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Pulmonary arterial hypertension (PAH) is caused by a pathological increase in pulmonary vascular resistance (PVR) and ultimately leads to right ventricular (RV) failure. On modern therapy, there is still 15% mortality within 1 year and median survival remains limited to 5-6 years, with insufficient functional improvement in many survivors. Bilateral lung transplantation (bLTx) remains the only curative option. Unfortunately, most patients are unlikely to survive until transplantation.We know that PAH-associated RV failure is potentially reversible because of the generally good recovery of the heart after bLTx. Therefore, the RV has become a potential therapeutic target. A medical PAH treatment strategy that both reduces PVR and improves RV function is likely difficult to develop because of contrasting priorities within the different cell populations of the heart and lungs. As such, surgical options to increase cardiac output (CO) and to reduce RV wall stress should be elaborated. Atrial septostomy (AS) decreases RV filling pressures and improves cardiac index, but has a procedural mortality up to 16% in PAH patients. A right ventricular assist device (RVAD) could offer the same advantages as an AS. Moreover, the fall in arterial oxygen saturation accompanying AS should not occur and the RV would be actively supported.With this thesis, we aimed to investigate the potential role of an RVAD as a new surgical treatment strategy for PAH. Two major problems arose with this treatment strategy: 1) The RV demonstrates a high afterload sensitivity. Increased pulmonary artery pressures (PAPs) caused by the RVAD might cause further RV dilatation and failure. 2) Historically, pulsatile devices for end-stage RV failure secondary to PAH often resulted in intraparenchymal pulmonary hemorrhage, hemoptysis, and death. It is though feared that also continuous flow devices with relatively high flow rates might result in increased PAPs and lung injury. We hypothesized that smaller continuous flow devices with lower flow capacities might be more appropriate.As a first step (chapter 4), we aimed to assess the feasibility of low flow RV mechanical support, and to describe the hemodynamic effects of low versus high flow support in an animal model of acute RV pressure overload. Therefore, a Synergy Micro-pump was implanted in seven sheep. Blood was withdrawn from the right atrium to the pulmonary artery. Hemodynamics and pressure-volume loops were recorded in baseline conditions, after banding the pulmonary artery, and after ligating the right coronary artery in these banded sheep. RV mechanical support improved arterial blood pressure (ABP) and CO, but intrinsic RV contractility was not significantly impacted. It provided RV diastolic unloading, but with a concomitant and RVAD flow-dependent increase of systolic afterload. These effects were most distinct in the pressure overloaded RV without profound ischemic damage. The low flow strategy avoided excessive increases in PAP, but sufficiently improved ABP and CO. Therefore, it was considered to be beneficial for the afterload sensitive RV. As it might also protect against the development of pulmonary hemorrhage and pulmonary edema, we advocated the use of this strategy for the acute pressure overloaded RV (e.g. heart transplant patients, acute lung injury, acute respiratory distress syndrome).RV mechanical support is well described in cases of sudden increase in RV afterload, e.g. after heart transplantation. In cases of chronic RV pressure overload, e.g. PAH, it has rarely been described. Therefore, we aimed in a second step (chapter 5) to assess the hemodynamic effects of low flow mechanical support of the acute vs the chronic pressure overloaded RV. The pulmonary artery was banded in 18 sheep. In the acute group, we immediately implanted a Synergy Micro-pump, as described before. In the chronic group, this pump was implanted 8 weeks after the banding. Hemodynamics and pressure-volume loops were recorded before and 15 minutes after pump activation. Low flow RV mechanical support significantly improved ABP in both groups, but CO only in the acute group. Intrinsic RV contractility was not affected. The RV contribution to the total right sided cardiac output was 54 ± 8% in the acute group vs 10 ± 13% in the chronic group (p<1.10-5), indicating a more profound unloading in the latter. Diastolic unloading was successful in both groups, but systolic unloading only in the chronic group.In a 3rd step we aimed to assess the hemodynamic and histological effects of long-term mechanical low flow support of the chronic pressure overloaded RV (chapter 6). Therefore, the pulmonary artery was banded in 20 sheep. Eight weeks later, a Synergy Micro-pump was inserted in 10 animals, as described before. Following magnetic resonance imaging, hemodynamics and RV pressure-volume loops were recorded. Another eight weeks later, RV function was assessed in the same way, followed by histological analysis of ventricular tissue. During support, RV volumes and central venous pressure significantly decreased while contractility increased. PAP increased modestly, mainly its diastolic component. The RV contribution to the total right sided CO increased from 12 ± 12 % towards 41 ± 9 % (p<1.10-4). After pump inactivation, and compared to eight weeks earlier, RV volumes had significantly decreased, tricuspid valve regurgitation had almost disappeared and RV contractility had significantly increased, resulting in a significantly increased RV forward power (0.25 ± 0.05 vs 0.16 ± 0.06 Watt, p<0.05). Also left ventricular (LV) dimensions and function had improved, despite the ongoing RV pressure overload. Fulton index and RV myocyte size were significantly smaller without changes in fibrosis, compared to control animals. Therefore, we concluded that long-term continuous low flow RV mechanical support significantly unloaded the chronic pressure overloaded RV and improved CO. After 8 weeks, the pressure overloaded RV showed clear signs of hemodynamic recovery and of reverse remodeling, without increase of fibrosis.Temporary LV dysfunction after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) is well described. True LV failure has only been described after bLTx in PAH patients. Therefore, in chapter 7, we sought to identify factors that contribute to this LV failure and hypothesized that an AS before bLTx could prevent this LV failure. From our database, all PAH patients that underwent bLTx (n=24) and all CTEPH patients that underwent PEA, with a minimal reduction of 800 dynes.s.cm-5 (n=27), were selected. Perioperative demographic and echocardiographic data were analyzed. Pulmonary hypertension was diagnosed at significant younger age and time between diagnosis and surgery was significantly longer in PAH patients. Before surgery, PAH patients had significant larger RV dimensions, a significant smaller LV wall thickness, but a similar LV diastolic dysfunction. Surgery caused significant decreases in RV dimensions, less extensive in CTEPH, and significant increases in LV dimensions. Preoperative AS for PAH caused increases in LV dimensions, stroke volume and cardiac index. Two PAH patients developed postoperative LV failure. Compared to other PAH patients, they were younger (< 12 years) at diagnosis, their time between diagnosis and surgery lasted 2.5 times longer, their LV mass was smaller and their pre-bLTx PVR was higher. Therefore, we concluded that a younger age at diagnosis and a longer duration of LV preload deprivation contribute to the development of a more undertrained LV compared to CTEPH patients. Together with a higher postoperative increase in preload and a lower postoperative residual PVR, this undertrained LV explains the occasional development of LV failure after bLTx. Preoperative AS, but also a low flow RVAD and other surgical strategies may train the LV before bLTx, by increasing its preload, and avoid postoperative LV failure.The results of this thesis support the future clinical application of a low flow RVAD as a new treatment strategy for patients with RV failure due to PAH. This can be applied as bridge to bLTx or as destination therapy. The low flow RVAD will unload the RV and will lead to hemodynamic recovery, to RV reverse remodeling, and to an improvement of LV function with likely little change on damage to the lungs.

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This paper presents an overview of the outcome in combined heart-kidney transplantation performed at UZ Leuven.

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ABSTRACT Objectives Minimally invasive techniques for mitral valve surgery have been proven to be as effective and durable as conventional sternotomy. Meanwhile, robotic systems continue to evolve and revolutionize several surgical specialities. We conducted a search of the current literature to critically evaluate different aspects of implementing robotic technology in minimally invasive mitral valve surgery, comparing indications, outcomes, costs, benefits and limitations to non-robotic techniques. Methods For this retrospective review of the literature, we performed structured searches of Pubmed, Embase, Web of Science and Cochrane databases for relevant articles. Results Robotic mitral valve surgery has the same indications as non-robotic techniques, following the recommendations of current guidelines. Several studies demonstrated similar results when comparing robotic surgery to minimally invasive and sternotomy approaches. Despite longer cardiopulmonary bypass and aortic cross-clamp times, evidence suggests lower mortality, superior cosmesis, fewer blood transfusions, shorter ICU and hospital stays and faster return to activity in robotic cases versus conventional methods. Careful patient selection, through a screening algorithm and the choice of pathological complexity, achieves great results. With experience, the same level of results can be achieved in complex pathologies such as extensive mitral annular calcification. Furthermore, robotic mitral valve surgery is cost-effective in high referral centers. Conclusion Current evidence suggests an experienced surgeon can adopt robotic mitral valve surgery without compromising safety, quality of repair, durability and cost. To attain the best results, we suggest the use of a screening algorithm for patient selection and a gradual increase in the complexity of pathology.

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Background: Heart-lung transplantation (HLTx) is the preferred treatment procedure for patients with end-stage cardiopulmonary failure. However, indications and patient selection algorithms for HLTx are controversial and continue to evolve. Objectives: This study aims to provide an assessment of current patient selection, early and late postoperative outcomes and overall survival in patients who underwent HLTx at our institution, and to compare these with the results collected by the International Society for Heart and Lung Transplantation (ISHLT). Methods: We performed a single-center retrospective observational study of all patients who underwent HLTx at our institution from 1991 to 2018. Results: 50 patients underwent HLTx at our institution. Four patients (8%) died within 30 days after surgery. In-hospital mortality was 24% (12 patients); these recipients were significantly older than patients discharged from the hospital alive. One-year, 5-year, 10-year and 15-year survival rates were 74%, 56%, 36% and 20%, respectively. Conditioned on 1-year survival, however, 5-year, 10-year and 15-year survival were 75.7%, 48.7% and 27%. Over time, we observed an increase in cardiac-related indications. Eisenmenger syndrome (ES) was the indication for 56% of all HLTx. Hazard ratios (HR) of ES as compared to non-ES were higher for 1-, 5-, 10- and 15-year survival (1.88, 1.61, 1.28 and 1.42, respectively), though none of these were statistically significant. In addition, there were no differences in overall survival between ES and non-ES patients. The same trends were seen when considering all cardiac-related versus non-cardiac-related HLTx indications. When considering the eras 1991-2003 and 2004-2018, 1-, 5, 10-, and 15-year survival rates were more favorable for the latter era; 15-year survival was significantly better for era 2004-2018 (HR 0.45). Moreover, when comparing with international data, overall survival was significantly better for the UZ Leuven (UZL) cohort. The major cause of late mortality in our population was rejection (41.4%), more specifically chronic lung allograft dysfunction (CLAD). Conclusions: ES has always formed the major indication for HLTx at our center. Over time, we observed an increase in cardiac-related HLTx-indications and thus, as our results suggest, in high-risk HLTx patients. However, overall survival was comparable for ES and non-ES patients. In addition, this analysis shows that our HLTx outcomes are above the average reported by ISHLT and continue to improve over time. Our results indicate that patient selection and rejection phenomena will be the major challenges for HLTx practice in the future.

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2.1 Background and objectives In our center extracorporeal life support (ECLS) is not used routinely during LTx. Instead, it is used to anticipate and overcome hemodynamic and respiratory problems occurring perioperatively. We aim to describe our single center experience with use of ECLS in LTx, focusing on ECLS related complications. 2.2 Methods All transplantations with perioperative use of ECLS (2010-2020) were retrospectively analyzed. Multiorgan and heart-lung transplantations were excluded. The demographics, type of ECLS and indications are described. Complications are categorized according to their underlying nature and type. 2.3 Results The overall use of ECLS was 22% (156/703 patients) with a mean age of 52 years (36-59). Per Indication, 94% (15/16) of pulmonary hypertension patients required ECLS, whereas 8% (29/382) of COPD patients did. In 16% (25/156) of all ECLS cases, veno-venous extracorporeal membrane oxygenation (ECMO) was initiated, while 77% (120/156) required veno-arterial ECMO and 7% (11/156) cardiopulmonary bypass (CPB). Sixteen % (25/156) of patients were bridged to LTx on ECLS and 24% (38/156) required ECLS postoperatively. LTx indications in ECLS cohort were pulmonary fibrosis (38%; 60/156), COPD (18%; 29/156), cystic fibrosis (17%; 26/156) and others (27%; 41/156). Main indications for ECLS were intraoperative hemodynamic instability (53%; 82/156), ventilation problems (21%; 33/156) and oxygenation problems (17%; 26/156). Overall incidence of patients with at least one ECLS complication was 67% (104/156). Thirty-day mortality was 6% (9/156). Most common complications were hemothorax (25%; 39/156), need for continuous renal replacement therapy (CRRT) (19%; 30/156), and vascular ischemia/embolization (14%; 22/156). 2.4 Conclusion ECLS was required in 22% of LTx, resulting in relatively high number of possible ECLS related complications. To avoid these in the future, more focus on strategies to manage coagulation and renal failure is needed. Larger databases will help to analyze complications and develop better strategies for ECLS use in LTx.