Do we have a new early marker of chronic transplant dysfunction now?

See article by Subramanian et al. [9] (pages 539 –548) ischemia time and reperfusion injury, disparity of the in this issue. major histocompatibility complex between donor and recipient, number of rejection episodes, and infection The development of chronic transplant dysfunction (especially by cytomegalovirus) [2,6]. (CTD) has become a limiting factor for long-term graft In the current issue of Cardiovascular Research, Subsurvival, and it is today’s most important problem in ramanian et al. [9] investigated the regulation of the clinical organ transplantation after the first perioperative expression of VSM a-actin in mouse heterotopic heart year. To date, CTD cannot be prevented by current transplantation. Recently, the authors showed, that after immunosuppressive protocols [1,2]. Depending on the type transplantation the VSM a-actin gene was activated in of organ transplanted (liver, kidney, heart, lung), the adult donor cardiomyocytes [10]. The expression of VSM incidence of CTD 3 years after engraftment varies from 4 a-actin was detected 30 days after transplantation and to .50% [3–5]. Irrespective of the organ grafted, graft localized predominantly in sarcomeres. The expression of vessels eventually develop so-called transplant vascular VSM a-actin in adult cardiomyocytes might be interpreted sclerosis (TVS), which is, however, most prominent in as a sign for the induction of an embryonic gene program. cardiac allografts [6,7]. This vascular remodeling process, This re-expression is a well known feature of cardiac also called chronic vascular rejection or graft vascular hypertrophy, including genes for natriuretic peptides and disease, is the main cause of morbidity and mortality in embryonic contractile proteins [11]. The natriuretic peptide long term survivors of many types of organ transplants. genes are induced in the hypertrophied myocardium in all The standard etiology of TVS following organ transplantamammalian species, and especially the induction of the tion is thought to be the local migration and proliferation atrial natriuretic peptide is a prognostic indicator of clinical of medial vascular smooth muscle (VSM) cells in response severity [12]. Besides VSM a-actin [13], other important to inflammatory signals and/or growth factor expression markers of the embryonic gene program of contractile with consequent thickening of the intima. Although this proteins are b-myosin heavy chain (MHC) [14] and etiology of TVS has never been demonstrated in its skeletal a-actin [15]. However, the induction of both entirety, several steps have been documented in vessels bMHC and skeletal a-actin genes during hypertrophy is with ongoing neointimal formation, including the exprespredominantly a feature of rodent species [16]. Ventricular sion of inflammatory cytokines and growth factors in both hypertrophy in larger animals (canine, pig, etc, including the media and neointima, as well as the proliferation of humans) is not associated with the induction of either VSM cells in the media [8]. The pathogenesis of TVS bMHC or skeletal a-actin genes, which are constitutively seems to be multifactorial, but precise mechanisms inexpressed in larger species [16]. Therefore, only VSM volved in the development of this remodeling process still a-actin from the contractile protein markers might be used remain obscure. Risk factors appear to include cold as an indicator of dysfunctional remodeling following heart transplantation in humans, which Subramanian et al. [9] postulated. The induction signal for the re-expression of VSM a-actin in myocytes of cardiac allografts has not been *Tel.: 149-341-971-5500; fax: 149-341-971-5509. E-mail address: [email protected] (W. Briest). elucidated until now. Subramanian et al. [9] deduced the