Background

Chronic allograft vasculopathy (CAV) is the leading cause of late failing heart allografts and is associated with mortality. The determinants of CAV integrating traditional cardiovascular risk factors with immune parameters have not been addressed at a population level.

Methods

Observational prospective cohort study, including 723 heart recipients from 2 centers between 2004 and 2011. Participants were extensively screened for cardiovascular risk factors and the presence of circulating DSA. All patients underwent prospective protocol endomyocardial biopsies and coronary heart allograft angiograms. Clinical, donor, recipient, transplant parameters and immunological factors were integrated into mathematic models to assess the independent determinants of CAV at 3 years post transplant.

Results

The mean recipient and donor age were 51 ± 15 and 45 ±12 years respectively. The mean cold ischemia time was 182 ± 60 minutes. A total of 145 patients (20.1%) had circulating DSA at the day of transplantation. A total of 170 patients (23.5%) experienced acute rejection with 128 cases (17.7%) of grade 2R ACR and 83 cases (11.5%) of pAMR+. At 3 years post transplant 29.7% of patients presented with CAV (20.8%, 7.4% and 1.5% having CAV1, 2 and 3 respectively). After adjusting on recipient cardiovascular risk factors (recipient age, gender, primary heart disease, CMV status, blood pressure profile, tobacco use, hyperlipidemia, diabetes mellitus and BMI), donor risk factors (age, gender, cause of death and BMI), transplant characteristics (cold ischemia time, emergency heart transplantation), immunological parameters (circulating-DSA, occurrence of acute rejection), the independent determinants of CAV at 3 years were: donor age (per year increment, RR=1.05; 95%CI=1.03-1.08), recipient hyperlipidemia (RR=2.1; 95%CI= 1.02-4.29) and the presence of circulating-DSA at the day of transplantation (RR=2.45 95%CI=1.45-4.12). Sensitivity analysis showed that occurrence of pAMR post transplant was also independently associated with increased risk of CAV at 3 years (RR=3.51, IC95%=1.84-6.69) and increased patient death (HR=1.8, p=0.01).

Conclusion

Using a population of extensively phenotyped heart transplants, we identify that circulating DSA and occurrence of pAMR are strong determinants of accelerated CAV post transplant, independently of traditional cardiovascular risk factors. These 2 factors are also associated with increased risk of patient death.

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