LAUSR

In the first year after orthotopic heart transplantation (OHT), acute cellular and/or humoral rejection is associated with coronary allograft vasculopathy (CAV) that can lead to graft failure. CAV is still an unsolved issue. In spite of the increasingly successful treatment of rejection, 5-year survival after OHT for CAV detected within 3 years of transplant has improved only by 5% and remains lower than in patients without OHT (76 vs. 82%). Coronary allograft vasculopathy affects both epicardial arteries and intramural small arteries and arterioles which constitute the microcirculation. Indeed, microvascular dysfunction often occurs in the absence of detectable epicardial lesions. In addition to the arterial district, CAV can also involve cardiac veins. A number of factors contribute to microvascular remodelling and dysfunction (Take home figure); they can be classified as alloantigen dependent or alloantigen independent, and the latter can be specific for OHT or a generic risk factors for type 1 microvascular dysfunction. Immediately after OHT, HLA mismatch, cytomegalovirus mismatch between donor and recipient, donor age, recipient ischaemic cardiomyopathy, donor cause of death (brain injury), ischaemic time, and ischaemia/reperfusion insult are associated with development of CAV. Over time, other important factors contribute to aggravate CAV: multiple episodes of acute rejection, immunosuppressive therapy, and related hypertension. On the basis of endomyocardial biopsies, it has been postulated that endothelial lesions develop at first in the microcirculation. This hypothesis was substantiated by invasive measurement of the index of microvascular resistance 1 year after OHT. Evidence of microvascular dysfunction 1 year after OHT was associated with mild depression of cardiac index, graft dysfunction, and worse prognosis, with a higher incidence of major cardiovascular adverse events at 5-year follow-up. Cytokines released by T lymphocytes promote activation of alloreactive T cells, and activate macrophages and monocytes, which in turn stimulate the expression of adhesion molecules by endothelial cells. The activated macrophages infiltrating the vessel wall accelerate smooth muscle cell proliferation and synthesis of extracellular matrix through cytokines and growth factors. The changes observed in small arteries were concentric intimal thickening, subendothelial accumulation of lymphocytes, and perivascular fibrosis, although arterioles <100 lm were not affected in the first year. Due to allograft denervation, patients with CAV are often asymptomatic or complain of atypical symptoms. The ISHLT 2010 guidelines for heart transplant care suggest annual or biannual coronary angiography to assess the development of CAV (level of evidence A). Patients free of CAV at 3–5 years after OHT may undergo less frequent invasive evaluation. The use of intravascular ultrasound (IVUS) and assessment of coronary flow reserve (CFR) have been classified as level of evidence C, and the functional assessment, when significant CAV is suspected, is mainly performed by means of single photon computed emission tomography (SPECT) that does provide information on small vessel disease. In this issue of the journal, Bravo et al. report their findings in a cohort of 94 transplanted patients in whom myocardial blood flow (MBF) was quantified by positron emission tomography (PET). Sixtysix out of the 94 patients had undergone invasive coronary angiography (ICA) within 1 year of PET. The ISHLT classification was used as the standard definition for CAV. PET evaluation included semiquantitative myocardial perfusion imaging (MPI), quantitative MBF (mL/min/g), and left ventricular ejection fraction (LVEF). The authors