Everolimus in the Prevention of Calcineurin-Inhibitor-Induced Left Ventricular Hypertrophy in Heart Transplantation (RAD-TAC Study)

Purpose To determine whether low-dose everolimus in combination with low-dose tacrolimus compared to full-dose tacrolimus without everolimus safely attenuates left ventricular hypertrophy after heart transplantation Methods In this prospective study, orthotopic heart transplant (OHT) transplant recipients were randomized at 12 weeks post-transplant to a combination of everolimus, tacrolimus (low dose), mycophenolate and prednisolone (RAD-TAC group) OR tacrolimus (normal dose) mycophenolate and prednisolone (TAC group). Left ventricular mass (LVM), mass index (LVMi), function and fibrosis markers (T1 mapping) were assessed by Cardiac MRI (CMR) at baseline and at 52 weeks post-transplant Results Forty patients were randomized. Patient characteristics, including LVMi, age and gender were evenly matched between groups at baseline. Patients in the RAD-TAC group had significantly lower tacrolimus levels (5.5 (1.5) ug/L vs. 8. 3 (3.1) ug/L, mean (SD); p=0.03). The mean everolimus level was 6.8 (1.8) ug/L. LV Mass in the RAD-TAC group significantly reduced over the 40-week study period; in contrast, LV Mass in the TAC group increased (LV Mass change -11.1g (18.3) vs. +0.4g (6.3); p=0.001, LVMi change -6.1g/m2 (8.8) vs.+1.4g/m2 (5.8); p=0.001). Interstitial fibrosis (by CMR T1 mapping) in the RAD-TAC group significantly reduced over the 40-week period; in contrast, interstitial fibrosis in the TAC group increased (fibrosis change -31 (51) ms vs. +33 (-94) ms; p=0.002). No significant differences were observed in measures of myocardial function, significant rejection episodes, hypertension (systolic BP 131 (9.2) mmHg vs. 132 (8.5) mmHg; p=0.51) or serious adverse events between groups Conclusion Low-dose everolimus in combination with low-dose tacrolimus compared to full-dose tacrolimus safely attenuates left ventricular hypertrophy after heart transplantation. The reduction in CMR-determined fibrosis also provides insights into a potential mechanistic role of everolimus in the pathophysiology of cardiac hypertrophy after transplantation.