These observations challenge current assumptions about the treatment of selected patients with end-stage lung disease and suggest that "salvage transplant" is both technically feasible and logistically viable. Widespread adoption of artificial lung technology in lung transplant will require the design of clinical trials that establish the most effective circumstances in which to use these technologies. A discussion of a clinical trial and reconsideration of current allocation policy is warranted.

Background Heart failure is a growing epidemic and a typical aspect of heart failure pathophysiology is altered calcium transients. Normal cardiac calcium transients are initiated by Cav1.2 channels at cardiac T-tubules. BIN1 is a membrane scaffolding protein that causes Cav1.2 to traffic to T-tubules in healthy hearts. The mechanisms of Cav1.2 trafficking in heart failure are not known. Objective To study BIN1 expression and its effect on Cav1.2 trafficking in failing hearts. Methods Intact myocardium and freshly isolated cardiomyocytes from non-failing and end-stage failing human hearts were used to study BIN1 expression and Cav1.2 localization. To confirm Cav1.2 surface expression dependence on BIN1, patch clamp recordings were performed of Cav1.2 current in cell lines with and without trafficking competent BIN1. Also, in adult mouse cardiomyocytes, surface Cav1.2 and calcium transients were studied after shRNA mediated knockdown of BIN1. For a functional readout in intact heart, calcium transients and cardiac contractility were analyzed in a zebrafish model with morpholino mediated knockdown of BIN1. Results BIN1 expression is significantly decreased in failing cardiomyocytes at both mRNA (30% down) and protein (36% down) levels. Peripheral Cav1.2 is reduced 42% by imaging and biochemical T-tubule fraction of Cav1.2 is reduced 68%. Total calcium current is reduced 41% in a cell line expressing non-trafficking BIN1 mutant. In mouse cardiomyocytes, BIN1 knockdown decreases surface Cav1.2 and impairs calcium transients. In zebrafish hearts, BIN1 knockdown causes a 75% reduction in calcium transients and severe ventricular contractile dysfunction. Conclusions The data indicate that BIN1 is significantly reduced in human heart failure, and this reduction impairs Cav1.2 trafficking, calcium transients, and contractility.

Long-term success in xenotransplantation is currently hampered by acute vascular rejection. The inciting cause of acute vascular rejection is not yet known; however, a variety of observations suggest that the humoral immune response of the recipient against the donor may be involved in the pathogenesis of this process. Using a pig-to-baboon heterotopic cardiac transplant model, we examined the role of antibodies in the development of acute vascular rejection. After transplantation into baboons, hearts from transgenic pigs expressing human decay-accelerating factor and CD59 underwent acute vascular rejection leading to graft failure within 5 d; the histology was characterized by endothelial injury and fibrin thrombi. Hearts from the transgenic pigs transplanted into baboons whose circulating antibodies were depleted using antiimmunoglobulin columns (Therasorb, Unterschleisshein, Germany) did not undergo acute vascular rejection in five of six cases. Biopsies from the xenotransplants in Ig-depleted baboons revealed little or no IgM or IgG, and no histologic evidence of acute vascular rejection in the five cases. Complement activity in the baboons was within the normal range during the period of xenograft survival. In one case, acute vascular rejection of a xenotransplant occurred in a baboon in which the level of antidonor antibody rose after Ig depletion was discontinued. This study provides evidence that antibodies play a significant role in the pathogenesis of acute vascular rejection, and suggests that acute vascular rejection might be prevented or treated by therapies aimed at the humoral immune response to porcine antigens. (

Prior work has shown that transforming growth factor-β (TGF-β) can mediate transition of alveolar type II cells into mesenchymal cells in mice. Evidence this occurs in humans is limited to immunohistochemical studies colocalizing epithelial and mesenchymal proteins in sections of fibrotic lungs. To acquire further evidence that epithelial-to-mesenchymal transition occurs in the lungs of patients with idiopathic pulmonary fibrosis (IPF), we studied alveolar type II cells isolated from fibrotic and normal human lung. Unlike normal type II cells, type II cells isolated from the lungs of patients with IPF express higher levels of mRNA for the mesenchymal proteins type I collagen, α-smooth muscle actin (α-SMA), and calponin. When cultured on Matrigel/collagen, human alveolar type II cells maintain a cellular morphology consistent with epithelial cells and expression of surfactant protein C (SPC) and E-cadherin. In contrast, when cultured on fibronectin, the human type II cells flatten, spread, lose expression of pro- SPC, and increase expression of vimentin, N-cadherin, and α-SMA; markers of mesenchymal cells. Addition of a TGF-β receptor kinase inhibitor (SB431542) to cells cultured on fibronectin inhibited vimentin expression and maintained pro-SPC expression, indicating persistence of an epithelial phenotype. These data suggest that alveolar type II cells can acquire features of mesenchymal cells in IPF lungs and that TGF-β can mediate this process.

A majority of patients with idiopathic pulmonary fibrosis have pathologic reflux. Symptoms do not distinguish between those with and without reflux. In these patients, reflux is associated with a hypotensive lower esophageal sphincter and abnormal esophageal peristalsis, and often extends into the proximal esophagus.

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Rationale: In 2005, lung allocation for transplantation in the United States changed from a system based on waiting time to a system based on the Lung Allocation Score (LAS). Objectives: To study the effect of the LAS on lung transplantation for idiopathic pulmonary arterial hypertension (IPAH) compared with other major diagnoses. Methods: We studied 7,952 adults listed for lung transplantation between 2002 and 2008. Analyses were restricted to patients with IPAH, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). Transplantation, waiting list mortality, and post-transplant mortality were compared between diagnoses for patients listed before and after implementation of the LAS. Measurements and Main Results: The likelihood of transplantation from the waiting list increased for all diagnoses after implementation of the LAS. Waiting list mortality decreased for every diagnosis, except for IPAH, which remained unchanged. Implementation of the LAS was not associated with changes in post-transplant mortality for any diagnosis. Under the LAS system, patients with IPAH were less likely to be transplanted than patients with IPF (hazard ratio [HR], 0.53; P , 0.001) or CF (HR, 0.49; P , 0.001) and at greater risk of death on the waiting list than patients with COPD (HR, 3.09; P , 0.001) or CF (HR, 1.83; P 5 0.025) after adjustment for demographics and transplant type. Post-transplant mortality for IPAH was not statistically different from that of other diagnoses. Conclusions: Implementation of the LAS has improved the likelihood of lung transplantation for listed patients with IPAH, but mortality on the waiting list remains high compared with other major diagnoses.

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