Serial Assessment of Coronary Flow Reserve by Rubidium-82 Positron Emission Tomography Predicts Mortality in Heart Transplant Recipients

Abstract

Objectives: This study aimed to evaluate the long-term prognostic value of serial assessment of coronary flow reserve (CFR) by rubidium Rb 82 (82Rb) positron emission tomography (PET) in heart transplantation (HT) patients.

Background: Cardiac allograft vasculopathy is a major determinant of late mortality in HT recipients. The long-term prognostic value of serial CFR quantification by PET imaging in HT patients is unknown.

Methods: A total of 89 patients with history of HT (71% men, 7.0 ± 5.7 years post-HT, age 57 ± 11 years) scheduled for dynamic rest and stress (dipyridamole) 82Rb PET between March 1, 2008 and July 31, 2009 (PET-1) were prospectively enrolled in a single-center study. PET myocardial perfusion studies were reprocessed using U.S. Food and Drug Administration-approved software (Corridor 4DM, version 2017) for calculation of CFR. Follow-up PET (PET-2) imaging was performed in 69 patients at 1.9 ± 0.3 years following PET-1. Patients were categorized based on CFR values considering CFR ≤1.5 as low and CFR >1.5 as high CFR.

Results: Forty deaths occurred during the median follow-up time of 8.6 years. Low CFR at PET-1 was associated with a 2.77-fold increase in all-cause mortality (95% confidence interval [CI]: 1.34 to 5.74; p = 0.004). CFR decreased over time in patients with follow-up imaging (PET-1: 2.11 ± 0.74 vs. PET-2: 1.81 ± 0.61; p = 0.003). Twenty-five patients were reclassified based on PET-1 and PET-2 (high to low CFR: n = 18, low to high CFR: n = 7). Overall survival was similar in patients reclassified from high to low as patients with low to low CFR, whereas patients reclassified from low to high had similar survival as patients with high to high CFR. In multivariate Cox regression of patients with PET-2, higher baseline CFR (hazard ratio [HR] for a 0.73 unit (one SD) increase: 0.36, 95% CI: 0.16 to 0.82) and reduction in CFR from PET-1 to PET-2 (HR for a 0.79 unit (one SD) decrease: 1.50 to 7.84) were independent predictors of all-cause mortality.

Conclusions: Serial assessment of CFR by 82Rb PET independently predicts long-term mortality in HT patients.

Keywords: cardiac allograft vasculopathy; coronary flow reserve; heart transplantation; myocardial blood flow; positron emission tomography; prognosis.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

FIGURE 1. Study Design and Timeline

PET = positron emission tomography; SPECT = single-photon emission computed tomography.

FIGURE 2. Representative PET Perfusion Images for a Patient With Heart Transplant

Representative relative perfusion images, polar maps, and rate pressure product–corrected myocardial blood flow and coronary flow reserve (CFR) values for a 48-year-old male patient who underwent dynamic positron emission tomography (PET) perfusion imaging 6 months after heart transplantation (A). Both stress (top) and rest (bottom) images demonstrate normal relative perfusion. Polar maps of stress and rest images and CFR demonstrate homogenously normal perfusion with normal global CFR of 3.31. Follow-up PET scan 2 years later showed a small equivocal inferolateral perfusion defect (B). Polar map of CFR at this time showed severe, diffuse reduction in CFR (mean global CFR: 1.29), which was due to reduction in stress myocardial blood flow, whereas rest flow was unchanged. Coronary angiography after PET-2 revealed severe triple vessel allograft vasculopathy. LAD = left anterior descending artery; LCX = left circumflex artery; RCA = right coronary artery.

FIGURE 3. Baseline MBF and CFR

Rest and stress myocardial blood flow (MBF) and coronary flow reserve (CFR) values at baseline positron emission tomography based on CFR.

FIGURE 4. CFR and Rejection Episodes

CFR values at baseline positron emission tomography imaging grouped based on the number of rejection (R) episodes prior to imaging. R0 = no rejection prior to PET-1 (baseline); R1 = 1 rejection episode; R2 = 2 rejection episodes; R3+ = 3 or more rejection episodes; other abbreviations as in Figures 1 and 2.

FIGURE 5. Change in MBF and CFR Over Time

Rest and stress MBF and CFR values derived from PET-1 and PET-2. PET-1 = baseline positron emission tomography; PET-2 = follow-up positron emission tomography; other abbreviations as in Figures 1 and 2.

FIGURE 6. Mortality and Composite Outcomes

Kaplan-Meier plots for cumulative survival in the entire cohort based on baseline PET-1 CFR (A) and in patients with available follow-up imaging based on PET-1 and PET-2 CFR values (B). High → high represents patients with CFR >1.5 at both PET-1 and PET-2. Low → high CFR represents patients with CFR ≤1.5 at PET-1 and CFR >1.5 at PET-2. Low → low CFR represents patients with CFR ≤1.5 at both PET-1 and PET-2. High → low represents patients with CFR >1.5 at PET-1 and CFR ≤1.5 at PET-2. (C, D) Similar Kaplan-Meier plots are presented for the combined endpoints of death, myocardial infarction (MI), and revascularization. CI = confidence interval, other abbreviations as in Figures 2 and 5.

FIGURE 7. Forest Plot of HR for Overall Survival

Forest plot of hazard ratios (HR) of overall mortality in univariate (A) and multivariate (B) Cox proportional hazards regression models in patients with available follow-up imaging. The risk represented by CFR is presented in 2 separate ways in Cox regression modeling: the hazard HR for PET-1 CFR is presented for a 0.73 ± 1.00-U increase in CFR, the HR for change in CFR from PET-1 to PET-2 is presented for a 0.79 ± 1.00-U decrease in CFR from PET-1 to PET-2. For other continuous variables, HR are presented as an SD increase for rate pressure product (RPP) and left ventricular (LV) perfusion defect size, a 10-year increase in age, a 5-kg/m2 increase for body mass index, a 5.7 ± 1-year increase for post-transplantation years, a 1 mg/dl increase in creatinine, and a 10 mg/dl increase in low-density lipoprotein. HR of previous rejections is presented as an increase of 1 in the number of prior rejections. Abbreviations as in Figures 2, 5, and 6.