Assessment of Cardiac Allograft Vasculopathy with Coronary Flow Reserve in Japanese Pediatric Heart Transplant Recipients

Abstract

Introduction: Cardiac allograft vasculopathy (CAV) is one of the major concerns for long-term survival in patients after heart transplantation. Risk factors associated with CAV have been investigated, and evaluation of intravascular ultrasounds (IVUS) image and coronary flow reserve (CFR) has been established for diagnosis of CAV in adult transplant patients. However, its adequacy in pediatric patients is still unclear, especially in Japanese children who have undergone heart transplantation overseas from donors with different genetic background. The objective of this study is to investigate CAV morbidity in Japanese pediatric heart transplant recipients and whether the measurement of CFR predicts progression of CAV. Methods: The coronary angiography and IVUS image were evaluated once a year in Japanese patients who underwent heart transplantation in the US or Germany under 18 years of age. At the same time, CFR was evaluated by the endothelium-dependent vasodilatation (response to acetylcholine (10-5M)) and endothelium-independent vasodilatation (response to nitroglycerin (2μg/kg)) using a 0.014-inch Doppler FloWire (Volcano) at the left anterior descending (LAD) artery. CFR was defined as the ratio of hyperemic to basal average peak velocity of the LAD flow. Results: Fifteen patients were included in this study (M: F= 5: 10). The median age at transplantation was 4.3 (1.4 to 15.9) years and median post-transplant time was 6 (3 to 11) years. Nine (60%) of the 15 patients had epicardial CAV only at the left main (LMT) coronary artery. Two had CAV within 3 years after transplantation and four after 6 years or more. CFR at 3, 6, and 9 years after transplantation was 1.45 ± 0.34, 1.15 ± 0.22, 1.26 ± 0.14, respectively, for acetylcholine application and 2.35 ± 0.61, 1.98 ± 0.31, 2.07 ± 0.48, respectively, for nitroglycerin application. Both the endothelium-dependent and endothelium-independent CFR did not correlate with the grade of CAV, serum BNP levels and LVEDP. Patients with CAV have more frequently had episodes of acute rejection (grade 2 or more) than those without CAV. Conclusion: More than half of Japanese pediatric patients had epicardial CAV during mid-term follow-up after heart transplantation. The CAV lesion was localized only in the LMT during the study period. Regardless of the evidence of CAV, the endothelium-dependent CFR was impaired and the endothelium-independent CFR was preserved in all patients. So far, the measurements of CFR did not predict early and localized CAV in the present study, but the further follow-up study is mandatory to support conclusion.