Sensitivity to perioperative ischemia/reperfusion injury in male and female donor myocardium.

Many functions of the cardiovascular apparatus are affected by gender. The aim of our study was find out whether markers of cell death present in the donor myocardium differ in male and female hearts. The study involved 81 patients undergoing heart transplantation from September 2010 to January 2013. Patients were divided into two groups: male allograft (n=49), and female allograft (n=32). Two types of myocardial cell death were analyzed. High-sensitive cardiac troponin T as a necrosis marker and protein bcl-2, caspase 3 and TUNEL as apoptosis markers were measured. We observed a significantly higher level of high-sensitive cardiac troponin T after correcting for predicted ventricular mass in female donors before transplantation as well as in the female allograft group after transplantation throughout the monitored period (P=0.011). There were no differences in apoptosis markers (bcl-2, caspase 3, TUNEL) between male and female hearts before transplantation. Both genders showed a significant increase of TUNEL-positive myocytes one week after transplantation without differences between the groups. Moreover, there were no differences in caspase 3 and bcl-2 expression between the two groups. Our results demonstrated the presence of necrotic and apoptotic cell death in human heart allografts. High-sensitive cardiac troponin T adjusted for predicted ventricular mass as a marker of myocardial necrosis was higher in female donors, and this gender difference was even more pronounced after transplantation.

Pathophysiological mechanisms of calcineurin inhibitor-induced nephrotoxicity and arterial hypertension.

Solid organ transplantation is an established treatment modality in patients with end-stage organ damage in cases where other therapeutic options fail. The long-term outcomes of solid organ transplant recipients have improved considerably since the introduction of the first calcineurin inhibitor (CNI) - cyclosporine. In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered. The immunosuppressive effects of CNIs result from the inhibition of interleukin-2 synthesis and reduced proliferation of T cells due to calcineurin blockade. The considerable side effects that are associated with CNIs therapy include arterial hypertension and nephrotoxicity. The focus of this article was to review the available literature on the pathophysiological mechanisms of CNIs that induce chronic nephrotoxicity and arterial hypertension. CNIs lead to activation of the major vasoconstriction systems, such as the renin-angiotensin and endothelin systems, and increase sympathetic nerve activity. On the other hand, CNIs are known to inhibit NO synthesis and NO-mediated vasodilation and to increase free radical formation. Altogether, these processes cause endothelial dysfunction and contribute to the impairment of organ function. A better insight into the mechanisms underlying CNI nephrotoxicity could assist in developing more targeted therapies of arterial hypertension or preventing CNI nephrotoxicity in organ transplant recipients, including heart transplantation.

Safety and Efficacy of Immunoadsorption in Heart Transplantation Program.

BACKGROUND: Antibody-mediated rejection (AMR) is a serious complication of organ transplantation, and its treatment is complex. The aim of this study was to assess immunoadsorption (IA) for treatment-immunized patients before heart transplantation (HTX) and as the first step of AMR treatment after HTX. METHODS: The cohort consisted of 10 patients (8 men, 2 women; age range, 20-57 years). For 3 of these patients, IA was included in the desensitization protocol before HTX; for 7 patients, IA was the first step of the treatment protocol. One patient underwent IA before and after HTX. RESULTS: A comparison of values before IA and after the last procedure showed a decrease in immunoglobulin subgroups (G, M, and A). In patients before HTX, a decline was noted in panel reactive antibodies. After HTX, IA procedures led to a significant decrease in donor-specific antibody (DSA) class I; DSA class II fell in 6 of 7 patients, with 51% falling below the detection limit. CONCLUSIONS: IA in patients during HTX is safe procedure for reducing DSA. The removal of antibodies is the first step in comprehensive treatment and must be followed by a procedure that prevents their further development.

Biomarkers of cellular apoptosis and necrosis in donor myocardium are not predictive of primary graft dysfunction.

Primary graft dysfunction (PGD) is a life-threatening complication among heart transplant recipients and a major cause of early mortality. Although the pathogenesis of PGD is still unclear, ischemia/reperfusion injury has been identified as a predominant factor. Both necrosis and apoptosis contribute to the loss of cardiomyocytes during ischemia/reperfusion injury, and this loss of cells can ultimately lead to PGD. The aim of our prospective study was to find out whether cell death, necrosis and apoptosis markers present in the donor myocardium can predict PGD. The prospective study involved 64 consecutive patients who underwent orthotopic heart transplantation at our institute between September 2010 and January 2013. High-sensitive cardiac troponin T (hs-cTnT) as a marker of minor myocardial necrosis was detected from arterial blood samples before the donor's pericardium was opened. Apoptosis (caspase-3, active + pro-caspase-3, bcl-2, TUNEL) was assessed from bioptic samples taken from the right ventricle prior graft harvesting. In our study, 14 % of transplant recipients developed PGD classified according to the standardized definition proposed by the ISHLT Working Group. We did not find differences between the groups in regard to hs-cTnT serum levels. The mean hs-cTnT value for the PGD group was 57.4+/-22.9 ng/l, compared to 68.4+/-10.8 ng/l in the group without PGD. The presence and severity of apoptosis in grafted hearts did not differ between grafts without PGD and hearts that subsequently developed PGD. In conclusion, our findings did not demonstrate any association between measured myocardial cell death, necrosis or apoptosis markers in donor myocardium and PGD in allograft recipients. More detailed investigations of cell death signaling pathways in transplanted hearts are required.

Heart transplantations at the Heart Center IKEM, Prague, Czech Republic.

The heart transplant program at the Institute for Clinical and Experimental Medicine in Prague was established on January 31, 1984. Through November 2012, 881 orthotopic cardiac transplantations have been performed, with an annual rate of about 40 procedures. Current legislation concerning solid organ transplantations in the Czech Republic is described. Like other centers, we have noticed an increasing age of donors, and, reflecting the shortage of grafts, we have expanded our selection criteria for heart transplantation. The advent of a mechanical circulatory support program at our center in April 2003 has given us another valuable tool in the management of chronic heart failure patients. Currently, around half of our patients are transplanted from mechanical support. Nonischemic etiology of heart failure is a leading cause of transplantation at our center, followed by ischemic cardiomyopathy, valvular heart lesions, and adult congenital heart diseases. Our current immunosupression protocol, including induction therapy, is outlined in detail and survival rates, as well as most common complications and our treatment strategies, are also discussed.

[Surgical treatment of gastrointestinal complications after the heart transplantation]. / Chirurgické výkony na gastrointestinálním traktu po transplantaci srdce.

BACKGROUND: Orthotopic heart transplantation (OHT) is standard treatment of patients with end-stage heart failure. Long-term immunosuppressive therapy leads to the increased risk of the infection and cancer. METHODS AND RESULTS: Our retrospective study was aimed to evaluate gastrointestinal surgery procedures after OHT. The retrospective study was carried out at the Institute of clinical and experimental medicine (IKEM), between January 1, 1996 and December 31, 2006. Our group of patients includes 587 transplant recipients and 22 gastrointestinal surgery procedures. CONCLUSIONS: Results from our department did not show statistical differences in the length of hospital stay, morbidity and mortality in comparison with patients after OHT and control group.

[Post-transplantation lymphoproliferation in patients with intensive immunosuppression]. / Posttransplantacní lymfoproliferace u nemocného s intenzivní imunosupresí: kazuistika.

Organ allograft recipients are at higher risk for malignancies development. This risk is known to be different in different types of tumours. Skin cancers and lymphoproliferative disorders have been described to be ones the most frequent (comprising 15-25% of all malignancies). Here, we present the case of expansive formation localized near the renal allograft in patient, whose native kidneys failed as a consequence of long-term cyclosporine A therapy after orthotopic heart transplantation. The maintenance immunosuppression consisted of combination of cyclosporine A, mycophenolate mofetil and steroids. The expansion offside of transplanted kidney was detected by routine ultrasound examination. After indifferent neurological symptoms, sepsis, and then multiorgan failure occured. Shortly after acute surgery patient died. Autopsy and histopathology showed lymphoproliferative disorder--mo- nomorphic type of posttransplant lymphoproliferative disorder (PTLD). Occurence of PTLD in organ transplantation is discussed.

[Electrocardiographic changes after heart transplantation]. / Elektrokardiografické zmeny po transplantaci srdce.

Electrocardiographic (ECG) changes are described after heart transplantation in almost 75% patients. During the early postoperative period the usual finding are conduction disorders which in 3-5% call for implantation of a pacemaker. The most frequent persisting disorder is bundle branch block which is of clinical importance only when it has a progressive character. The incidence of postoperative atrial fibrillation or flutter is lower as compared with other cardiosurgical operations and their sudden development may be associated with acute rejection. Ventricular arrhythmias develop as a rule as a complication of advanced coronary disease of the graft and are frequently the cause of sudden death. Before the introduction of cyclosporin A a relatively reliable sign of acute rejection was a reduction of the QRS complex voltage. During contemporary treatment ECG changes develop only in severe forms of rejection, incipient changes can be recorded only by an intracardial electrogram.