physiology and high prevalence of pulmonary disorders. Their evaluation can be further complicated by limitations of certain imaging techniques. The ideal modality for CAD assessment would have good sensitivity and specificity, meaning that a negative result would have good prognostic value to predict low-risk subjects. The common problem of increased frequency of artifacts in patients with EO contributes to low specificity and can lead to repeat noninvasive testing or unnecessary heart catheterizations. As EO is becoming more common there is a need for a cost-effective strategy to evaluate these patients. In the last decade, there has been considerable technological advancement in cardiovascular testing. A careful understanding of the advantages and limitations of each technique should allow for better resource allocation. TEE-SE was described nearly 30 years ago, and more recent small studies support that it may be a valuable tool in the EO population. Besides lower cost and general availability, the advantages of this test include the evaluation of inducible ischemia along with determination of LV function, and valve structure and function. The potential disadvantages include patient intolerance of the TEE probe, poor acoustic windows, and tenuous airway management during conscious sedation. For this reason, we propose an algorithm-based strategy to guide choice of imaging modality for risk stratification, starting with nuclear MPI as “first-line” followed by TEE-based imaging if technical limitations such as patient weight and bore size are present (Figure 2). There are limits to each imaging modality discussed for assessment of CAD in patients with EO. Clinicians must carefully consider these during evaluation. We feel a multidisciplinary approach to symptoms and CAD assessment in patients with EO is optimal. More prospective studies are needed to define the best manner to address CAD assessment in the extremes of obesity. W.N.I. is speaker for Lantheus Medical Imaging. We thank Charles J. Vaughn for his assistance with graphics preparation. J.P.D. received support from the Vanderbilt Environmental Health Science Scholars Program (NIEHS K12 ES015855). M.M.H. received support from the Vanderbilt Environmental Health Science Scholars Program (NIEHS 1K12ES015855) and the Johns Hopkins Clinical Research Scholars Program (NCR 5K12RR023266).