Coronary microvascular dysfunction predicts acute cellular rejection after heart transplantation

In the last few decades, coronary microvascular dysfunction (CMD) has been shown to play a key role in the pathophysiology and prognosis of chronic and acute coronary syndromes, and similarly affects various heart diseases, such as hypertrophic cardiomyopathy, or neuro-mediated Takotsubo myocarditis [1-4]. Recently, pathologic evaluation revealed that structural distortion of microvasculature and interstitial tissues are common phenotypes of acute allograft rejection [5]. Both arteriolar obliteration and capillary rarefaction seem to influence microcirculatory hemodynamics independently [6].
The microvasculature is a complex entity, which is challenging to investigate. Assessment of the microvasculature is primarily functional and not anatomic. In order to assess the integrity of the microvascular bed, Doppler wire coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) are the most used tests in the cardiac catheterization laboratory. CFR is a marker of the integrity of both epicardial and microvascular domains of coronary circulation, therefore, CFR represents the microvascular status when there is no significant epicardial disease, while IMR is a direct measurement of microcirculatory resistance independent of epicardial stenoses [7]. Recent studies have shown that IMR may help guide treatment in patients with chest pain and “normal coronary arteries” and in those undergoing elective percutaneous coronary intervention (PCI) [8]. It also has a prognostic role in patients with acute myocardial infarction [9]. Likewise, a strong association between high IMR, measured at 1 year after heart transplantation, and all-cause death and re-transplantation during mean follow-up of 4.5 years has been demonstrated [10].
In the upcoming issue of Circulation, Joo Myung Lee et al evaluated the prognostic implication of CMD, assessed by both CFR and IMR, in predicting the risk of acute cellular rejection after heart transplantation [11]. Th authors studied 154 patients. Patients received coronary physiologic evaluation approximately one month after heart transplantation and at 2-year follow-up. Additionally, patients underwent scheduled endomyocardial biopsy to detect occurrence of acute cellular rejection (at 2, 4, 8, 12, 18, weeks and 6, 9, 12 months after transplantation). The authors found that IMR identified functional microcirculatory dysfunction before biopsy-detectable architectural distortion of myocardium. IMR measured approximately one month after heart transplantation showed a significant independent association with the risk of acute cellular rejection in the following 2 years. Patients with IMR≥15 had about 15 times higher risk of developing acute cellular rejection. CFR was also associated with the risk of acute cellular rejection, but it had significantly lower reproducibility than IMR and did not show any additive prognostic value over IMR in predicting acute cellular rejection.
Acute allograft rejection and cardiac allograft vasculopathy are major drawbacks for heart transplant recipients. The study by Joo Myung Lee et al suggests that 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. Intensified surveillance and immunosuppression therapy could improve outcome. However, further studies are warranted to evaluate whether specific immunosuppressive agents or other medications have any differential effect on microcirculatory function or the risk of acute cellular rejection.