Orthostatic Ex-Vivo Lung Perfusion (EVLP): A Proof of Concept.

The key goal in lung donation remains the improvement of graft preservation with the ultimate objective of increasing the number and quality of lung transplants (LTx). Therefore, in recent years the field of graft preservation focused on improving outcomes related to solid organ regeneration and restoration. In this contest Ex-Vivo Lung Perfusion (EVLP) plays a crucial role with the purpose to increase the donor pool availability transforming marginal and/or declined donor lungs suitable for transplantation. Aim of this proof of concept is to test the safety, suitability and feasibility of a new tilting dome for EVLP designed considering the dorsal lung areas as the "Achilles' heel" of the EVLP due to a more fluid accumulation than in the supine standard position.

Homograft Aortic Root Replacement for Destructive Prosthetic Valve Endocarditis: Results in the Current Era.

Background: Destructive aortic prosthetic valve endocarditis portends a high morbidity and mortality, and requires complex high-risk surgery. Homograft root replacement is the most radical and biocompatible operation and, thus, the preferred option. Methods: A retrospective analysis was conducted on 61 consecutive patients who underwent a cardiac reoperation comprising homograft aortic root replacement since 2010. The probabilities of survival were calculated with the Kaplan-Meier method, whereas multivariable regression served to outline the predictors of adverse events. The endpoints were operative/late death, perioperative low cardiac output and renal failure, and reoperations. Results: The operative (cumulative hospital and 30-day) mortality was 13%. The baseline aspartate transaminase (AST) and associated mitral procedures were predictive of operative death (p = 0.048, OR [95% CIs] = 1.03 [1-1.06]) and perioperative low cardiac output, respectively (p = 0.04, OR [95% CIs] = 21.3 [2.7-168.9] for valve replacement). The latter occurred in 12 (20%) patients, despite a normal ejection fraction. Survival estimates (±SE) at 3 months, 6 months, 1 year, and 3 years after surgery were 86.3 ± 4.7%, 82.0 ± 4.9%, 75.2 ± 5.6, and 70.0 ± 6.3%, respectively. Survival was significantly lower in the case of AST ≥ 40 IU/L (p = 0.04) and aortic cross-clamp time ≥ 180 min (p = 0.01), but not when excluding operative survivors. Five patients required early (two out of the five, within 3 months) or late (three out of the five) reoperation. Conclusions: Homograft aortic root replacement for destructive prosthetic valve endocarditis can currently be performed with a near 90% operative survival and reasonable 3-year mortality and reoperation rate. AST might serve to additionally stratify the operative risk.

Prognostic Value of APACHE IV Score in Patients Bridged to Heart Transplantation on ECMO.

BACKGROUND: Methods for risk stratification of candidates for heart transplantation (HTx) supported by extracorporeal membrane oxygenation (ECMO) are limited. We evaluated the reliability of the APACHE IV score to identify the risk of mortality in this patient subset in a multicenter study. METHODS: Between January 2010 and December 2022, 167 consecutive ECMO patients were bridged to HTx; they were divided into two groups, according to a cutoff value of APACHE IV score, obtained by receiver operating characteristic curve analysis for 90-day mortality. Kaplan-Meier survival curves were plotted, and compared through the log-Rank test. Cox regression model was used to estimate which factors were associated with survival. RESULTS: The 90-day mortality prediction of the APACHE IV score showed an area under the curve of 0.87 (95% CI: 0.80-0.94), with a cutoff value of 49 (specificity 91.7%-sensibility 69.6%). 125 patients (74.8%) showed an APACHE IV score value < 49 (Group A), and 42 (25.2%) ≥ 49 (Group B). 90-day mortality was 11.2% in Group A and 76.2% in Group B (p < 0.01). Survival at 1 and 5 years was 85.5%, 77% versus 23.4%, 23.4% (p < 0.01) in Groups A and B. Mortality correlated at univariable analysis with recipient age, body mass index, mechanical ventilation, APACHE IV score, and platelets number. At multivariable analysis only APACHE IV score (HR: 1.07 [1.05-1.09, 95% CI]) independently affected survival. CONCLUSIONS: The APACHE IV score represents a powerful predictor of survival in patients bridged to HTx on ECMO support, and could guide candidacy of patients on ECMO.

Transcatheter Mitral Valve Implantation in Failed Transventricular Mitral Valve Repair.

An 84-year-old man presented with dyspnea at rest due to severe mitral regurgitation. He first underwent transventricular mitral valve repair with the Harpoon system, which relapsed owing to rupture of neochords. He was definitively treated with transcatheter mitral valve implantation of the Tendyne system 8 months later.

Viability assessment of livers donated after circulatory determination of death during normothermic regional perfusion.

BACKGROUND: Abdominal normothermic regional perfusion (A-NRP) allows in-situ reperfusion and recovery of abdominal organs metabolism in donors after circulatory death (DCD). Besides improving liver transplantation outcomes, liver injury and function can be assessed during A-NRP. METHODS: To refine liver viability assessment during A-NRP, prospectively collected data of controlled DCD donors managed at our Institution between October 2019 and May 2022 were retrospectively analyzed. Baseline characteristics, procedural variables and A-NRP parameters of donors whose liver was successfully transplanted were compared to those of donors whose liver was discarded. RESULTS: Twenty-seven donors were included and in 20 (74%) the liver was accepted (positive outcome). No differences between study groups were observed concerning baseline characteristics and warm ischemia times (WIT). Initial lactate levels were positively correlated with functional WIT (r2 = 0.4, p = 0.04), whereas transaminase levels were not. Blood flow during A-NRP was comparable, whereas oxygen consumption (VO2 ) was significantly higher in the positive outcome group after 1 h. Time courses of lactate, AST and ALT were significantly different between study groups (p < 0.001). Donors whose liver was accepted showed faster lactate clearance, a difference which was amplified by normalizing lactate clearance to oxygen delivery (DO2 ) and VO2 . Lactate clearance was correlated to transaminase levels and DO2 -normalized lactate clearance was the parameter best discriminating between study groups. CONCLUSIONS: DO2 -normalized lactate clearance may represent an element of liver viability assessment during A-NRP.

Three-Dimensional Finger Test: A New Echocardiographic Method to Locate the Best Access Site During NeoChord Procedure.

OBJECTIVE: Transventricular beating-heart mitral valve repair (TBMVR) with artificial chordae implantation is a technique to treat mitral valve prolapse. Two-dimensional (2D) echocardiography completed with simultaneous biplane view during surgeon finger pushing on the left ventricular (LV) wall (finger test [FT]) is currently used to localize the desired LV access, on the inferior-lateral wall, between the papillary muscles (PMs). We aimed to compare a new three-dimensional (3D) method with conventional FT in terms of safety and better localization of LV access. METHODS: During TBMVR, conventional FT was completed using 3D transesophageal echocardiography by placing the sample box in the bicommissural view of the LV, including the PMs and the apex. The 3D volume was subsequently edited to visualize the LV from above (surgical view) to localize the bulge of the operator's finger pushing on the LV. We asked the first operator, the second operator, and the cardiac surgery fellow, separately, to evaluate the location of their finger pushing, both with the 2D method and the 3D method, to estimate the interoperator concordance. RESULTS: From 2019 to 2021, 42 TBMVRs were performed without complications related to access using FT completed with the 3D method. Regarding the choice of the right and safe entry site, the operator's agreement was higher using 3D rendering compared with conventional FT (mean agreement 0.59 ± 0.29 for 2D vs 0.83 ± 0.20 for 3D), while full operator agreement was 10 of 42 for 2D and 23 of 42 for 3D (P = 0.004). CONCLUSIONS: Three-dimensional FT is easy to perform and facilitates surgeons choosing the best access for TBMVR in term of anatomical localization and safety.

Cytokines Removal During Ex-Vivo Lung Perfusion: Initial Clinical Experience.

Ex Vivo Lung Perfusion (EVLP) can be potentially used to manipulate organs and to achieve a proper reconditioning process. During EVLP pro-inflammatory cytokines have been shown to accumulate in perfusate over time and their production is correlated with poor outcomes of the graft. Aim of the present study is to investigate the feasibility and safety of cytokine adsorption during EVLP. From July 2011 to March 2020, 54 EVLP procedures have been carried out, 21 grafts treated with an adsorption system and 33 without. Comparing the grafts perfused during EVLP with or without cytokine adsorption, the use of a filter significantly decreased the levels of IL10 and GCSFat the end of the procedure. Among the 38 transplanted patients, the adsorption group experienced a significant decreased IL6, IL10, MCP1 and GCSF concentrations and deltas compared to the no-adsorption group, with a lower in-hospital mortality (p = 0.03) and 1-year death rate (p = 0.01). This interventional study is the first human experience suggesting the safety and efficacy of a porous polymer beads adsorption device in reducing the level of inflammatory mediators during EVLP. Clinical impact of cytokines reduction during EVLP must be evaluated in further studies.

New Echocardiographic Parameters Predicting Successful Trans-Ventricular Beating-Heart Mitral Valve Repair with Neochordae at 3 Years: Monocentric Retrospective Study.

The NeoChord procedure is an echo-guided trans-ventricular beating-heart mitral valve repair technique to treat degenerative mitral regurgitation (MR) due to prolapse and/or flail. The aim of this study is to analyze echocardiographic images to find pre-operative parameters to predict procedural success (≤moderate MR) at 3-year follow-up. Seventy-two consecutive patients with severe MR underwent the NeoChord procedure between 2015 and 2021. MV pre-operative morphological parameters were assessed using 3D transesophageal echocardiography with dedicated software (QLAB, Philips). Three patients died during their hospitalization. The remaining 69 patients were retrospectively analyzed. At follow-up, MR > moderate was found in 17 patients (24.6%). In the univariate analysis, end-systolic annulus area (12.5 ± 2.5 vs. 14.1 ± 2.6 cm2; p = 0.038), end-systolic annulus circumference (13.2 ± 1.2 vs. 14 ± 1.3 cm; p = 0.042), indexed left atrial volume (59 ± 17 vs. 76 ± 7 mL/m2; p = 0.041), and AF (25% vs. 53%; p = 0.042) were lower in the 52 patients with ≤ MR compared to those with > moderate MR. Annular dysfunction parameters were the best predictors of procedural success: 3D early-systolic annulus area (AUC 0.74; p = 0.004), 3D early-systolic annulus circumference (AUC 0.75; p = 0.003), and 3D annulus area fractional change (AUC 0.73; p = 0.035). Patient selection relying on 3D dynamic and static MA dimensions may improve the maintenance of procedural success at follow-up.

Lung Transplantation for Primary Ciliary Dyskinesia and Kartagener Syndrome: A Multicenter Study.

Primary ciliary dyskinesia, with or without situs abnormalities, is a rare lung disease that can lead to an irreversible lung damage that may progress to respiratory failure. Lung transplant can be considered in end-stage disease. This study describes the outcomes of the largest lung transplant population for PCD and for PCD with situs abnormalities, also identified as Kartagener's syndrome. Retrospectively collected data of 36 patients who underwent lung transplantation for PCD from 1995 to 2020 with or without SA as part of the European Society of Thoracic Surgeons Lung Transplantation Working Group on rare diseases. Primary outcomes of interest included survival and freedom from chronic lung allograft dysfunction. Secondary outcomes included primary graft dysfunction within 72 h and the rate of rejection ≥A2 within the first year. Among PCD recipients with and without SA, the mean overall and CLAD-free survival were 5.9 and 5.2 years with no significant differences between groups in terms of time to CLAD (HR: 0.92, 95% CI: 0.27-3.14, p = 0.894) or mortality (HR: 0.45, 95% CI: 0.14-1.43, p = 0.178). Postoperative rates of PGD were comparable between groups; rejection grades ≥A2 on first biopsy or within the first year was more common in patients with SA. This study provides a valuable insight on international practices of lung transplantation in patients with PCD. Lung transplantation is an acceptable treatment option in this population.

Is there life on the airway tree? A pilot study of bronchial cell vitality and tissue morphology in the ex vivo lung perfusion (EVLP) era of lung transplantation.

BACKGROUND: Ex vivo lung perfusion (EVLP) is a relevant procedure to increase the lung donor pool but could potentially increase the airway tree ischemic injury risk. METHODS: This study aimed to evaluate the direct effect of EVLP on the airway tree by evaluating bronchial cell vitality and tissue signs of injury on a series of 117 bronchial rings collected from 40 conventional and 19 EVLP-treated lung grafts. Bronchial rings and related scraped bronchial epithelial cells were collected before the EVLP procedure and surgical anastomosis. RESULTS: The preimplantation interval was significantly increased in the EVLP graft group (p < 0.01). Conventional grafts presented cell viability percentages of 47.07 ± 23.41 and 49.65 ± 21.25 in the first and second grafts which did not differ significantly from the EVLP group (first graft 50.54 ± 25.83 and second graft 50.22 ± 20.90 cell viability percentage). No significant differences in terms of histopathological features (edema, inflammatory infiltrate, and mucosa ulceration) were observed comparing conventional and EVLP samples. A comparison of bronchial cell viability and histopathology of EVLP samples retrieved at different time intervals revealed no significant differences. Accordingly, major bronchial complications after lung transplant were not observed in both groups. CONCLUSIONS: Based on these data, we observed that EVLP did not significantly impact bronchial cell vitality and airway tissue preservation nor interfere with bronchial anastomosis healing, further supporting it as a safe and useful procedure.

Validation of a Simple, Rapid, and Cost-Effective Method for Acute Rejection Monitoring in Lung Transplant Recipients.

Despite advances in immunosuppression therapy, acute rejection remains the leading cause of graft dysfunction in lung transplant recipients. Donor-derived cell-free DNA is increasingly being considered as a valuable biomarker of acute rejection in several solid organ transplants. We present a technically improved molecular method based on digital PCR that targets the mismatch between the recipient and donor at the HLA-DRB1 locus. Blood samples collected sequentially post-transplantation from a cohort of lung recipients were used to obtain proof-of-principle for the validity of the assay, correlating results with transbronchial biopsies and lung capacity tests. The results revealed an increase in dd-cfDNA during the first 2 weeks after transplantation related to ischemia-reperfusion injury (6.36 ± 5.36%, p < 0.0001). In the absence of complications, donor DNA levels stabilized, while increasing again during acute rejection episodes (7.81 ± 12.7%, p < 0.0001). Respiratory tract infections were also involved in the release of dd-cfDNA (9.14 ± 15.59%, p = 0.0004), with a positive correlation with C-reactive protein levels. Overall, the dd-cfDNA percentages were inversely correlated with the lung function values measured by spirometry. These results confirm the value of dd-cfDNA determination during post-transplant follow-up to monitor acute rejection in lung recipients, achieved using a rapid and inexpensive approach based on the HLA mismatch between donor and recipient.

Surgical left ventricle remodeling to treat functional mitral valve regurgitation.

A left ventricular aneurysm complicates an acute myocardial infarction in 4-20% of patients. The loss of the physiological geometry of the ventricle can lead to a dislocation of the papillary muscles with subsequential mitral valve regurgitation. The goal of this case report is to demonstrate that a proper operation to restore the left ventricular anatomy can be a feasible procedure to correct functional mitral regurgitation.

HLA-DRB1 mismatch-based identification of donor-derived cell free DNA (dd-cfDNA) as a marker of rejection in heart transplant recipients: A single-institution pilot study.

BACKGROUND: Donor-derived cell-free DNA (dd-cfDNA) is considered a reliable marker of organ damage with potential applications in the follow-up of transplant recipients. METHODS: In this work we present an assay based on the donor-recipient HLA-mismatch (human leukocyte antigen) at the HLA-DRB1 locus to monitor rejection by quantifying the percentage of dd-cfDNA using a droplet digital PCR (polymerase chain reaction) technique. A panel of probes targeting the HLA-DRB1 locus and covering >85% genetic variability was validated and used to assess dd-cfDNA levels in a prospective cohort of 19 adult heart transplant recipients (mean age 50.9±14.8 years). The assay was carried out on a total of 232 liquid biopsies collected at the same time as endomyocardial biopsy (EMB) during routine post-transplant follow-up. RESULTS: Results show a significant increase of dd-cfDNA related to ischemia-reperfusion injury (2.22±2.09%) and to acute cellular rejection (1.71±3.10%) compared to stable conditions (0.43±1.04%, p < 0.0001). On the contrary, no increase was observed during infections or vascular complications, underlining the potential role of this biomarker for rejection monitoring. With a cut-off of 0.11%, the test showed 70.8% specificity (95% CI, 58.17% - 81.40%) and 64.2% sensitivity (95% CI, 49.80% - 76.86%) in discriminating acute rejection from no rejection. CONCLUSIONS: These data demonstrate that this HLA mismatch-based droplet digital PCR method is effective for monitoring rejection in heart transplant recipients. Compared to next generation sequencing approaches, it is far more flexible, less expensive and provides faster results.

Nonresponse to Acute Vasodilator Challenge and Prognosis in Heart Failure With Pulmonary Hypertension.

BACKGROUND: An acute vasodilator challenge is recommended in patients with heart failure and pulmonary hypertension during heart transplant evaluation. The aim of the study was to assess which hemodynamic parameters are associated with nonresponsiveness to the challenge. METHODS AND RESULTS: This study is a retrospective analysis of 402 patients with heart failure with pulmonary hypertension who underwent right heart catheterization and a pulmonary vasodilator challenge. Among the 140 who fulfilled the transplant guidelines eligibility criteria for the vasodilator challenge, 38 were responders and 102 nonresponders. At multivariable analysis, a diastolic blood pressure of <70 mm Hg, pulmonary vascular resistance of >5 Woods units, and pulmonary artery compliance of <1.2 mL/mm Hg were independently associated with poor response to vasodilator challenge (all P < .001). The presence of any 2 of these 3 conditions was associated with a 90% probability of being a nonresponder. The covariate-adjusted hemodynamic predictors of death in the entire population were a low baseline systolic blood pressure (P = .0017) and a low baseline right ventricular stroke work index (P = .0395). CONCLUSIONS: In patients with heart failure and pulmonary hypertension, low pulmonary arterial compliance, high pulmonary vascular resistance, and low diastolic blood pressure predict the nonresponsiveness to acute vasodilator challenge whilst a poor right ventricular function predicts a dismal prognosis.

Noncalcific Mechanisms of Bioprosthetic Structural Valve Degeneration.

Bioprosthetic heart valves (BHVs) largely circumvent the need for long-term anticoagulation compared with mechanical valves but are increasingly susceptible to deterioration and reduced durability with reoperation rates of ≈10% and 30% at 10 and 15 years, respectively. Structural valve degeneration is a common, unpreventable, and untreatable consequence of BHV implantation and is frequently characterized by leaflet calcification. However, 25% of BHV reoperations attributed to structural valve degeneration occur with minimal leaflet mineralization. This review discusses the noncalcific mechanisms of BHV structural valve degeneration, highlighting the putative roles and pathophysiological relationships between protein infiltration, glycation, oxidative and mechanical stress, and inflammation and the structural consequences for surgical and transcatheter BHVs.

COVID-19 in Heart Transplant Recipients: A Multicenter Analysis of the Northern Italian Outbreak.

OBJECTIVES: The aim of this study was to assess the clinical course and outcomes of all heart transplant recipients affected by coronavirus disease-2019 (COVID-19) who were followed at the leading heart transplant centers of Northern Italy. BACKGROUND: The worldwide severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has created unprecedented challenges for public health, demanding exceptional efforts for the successful management and treatment of affected patients. Heart transplant patients represent a unique cohort of chronically immunosuppressed subjects in which SARS-CoV-2 may stimulate an unpredictable clinical course of infection. METHODS: Since February 2020, we enrolled all 47 cases (79% male) in a first cohort of patients, with a mean age of 61.8 ± 14.5 years, who tested positive for SARS-CoV-2, out of 2,676 heart transplant recipients alive before the onset of the COVID-19 pandemic at 7 heart transplant centers in Northern Italy. RESULTS: To date, 38 patients required hospitalization while 9 remained self-home quarantined and 14 died. Compared to the general population, prevalence (18 vs. 7 cases per 1,000) and related case fatality rate (29.7% vs. 15.4%) in heart transplant recipients were doubled. Univariable analysis showed older age (p = 0.002), diabetes mellitus (p = 0.040), extracardiac arteriopathy (p = 0.040), previous PCI (p = 0.040), CAV score (p = 0.039), lower GFR (p = 0.004), and higher NYHA functional classes (p = 0.023) were all significantly associated with in-hospital mortality. During the follow-up two patients died and a third patient has prolonged viral-shedding alternating positive and negative swabs. Since July 1st, 2020, we had 6 new patients who tested positive for SARS-CoV-2, 5 patients asymptomatic were self-quarantined, while 1 is still hospitalized for pneumonia. A standard therapy was maintained for all, except for the hospitalized patient. CONCLUSIONS: The prevalence and mortality of SARS-CoV-2 should spur clinicians to immediately refer heart transplant recipients suspected as having SARS-CoV2 infection to centers specializing in the care of this vulnerable population.

Insidious postoperative Aspergillus niger graft aortitis.

Fungal endocarditis/aortitis is an uncommon yet emerging entity accounting for 2% to 4% of all cases of infective endocarditis and continues to be associated with a poor prognosis. We present the first case of polyethylene-terephthalate (PETE) graft aortitis caused by A. niger, a rare fungal agent. Early diagnosis with frequent transoesophageal echocardiography (TEE) and a prompt surgical intervention coupled with optimal antifungal therapy are still the only option to reduce the exceedingly high mortality and morbidity.

Use of a photo-realism 3D rendering technique to enhance echocardiographic visualization of the anatomical details during beating-heart mitral valve repair.

The NeoChord procedure is an innovative microinvasive, transventricular, beating-heart chordal replacement technique for patients with severe degenerative mitral valve regurgitation resulting from prolapsed or flail leaflets. Use of three-dimensional (3D) transoesophageal echocardiographic imaging is crucial to the physician operator for device navigation during the procedure and to assess the functional results of the repair at the end of the procedure. Photo-realistic, 3D rendering techniques have been recently developed for medical use. Philips TrueVue (Philips Healthcare, Eindhoven, NL) is a photo-realism technique that employs the use of a virtual light source that simulates the interaction of light on 3-dimensional surfaces. Use of photo-realism techniques, in conjunction with 3D echocardiography, improves the visualization of morphological characteristics of the mitral valve before, during, and after beating-heart mitral valve repair procedures.

"The Starry Sky." A new intraprocedural three-dimensional echocardiographic technique.

The NeoChord procedure is a micro-invasive, trans-ventricular, beating-heart chordal replacement technique for patients with severe degenerative mitral valve regurgitation resulting from prolapsed or flail leaflets. Three dimensional transoesophageal echocardiographic guidance is crucial to assist the operator during the procedure. Equidistant placement of neochordae along the free edge of the prolapsing leaflet segment is important to ensure uniform stress distribution and to avoid damaging any of the previously placed neochordae. Lowering the image gain associated with the three-dimensional surgical view of the mitral valve allows for signal attenuation of the native structures delineating the precise placement location of the neochordae.