Association of Pre-Transplant Stress Echocardiography Findings in 354 Kidney Transplant Recipients With Posttransplant Major Adverse Cardiovascular Events

Introduction

As of 2023, end-stage renal disease (ESRD) is estimated to affect over 800 000 individuals in the United States. ESRD portends significantly elevated risks for many negative outcomes, most prominently cardiovascular disease [1]. Studies have shown a 3.5% to 5% annual rate of nonfatal cardiac events in this population, which is roughly 50 times that of the general population [2]. Some of this can be explained by a higher prevalence of traditional cardiovascular risk factors in kidney transplantation (KT) candidates, stemming from ESRD-related pathophysiology and posttransplant factors, including immunosuppressive therapy [3,4]. The gold standard treatment for patients with ESRD is KT, as it has been shown to have the greatest reduction in morbidity and mortality [3,5]. One of the most common etiologies of kidney loss is premature death of the KT recipient [6,7], and the leading cause of death among the KT population is cardiovascular disease [8]. There is marked heterogeneity in the cardiovascular evaluation of KT candidates, with centers varying widely in the choice of screening modality (stress echocardiography [STE], nuclear perfusion imaging, coronary computed tomography [CT] angiography, or direct invasive angiography) and in the thresholds for referral [8]. STE, particularly dobutamine, is one of the most commonly used tests for ischemic evaluation prior to KT in the United States and Europe, as it avoids ionizing radiation and nephrotoxic contrast (unlike CT angiography), provides additional information on left ventricular function, valvular disease, and pulmonary pressures, and is widely available. High-risk STE features include extensive inducible wall motion abnormalities, reduced exercise capacity, abnormal blood pressure response, and increased left ventricular cavity dilation with stress [8]. Therefore, this retrospective study from a single-center aimed to evaluate the association of pretransplant STE findings in 354 KT recipients with posttransplant major adverse cardiovascular events (MACE).

Material and Methods

DATA SOURCE AND STUDY POPULATION:

Study approval was obtained from the Institutional Review Board of Saint Louis University (protocol #34091), along with a waiver for informed consent. The study protocol conformed to the ethical guidelines of the 1975 Helsinki Declaration. This was a single-center retrospective cohort study. We included adult KT recipients at Saint Louis University Hospital between January 1, 2015, and December 31, 2023. Ischemic evaluation was part of the routine pretransplant clinical testing. Patients without a pretransplant STE were excluded from the primary analysis. Patient electronic health records were reviewed for demographic information, clinical comorbidities, laboratory values, medications at the time of KT listing, and data related to pretransplant cardiac ischemic evaluation and revascularization. Eligible stress tests included exercise or pharmacologic echocardiographic testing. Our laboratory’s dobutamine stress echocardiography involves incremental dosing of dobutamine, typically starting at 5 μg/kg/min and increasing every 3 minutes to 10, 20, 30, and up to a maximum of 40 μg/kg/min. If the target heart rate (85% of the age-predicted maximum) is not achieved at the highest dobutamine dose, atropine may be administered in 0.25–0.5 mg increments, up to a total of 1–2 mg, unless contraindicated. Stress test results were categorized as normal or abnormal. Our data source included the stress test interpretations documented in patient records, without access to the raw quantitative stress imaging data. Per our laboratory protocol, a positive STE was defined by the presence of new or worsening regional wall motion abnormalities in 1 or more myocardial segments at peak stress compared with rest, consistent with inducible ischemia (Figure 1). In addition, stress electrocardiographic criteria for ischemia – defined as horizontal or downsloping ST-segment depression ≥1 mm measured 60–80 ms after the J point in 2 or more contiguous leads, or ST-segment elevation ≥1 mm in non–Q-wave leads – were considered supportive of an abnormal study. Stress ECG changes or symptoms alone, in the absence of stress-induced wall motion abnormalities, were not considered sufficient to classify a study as positive. Patients were divided into 2 groups based on the overall result of their STE: positive (n=58) vs negative (n=296) STE. We also evaluated the association of nuclear stress test results with the outcome. Nuclear tests were categorized as abnormal if there was evidence of fixed or reversible perfusion defects (ie, hypoperfused myocardial segments) or transient ischemic dilation.

STUDY OUTCOMES:

The mean follow-up duration of the patients included was 54±19 months. Survival status and outcome events were obtained from longitudinal follow-up documented in institutional electronic health records, including inpatient admissions, outpatient encounters, and recorded deaths. The primary outcome for the study was the occurrence of MACE, defined as a nonfatal acute coronary syndrome, heart failure hospitalization, fatal arrhythmia, stroke, or cardiovascular death, using standard American College of Cardiology/American Heart Association (ACC/AHA) guideline definitions. Events were identified through systematic medical record review and adjudicated by physician reviewers (internal medicine residents) blinded to pretransplant stress testing results. Heart failure hospitalizations were scrutinized by the investigators to ensure that the hospitalization was primarily for worsening heart failure and that patients met criteria for inpatient treatment of heart failure.

STATISTICAL ANALYSIS:

Continuous variables are presented as mean±SD if normally distributed and as median with interquartile range if not normally distributed. Variables with more than 20% missing data were excluded from analysis. Normality of data was assessed using the Shapiro-Wilk test. Categorical variables are presented as frequencies and percentages. Differences between group means were evaluated using t tests for continuous variables and the chi-square or Fisher exact test for categorical variables, as appropriate. Kaplan-Meier survival analysis was used to compare MACE-free survival between normal and abnormal STE groups, with differences evaluated using the log-rank test. To evaluate the association between STE parameters and the study outcome, univariate logistic regression analyses were conducted to identify variables associated with MACE; multivariable Cox proportional hazards models were then constructed adjusting for age, sex, and potentially confounding variables associated with MACE identified from univariate regression. Time-to-event was calculated from the date of KT to the occurrence of the first event of interest or last known follow-up. To avoid collinearity, stress test variables were entered into the model one at a time. The proportional hazards assumption was assessed using Schoenfeld residuals, with global and covariate-specific tests performed, and by visual inspection of scaled Schoenfeld residual plots. The assumption was not violated for all variables except left ventricular ejection fraction (LVEF); therefore, a time-dependent interaction term for LVEF was included in our final Cox proportional hazards model. The same variables, outcomes, and statistical models were used for nuclear stress testing subgroup analysis. All statistical analyses, including multivariable modeling and time-to-event analyses, were performed using Statistical Analysis Software (SAS Institute, Cary, NC, USA), and a 2-tailed P value <0.05 was considered statistically significant.

Results

BASELINE CHARACTERISTICS:

Baseline patient characteristics are presented in Table 1. Of the 518 adult KT recipients, 354 were included in the STE cohort after exclusion of patients without pretransplant STE. Of those, 296 (83.4%) had a negative result. A total of 147 patients underwent nuclear stress testing, of whom 133 (90.5%) had negative results. There were no significant differences between patients with negative vs positive STE in age, sex, or race. A higher incidence of smoking and greater beta-blocker use were observed in the negative STE group (Table 1). Echocardiographic findings are summarized in Table 2, in which patients with negative STE demonstrated significantly higher LVEF. Figure 2 illustrates the proportion of patients with positive stress tests who subsequently underwent invasive coronary angiography with or without revascularization. Of the 58 patients with a positive STE, 42 underwent left heart catheterization; among these, 24 were found to have obstructive disease (≥70% coronary stenosis), and 9 ultimately underwent coronary revascularization.

STUDY OUTCOMES:

Over a median follow-up of 54±19 months, 67 patients (18.9%) experienced MACE. At 60 months of follow-up, there were no significant differences in individual MACE components or the composite outcome between both groups (Table 3).

SURVIVAL ANALYSIS AND REGRESSION MODELS:

Kaplan-Meier survival analysis demonstrated no significant difference in MACE-free survival between groups at 60 months (Figure 3). On univariate regression analysis (Table 4), several baseline characteristics, including age (P=0.02), diabetes (P=0.03), coronary artery disease (<0.001), and prior percutaneous coronary intervention (P=0.003), were significantly associated with increased risk of MACE. After adjustment for confounders in the Cox proportional hazards model (Table 5), only coronary artery disease remained independently associated with MACE. None of the STE-derived parameters were associated with MACE or its individual components. Wall-motion abnormalities (P=0.67), LVEF (P=0.74), and an abnormal stress echocardiogram (P=0.89) were not independently associated in the multivariate Cox model. For nuclear stress test subgroup analysis, nuclear stress testing was not significantly associated with MACE in univariate analysis (OR, 0.85; 95% CI, 0.17–4.26; P=0.85) or multivariate analysis (HR, 0.38; 95% CI, 0.06–2.23; P=0.28).

Discussion

In this retrospective cohort of KT recipients, abnormal pretransplant STE and individual STE parameters were not independently associated with posttransplant MACE. Our results align with a growing body of literature questioning the predictive value of traditional noninvasive ischemia testing in advanced kidney disease and transplant populations [9–11]. Prior studies have suggested that abnormal perfusion or wall motion imaging is common in patients with ESRD, yet its correlation with clinical events after KT is inconsistent [12]. Several factors may explain these observations. First, microvascular disease and uremic cardiomyopathy, both highly prevalent in ESRD, may contribute to adverse outcomes independent of epicardial coronary artery disease, thereby limiting the prognostic yield of ischemia-focused testing. Second, the relatively high prevalence of abnormal test findings [10,13], combined with limited specificity, may dilute predictive accuracy. Finally, improvements in perioperative management, immunosuppression, and cardiovascular risk modification may reduce the incremental value of STE in identifying patients at greatest risk [14,15].

Despite the lack of prognostic association with long-term outcomes, STE remains widely used in pretransplant evaluation. In our cohort, more than 70% of patients with abnormal STE underwent invasive coronary angiography, and nearly one-third required revascularization. These findings suggest that STE may still influence management decisions, although its long-term benefit remains unclear [16]. Previous studies have demonstrated that the diagnostic accuracy of STE may not be as high in certain populations as in the general population [17]. Similar limitations have also been observed with nuclear stress testing [12]. A paradigm shift is already in place toward identifying and treating high-risk atherosclerotic plaque rather than basing management decisions solely on myocardial ischemia [18]. Recent guidelines, including the 2024 ACC/AHA/ASE/ASNC Appropriate Use Criteria and the ACC/AHA perioperative cardiovascular management guideline, reaffirm the value of noninvasive imaging in refining risk stratification before noncardiac surgery, particularly in patients with significant comorbidities [19,20]. In the context of transplantation, the 2022 AHA Scientific Statement further emphasizes the importance of coronary disease screening in kidney and liver transplant candidates, highlighting stress echocardiography as a practical and widely available modality to detect functionally significant ischemia [21]. However, these documents have noted the paucity of data to support ischemia testing in transplant candidates, and our study reinforces the need for prospective trials to determine whether such strategies meaningfully improve posttransplant outcomes [8,21]. More novel coronary imaging modalities, such as coronary CT angiography, particularly when augmented with artificial intelligence-based plaque characterization, may offer a more refined cardiovascular risk stratification beyond traditional stress testing by providing detailed anatomical and compositional insights into coronary atherosclerosis [21,22].

Strengths of our study include the use of a well-characterized cohort with detailed longitudinal follow-up, which minimizes heterogeneity in practice patterns and outcome adjudication. Several limitations should be considered when interpreting our results. Its retrospective design comes with inherent limitations including the lack of causal inference. Our database did not include the details of ABO compatibility, immunosuppressive regimens, tacrolimus trough levels, or rejection and infectious episodes. Although historically not strongly associated with MACE, these unmeasured factors could have introduced some confounding. We relied on studies interpreted by multiple readers, which could introduce bias from interobserver variability. This limitation is mitigated by the fact that our echocardiography laboratory is nationally accredited, and studies undergo periodic peer review audits, as required to maintain accreditation. The single-center setting may restrict generalizability, and the modest number of positive STE cases reduces power to detect small effect sizes. Finally, medication use, adherence, and posttransplant management strategies including revascularization were not investigated and may have influenced outcomes in ways not fully captured in our models.

Conclusions

In this retrospective study, neither pretransplant STE results nor individual STE parameters were significantly associated with long-term MACE among KT recipients at our institution. These results highlight the need to re-evaluate the role of traditional stress testing targeted toward detecting myocardial ischemia in pre-KT evaluation.