An acquired Gerbode defect from the left ventricle to the coronary sinus following mitral valve replacement.

We report the management of an acquired Gerbode defect, from the left ventricle to the coronary sinus, following mechanical mitral valve replacement. Following a failed percutaneous closure, surgical patch closure of the defect was performed.

Pre-clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique.

Background: As a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipient's native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (IS) were investigated first, then treatments known to be effective in hypersensitized patients or those with recalcitrant rejection reactions.

Methods: Consecutive experiments were carried out between 2009 and 2013.

A pig-to-mouse coronary artery transplantation model for investigating the pathogenicity of anti-pig antibody.

Background: Rejection of Gal-free (GTKO) donor pig cardiac xenografts is strongly associated with vascular non-Gal antibody binding, endothelial cell (EC) injury, and activation and microvascular thrombosis. We adopted a pig-to-SCID/beige small animal transplant model to compare the pathogenicity of baboon and human anti-pig antibody.

Methods: Wild-type (GT(+) ) or GTKO porcine coronary arteries (PCAs) were transplanted into the infrarenal aorta of SCID/beige mice.

A retrospective analysis of myocardial preservation techniques during coronary artery bypass graft surgery: are we protecting the heart?

Background: Retrograde perfusion into coronary sinus during coronary artery bypass graft (CABG) surgery reduces the need for cardioplegic interruptions and ensures the distribution of cardioplegia to stenosed vessel territories, therefore enhancing the delivery of cardioplegia to the subendocardium. Peri-operative myocardial injury (PMI), as measured by the rise of serum level of cardiac biomarkers, has been associated with short and long-term clinical outcomes. We conducted a retrospective analysis to investigate whether the combination of antegrade and retrograde techniques of cardioplegia delivery is associated with a reduced PMI than that observed with the traditional methods of myocardial preservation.

Development of a consensus protocol to quantify primate anti-non-Gal xenoreactive antibodies using pig aortic endothelial cells.

Background: Scientists working in the field of xenotransplantation do not employ a uniform method to measure and report natural and induced antibody responses to non-Galα(1,3)Gal (non-Gal) epitopes. Such humoral responses are thought to be particularly pathogenic after transplantation of vascularized GalTKO pig organs and having a more uniform assay and reporting format would greatly facilitate comparisons between laboratories.

Methods: Flow cytometry allows examination of antibody reactivity to intact antigens in their natural location and conformation on cell membranes.

Cloning and expression of porcine β1,4 N-acetylgalactosaminyl transferase encoding a new xenoreactive antigen.

Background: Xenograft rejection of pigs organs with an engineered mutation in the GGTA-1 gene (GTKO) remains a predominantly antibody mediated process which is directed to a variety of non-Gal protein and carbohydrate antigens. We previously used an expression library screening strategy to identify six porcine endothelial cell cDNAs which encode pig antigens that bind to IgG induced after pig-to-primate cardiac xenotransplantation. One of these gene products was a glycosyltransferase with homology to the bovine β1,4 N-acetylgalactosaminyltransferase (B4GALNT2).

Histopathologic insights into the mechanism of anti-non-Gal antibody-mediated pig cardiac xenograft rejection.

The histopathology of cardiac xenograft rejection has evolved over the last 20 yr with the development of new modalities for limiting antibody-mediated injury, advancing regimens for immune suppression, and an ever-widening variety of new donor genetics. These new technologies have helped us progress from what was once an overwhelming anti-Gal-mediated hyperacute rejection to a more protracted anti-Gal-mediated vascular rejection to what is now a more complex manifestation of non-Gal humoral rejection and coagulation dysregulation. This review summarizes the changing histopathology of Gal- and non-Gal-mediated cardiac xenograft rejection and discusses the contributions of immune-mediated injury, species-specific immune-independent factors, transplant and therapeutic procedures, and donor genetics to the overall mechanism(s) of cardiac xenograft rejection.

Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous genetic heart disease characterized by left ventricular hypertrophy in the absence of another disease that could explain the wall thickening. Elucidation of the genetic basis of HCM lead to the identification of several genes encoding sarcomeric proteins, such as MYH7, MYBPC3, TPM1, TNNT2, and TNNI3. Sarcomeric genes are mutated in approximately 40% of HCM patients and a possible explanation for the incomplete yield of mutation-positive HCM may be somatic mutations.

Seligman's theory of attributional style: optimism, pessimism, and quality of life after heart transplant.

Context: Posttransplant quality of life can be significantly affected by personality characteristics identified before transplant.

Objective: Although overall quality of life in heart transplant patients improves after transplant, many studies reveal poorer mental health outcomes after transplant. We aimed to determine whether transplant recipients with an optimistic explanatory style had improved quality of life, fewer depressive symptoms, and increased survival.

Human CD55 expression blocks hyperacute rejection and restricts complement activation in Gal knockout cardiac xenografts.

Background: Transgenic expression of human complement regulatory proteins reduces the frequency of hyperacute rejection (HAR) in Gal-positive cardiac xenotransplantation. In this study, we examined the impact of human CD55 (hCD55) expression on a Gal knockout (GTKO) background using pig-to-primate heterotopic cardiac xenotransplantation.

Methods: Cardiac xenotransplantation was performed with GTKO (group 1; n=6) and GTKO.

Cardiac xenotransplantation: progress and challenges.

Purpose Of Review: Cardiac xenotransplantation (CXTx) remains a promising approach to alleviate the chronic shortage of donor hearts. This review summarizes recent results of heterotopic and orthotopic CXTx, highlights the role of non-Gal antibody in xenograft rejection, and discusses challenges to clinical orthotopic CXTx.

Recent Findings: Pigs mutated in the α 1,3 galactosyltransferase gene (GTKO pigs) are devoid of the galactose α1,3 galactose (αGal) carbohydrate antigen.

Comparison of Gal and non-Gal-mediated cardiac xenograft rejection.

Background: This study compares the pathologic condition of delayed xenograft rejection in Gal-positive and Gal-knockout cardiac xenografts after pig-to-baboon heterotopic cardiac xenotransplantation when the induced anti-Gal antibody response is unregulated, blocked, or absent.

Methods: Baboon recipients of Gal-positive, CD46 pig hearts were treated with an αGal polymer (group 1; n=11) or Gal-specific immunoapheresis (group 2; n=8) to block anti-Gal antibody. Gal-knockout cardiac xenografts recipients (group 3; n=5) received no anti-Gal therapy.

Changes in cardiac gene expression after pig-to-primate orthotopic xenotransplantation.

Background: Gene profiling methods have been widely useful for delineating changes in gene expression as an approach for gaining insight into the mechanism of rejection or disease pathology. Herein, we use gene profiling to compare changes in gene expression associated with different orthotopic cardiac xenotransplantation (OCXTx) outcomes and to identify potential effects of OCXTx on cardiac physiology.

Methods: We used the Affymetrix GeneChip Porcine Genomic Array to characterize three types of orthotopic cardiac xenograft outcomes: 1) rejected hearts that underwent delayed xenograft rejection (DXR); 2) survivor hearts in which the xenograft was not rejected and recipient death was due to model complications; and 3) hearts which failed to provide sufficient circulatory support within the first 48 h of transplant, termed "perioperative cardiac xenograft dysfunction" (PCXD).

Coagulopathy in α-galactosyl transferase knockout pulmonary xenotransplants.

Background: After substantial progress on many fronts, one of the remaining barriers still opposing the clinical application of xenotransplantation is a disseminated intravascular coagulopathy (DIC) that is observed in the pre-clinical model of porcine-to-primate transplantation. The onset of DIC is particularly rapid in recipients of pulmonary xenografts, usually occurring within the first days or even hours of reperfusion.

Methods: In this study, we describe the results of two porcine-to-baboon transplants utilizing porcine lungs depleted of macrophages, deficient in the α-1,3-galactosyltransferase gene, and with the expression of human decay-accelerating factor, a complement regulatory protein.

B-type natriuretic peptide levels and continuous-flow left ventricular assist devices.

We postulated that postoperative B-type natriuretic peptide (BNP) levels would be reflective of the degree of hemodynamic support rendered by various pump speeds settings (RPM) of continuous-flow left ventricular assist devices (LVADs). Twenty LVAD patients were evaluated prospectively (Jarvik 2000: n = 9, HeartMate II: n = 11). The mean age was 57.

Cardiac xenotransplantation technology provides materials for improved bioprosthetic heart valves.

Objectives: Human subjects and Old World primates have high levels of antibody to galactose-α-1,3 galactose β-1,4-N-acetylglucosamine (α-Gal). Commercially available bioprosthetic heart valves of porcine and bovine origin retain the Gal antigen despite current processing techniques. Gal-deficient pigs eliminate this xenoantigen.

Identification of new carbohydrate and membrane protein antigens in cardiac xenotransplantation.

Background: α1,3-Galactosyltransferase gene knockout (GTKO) pigs reduced the significance of antibody to galactose alpha 1,3-galactose (Gal) antigens but did not eliminate delayed xenograft rejection (DXR). We hypothesize that DXR of GTKO organs results from an antibody response to a limited number of non-Gal endothelial cell (EC) membrane antigens. In this study, we screened a retrovirus expression library to identify EC membrane antigens detected after cardiac xenotransplantation.

Pulmonary thromboendarterectomy in adolescents and young adults.

Objectives: Chronic thromboembolic pulmonary hypertension (CTEPH) occurs in patients with recurrent or chronic pulmonary embolism, and is a rare but potentially devastating disease in adolescents and young adults. Pulmonary thromboendarterectomy (PTE) is an important curative therapy for patients with CTEPH. The importance of this treatment may be under-appreciated and under-utilized in adolescents and young adults.

Gal knockout pig pericardium: new source of material for heart valve bioprostheses.

Background: Although glutaraldehyde fixation is known to reduce immunogenicity and degeneration of heart valve bioprostheses, some degree of immunogenicity persists, which may trigger calcification. The aims of this study were to: (1) define the role of alpha-1,3-galactosyltransferase (alpha-Gal) antigen in valve calcification by comparing alpha-Gal-positive and alpha-Gal-deficient (GT-KO) pig pericardium; and (2) elucidate the role of human anti-Gal antibodies in the process of calcification and to determine the potential influence of different tissue-fixation techniques.

Methods: Glutaraldehyde-treated pericardium from alpha-Gal-positive and GT-KO pigs, with or without pre-labeling with human anti-Gal antibodies, were implanted in rats during 1 month.