Increased fibrosis and microvessel disease in allograft endomyocardial biopsies of children with chronic graft failure due to cardiac allograft vasculopathy

Pediatric heart transplant (PHT) is currently the gold standard for end-stage heart failure. Since the first successful PHT in the 1980’s, modifications to immunosuppression regimens and surveillance has improved PHT outcomes. Unfortunately, chronic graft failure (CGF) remains the number one cause of graft loss. The pathophysiologic process involved in CGF is complex including myocardial ischemia, which could be related to coronary allograft vasculopathy (CAV), accumulation of allograft rejection episodes, ischemic reperfusion injury occurring around transplantation time as well as co-existing conditions in the patient including hypertension and chronic renal failure [1]. Coronary microvascular dysfunction, which is detectable in 15-20% of patients after heart transplant (HT) [2] is also emerging as a strong predictor of outcome [3]. Stenotic microvasculopathy/microvessel disease detected in endomyocardial biopsy (EMB) samples portends a poor outcome in adult heart transplant (AHT) recipients [4]. The study by Hiemann et al. [4] defined microvessel disease (MVD) as presence of microvessels in the myocardium with stenotic wall thickening leading to a ratio of luminal radius to wall thickness of <1. In others newer studies [5, 6], capillary density per surface area was also considered as histologic evidence of microvasculopathy.

Due to the complexity of their pathogenesis, there has not been established surveillance for subclinical CGF or MVD. Current gold standard to evaluate for CAV with coronary angiography is imperfect and does not assess for MVD, which could be a subtle process underlying CGF. In addition, correlation analysis between CAV and MVD lead to conflicting results. In the study by Tona [3], microvascular dysfunction as defined by means of a reduced coronary flow reserve detected by transthoracic Doppler echocardiography was associated with the onset of epicardial CAV as detected by coronary angiography. However, in AHT patients Zakliczyński et al. [7] did not find a relationship between microvasculopathy (defined histologically as the presence of prominent endothelial cells, vacuolation of the endothelium, thickening of the basal membrane and/or muscle layer, the presence of lymphocytes in the arteriolar wall, periarteriolar fibrosis, or stenotic lumina) observed early or late after HT and angiographically confirmed CAV.

Furthermore, studies in explanted heart grafts in both PHT and AHT subjects that have needed re-transplantation showed severe fibrosis, suggesting that fibrosis is a histopathological process occurring in CGF [8], [9], [10]. This is further supported by an AHT study concluding that increased fibrosis on EMB in the first year post-HT correlated with future CAV development [11].

There are no studies comparing EMB histologic findings such as fibrosis and MVD in PHT patients with and without CGF. We sought to investigate EMB histopathologic markers that could be related to CGF including microvessel wall thickness leading to luminal obstruction for quantification of MVD along with quantification of fibrosis and to compare the extent of these findings between PHT patients that have CGF secondary to moderate- severe (M-S) CAV and no CAV subjects.

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