Objective
Major adverse cardiac events (MACE) frequently determine the outcome of renal transplantation (RT). Stress testing is advocated for preoperative risk assessment, but limited information is available on the prognostic value of these tests. We aimed to retrospectively assess the value of preoperative dobutamine stress echocardiography (DSE) in predicting MACE in patients undergoing RT.
Methods
A total of 185 patients (age 56 ± 11 years, 64% were men, creatinine level of 7.3 ± 2.9 mg/d, 27% were smokers, 86% had hypertension, 54% had diabetes, 57% were dyslipidemic) with end-stage renal disease (ESRD) underwent DSE before RT. A standard DSE protocol was used with the administration of 5-50 μg/kg/min incremental doses in 3-minute intervals and up to 1 mg of atropine if needed to reach prespecified end points.
Results
Regional left ventricular wall motion abnormality (WMA) at rest (fixed), with stress (inducible), or both were present in 54, 35, and 18 patients, respectively. In 38 patients who underwent coronary angiography, the sensitivity, specificity, and positive and negative predictive values of inducible WMA for predicting angiographic coronary artery disease (≥70% luminal diameter reduction) were 88%, 62%, 65%, and 87%, respectively. Cox regression analysis identified the presence of combined fixed and inducible WMA (ie, resting WMA that did not change during DSE, accompanied by new WMA evident during DSE; hazard ratio [HR] 5.6, P = .012), left atrial enlargement (HR 4.2, P = .002), and aortic valve sclerosis (HR 3.9, P = .013) as independent predictors of 48-month MACE (cardiac death, nonfatal acute myocardial infarction, and coronary revascularization after RT). Patients with all 3 predictors had a 48-month MACE of 60% compared with 5% in those with none ( P = .007). Compared with those without WMA, patients with both fixed and inducible WMA had a higher rate of MACE at 48 months (7% vs 33%, P = .004).
Conclusion
In RT candidates, DSE can effectively identify those at low and high risk of MACE.
Cardiovascular disease, predominantly coronary artery disease (CAD), is the leading cause of morbidity and mortality among renal transplant (RT) recipients. Therefore, screening for and treatment of CAD has been advocated before RT. Patients with end-stage renal disease (ESRD) are often asymptomatic despite significant CAD, frequently have abnormal resting electrocardiogram, and are unable to perform adequate exercise when tested noninvasively. Routine invasive coronary angiography, advocated by some, is not cost-effective and carries the risk of further kidney damage, particularly in those with residual renal function. Many centers have adopted a strategy of clinical risk stratification in combination with pharmacologic noninvasive stress testing in higher risk individuals for preoperative diagnosis of CAD in RT candidates. Dobutamine stress echocardiography (DSE) has been used as the noninvasive modality for diagnosis of CAD and prediction of outcome in patients with chronic kidney disease (CKD) or in RT candidates. Among the latter group of patients, however, only small proportions have undergone RT during the follow-up period. Only 2 previous studies have reported on the predictive value of preoperative DSE for cardiovascular outcomes after RT. In addition, structural and functional echocardiographic parameters other than inducible myocardial ischemia may be of predictive value in RT recipients. The current study aimed to assess the value of rest and DSE in predicting cardiovascular outcome after RT.
Materials and Methods
Study Patients
Between December 19, 1994, and October 26, 2006, 572 patients with ESRD underwent RT at the Geisinger Medical Center. A total of 185 patients with intermediate to high risk for CAD (defined as the presence of at least 1 of the following characteristics: age ≥ 50 years, diabetes mellitus, previous myocardial infarction or stroke, or extracardiac atherosclerosis) underwent DSE 1 to 12 months (median 5 months) before RT and were included in this retrospective single-center study. The demographic, clinical, laboratory, and transplantation data were obtained from the electronic medical records, and the echocardiographic data were reviewed from the digital archives. The study was approved by the Geisinger Medical Center Institutional Review Board.
Dobutamine Stress Echocardiography
DSE was performed according to a standard dobutamine-atropine protocol and included complete resting echo-Doppler cardiography. Incremental doses of dobutamine (5-50 mg/kg/min) were infused at 3-minute intervals. If the target (85% predicted maximum for age) heart rate was not reached and in the absence of inducible ischemia, atropine was injected intravenously at 0.25 mg doses up to a maximum dose of 1 mg. Echocardiographic images were obtained in the standardized parasternal long- and short-axes (midventricular and apical), and in apical 2-, 3-, 4-, and 5-chamber views at each stage, and were stored digitally. During dobutamine infusion, a 12-lead electrocardiogram was recorded and blood pressure was measured at each stage. A single electrocardiographic lead continuously monitored the heart rate. End points for DSE were defined as the development of new or worsening wall motion abnormality (WMA) (ischemia), achievement of ≥ 85% of the predicted maximum heart rate for age, severe symptoms of angina or dyspnea, systolic blood pressure < 85 or > 220 mm Hg or a decrease in systolic blood pressure of > 20 mm Hg from one stage to the next, ≥ 2 mV ST segment depression in at least 2 consecutive leads, or significant arrhythmias (nonsustained/sustained ventricular/supraventricular tachycardia or high-grade atrioventricular block).
Echocardiographic Image Analysis
All echocardiographic images were stored digitally and analyzed off-line. For wall motion assessment, all echocardiographic views were stored in cineloops and different stages were synchronized and displayed in quad-screen format (including baseline and low, pre-peak, and peak doses of dobutamine). A 16-segment model of left ventricle was used, and wall motion was scored on a 4-point scale as 1 = normal or hyperkinetic, 2 = hypokinetic, 3 = akinetic, and 4 = dyskinetic or aneurismal. Normal (negative for ischemia) DSE was defined as the presence of hyperkinetic systolic motion in all left ventricular segments at peak dobutamine effusion. Fixed (scarred) left ventricular segments were defined by the presence of resting WMA without change during dobutamine infusion.
Left ventricular mass was calculated using the standard cube formula and indexed to body surface area. Left ventricular hypertrophy was defined as a left ventricular mass index of ≥ 110 g/m 2 for women and ≥ 134 g/m 2 for men. Left atrial enlargement was defined as a diameter of > 4.0 cm measured in the parasternal long-axis view. Aortic valve sclerosis was defined as focal areas of increased echogenicity and thickening of the aortic valve leaflets without commissural fusion and in the absence of aortic stenosis (aortic valve peak continuous wave Doppler flow velocity < 2.5 m/sec).
Follow-up
Follow-up began from the date of the index DSE. Clinical status was obtained by the review of medical records and telephone interviews. Patients were followed up for a mean of 60 months (range 3-145 months) after DSE. The time from RT to follow-up was 1 to 135 months (median 49 months). Records were kept of the occurrence and timing of major adverse cardiac events (MACE) (cardiac death, nonfatal myocardial infarction, or coronary revascularization). Hospital or physician records were used to determine the cause of death. For patients who had multiple events, data were censored at the time of the first event.
Statistical Analysis
Data are expressed as mean ± standard deviation for continuous variables and as frequencies and percentages for categoric variables. Continuous variables were compared between groups using the 2-tailed Student t test. Categoric variables were tested using the chi-square test or Fisher exact test. Event-free survival was analyzed with the first cardiac event per patient, using the Kaplan–Meier curves and log-rank statistics. Multiple Cox regression analysis was performed on the first occurrence of MACE for baseline variables. Multivariate regression analysis was used to identify independent predictors of MACE. A P value < .05 was considered statistically significant. All statistical analyses were performed on SPSS software for Windows (version 8.0, SPSS Inc, Chicago, IL).
Results
Baseline Data
The mean age of the 185 RT recipients was 56 ± 11 years, and the prevalence of CAD risk factors was as follows: male gender, 118 (64%); smoking, 49 (27%); hypertension, 159 (86%); diabetes, 99 (54%); and hypercholesterolemia, 105 (57%). Overall, 42 patients (23%) had a history of myocardial infarction, percutaneous coronary intervention, or coronary bypass graft surgery; 21 patients (11%) had a history of stroke; and 27 patients (15%) had peripheral vascular disease. Transplant was performed using living donors (30 [16%]) or cadaveric organs. Previous RT had been performed in 16 patients (9%) Beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, statins, and aspirin were taken by 73 patients (40%), 35 patients (19%), 44 patients (24%), and 36 patients (20%), respectively. The mean serum creatinine value was 7.3 ± 2.9 mg/dL.
DSE Results
Regional left ventricular WMA at rest (fixed), with stress (inducible), or both were present in 54, 35, and 18 patients, respectively. Among the 185 patients, 122 (66%) reached > 85%, 30 (16%) reached 80% to 84%, and 33 (18%) reached < 80% predicted maximal heart rate for age. Of the 63 patients with submaximal heart rate response, 41 had a negative DSE, 7 had rest WMA alone, 7 had inducible WMA alone, and 8 had both rest and inducible WMA (ie, WMA at rest that did not change during DSE and new WMA that developed during DSE). Among those with submaximal DSE, the test was terminated prematurely in approximately 30% because of significantly elevated blood pressure as per protocol. Overall, 73 patients (39%) had normal wall motion on DSE. All patients were in sinus rhythm at the start of DSE; information regarding the development of cardiac rhythm abnormalities during the test was not systematically retrieved.
Accuracy of DSE in Predicting CAD
A total of 38 patients (23 with and 15 without inducible ischemia on DSE) underwent coronary angiography after DSE. Among these, 17 patients were found to have significant CAD defined as luminal diameter narrowing of ≥ 70% in ≥ 1 major epicardial coronary artery. The sensitivity, specificity, and positive and negative predictive values of inducible ischemia on DSE in predicting significant CAD were 88%, 62%, 65%, and 87% respectively.
Prognostic Value of DSE for 48-Month MACE
Patients were divided into 4 subgroups on the basis of their DSE wall motion response: normal DSE, fixed WMA (scar), inducible ischemia only, and both fixed WMA and inducible ischemia. At a mean follow-up of 48 months, 24 patients (13%) had at least 1 MACE, including 10 cardiac deaths (7 acute myocardial infarctions, 1 cardiogenic shock, and 2 sudden cardiac deaths), 7 nonfatal myocardial infarctions, and 7 coronary artery revascularization procedures. Only 3 patients underwent coronary revascularization before RT. The remaining patients were managed conservatively for different reasons, including diffuse disease, small-caliber vessels not suitable for intervention, poor vascular targets, small ischemic burden, or patients’ preference. Compared with patients with normal DSE, MACE at 48 months of follow-up occurred more frequently in patients with both fixed and inducible WMA (7% vs 33%, P = .007) ( Table 1 ). Figure 1 shows the Kaplan–Meier MACE-free survival curve for the 2 groups. There was no difference in 48-month MACE between patients with inducible ischemia alone and those with normal DSE. In addition, fixed WMA was not a predictor of MACE. Of 114 patients with negative DSE, 4 underwent coronary revascularization during follow-up, including 2 percutaneous coronary interventions and 2 surgical coronary revascularizations.
| DSE | 48-month MACE | P vs normal study |
|---|---|---|
| Normal | 8/114 (7%) | N/A |
| Fixed WMA alone | 8/36 (22%) | .025 |
| Inducible ischemia alone | 2/17 (12%) | .618 |
| Both fixed and inducible WMA | 6/18 (33%) | .004 |
Echocardiographic Predictive Model for 48-Month MACE
By univariate analysis, history of hypertension, lower high-density lipoprotein levels, aortic valve sclerosis, higher left ventricular posterior wall thickness in diastole, larger left atrial size, and presence of combined fixed and inducible WMA on DSE were identified as predictors of 48-month MACE ( Tables 2 and 3 ). By Cox proportional hazard analysis, only 3 independent predictors of 48-month MACE were identified: presence of both fixed and inducible WMA (hazard ratio [HR] 5.6, P = .012), left atrial size (HR 4.2, P = .002), and aortic valve sclerosis (HR 3.9, P = .013) ( Table 4 ). The presence of fixed WMA alone was not a predictor of MACE. Baseline demographic, clinical, and electrocardiographic, laboratory, and transplantation variables were not predictive of 48-month MACE. On the basis of this analysis, an echocardiographic model was constructed for predicting MACE in RT recipients. In this model, risk of MACE significantly increased directly in association with the number of predictors present. As shown in Figure 2 , patients with all 3 independent predictors had a 60% risk of MACE at 48 months compared with 5% in those with none of the predictors.
| MACE | No (n = 161) | Yes (n = 24) | P |
|---|---|---|---|
| Age (y) | 55.7 ± 11.3 | 59.8 ± 9.8 | .095 |
| Height (cm) | 171.2 ± 9.4 | 172.1 ± 11.6 | .710 |
| Weight (kg) | 86.4 ± 19.0 | 83.8 ± 18.8 | .553 |
| Body mass index (kg/m 2 ) | 29.3 ± 5.9 | 28.2 ± 4.9 | .412 |
| Male | 100 (62.1%) | 18 (9.7%) | .220 |
| Smoker | 41 (26.1%) | 7 (29.2%) | .750 |
| Hypertension | 142 (88.2%) | 17 (70.8%) | .022 |
| Diabetes mellitus | 86 (53.4%) | 13 (54.2%) | .945 |
| Hypercholesterolemia | 90 (55.9%) | 15 (62.5%) | .543 |
| Myocardial infarction | 14 (8.7%) | 2 (8.3%) | .953 |
| Percutaneous coronary intervention | 10 (6.2%) | 3 (12.5%) | .382 |
| Coronary artery bypass graft | 22 (13.7%) | 5 (20.8%) | .357 |
| Cerebrovascular accident | 18 (11.2%) | 3 (12.5%) | .740 |
| Peripheral vascular disease | 21 (13.0%) | 6 (25.0%) | .122 |
| Medication use: | |||
| Beta-adrenergic blockers | 60 (37.3%) | 13 (54.2%) | .114 |
| ACE inhibitor or ARB | 34 (21.1%) | 1 (4.2%) | .052 |
| Statins | 40 (24.8%) | 4 (16.7%) | .452 |
| Aspirin | 32 (19.9%) | 4 (16.7%) | 1.000 |
| Living donor | 29 (18.0%) | 1 (4.2%) | .134 |
| Previous transplantation | 12 (7.5%) | 4 (16.7%) | .135 |
| Transplant failure | 19 (11.8%) | 1 (4.2%) | .479 |
| Human leukocyte antigen mismatch | 3.2 ± 1.7 | 3.1 ± 1.4 | .853 |
| Hemoglobin (g/dL) | 11.9 ± 1.8 | 11.9 ± 1.7 | .834 |
| Total cholesterol (mg/dL) | 200.4 ± 58.9 | 200.5 ± 63.0 | .992 |
| High-density cholesterol (mg/dL) | 45.7 ± 16.5 | 38.2 ± 9.3 | .004 |
| Low-density cholesterol (mg/dL) | 113.9 ± 49.2 | 114.8 ± 50.3 | .944 |
| Triglycerides (mg/dL) | 222.4 ± 132.3 | 245.9 ± 159.0 | .475 |
| Erythrocyte sedimentation rate (mm/h) | 48.6 ± 39.3 | 70.3 ± 51.2 | .166 |
| Parathyroid hormone (pg/mL) | 221.7 ± 221.2 | 201.0 ± 171.2 | .689 |
| Hemoglobin A1c (%) | 7.8 ± 2.1 | 7.5 ± 1.4 | .587 |
| MACE | No (n = 161) | Yes (n = 24) | P |
|---|---|---|---|
| Left ventricular ejection fraction (%) | 55.0 ± 9.5 | 53.3 ± 10.2 | .418 |
| Diastolic dysfunction (%) | 48 (30%) | 10 (42%) | .086 |
| Mitral annular calcification | 37 (23.0%) | 8 (33.3%) | .270 |
| Aortic valve sclerosis | 45 (28.0%) | 14 (58.3%) | .003 |
| Left ventricular hypertrophy | 71 (44.4%) | 16 (66.7%) | .077 |
| Left ventricular mass index (g/m 2 ) | 123.7 ± 49.4 | 145.4 ± 28.6 | .072 |
| Aortic root diameter (cm) | 3.4 ± 0.4 | 3.4 ± 0.5 | .530 |
| Left atrial size (cm) | 4.0 ± 0.6 | 4.5 ± 0.6 | .000 |
| Interventricular septal thickness in diastole (cm) | 1.3 ± 0.4 | 1.4 ± 0.3 | .400 |
| Left ventricular posterior wall thickness in diastole (cm) | 1.2 ± 0.2 | 1.3 ± 0.3 | .038 |
| Left ventricular internal diameter in diastole (cm) | 4.9 ± 0.7 | 5.2 ± 0.7 | .084 |
| Left ventricular internal diameter in systole (cm) | 3.2 ± 0.8 | 3.3 ± 0.7 | .458 |
| Mitral regurgitation | 71 (44.1%) | 13 (54.2%) | .355 |
| Tricuspid regurgitation | 59 (36.6%) | 8 (33.3%) | .753 |
| Tricuspid regurgitation velocity (cm/sec) | 265.4 ± 51.5 | 251.7 ± 75.7 | .586 |
| Both fixed and inducible WMA | 12 (7.5%) | 6 (25.0%) | .007 |
| Fixed WMA alone | 28 (17.4%) | 8 (33.3%) | .066 |
| Inducible ischemia alone | 27 (16.8%) | 8 (33.3%) | .053 |
| Chest pain during DSE | 7 (4.3%) | 2 (8.3%) | .330 |
| Abnormal resting electrocardiogram | 64 (39.8%) | 7 (29.2%) | .320 |
| Abnormal stress electrocardiogram (≥2 mV ST segment depression) | 7 (4.3%) | 1 (4.2%) | 1.000 |
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