Abstract
Background The renin-angiotensin-aldosterone (RAAS) and adrenergic receptor (ADR) genotypes affect cardiac function in heart failure. It is not known if recipient genotype affects function of the transplanted heart. We investigated the influence of recipient RAAS or ADR genotype on cardiac function and outcomes after transplant (Tx). Methods Patients (Pts) < 25 yrs old, post cardiac Tx, were enrolled (2003–06) and genotyped for polymorphisms in genes associated with RAAS upregulation (ACE-D, AGTR1-C, AGT-G, CYP11B2-G and CMA1-A) and β-ADR downregulation (β1Arg389 and β2Gly16). Hetero- or homozygosity for the high risk allele was considered a high-risk genotype. Univariate associations between genotypes and incidence of rejection, cardiac dysfunction (hemodynamic/echocardiographic), graft vasculopathy (GV), death and reTx were assessed via logistic or linear regression models with time dependent models as needed. Results Of 222 pts transplanted, 107 pts were studied. Age at Tx was 8.4±6.8 yrs (follow-up, 6.3±5.3 yrs; 42% male). The high risk allele frequency was: ACE 51%, AGTR1 23%, AGT 59%, CYP 35%, CMA 42%, β1Arg389 74% and β2Gly16 37% (in Hardy-Weinberg equilibrium). During follow-up, 81% pts had rejection, 51% graft dysfunction, 13% developed GV, 7% died and 8% were re-transplanted. 24% pts were receiving ACE/Angiotensin receptor inhibitors and 5% were receiving β-blockers at 5 yrs post-Tx. The presence of a high risk AGT or AGTR genotype was associated with greater severity of graft dysfunction at last follow-up (p=0.05), elevated CVP and PA pressures (p<0.001) and higher mortality. ADR genotype had no effect on outcomes. Cumulatively, a higher number of homozygous high risk RAAS genotypes was associated with a higher incidence of rejection (Hazard ratio/HR,1.3), graft dysfunction (HR,1.5) and higher probability of death (HR,2.5) (p<0.05). Conclusion RAAS polymorphisms in the recipient are associated with higher mortality after cardiac Tx possibly related to greater impairment of graft function with rejection. Whether wider use of RAAS inhibitors in this high risk cohort can improve outcomes after Tx requires further investigation. The lack of effect of the ADR genotype may relate to sympathetic denervation of the transplanted heart.
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