Effect of Pharmacologic Stress Test Results on Outcomes in Obese versus Nonobese Subjects Referred for Stress Perfusion Echocardiography


Real-time contrast stress echocardiography (RTCSE) permits the simultaneous analysis of myocardial perfusion and wall motion during stress echocardiography, which has resulted in improved coronary artery disease detection. Although several studies have confirmed a protective effect of obesity in coronary artery disease, it is unclear whether this benefit is dependent on the functional significance of the disease. The objective of this study was to compare outcomes in obese versus nonobese subjects referred for pharmacologic RTCSE.


A retrospective comparison of wall motion and myocardial perfusion with RTCSE was assessed in 481 obese and 961 nonobese patients matched for age and gender without known coronary artery disease referred for either dobutamine ( n = 1,056) or dipyridamole ( n = 386) stress echocardiography at two separate institutions. Outcomes (death or nonfatal infarction) were determined over a median follow-up period of 1,195 days.


Abnormal myocardial perfusion and/or wall motion was seen in 207 (20%) dobutamine and 61 (16%) dipyridamole studies. Abnormal rates were similar in obese (17%) and nonobese (19%) subjects. Event-free survival was significantly worse only for nonobese subjects referred for dobutamine RTCSE, with obesity (not test result) being an independent predictor of event-free survival on multivariate analysis ( P = .001). No protective effect of obesity was observed following dipyridamole RTCSE.


Obese subjects in the United States referred for demand stress testing have better outcomes when directly compared with age- and gender-matched nonobese subjects with similar degrees of inducible ischemia.


  • Real-time stress perfusion imaging has predictive value in both OS and nOS.

  • Obesity does appear to have a paradoxical protective effect in patients undergoing DOB stress echocardiographic perfusion imaging, regardless of test results.

  • This paradoxical protective effect appears to be dependent on the type of pharmacologic stress agent used.

Real-time contrast stress echocardiography (RTCSE) has been used to assess myocardial perfusion (MP) during stress testing and has the advantage of allowing the simultaneous analysis of wall motion (WM). MP assessment during RTCSE has increased the sensitivity of the test for both detecting coronary artery disease (CAD) and predicting cardiac events. This added sensitivity of RTCSE may be useful in several clinical subgroups, among which obese subjects (OS) are of particular interest, because of the highly debated “obesity paradox.”

Current data suggest that overweight subjects with established cardiovascular (CV) disease typically have a better prognosis compared with subjects with normal body mass index values between 20 and 25 kg/m 2 , a counterintuitive association between obesity as an established risk factor for incident cardiac disease and better event-free survival in OS that is referred to as the obesity paradox. The paradox is generally considered specific to OS with cardiac disease, but a recent systematic review in unselected populations suggested that it might extend to overweight subjects or those with mild obesity without established CV disease.

Only a few studies have investigated the obesity paradox in patients undergoing provocative testing for suspected CAD, and these have suggested that a better prognosis exists for OS in this setting. What is unclear is how protective obesity is compared with other pertinent clinical variables, as well as the outcomes from different stress imaging responses. This is especially important with pharmacologic stress testing, which is often required in OS because of comorbidities that prevent diagnostic treadmill electrocardiographic testing. In this study, we aimed to determine what independent role the obesity paradox plays in a population of patients undergoing different forms of pharmacologic RTCSE for suspected CAD. Furthermore, we also sought to determine whether the paradox relates to the result of the test (ischemic or normal). Specifically, we analyzed whether obesity has a favorable prognostic impact in patients on the basis of the type of pharmacologic RTCSE (dobutamine [DOB] or dipyridamole [DIP]) and on the basis of whether the results were normal or abnormal, using both MP and WM responses during stress imaging.


Data Sources

A retrospective analysis of OS and nonobese subjects (nOS) was performed from consenting patients, recorded in the data banks of the University of Nebraska Medical Center (Omaha, NE) (from 2005 to 2009) and the University of Parma Medical Center (Parma, Italy) (from 2008 to 2010). OS and nOS were age and gender matched (one OS for every two nOS) from the same source of data.

Study Selection

Eligible patients were those who required pharmacologic RTCSE to evaluate suspected CAD or risk stratification and who provided written informed consent to participate in the pharmacologic stress database. Patients at the University of Nebraska Medical Center underwent DOB stress, while those at Parma underwent DIP stress. Exclusion criteria were history of known CAD (defined as a history of myocardial infarction, coronary revascularization, or the presence of an angiographically documented coronary stenosis >50% before RTCSE), severe valvular or congenital heart disease, pregnancy, known hypersensitivity to ultrasound contrast media, inability to obtain follow-up data, and inadequate acoustic window. Hypertension was defined as a history of blood pressure elevations >140/90 mm Hg or use of antihypertensive medications at the time of the stress study. Hyperlipidemia was defined as total cholesterol >200 mg/dL or use of lipid-lowering medications at the time of the study. This resulted in a total of 1,442 patients who underwent either DOB ( n = 1,056) or DIP ( n = 386) contrast RTCSE. Patients in the DIP database had their short-term prognostic results published previously. Beta-blockers were withheld for 24 hours before all stress echocardiographic examinations, as recommended in current guidelines.

Of these 1,442 patients, 481 (33%) met criteria for obesity (body mass index ≥ 30 kg/m 2 ). Table 1 describes the demographics of the OS and nOS. Within the entire study population, the mean age was 59 ± 12 years, 811 subjects (56%) were women, 429 (30%) had diabetes, 999 (69%) had hypertension, and 687 (48%) had hyperlipidemia.

Table 1

Baseline clinical and real-time contrast stress echocardiographic characteristics according to study population

Variable Total ( n = 1,442) Obese ( n = 481) Not obese ( n = 961) P
Age 59.3 ± 12.3 59.2 ± 12.2 59.3 ± 12.3 .934
65.0 ± 12.1, 57.1 ± 11.6 65.0 ± 12.0, 57.2 ± 11.7 <.001, <.001
Male 631 (43.8%) 203 (42.2%) 428 (44.5%) .400
62 (48.1%), 141 (40.1%) 123 (47.9%), 305 (43.3%) .115, .210
LVEF < 50% 129 (9.0%) 45 (9.4%) 84 (8.7%) .700
Hypertension 990 (68.7%) 347 (72.1%) 643 (66.9%) .043
102 (79.1%), 245 (69.6%) 173 (67.3%), 470 (66.8%) .040, .872
Diabetes 429 (29.8%) 163 (33.9%) 266 (27.7%) .015
48 (37.2%), 115 (32.7%) 53 (20.6%), 213 (30.3%) .351, .003
Hyperlipidemia 687 (47.6%) 227 (47.2%) 460 (47.9%) .809
71 (55.0%), 156 (44.3%) 126 (49.0%), 334 (47.4%) .037, .663
Current smoking 421 (29.2%) 146 (30.4%) 275 (28.6%) .494
33 (25.6%), 113 (32.1%) 56 (21.8%), 219 (31.1%) .168, .005
Family history 431 (29.9%) 170 (35.3%) 261 (27.2%) .001
53 (41.1%), 117 (33.2%) 68 (26.5%), 193 (27.4%) .111, .768
Test type: DIP 386 (26.8%) 129 (26.8%) 257 (26.7%) .975
Test type: DOB 1,056 (73.2%) 352 (73.2%) 704 (73.3%)
Inducible MPA 259 (18.0%) 82 (17.1%) 177 (18.4%) .523
18 (14.0%), 64 (18.25%) 43 (16.7%), 134 (19.0%) .275, .415
Inducible MPA: single vessel 203 (14.1%) 67 (13.9%) 136 (14.2%) .556
12 (9.3%), 55 (15.6%) 29 (11.3%), 107 (15.2%)
Inducible MPA: multivessel 56 (3.9%) 15 (3.1%) 41 (4.3%)
6 (4.7%), 9 (2.6%) 14 (5.5%), 27 (3.8%) .120, .191
Inducible WMA 131 (9.1%) 44 (9.2%) 87 (9.1%) .953
10 (7.8%), 34 (9.7%) 19 (7.4%), 68 (9.7%) .520, .279
Inducible WMA: single vessel 94 (6.5%) 35 (7.3%) 59 (6.1%) .396
6 (4.7%), 29 (8.2%) 15 (5.8%), 44 (6.3%)
Inducible WMA: multivessel 37 (2.6%) 9 (1.9%) 28 (2.9%)
4 (3.1%), 5 (1.4%) 4 (1.6%), 24 (3.4%) .209, .305

LVEF , Left ventricular ejection fraction; MPA , MP abnormality.

Data are expressed as mean ± SD or as number (percentage).

Study Protocols

The lipid-encapsulated microbubble contrast agent Definity (Lantheus Medical Imaging, North Billerica, MA), as a 3% continuous infusion, and the lipid-encapsulated microbubble contrast agent SonoVue (Bracco Imaging, Milan, Italy), as a continuous 1 mL/min diluted infusion or repeated 0.5-mL slow boluses, were used as ultrasound contrast media for DOB and DIP studies, respectively. RTCSE was performed using commercially available ultrasound scanners (Sonos 5500 or iE33 [Philips Medical Systems, Andover, MA] or Acuson Sequoia 512 [Siemens Medical Solutions USA, Mountain View, CA]) equipped with low–mechanical index (MI) real-time pulse sequence schemes. The low-MI setting was set between 0.09 and 0.20 and the frame rate between 20 and 40 Hz. The high-MI impulses, or flash impulses, were a brief number of frames at an MI > 1.0 applied in each view during the infusion, and myocardial contrast replenishment was analyzed at the low-MI setting in real time for analysis of changes in MP.

For DOB studies, DOB was infused at a starting dose of 5 μg/kg/min, followed by increasing doses of 10, 20, 30, and 40 μg/kg/min to a maximal dose of 50 μg/kg/min in 3- to 5-min stages. Atropine (up to 2 mg) was added in patients without symptoms or signs of myocardial ischemia to achieve 85% of the age-predicted maximal heart rate (HR). Blood pressure and cardiac rhythm were monitored before and during the DOB infusion. Twelve-lead electrocardiograms were obtained at 3-min intervals. End points of the stress test were achievement of target HR, maximal DOB and atropine doses, development of severe or extensive WM abnormalities (WMAs), ST-segment elevation > 0.1 mV in non-Q-wave leads, sustained arrhythmias, severe chest pain, and intolerable side effects.

For DIP studies, DIP was infused at a total dose of 0.84 mg/kg in all patients using either a 10-min 0.84 mg/kg DIP infusion plus atropine administration (up to 1 mg) or a 6-min protocol, consisting of the 0.84 mg/kg DIP infusion and no additional atropine administration. Two-dimensional echocardiography, 12-lead electrocardiography, and blood pressure monitoring were performed in accordance with established standard protocols. Aminophylline was routinely used to reverse the effect of DIP.

Data Analysis

The left ventricle was divided into 17 segments according to the recommendations of the American Society of Echocardiography and the European Association of Echocardiography. MP was visually assessed by experienced reviewers (N.G. read 386 studies, T.R.P. read or directly supervised 1,056 studies). The criteria for analysis were as follows: normal MP during stress imaging was assigned if myocardium was fully replenished with contrast within 2 sec after the end of the flash impulse, and an MP defect was defined as any two contiguous myocardial segments that did not fully replenish with contrast in this time period. Normal MP at rest was defined as complete replenishment within 4 sec after the flash impulse. An MP defect was scored as reversible on the basis of its absence at rest. Basal segments were excluded from MP analysis if there was attenuation (defined as failure to delineate endocardial and epicardial borders). Reversible WMAs were defined as stress-induced new WMAs or worsening of rest hypokinesis in at least one contiguous segment. In all cases, the results of both MP and WM analysis were made available to the referring physicians. Interobserver agreement data for WMAs and MP within each center have been previously published, but a repeat analysis of 40 study cases (20 DIP, 20 DOB) was performed at each site to assess interinstitutional agreement.

Data collection was performed through June 2012. Outcomes were determined from patient interviews at outpatient clinics, hospital chart reviews, and telephone interviews with patients or referring physicians. Primary outcome variables were death and nonfatal myocardial infarction (hard events). To avoid misclassification of the cause of death, we considered overall mortality. Myocardial infarction was defined by typical symptoms, electrocardiographic findings, and serial cardiac-specific biomarker changes. Follow-up time was considered starting from the date of RTCSE until the first event or the last contact date. Follow-up data were analyzed to evaluate event-free survival according to classical risk factors, resting ejection fraction, and real-time contrast stress echocardiographic variables.

Statistical Analysis

Differences in continuous variables between OS and nOS were assessed using independent t tests, and proportions were compared using χ 2 tests. Event-free survival time was estimated using Kaplan-Meier curves, and differences according to clinical and echocardiographic parameters were compared using log-rank tests. Univariate and multivariate Cox proportional-hazard models were used to estimate the incidence of events. Covariate selection in multivariate models was done using clinical and statistical criteria. Multicollinearity was examined in all models, and the proportional-hazards assumption was verified using the Schoenfeld test.

To evaluate the association of obesity and results of RTCSE with outcomes, first a multivariate clinical model was determined, and then test positivity (on the basis of both MP and WM data) was added. This was also performed for each type of stressor (DIP vs DOB). The clinical utility of the addition of stress echocardiographic data (WM and MP) on clinical variables was evaluated in terms of discrimination power using Harrell’s C index. All tests were two tailed, and a P value <.05 was considered to indicate statistical significance.


Comparison of Study Populations and Test Results

No serious adverse events were reported following contrast injections. OS more frequently had diabetes (34% vs 28%) and hypertension (72% vs 67%) and were more likely to report a family history of CAD (35% vs 27%) ( Table 1 ). The number of OS who underwent DOB RTCSE (American population) was 352, accounting for 73% of the OS group, while 129 OS (27%) underwent DIP RTCSE (Italian population), highlighting the expected higher prevalence of OS in the North American study cohort. The patients from Parma (DIP stress) were older ( Table 1 ).

Among OS, 83% ( n = 398) had normal test results, and 82 (17%) had abnormal results (39 had isolated MP defects with otherwise normal WM, and 43 had both MP defects and WMAs). Among nOS, normal test results were seen in 81% ( n = 776) and abnormal results in 19% (98 with isolated MP defects and 79 with both MP defects and WMAs; P = .24 vs OS proportions with isolated MP defects and both MP defects and WMAs). The proportions of abnormal test results were similar in the DIP and DOB groups overall (16% vs 20%, P = .117) and in the OS (14% vs 18%, P = .306), and the proportions of abnormal test results in a multivessel territory distribution were not different (3.1% in OS and 4.3% in nOS, P = .15). Interobserver agreement for the interpretation of DIP stress echocardiographic segmental MP was 80% (κ = 0.60) and 95% (κ = 0.83) for segmental WM, while interobserver agreement for DOB RTCSE was 90% (κ = 0.79) for MP and 95% (κ = 0.90) for WMAs.

Death and Nonfatal Myocardial Infarction Rates in OS versus nOS

The follow-up period ranged from 1 to 90 months (median, 40 months; interquartile range, 19–63 months). During follow-up, 88 patients (6.1%) in the entire study cohort ( n = 1,442) had hard events (69 deaths, 19 nonfatal myocardial infarctions), of which 25 (15 deaths, 10 myocardial infarctions) were recorded in OS (5.2%) and 63 (54 deaths, nine nonfatal myocardial infarctions) in nOS (6.6%).

The 3-year rate of death or nonfatal myocardial infarction in OS was 4.1%, compared with 5.1% in nOS, and Kaplan-Meier event-free survival for all OS compared with all nOS showed slightly improved survival in OS (log-rank P = .056). In nOS, abnormal findings resulted in significantly worse outcomes ( P < .001), while abnormal results were not associated with worse outcome in OS ( P = .081) ( Figure 1 ). When broken down by type of stress agent (DOB stress patients from the United States, DIP stress patients from Italy), age- and gender-matched OS with normal DOB stress results had significantly better outcome compared with nOS, and OS with abnormal DOB stress had a slight but not statistically significant ( P = .054) survival advantage. In all DOB stress echocardiographic studies combined, there was a highly significant protective effect associated with obesity ( P = .001). This was not true for normal ( P = .087) or abnormal ( P = .602) DIP stress studies ( Figures 2 and 3 ).

Figure 1

Event-free survival curves, paired for OS (A) and nOS (B) , on the basis of test type and response (combining MP and WM responses). Significant predictive value of MP and WM responses was seen only in nOS.

Figure 2

Event-free survival curves for OS vs nOS with normal DIP (A) vs normal DOB (B) real-time contrast stress echocardiographic findings.

Figure 3

Event-free survival curves for OS vs nOS with abnormal DIP (A) vs normal DOB (B) real-time contrast stress echocardiographic findings.

Multivariate Predictors of Outcomes with RTCSE

On univariate analysis in the entire study population ( Table 2 ), obesity was not significantly associated with outcome (hazard ratio, 0.64; 95% CI, 0.40–1.02; P = .058) of hard events; other univariate clinical predictors included age and male gender (increased risk for hard events). Hypertension was associated with a paradoxically lower risk, most likely because hypertension was defined as the use of blood pressure–lowering agents. Abnormal responses during RTCSE in all patients were also associated with worse outcomes (abnormal MP: hazard ratio, 2.16 [95% CI, 1.38–3.39; P = .001]; WMAs: hazard ratio, 2.86 [95% CI, 1.72–4.76; P < .001]).

Table 2

Univariate analysis for predictors of hard cardiac events in all patients and for the DOB stress patients only

Variable Hard events
HR (95% CI) P
All patients
Male gender 2.39 (1.56–3.69) <.001
Age 1.05 (1.03–1.06) <.001
Obesity 0.64 (0.40–1.02) .058
Hypertension 0.58 (0.38–0.89) .012
Diabetes 1.22 (0.78–1.88) .381
Hyperlipidemia 0.80 (0.53–1.23) .310
Current smoking 1.15 (0.73–1.79) .549
Family history of CAD 1.34 (0.86–2.11) .187
LVEF < 50% 1.72 (0.96–3.11) .070
Stress echocardiographic data
Inducible MP 2.16 (1.38–3.39) .001
Inducible WM 2.86 (1.72–4.76) <.001
Inducible MP and/or WM 2.06 (1.31–3.22) .002
DOB stress only
Male gender 1.99 (1.18–3.40) .010
Age 1.03 (1.01–1.05) .015
Hypertension 0.56 (0.33–0.96) .035
Diabetes 0.98 (0.56–1.72) .945
Hyperlipidemia 0.80 (0.47–1.36) .417
Current smoking 1.63 (0.96–2.76) .071
Family history of CAD 0.94 (0.51–1.73) .850
Obesity 0.36 (0.18–0.69) .002
LVEF < 50% 0.78 (0.28–2.15) .629
Stress echocardiographic data
Inducible MP 1.48 (0.81–2.70) .207
Inducible WM 1.38 (0.62–3.05) .426
Inducible MP and/or WM 1.39 (0.76–2.55) .281

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Apr 17, 2018 | Posted by in CARDIOLOGY | Comments Off on Effect of Pharmacologic Stress Test Results on Outcomes in Obese versus Nonobese Subjects Referred for Stress Perfusion Echocardiography

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