Non-immune risk predictors of cardiac allograft vasculopathy: Results from the U.S. organ procurement and transplantation network

https://doi.org/10.1016/j.ijcard.2021.02.002Get rights and content

Highlights

  • In this large-scale registry study with more than 40,000 patients, CAV incidence was higher in males than in females.

  • Next to male sex, older donor age and ischemic cardiomyopathy, the classical cardiovascular risk factors were related to new-onset CAV.

  • Classical cardiovascular risk factors of the recipient combined, which are potentially modifiable in HT recipient's aftercare, accounted only for about 9% of attributable 5-year CAV risk.

Abstract

Background

Cardiac allograft vasculopathy (CAV) remains a major long-term complication in heart transplant (HT) recipients related to increased mortality. We aimed to identify non-immune recipient- and donor-related risk factors for the development of CAV in HT patients.

Methods

40,647 recipients, prospectively enrolled from April 1995 to January 2019 in the Organ Procurement and Transplantation Network (OPTN), were analyzed after exclusion of pediatric patients, those with missing information on CAV, and re-transplantation. Multivariable-adjusted Cox regression analyses were performed to identify recipient- and donor-related risk factors for CAV. 5-year population attributable risk for classical cardiovascular risk factors was calculated to estimate the recipients' CAV risk. Analyses were based on OPTN data (June 30, 2019).

Results

Of 40,647 post-transplant patients, 14,698 (36.2%) developed CAV with a higher incidence in males (37.3%) than in females (32.6%) (p < 0.001). The mean follow-up time was 68.2 months. In recipients, male sex, African American and Asian ethnicity, ischemic cardiomyopathy, body mass index and smoking were associated with CAV occurrence. In donors, older age, male sex, smoking, diabetes and arterial hypertension were related to CAV. Results remained fairly stable after analysis of different time periods. 5-year attributable CAV risk for classical cardiovascular risk factors was 9.1%.

Conclusions

In this large registry with known limitations concerning data completeness, CAV incidence was higher in males than in females. Next to male sex and donor age, the classical cardiovascular risk factors were related to incident CAV. Classical cardiovascular risk factors played only a minor role for the 5-year attributable CAV risk.

Introduction

Heart transplantation (HT) is an established curative treatment strategy of selected patients with end-stage heart failure [1]. Besides malignancies, chronic graft failure and infections, cardiac allograft vasculopathy (CAV) is one of the most important long-term causes of mortality after HT [2,3]. Data from the Registry of the International Society for Heart and Lung Transplantation (ISHLT) showed that the cumulative morbidity rate for CAV increases over time from 29.3% in the first five years to 47.4% in the first ten years after HT [2].

Thus, early detection and CAV risk stratification are crucial to improve chronic graft failure and survival. In contrast to coronary artery disease, which is primarily characterized by focal, excentric epicardial lesions with an amorphous lipid core, CAV is a pan-arterial diffuse disease [4]. Additionally, CAV is characterized by endothelial cell injury, proliferation of smooth muscle cells and concentric intimal hyperplasia leading to narrowing of the coronary arteries [[4], [5], [6]]. Several risk factors including immune and non-immune factors are known to be involved in the development of CAV [6]. For instance, donor age and human leukocyte antigen (HLA)-antibodies have consistently been related to the development of CAV [[7], [8], [9], [10], [11], [12]].

However, the impact of other recipient- and donor-related risk factors e.g. recipient age, sex mismatch, and classical cardiovascular risk factors are controversially discussed in several studies, and may have changed over decades [7,9,13]. CAV risk stratification is imperative for a more personalized surveillance and therapy in HT recipients. It is important to identify risk factors for the development of CAV to improve long-term survival of HT recipients.

Therefore, we aimed to analyze (i) the incidence of CAV in males and females, (ii) the association of non-immune recipient and donor-related risk factors with CAV and (iii) the population attributable risk (PAR) of classical cardiovascular risk factors of the recipient as they are potentially modifiable and targetable in HT recipients' aftercare.

Section snippets

Study population

We used data from the United Network for Organ Sharing (UNOS) registry which operates under contract of the United States government administered by the Health Resources and Service Administration (HRSA) and has been described previously [14]. Its primary data source is the Organ Procurement and Transplantation Network (OPTN), which collects national data in the United States on the candidate waiting list, organ donation and matching and transplantation.

Overall, data from 71,399 HT patients

Baseline characteristics

Recipient and donor baseline demographic and clinical characteristics are presented in Table 1. Of 40,647 recipients, the mean age was 53 ± 12 years for recipients (75.8% females) and 31 ± 12 years for donors (70.8% males). The main indications for HT were ischemic (41.6%) and dilated cardiomyopathy (48.0%). Prior or current smoking was common in recipients (29.3%) and donors (21.9%). Diabetes was frequent among recipients (24.2%). 17.9% HT recipients had a VAD at listing or implanted while on

Discussion

In this large-scale study analysing more than 40,000 heart transplant recipients, we observed a higher CAV incidence in males compared to females. Next to male sex, older donor age and ischemic cardiomyopathy, classical cardiovascular risk factors were related to new-onset CAV. African American ethnicity was differentially associated with CAV incidence in recipients and donors. Classical cardiovascular risk factors of the recipient combined, which are potentially modifiable in HT recipient's

Conclusions

Next to male sex, older donor age and ischemic cardiomyopathy, the classical cardiovascular risk factors were related to new-onset CAV, but accounted only for 9% of 5-year CAV risk.

This indicates a rather subordinate role for classical cardiovascular risk factors in the development of CAV. Further studies involving immune factors are needed to assess the main drivers for CAV in this challenging patient population.

Declaration of Competing Interest

AMB has received honoraria from Abbott, Abiomed, AstraZeneca, BerlinHeart, Medtronic and Novartis (unrelated to the submitted work). BS has received speakers fee from AstraZeneca and Abiomed (unrelated to the submitted work). CM reports speaker fees from AstraZeneca, Novartis and Loewenstein Medical (unrelated to the current work). RBS has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under the grant agreement

Acknowledgments

This work was supported in part by Health Resources and Services Administration contract 234-2005-37011C. The content is the responsibility of the authors alone and does not necessarily reflect the view and polices of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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