Najbolji izbor – kako izabrati odgovarajući uređaj?

An increasing number of patients suffering from end-stage heart failure require VAD implantation as either a bridge-to-transplantation or destination therapy. The choice of the right device depends upon the medical urgency; the need of uni- or biventricular support; the duration of support expected; and the institutional availability. Patients with multi-organ failure and unclear neurological situation can be supported with rotary pumps/ECMO first, and in case of recovery, a paracorporeal system can be connected to the previously implanted cannulas. In stable patients qualifying for left ventricular support, an intracorporeal system of the second generation can be implanted, allowing freedom of movement for 6-8 hours before recharging becomes necessary, and support intervals exceeding 1 year. Restrictions are given by the need of high-dose anticoagulation and a certain complication rate, especially in the first 3 months (bleeding, thromboembolism, infection, mechanical failure). The survival rate after the primary LVAD implantation is 74 % after 12 months and 55 % after 24 months; this is significantly better than the survival rate after RVAD, BVAD or TAH.Sve veći broj pacijenata u terminalnoj fazi zatajivanja srca zahtijevaju ugradnju mehaničke potpore srcu i cirkulaciji, kao premoštenje do transplantacije srca ili kao destinacijska terapija. Odabir odgovarajućeg uređaja ovisi o kliničkom stanju pacijenta, potrebi za jednostrukom ili dvostrukom ventrikularnom potporom, očekivanom trajanju ugrađene potpore i mogućnostima institucije. Pacijentima s multi organskim zatajenjem i nejasnim neurološkim smetnjama može se prvo ugraditi rotacijska pumpa/ECMO, te u slučaju oporavka., parakorporalni uređaj može biti povezan s ranije implantiranim kanilama. Kod stabilnih pacijenata, predodređenih za ugradnju potpore lijevom ventriklu, moguće je ugraditi intrakorporalni uređaj druge generacije, koji dozvoljava slobodno kretanje 6-8 sati do punjenja baterija i podupire intervale preko jedne godine. Ograničenja nastaju zbog potrebe za visokim dozama antikoagulacijske terapije i pojave određenih komplikacija, posebno u prva tri mjeseca nakon implantacije (krvarenje, tromboembolija, infekcija, mehaničke nepravilnosti). Stopa preživljenja 12 mjeseci nakon ugradnje LVAD-a je 74% i 55% nakon 24 mjeseca što je značajno bolje nego preživljenje nakon ugradnje RVAD, BVAD or TAH

The activity of nintedanib in an animal model of allogenic left lung transplantation resembling aspects of allograft rejection

Aim of the Study: The prevention and treatment of chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx) remain unsatisfactory. Growth factors may play an important role in the development of CLAD. This study evaluated the effects of nintedanib, a receptor tyrosine kinase inhibitor, in the treatment of CLAD after experimental LTx. Materials and Methods: A rat model of left lung allo-transplantation (Fisher 344 to Wistar Kyoto) was used to evaluate the effect of nintedanib (50 mg/kg per day) on the development of CLAD. Therapy with nintedanib began 2 days before LTx and ended on postoperative day (POD) 20 (n = 6) or 60 (n = 6). Nontreated animals who underwent LTx (n = 12) were used as controls, whereas naive lungs (n = 24) served as reference for physiological healthy organs without transplantation damage or medical effects. Acute and chronic rejection were evaluated on POD 20 and 60, respectively. Results: Immunohistologic analysis showed a decrease in growth factors/receptors on POD 60 (nintedanib-treated vs. nontreated controls: platelet-derived growth factor (PDGF) A: [P <= 0.001]; PDGF receptor-alpha: [P <= 0.001]; vascular endothelial growth factor (VEGF) A: [P <= 0.001]; VEGF receptor-2: [P <= 0.001]). However, no reductions in fibrotic changes were observed in nintedanib-treated allografts compared with nontreated allografts. Although nintedanib treatment started before LTx none of the animals showed impaired wound healing. No dehiscence of the sutures of the bronchus, vessels or skin, or stenosis of the bronchus was found. Conclusion: In conclusion, while nintedanib reduced the expression of growth factors/receptors in a rat LTx model, a reduction in fibrotic alterations was not observed at POD 60

Synergism of imatinib, vatalanib and everolimus in the prevention of chronic lung allograft rejection after lung transplantation (LTx) in rats

Chronic lung allograft dysfunction (CLAD) still remains a major drawback in the outcome following lung transplantation (LTx). New therapeutic strategies are warranted. Growth factors and their receptors like platelet-derived growth factor-receptor (PDGFR) and vascular endothelial growth factor-receptor (VEGFR), may play a crucial role in the development of CLAD, especially bronchiolitis obliterans (BO) and vasculopathy. In this study, we used an orthotopic left lung transplantation model from Fischer (F344) to Wystar Kyoto (WKY) rats to investigate the effect of the receptor tyrosine kinase inhibitor (RTKI) vatalanib alone, the dual combination of the RTKIs vatalanib and imatinib and a triple therapy consisting of vatalanib, imatinib and the mammalian target of rapamycin inhibitor (mTORI) everolimus on the development of CLAD after LTx in rats. With this trial we demonstrated that monotherapy with vatalanib attenuated mild and severe chronic vascular rejection, whereas dual therapy (vatalanib and imatinib) after LTx also showed a significant reduction of chronic bronchiolar rejection and interstitial fibrosis. By adding everolimus, the effect of vatalanib and imatinib could additionally be increased. In conclusion, the combination of mTORI and RTKIs might be a possible strategy in the prevention of CLAD and BO

Everolimus in Heart Transplantation: An Update

The evidence base relating to the use of everolimus in heart transplantation has expanded considerably in recent years, providing clinically relevant information regarding its use in clinical practice. Unless there are special considerations to take into account, all de novo heart transplant patients can be regarded as potential candidates for immunosuppression with everolimus and reduced-exposure calcineurin inhibitor therapy. Caution about the use of everolimus immediately after transplantation should be exercised in certain patients with the risk of severe proteinuria, with poor wound healing, or with uncontrolled severe hyperlipidemia. Initiation of everolimus in the early phase aftertransplant is not advisable in patients with severe pretransplant end-organ dysfunction or in patients on a left ventricular assist device beforetransplant who are at high risk of infection or of wound healing complications. The most frequent reason for introducing everolimus in maintenance heart transplant patients is to support minimization or withdrawal of calcineurin inhibitor therapy, for example, due to impaired renal function or malignancy. Due to its potential to inhibit the progression of cardiac allograft vasculopathy and to reduce cytomegalovirus infection, everolimus should be initiated as soon as possible after heart transplantation. Immediate and adequate reduction of CNI exposure is mandatory from the start of everolimus therapy

Comparing everolimus‐based immunosuppression with reduction or withdrawal of calcineurin inhibitor reduction from 6 months after heart transplantation: The randomized MANDELA study

In the 12-month, open-label MANDELA study, patients were randomized at month 6 after heart transplantation to (1) convert to calcineurin inhibitor (CNI)-free immunosuppression with everolimus (EVR), mycophenolic acid and steroids (CNI-free, n = 71), or to (2) continue reduced-exposure CNI, with EVR and steroids (EVR/redCNI, n = 74). Tacrolimus was administered in 48.8% of EVR/redCNI patients and 52.6% of CNI-free patients at randomization. Both strategies improved and stabilized renal function based on the primary endpoint (estimated GFR at month 18 posttransplant postrandomization) with superiority of the CNI-free group vs EVR/redCNI: mean 64.1 mL/min/1.73 m(2) vs 52.9 mL/min/1.73 m(2); difference + 11.3 mL/min/1.73 m(2) (P = 10 mL/min/1.73 m(2) in 31.8% and 55.2% of EVR/redCNI and CNI-free patients, respectively, and by >= 25 mL/min/1.73 m(2) in 4.5% and 20.9%. Rates of biopsy-proven acute rejection (BPAR) were 6.8% and 21.1%; all cases were without hemodynamic compromise. BPAR was less frequent with EVR/redCNI vs the CNI-free regimen (P = .015); 6 of 15 episodes in CNI-free patients occurred with EVR concentration mL. Rates of adverse events and associated discontinuations were comparable. EVR/redCNI from month 6 achieved stable renal function with infrequent BPAR. One-year renal function can be improved by early conversion to EVR-based CNI-free therapy but requires close EVR monitoring. Clinical trials registry: ClinicalTrials.gov NCT00862979