Hypothermic oxygenated perfusion of the donor heart in heart transplantation: the short-term outcome from a randomised, controlled, open-label, multicentre clinical trial.

BACKGROUND: Static cold storage (SCS) remains the gold standard for preserving donor hearts before transplantation but is associated with ischaemia, anaerobic metabolism, and organ injuries, leading to patient morbidity and mortality. We aimed to evaluate whether continuous, hypothermic oxygenated machine perfusion (HOPE) of the donor heart is safe and superior compared with SCS. METHODS: We performed a multinational, multicentre, randomised, controlled, open-label clinical trial with a superiority design at 15 transplant centres across eight European countries. Adult candidates for heart transplantation were eligible and randomly assigned in a 1:1 ratio. Donor inclusion criteria were age 18-70 years with no previous sternotomy and donation after brain death. In the treatment group, the preservation protocol involved the use of a portable machine perfusion system ensuring HOPE of the resting donor heart. The donor hearts in the control group underwent ischaemic SCS according to standard practices. The primary outcome was time to first event of a composite of either cardiac-related death, moderate or severe primary graft dysfunction (PGD) of the left ventricle, PGD of the right ventricle, acute cellular rejection at least grade 2R, or graft failure (with use of mechanical circulatory support or re-transplantation) within 30 days after transplantation. We included all patients who were randomly assigned, fulfilled inclusion and exclusion criteria, and received a transplant in the primary analysis and all patients who were randomly assigned and received a transplant in the safety analyses. This trial was registered with ClicalTrials.gov (NCT03991923) and is ongoing. FINDINGS: A total of 229 patients were enrolled between Nov 25, 2020, and May 19, 2023. The primary analysis population included 204 patients who received a transplant. There were no patients who received a transplant lost to follow-up. All 100 donor hearts preserved with HOPE were transplantable after perfusion. The primary endpoint was registered in 19 (19%) of 101 patients in the HOPE group and 31 (30%) of 103 patients in the SCS group, corresponding to a risk reduction of 44% (hazard ratio 0·56; 95% CI 0·32-0·99; log-rank test p=0·059). PGD was the primary outcome event in 11 (11%) patients in the HOPE group and 29 (28%) in the SCS group (risk ratio 0·39; 95% CI 0·20-0·73). In the HOPE group, 63 (65%) patients had a reported serious adverse event (158 events) versus 87 (70%; 222 events) in the SCS group. Major adverse cardiac transplant events were reported in 18 (18%) and 33 (32%) patients in the HOPE and SCS group (risk ratio 0·56; 95% CI 0·34-0·92). INTERPRETATION: Although there was not a significant difference in the primary endpoint, the 44% risk reduction associated with HOPE was suggested to be a clinically meaningful benefit. Post-transplant complications, measured as major adverse cardiac transplant events, were reduced. Analysis of secondary outcomes suggested that HOPE was beneficial in reducing primary graft dysfunction. HOPE in donor heart preservation addresses the existing challenges associated with graft preservation and the increasing complexity of donors and heart transplantation recipients. Future investigation will help to further elucidate the benefit of HOPE. FUNDING: XVIVO Perfusion.

LVAD as a Bridge to Transplantation-Current Status and Future Perspectives.

Heart failure (HF) is a common disease associated with high morbidity and mortality rates despite advanced pharmacological therapies. Heart transplantation remains the gold standard therapy for end-stage heart failure; however, its application is curtailed by the persistent shortage of donor organs. Over the past two decades, mechanical circulatory support, notably Left Ventricular Assist Devices (LVADs), have been established as an option for patients waiting for a donor organ. This comprehensive review focuses on elucidating the benefits and barriers associated with this application. We provide an overview of landmark clinical trials that have evaluated the use of LVADs as a bridge to transplantation therapy, with a particular focus on post-transplant outcomes. We discuss the benefits of stabilizing patients with these systems, weighing associated complications and limitations. Further technical advancements and research on optimal implantation timing are critical to ultimately improve outcomes and securing quality of life. In a world where the availability of donor organs remains constrained, LVADs are an increasingly important piece of patient care, bridging the critical gap to transplantation in advanced heart failure management.

Quality of Life in Patients 20-31 Years After Heart Transplantation.

BACKGROUND: Survival rates after heart transplantation (HTx) have significantly improved over the last decades. There is a growing need to understand the long-term psychological and somatic outcomes, which constitute quality of life (QoL), for these long-term survivors. METHODS: The QoL of patients (N = 75) living 20-31 years (M = 24.9 years, SD = 2.3 years) after orthotopic HTx was evaluated. In a first step, a detailed overview of the patients' somatic condition was assessed. Secondly, patients were compared to 58 control subjects in terms of self-reported QoL (SF-36) and psychological domains (GBB-24; HADS). Finally, a cluster analysis was conducted to identify patterns within the patient-reported outcome measures (PROMs) and to relate them to somatic, psychosocial, and demographic variables. RESULTS: 95.7% of the HTx-patients were in NYHA functional class I or II, and only 15.2% had a reduced LVEF. Compared to controls, long-term HTx patients had significantly lower scores on the physical component summary (PCS) of QoL and on the GBB-24 but not in the mental component summary (MCS) of QoL, or anxiety and depression (HADS). Clustering revealed two distinct groups of patients characterized by high versus low functioning and different levels of social support. CONCLUSIONS: Long-term survivors have a good functional, cardiac, and mental status, but report a lower physical QoL and higher levels of subjective complaints. The importance of social support for HTx recipients is once again highlighted.

Left ventricular diastolic function assessed by speckle tracking echocardiography in patients with left ventricular aneurysm.

Speckle-tracking echocardiography (STE) parameters are an integral part of the assessment of left ventricular (LV) function. We aimed to evaluate established and novel STE parameters of LV diastolic function and their prognostic role in patients with LV anteroapical aneurysm undergoing surgical ventricular repair (SVR). We retrospectively examined the data of 137 patients with anteroapical LV aneurysm who underwent SVR. In 27 patients, the correlation of STE parameters with invasive hemodynamic parameters was evaluated. Preoperative echocardiographic parameters were assessed for their association with outcome, defined as all-cause mortality, LV assist device implantation, or heart transplantation. The late diastolic strain rate (GLSRa) showed a stronger correlation with mean pulmonary artery pressure (r = - 0.75, p < 0.001) than all other parameters. GLSRa was also significantly correlated with mean pulmonary capillary wedge pressure and LV end-diastolic pressure. In the multivariate model, GLSRa and the ratio of early diastolic filling velocity to GLSRa demonstrated incremental prognostic value in addition to clinical and echocardiographic parameters. Patients with GLSRa < 0.59 s-1 had significantly shorter event-free survival than those with GLSRa > 0.59 s-1 (6.7 vs. 10.9 years, p < 0.001). Peak reservoir left atrial strain showed a weaker association with hemodynamic parameters and outcome compared to GLSRa. In patients with LV aneurysm, late diastolic strain rate and left atrial strain can be used for the assessment of LV diastolic function and have a predictive value for the outcome after surgical ventricular restoration.

Combined Organ Transplantation in Patients with Advanced Liver Disease.

Transplantation of the liver in combination with other organs is an increasingly performed procedure. Over the years, continuous improvement in survival could be realized through careful patient selection and refined organ preservation techniques, in spite of the challenges posed by aging recipients and donors, as well as the increased use of steatotic liver grafts. Herein, we revisit the epidemiology, allocation policies in different transplant zones, indications, and outcomes with regard to simultaneous organ transplants involving the liver, that is combined heart-liver, liver-lung, liver-kidney, and multivisceral transplantation. We address challenges surrounding combined organ transplantation such as equity, utility, and logistics of dual organ implantation, but also advantages that come along with combined transplantation, thereby focusing on molecular mechanisms underlying immunoprotection provided by the liver to the other allografts. In addition, the current standing and knowledge of machine perfusion in combined organ transplantation, mostly based on center experience, will be reviewed. Notwithstanding all the technical advances, shortage of organs, and the lack of universal eligibility criteria for certain multi-organ combinations are hurdles that need to be tackled in the future.

Physical preconditioning on biventricular temporary mechanical circulatory support while awaiting heart transplantation.

Temporary mechanical circulatory support (tMCS) is increasingly used in patients with cardiogenic shock as a bridge to further treatment. We present the case of a 52-year-old female patient with biventricular heart failure who was bridged to heart transplantation employing biventricular tMCS through a non-femoral access. The 'groin-free' tMCS concept facilitates pre-habilitation while awaiting heart transplantation.

Endothelial Heterogeneity in the Response to Autophagy Drives Small Vessel Muscularization in Pulmonary Hypertension.

BACKGROUND: Endothelial cell (EC) apoptosis and proliferation of apoptosis-resistant cells is a hallmark of pulmonary hypertension (PH). Yet, why some ECs die and others proliferate and how this contributes to vascular remodeling is unclear. We hypothesized that this differential response may: (1) relate to different EC subsets, namely pulmonary artery (PAECs) versus microvascular ECs (MVECs); (2) be attributable to autophagic activation in both EC subtypes; and (3) cause replacement of MVECs by PAECs with subsequent distal vessel muscularization. METHODS: EC subset responses to chronic hypoxia were assessed by single-cell RNA sequencing of murine lungs. Proliferative versus apoptotic responses, activation, and role of autophagy were assessed in human and rat PAECs and MVECs, and in precision-cut lung slices of wild-type mice or mice with endothelial deficiency in the autophagy-related gene 7 (Atg7EN-KO). Abundance of PAECs versus MVECs in precapillary microvessels was assessed in lung tissue from patients with PH and animal models on the basis of structural or surface markers. RESULTS: In vitro and in vivo, PAECs proliferated in response to hypoxia, whereas MVECs underwent apoptosis. Single-cell RNA sequencing analyses support these findings in that hypoxia induced an antiapoptotic, proliferative phenotype in arterial ECs, whereas capillary ECs showed a propensity for cell death. These distinct responses were prevented in hypoxic Atg7EN-KO mice or after ATG7 silencing, yet replicated by autophagy stimulation. In lung tissue from mice, rats, or patients with PH, the abundance of PAECs in precapillary arterioles was increased, and that of MVECs reduced relative to controls, indicating replacement of microvascular by macrovascular ECs. EC replacement was prevented by genetic or pharmacological inhibition of autophagy in vivo. Conditioned medium from hypoxic PAECs yet not MVECs promoted pulmonary artery smooth muscle cell proliferation and migration in a platelet-derived growth factor-dependent manner. Autophagy inhibition attenuated PH development and distal vessel muscularization in preclinical models. CONCLUSIONS: Autophagic activation by hypoxia induces in parallel PAEC proliferation and MVEC apoptosis. These differential responses cause a progressive replacement of MVECs by PAECs in precapillary pulmonary arterioles, thus providing a macrovascular context that in turn promotes pulmonary artery smooth muscle cell proliferation and migration, ultimately driving distal vessel muscularization and the development of PH.

Microvascular dysfunction in heart transplantation is associated with altered cardiomyocyte mitochondrial structure and unimpaired excitation-contraction coupling.

INTRODUCTION: Microvascular dysfunction (MVD) is a hallmark feature of chronic graft dysfunction in patients that underwent orthotopic heart transplantation (OHT) and is the main contributor to impaired long-term graft survival. The aim of this study was to determine the effect of MVD on functional and structural properties of cardiomyocytes isolated from ventricular biopsies of OHT patients. METHODS: We included 14 patients post-OHT, who had been transplanted for 8.1 years [5.0; 15.7 years]. Mean age was 49.6 ± 14.3 years; 64% were male. Coronary microvasculature was assessed using guidewire-based coronary flow reserve(CFR)/index of microvascular resistance (IMR) measurements. Ventricular myocardial biopsies were obtained and cardiomyocytes were isolated using enzymatic digestion. Cells were electrically stimulated and subcellular Ca2+ signalling as well as mitochondrial density were measured using confocal imaging. RESULTS: MVD measured by IMR was present in 6 of 14 patients with a mean IMR of 53±10 vs. 12±2 in MVD vs. controls (CTRL), respectively. CFR did not differ between MVD and CTRL. Ca2+ transients during excitation-contraction coupling in isolated ventricular cardiomyocytes from a subset of patients showed unaltered amplitudes. In addition, Ca2+ release and Ca2+ removal were not significantly different between MVD and CTRL. However, mitochondrial density was significantly increased in MVD vs. CTRL (34±1 vs. 29±2%), indicating subcellular changes associated with MVD. CONCLUSION: In-vivo ventricular microvascular dysfunction post OHT is associated with preserved excitation-contraction coupling in-vitro, potentially owing to compensatory changes on the mitochondrial level or due to the potentially reversible cause of the disease.

Mediastinal transposition of the greater omentum for treatment of infected prostheses of the ascending aorta and aortic arch.

OBJECTIVES: The aim of this study was to evaluate the outcomes of transposition of the omentum into the mediastinum to support the replacement of infected aortic grafts or to cover infected aortic grafts that are not amenable for surgical replacement. METHODS: All patients with thoracic aortic graft infections who underwent mediastinal transposition of the omentum at our institution between 2005 and 2023 were included in this study. Mediastinal transposition of the omentum was performed either after replacement of the infected graft ('curative concept') or solely as bailout procedure by wrapping the infected graft ('palliative concept'). The diagnosis, including computed tomography scans during follow-up, was made according to the criteria of the Management of Aortic Graft Infection Collaboration. RESULTS: The patient cohort consisted of 31 patients. Both in-hospital and 1-year mortality were 0% (n = 0) for the curative concept (n = 9) compared to 23% (n = 5) and 41% (n = 9) for the palliative concept (n = 22), respectively. There was no graft infection-associated death or recurrence of infection after 3 years in the curative group. Survival was 52% at 3 years in the palliative group, with freedom of infection in 59% of the patients (n = 13). CONCLUSIONS: Transposition of the omentum and wrapping of the infected aortic prosthetic graft is a useful bailout strategy for patients who are ineligible for replacement of an infected aortic graft. However, mortality stays high. For radical treatment of aortic graft infections, it may prove an effective supportive therapy and represents an important tool in the armamentarium of cardiac surgeons.

Role of inflammatory signaling pathways involving the CD40-CD40L-TRAF cascade in diabetes and hypertension-insights from animal and human studies.

CD40L-CD40-TRAF signaling plays a role in atherosclerosis progression and affects the pathogenesis of coronary heart disease (CHD). We tested the hypothesis that CD40L-CD40-TRAF signaling is a potential therapeutic target in hyperlipidemia, diabetes, and hypertension. In mouse models of hyperlipidemia plus diabetes (db/db mice) or hypertension (1 mg/kg/d angiotensin-II for 7 days), TRAF6 inhibitor treatment (2.5 mg/kg/d for 7 or 14 days) normalized markers of oxidative stress and inflammation. As diabetes and hypertension are important comorbidities aggravating CHD, we explored whether the CD40L-CD40-TRAF signaling cascade and their associated inflammatory pathways are expressed in CHD patients suffering from comorbidities. Therefore, we analyzed vascular bypass material (aorta or internal mammary artery) and plasma from patients with CHD with diabetes and/or hypertension. Our Olink targeted plasma proteomic analysis using the IMMUNO-ONCOLOGY panel revealed a pattern of step-wise increase for 13/92 markers of low-grade inflammation with significant changes. CD40L or CD40 significantly correlated with 38 or 56 other inflammatory targets. In addition, specific gene clusters that correlate with the comorbidities were identified in isolated aortic mRNA of CHD patients through RNA-sequencing. These signaling clusters comprised CD40L-CD40-TRAF, immune system, hemostasis, muscle contraction, metabolism of lipids, developmental biology, and apoptosis. Finally, immunological analysis revealed key markers correlated with comorbidities in CHD patients, such as CD40L, NOX2, CD68, and 3-nitrotyrosine. These data indicate that comorbidities increase inflammatory pathways in CHD, and targeting these pathways will be beneficial in reducing cardiovascular events in CHD patients with comorbidities.

Acute Kidney Injury After Heart Transplantation: Risk Factors and Clinical Outcomes.

OBJECTIVE: Acute kidney injury (AKI) requiring renal-replacement therapy (RRT) after heart transplantation (OHT) is common and impairs outcomes. This study aimed to identify independent donor and recipient risk factors associated with RRT after OHT. DESIGN: A retrospective data analysis. SETTING: Data were collected from clinical routines in a maximum-care university hospital. PARTICIPANTS: Patients who underwent OHT. INTERVENTIONS: The authors retrospectively analyzed data from 264 patients who underwent OHT between 2012 and 2021; 189 patients were eligible and included in the final analysis. MEASUREMENTS AND MAIN RESULTS: The mean age was 48.0 ± 12.3 years, and 71.4% of patients were male. Ninety (47.6%) patients were on long-term mechanical circulatory support (lt-MCS). Posttransplant AKI with RRT occurred in 123 (65.1%) patients. In a multivariate analysis, preoperative body mass index >25 kg/m² (odds ratio [OR] 4.74, p < 0.001), elevated preoperative creatinine levels (OR for each mg/dL increase 3.44, p = 0.004), administration of red blood cell units during transplantation procedure (OR 2.31, p = 0.041) and ischemia time (OR for each hour increase 1.77, p = 0.004) were associated with a higher incidence of RRT. The use of renin-angiotensin-aldosterone system blockers before transplantation was associated with a reduced risk of RRT (OR 0.36, p = 0.013). The risk of mortality was 6.9-fold higher in patients who required RRT (hazard ratio 6.9, 95% CI: 2.1-22.6 p = 0.001). Previous lt-MCS, as well as donor parameters, were not associated with RRT after OHT. CONCLUSIONS: The implementation of guideline-directed medical therapy, weight reduction, minimizing ischemia time (ie, organ perfusion systems, workflow optimization), and comprehensive patient blood management potentially influences renal function and outcomes after OHT.

Patterns in acute aortic dissection and a connection to meteorological conditions in Germany.

Acute type A aortic dissection (ATAAD) is a dramatic emergency exhibiting a mortality of 50% within the first 48 hours if not operated. This study found an absolute value of cosine-like seasonal variation pattern for Germany with significantly fewer ATAAD events (Wilcoxon test) for the warm months of June, July, and August from 2005 to 2015. Many studies suspect a connection between ATAAD events and weather conditions. Using ERA5 reanalysis data and an objective weather type classification in a contingency table approach showed that for Germany, significantly more ATAAD events occurred during lower temperatures (by about 4.8 K), lower water vapor pressure (by about 2.6 hPa), and prevailing wind patterns from the northeast. In addition, we used data from a classification scheme for human-biometeorological weather conditions which was not used before in ATAAD studies. For the German region of Berlin and Brandenburg, for 2006 to 2019, the proportion of days with ATAAD events during weather conditions favoring hypertension (cold air advection, in the center of a cyclone, conditions with cold stress or thermal comfort) was significantly increased by 13% (Chi-squared test for difference of proportions). In contrast, the proportion was decreased by 19% for conditions associated with a higher risk for patients with hypotension and therefore a lower risk for patients with hypertension (warm air advection ahead of warm fronts, conditions with no thermal stress or heat stress, in the center of a cyclone with thermal stress). As many studies have shown that hypertension is a risk factor for ATAAD, our findings support the hypothesized relation between ATAAD and hypertension-favoring weather conditions.

Ultrasonographic assessment of pulmonary and Central venous congestion in experimental heart failure.

Pulmonary and systemic congestion as a consequence of heart failure are clinically recognized as alarm signals for clinical outcome and mortality. Although signs and symptoms of congestion are well detectable in patients, monitoring of congestion in small animals with heart failure lacks adequate noninvasive methodology yet. Here, we developed a novel ultrasonography-based scoring system to assess pulmonary and systemic congestion in experimental heart failure, by using lung ultrasound (LUS) and imaging of the inferior vena cava (Cava), termed CavaLUS. CavaLUS was established and tested in a rat model of supracoronary aortic banding and a mouse model of myocardial infarction, providing high sensitivity and specificity while correlating to numerous parameters of cardiac performance and disease severity. CavaLUS, therefore, provides a novel comprehensive tool for experimental heart failure in small animals to noninvasively assess congestion.NEW & NOTEWORTHY As thorough, noninvasive assessment of congestion is not available in small animals, we developed and validated an ultrasonography-based research tool to evaluate pulmonary and central venous congestion in experimental heart failure models.