Coronary Microcirculatory Dysfunction and Acute Cellular Rejection After Heart Transplantation

Abstract

Background: Acute cellular rejection is a major determinant of mortality and re-transplantation after heart transplantation. We sought to evaluate prognostic implications of coronary microcirculatory dysfunction assessed by index of microcirculatory resistance (IMR) for risk of acute cellular rejection after heart transplantation. Methods: The current study prospectively enrolled 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiologic assessment 1 month after transplantation. IMR is microcirculatory resistance under maximal hyperemia. By measuring hyperemic mean transit time using 3 injections (4 mL each) of room-temperature saline under maximal hyperemia, IMR was calculated as hyperemic distal coronary pressure × hyperemic mean transit time. The primary endpoint was biopsy-proven acute cellular rejection of grade ≥2R during 2 years of follow-up after transplantation and was compared using multivariable Cox proportional hazard regression according to IMR. The incremental prognostic value of IMR, in addition to the model with clinical factors, was evaluated by comparison of c-index, net reclassification index (NRI), and integrated discrimination index (IDI). Results: Mean age of recipients was 51.2±13.1 years (81.2% male), and cumulative incidence of acute cellular rejection was 19.0% at 2 years. Patients with acute cellular rejection had significantly higher IMR values at 1 month than those without acute cellular rejection (23.1±8.6 vs. 16.8±11.1, P=0.002). IMR was significantly associated with the risk of acute cellular rejection (per 5-unit increase: adjusted HR 1.18, 95% CI 1.04-1.34, P=0.011) and the optimal cut-off value of IMR to predict acute cellular rejection was 15. Patients with IMR≥15 showed significantly higher risk of acute cellular rejection than those with IMR<15 (34.4% vs. 3.8%, adjusted HR 15.3, 95% CI 3.6-65.7, P<0.001). Addition of IMR to clinical variables showed significantly higher discriminant and reclassification ability for risk of acute cellular rejection (C-index 0.87 vs. 0.74, P<0.001; NRI 1.05, P<0.001, IDI 0.20, P<0.001). Conclusions: Coronary microcirculatory dysfunction assessed by IMR measured early after heart transplantation showed significant association with the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02798731

Predictive Efficacy of the Index of Microcirculatory Resistance for Acute Allograft Rejection and Cardiac Events After Heart Transplantation: A Systematic Review and Meta-Analysis

“…One paper was not related to the topic and one paper failed to meet the criteria among them. The metaanalysis eventually included five articles published between 2012 and 2021 [Ahn 2021;Lee 2021;Haddad 2012;Okada 2019;Yang 2016]. Table 1 lists the main characteristics of the included studies.…”

“…As shown in Figure 2, five studies were conducted to assess the predictive efficacy of the IMR for AAR [Ahn 2021;Lee 2021;Haddad 2012;Okada 2019;Yang 2016], and meta-analysis revealed significant difference between heart transplant patients with low IMR and those with high IMR. (Figure 2) The pooled RR was 4.08 (95% confidence interval (CI)…”

“…Currently, however, the acute allograft rejection (AAR) has been a major barrier to favorable outcomes after heart transplantation [Ahn 2021]. Heart transplantation for patients with end-stage heart failure as the only curative treatment have been shown to be more effective than conservative therapies [Lee 2021]. Advances in immunosuppression, donor heart procurement, surgical techniques, and post-transplantation care can decrease acute allograft rejection rates and improve survival after heart transplantation [Lee 2021].…”

“…Heart transplantation for patients with end-stage heart failure as the only curative treatment have been shown to be more effective than conservative therapies [Lee 2021]. Advances in immunosuppression, donor heart procurement, surgical techniques, and post-transplantation care can decrease acute allograft rejection rates and improve survival after heart transplantation [Lee 2021]. Nevertheless, 13% to 30% of patients with heart transplant experience acute allograft rejection within the first year after transplantation, and it remains as one of the leading causes of late cardiac allograft vasculopathy, graft loss, and mortality [Ahn 2021;Lee 2021].…”

“…Advances in immunosuppression, donor heart procurement, surgical techniques, and post-transplantation care can decrease acute allograft rejection rates and improve survival after heart transplantation [Lee 2021]. Nevertheless, 13% to 30% of patients with heart transplant experience acute allograft rejection within the first year after transplantation, and it remains as one of the leading causes of late cardiac allograft vasculopathy, graft loss, and mortality [Ahn 2021;Lee 2021]. As a result, identifying predictive index to identify AAR is critical.…”