Author Correction: Consistent success in life-supporting porcine cardiac xenotransplantation.

In this Letter, Mayuko Kurome and Valeri Zakhartchenko have been added to the author list (affiliated with Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany). The author list and 'Author contributions' section have been corrected online; see accompanying Amendment.

Consistent success in life-supporting porcine cardiac xenotransplantation.

Heart transplantation is the only cure for patients with terminal cardiac failure, but the supply of allogeneic donor organs falls far short of the clinical need1-3. Xenotransplantation of genetically modified pig hearts has been discussed as a potential alternative4. Genetically multi-modified pig hearts that lack galactose-α1,3-galactose epitopes (α1,3-galactosyltransferase knockout) and express a human membrane cofactor protein (CD46) and human thrombomodulin have survived for up to 945 days after heterotopic abdominal transplantation in baboons5. This model demonstrated long-term acceptance of discordant xenografts with safe immunosuppression but did not predict their life-supporting function. Despite 25 years of extensive research, the maximum survival of a baboon after heart replacement with a porcine xenograft was only 57 days and this was achieved, to our knowledge, only once6. Here we show that α1,3-galactosyltransferase-knockout pig hearts that express human CD46 and thrombomodulin require non-ischaemic preservation with continuous perfusion and control of post-transplantation growth to ensure long-term orthotopic function of the xenograft in baboons, the most stringent preclinical xenotransplantation model. Consistent life-supporting function of xenografted hearts for up to 195 days is a milestone on the way to clinical cardiac xenotransplantation7.

Comparable bleeding and inflammation outcomes between heparin-coated and uncoated minimal invasive extracorporeal circuits in isolated coronary artery bypass surgery - A double-blinded randomized control trial.

OBJECTIVE: Minimally invasive extracorporeal circulation has been shown to be non-inferior or even superior to conventional cardiopulmonary bypass circuits in isolated coronary artery bypass grafting, but there is little evidence whether the addition of a heparin-coated circuit can further reduce the inflammatory response and amount of bleeding in these patients. METHODS: A single-center randomized control trial enrolled 49 adult patients scheduled to undergo isolated coronary artery bypass grafting with minimally invasive extracorporeal circulation (MiECC) between January 2015 and December 2018. Patients were randomized 1:1 to either the heparin-coated circuit group, or the uncoated (control) circuit group. The primary outcome was chest tube output 18 h after weaning from MiECC, and secondary outcomes included inflammatory (TNF-α, IL-6, IL-8, IL-10) and complement (C3a, C4d, C5a, sC5b-9) biomarkers, platelet count and function (D2D, TAT, SDC1, PF4), number of transfused blood products, and 30-day survival. RESULTS: Patients were randomized to undergo myocardial revascularization using heparin-coated circuits (n = 25), and to the uncoated MiECC circuit (n = 24), with comparable baseline demographics. No significant difference was observed in chest tube output and for all secondary outcomes. IL-6 and IL-8 were increased from baseline at 18 h after weaning (effect size 0.29 and 0.05, respectively) and sC5b-9 was lower (effect size 0.11) in the heparin-coated than in the uncoated MiECC, although not significantly different. CONCLUSIONS: Compared with an uncoated MiECC circuit, heparin-coated MiECC circuit was not associated with a reduction in postoperative bleeding, transfusion, inflammation, complement activation, and platelet biomarkers, following isolated coronary artery bypass grafting.

Ten-year retrospective cohort analysis of ventricular assist device infections.

BACKGROUND: The number of patients treated by ventricular assist devices (VAD) and the duration of VAD treatment is increasing. One of the main complications in terms of morbidity and mortality for VAD patients are microbial infections. With this study, we aimed to investigate the epidemiology and microbiological characteristics of infections occurring in a VAD population to identify modifiable factors. METHODS: We retrospectively analyzed patient characteristics, treatments and outcomes of VAD-specific/related infections. All patients implanted in our institution with a continuous flow VAD between January 2009 and January 2019 were included. Risk factors for VAD infection were assessed using simple and multiple linear regressions. RESULTS: Of the 104 patients screened, 99 were included in the analysis, the majority of which were men (78%). At implantation, the mean age was 56 years and the median time on VAD support was 541 days. The overall infection rate per year per patient was 1.4. Forty-seven patients (60%) suffered from VAD-specific/related infection. Half of all infection episodes occurred in the first 4 months but the proportion of VAD-specific/related infection was higher after the first 4 months (74% of all infection). Using regression models, no patient specific risk factors were associated with VAD-specific/related infections. CONCLUSION: No predictive factors for infection during VAD support were identified in this study. By extension, diabetes, renal insufficiency, age or high BMI are not sufficient to deny a patient access to ventricular support.

Update and breakthrough in cardiac xenotransplantation.

PURPOSE OF REVIEW: Considerable advancements have been made in the field of cardiac xenotransplantation in the recent years, achieving prolonged survival of the life-supporting cardiac xenograft and paving the way toward first clinical implications. RECENT FINDINGS: The combination of genetic modifications and novel immunosuppression with costimulation blockade, as well as supporting therapy with antiinflammatory treatment, growth prevention, and adaptation of the heart procurement system to reduce myocardial ischemia and reperfusion injury improves the overall cardiac xenograft function and overall survival in nonhuman primates. Through the newly identified xenoantigens and novel gene-editing techniques, further genetic modification of the porcine xenografts should be explored, to ensure clinical safety. SUMMARY: With continuous progress in all fields of cardiac xenotransplantation, first clinical use in humans seems accomplishable. To ensure the clinical safety and to conform to the ethical regulations, further investigation of the infectious and immunological implications on humans should be explored prior to first clinical use. The first clinical use of cardiac xenotransplantation will be limited to only highly selected patients.

Right ventricular function in Marfan patients remains stable despite multiple cardiac interventions.

OBJECTIVES: Mitral valve regurgitation and left ventricular dysfunction are cardiovascular symptoms of Marfan syndrome. There is a paucity of information on tricuspid valve regurgitation and right ventricular function. In patients with Marfan syndrome, we looked at long-term changes in right ventricular function, tricuspid valve regurgitation and freedom from tricuspid valve repair. METHODS: Retrospective-observational single-centre analysis on right ventricular function and tricuspid regurgitation in Marfan patients who underwent surgery with cardioplegic arrest between 1995 and 2020. Patients were followed-up from 1st operation until death, with echocardiographic changes analysed longitudinally. Composite end point was tricuspid annular plane systolic excursion (TAPSE) ≤16 mm, severe tricuspid regurgitation or tricuspid repair. RESULTS: The study included 135 patients who underwent 193 operations, 58 of those were reoperations in 40 patients. Median age at 1st operation was 35 years [interquartile range (IQR) 26-46], median follow-up was 8.0 years (IQR 3.0-16.0) and median time to 1st reoperation was 7.5 years (IQR 3.4-12.5). The composite end point occurred in 81 observations in 40 patients, mostly as a recurrent event, after median 7.0 years (IQR 1.0-13.0). Ten-year cumulative incidence for composite end point was 22.0% (95% CI 15-31) and 9.0% (95% CI 4.4-16) for new-onset TAPSE ≤16 mm, but no significant change in TAPSE was observed at 10 years. Tricuspid regurgitation was associated with increased risk of annual progression (P < 0.001), but not clinically relevant at 10 years. Actuarial 10-year survival was 91.1%. CONCLUSIONS: In Marfan patients with a history of cardiac surgery and subsequent reoperations, the right ventricular function remains stable. The incidence of severe tricuspid regurgitation and tricuspid repair remain low.

Open- vs. closed-chest pig models of donation after circulatory death.

Background: During donation after circulatory death (DCD), cardiac grafts are exposed to potentially damaging conditions that can impact their quality and post-transplantation outcomes. In a clinical DCD setting, patients have closed chests in most cases, while many experimental models have used open-chest conditions. We therefore aimed to investigate and characterize differences in open- vs. closed-chest porcine models. Methods: Withdrawal of life-sustaining therapy (WLST) was simulated in anesthetized juvenile male pigs by stopping mechanical ventilation following the administration of a neuromuscular block. Functional warm ischemic time (fWIT) was defined to start when systolic arterial pressure was <50 mmHg. Hemodynamic changes and blood chemistry were analyzed. Two experimental groups were compared: (i) an open-chest group with sternotomy prior to WLST and (ii) a closed-chest group with sternotomy after fWIT. Results: Hemodynamic changes during the progression from WLST to fWIT were initiated by a rapid decline in blood oxygen saturation and a subsequent cardiovascular hyperdynamic (HD) period characterized by temporary elevations in heart rates and arterial pressures in both groups. Subsequently, heart rate and systolic arterial pressure decreased until fWIT was reached. Pigs in the open-chest group displayed a more rapid transition to the HD phase after WLST, with peak heart rate and peak rate-pressure product occurring significantly earlier. Furthermore, the HD phase duration tended to be shorter and less intense (lower peak rate-pressure product) in the open-chest group than in the closed-chest group. Discussion: Progression from WLST to fWIT was more rapid, and the hemodynamic changes tended to be less pronounced in the open-chest group than in the closed-chest group. Our findings support clear differences between open- and closed-chest models of DCD. Therefore, recommendations for clinical DCD protocols based on findings in open-chest models must be interpreted with care.

Association between caseload volume and outcomes in left ventricular assist device implantations - a EUROMACS analysis.

AIMS: This EUROMACS study was conducted with the primary aim of investigating the association between a centre's annual caseload and postoperative outcomes among patients undergoing left ventricular assist device (LVAD) implantation. METHODS AND RESULTS: A total of 4802 patients identified between 2011 and 2020 from 35 participating centres were dichotomized based on the annual caseload of the treating centre at the time of device implant (≤30 vs. >30 LVAD implantations/year). The primary endpoint was 1-year survival. Secondary outcomes included overall survival analysis, device-related adverse events and readmissions. Cumulative follow-up was 10 003 patient-years, with a median follow-up of 1.54 years (interquartile range 0.52-3.15). Patients from higher volume centres more frequently presented in INTERMACS levels 1 and 2, suffered from right heart dysfunction and needed inotropic support. No difference was observed in adjusted 1-year survival. Adjusted overall survival probability was lower in higher volume centres (p = 0.002). In the subgroup analysis of HeartMate 3 devices only, higher volume centres were associated with decreased odds of 1-year survival (adjusted odds ratio 0.43, 95% confidence interval 0.20-0.97, p = 0.041). Similar findings were observed in the cumulative (i.e. learning curve) caseload analyses. CONCLUSION: In patients undergoing LVAD implantation, centre volume was not associated with 1-year survival, but was related to device-related adverse events. Patient profiles differed with respect to centre size. These findings underscore the necessity for ongoing quality improvement initiatives in all centres, regardless of their annual caseload. Efforts are needed to standardize patient selection and preconditioning to further improve patient outcome.

Surgical versus transcatheter repair for secondary mitral regurgitation: A propensity score-matched cohorts comparison.

OBJECTIVES: To compare the efficacy and clinical outcomes of transcatheter edge-to-edge mitral valve repair (TMVr) and surgical mitral valve repair (SMVr) among patients with secondary mitral regurgitation (SMR). METHODS: Consecutive patients with SMR treated using either TMVr (n = 199) or SMVr (n = 222) at 2 centers were included and retrospectively analyzed. To account for differences in patient demographic characteristics, 1:1 propensity score matching was performed. The primary endpoint was all-cause death within 2 years after the procedure. RESULTS: The study population consisted of 202 matched patients. At 2 years, all-cause mortality was 24.3% for TMVr and 23.0% for SMVr (hazard ratio, 0.97; 95% confidence interval, 0.55-1.71; P = .909). Severe heart failure symptoms at 2 years were less prevalent after SMVr (New York Heart Association functional class III or IV: 13.5% vs 29.5%; P = .032) than after TMVr. A higher proportion of the SMVr patients had SMR reduction to none or mild at discharge (90.8% vs 72.0%; P < .001) and 2 years (86.5% vs 59.6%; P < .001). Among patients who achieved none or mild MR at discharge, 7 patients (10.1%) in the SMVr group and 15 (34.9%) in the TMVr group had progression to moderate or greater MR at 2 years (P = .003). Left ventricular ejection fraction (LVEF) significantly improved (+10.1% ± 11.1%; P < .001) after SMVr (LVEF at 2 years: 45.7% ± 12.8%), whereas it remained unchanged (-1.3% ± 8.9%; P = .260) after TMVr (LVEF at 2 years: 34.0% ± 13.2%). CONCLUSIONS: In this propensity score-matched analysis, there was no significant difference in 2-year survival between TMVr and SMVr, despite greater and more durable SMR reduction, as well as LVEF improvement in the surgical group.

The 'beating-heart butterfly technique' for repair of basal post-infarction ventricle septum defect.

Ischaemic ventricular septal defect is a serious complication of acute myocardial infarction with poor outcome. We present the 'beating-heart butterfly' technique to close the ventricular septal defect with a double-layered pericardial patch sewn to the intact septum under beating-heart cardiopulmonary bypass in 4 highest-risk patients. This technique combined with a liberal postoperative mechanical circulatory support and open-chest treatment allowed excellent results with 12 months of survival in all patients.

Managing bottlenecks in the perioperative setting: Optimizing patient care and reducing costs.

Bottlenecks limit the maximum output of a system and indicate operational congestion points in process management. Bottlenecks also affect perioperative care and include dimensions such as infrastructure, architectural design and limitations, inefficient equipment and material supply chains, communication-related limitations on the flow of information, and patient- or staff-related factors. Improvement of workflow is, therefore, becoming a priority in most healthcare settings. We provide an overview of bottleneck management in the perioperative setting and introduce dimensions, including aligned strategic decision-making, tactical planning, and operational adjustments.

The impact of sex and gender on aortic events in patients with Marfan syndrome.

OBJECTIVES: The aim of this study was to explore sex and gender differences regarding aortic events in Marfan patients. METHODS: We analysed all data from our connective tissue disorder database. Only patients with Marfan syndrome were included. For analysis, patients were divided by sex. Female patients were further divided into 2 subgroups: with versus without children. Aortic events were defined as Stanford type A aortic dissection (TAAD) or type B aortic dissection (TBAD) or any aortic intervention. RESULTS: A population of 183 Marfan patients was analysed for the purpose of this study. One hundred four (57%) were male and 79 (43%) were female patients. Thirty-seven (47%) of the 79 female patients had at least 1 child. Male patients had a significantly higher probability of experiencing an aortic event (P = 0.015) compared to female patients. However, there was no increased probability for recurrent events in male patients compared to female patients (P = 0.063). Follow-up revealed no sex and gender differences in the occurrence of Stanford TAAD or TBAD between male and female patients (P = 0.324/P = 0.534). While 11% of women with children suffered from peripartum aortic events, 24% experienced Stanford TAAD unrelated to pregnancy. CONCLUSIONS: Male patients have a higher risk of aortic events than female patients. The majority of women were not aware of their Marfan syndrome diagnosis before conceiving. One out of 10 women suffered from peripartum Stanford TAAD or TBAD. Twice as many female patients with children suffered from aortic dissection unrelated to childbirth. There were no sex and gender differences affecting mortality in Marfan patients.

Initial experience with minimally invasive extracorporeal circulation in coronary artery bypass graft reoperations

AIMS OF THE STUDY: Minimally invasive extracorporeal circulation (MiECC) is an established alternative to conventional extracorporeal circulation (CECC) in coronary artery bypass graft surgery (CABG), but data on its use in cardiac reoperations are limited. We aimed to analyse perioperative morbidity and mortality in adult patients undergoing reoperations for isolated CABG using either CECC or MiECC circuits at our centre. METHODS AND RESULTS: In a single centre retrospective observational study of all adult patients undergoing cardiac reoperations for isolated CABG between 2004 and 2016, we identified 310 patients, and excluded those who received concomitant cardiac procedures (n = 205). Of the remaining 105 patients, 47 received isolated redo-CABG using MiECC, and 58 received CECC. Propensity score modelling was performed, and inversed probability treatment analysis was used between the treatment groups. Primary endpoint was 30-day all-cause mortality. Secondary endpoints included major adverse cardiac or cerebrovascular events or need for conversion to CECC. Groups were comparable, apart from a higher incidence of NYHA class III or higher in CECC group (33.5% vs 8.6%, p= 0.004). Shorter times for operation, cardiopulmonary bypass and aortic cross-clamp were observed in the MiECC group. The incidence of postoperative atrial fibrillation was significantly lower with MiECC (22.1%, p = 0.012). No significant difference was observed in all-cause 30-day mortality between the MiECC and CECC groups (6.8% vs. 8.3%, p = 0.81). CONCLUSION: We found no difference in overall mortality between CECC and MiECC in patients undergoing reoperation for isolated CABG. Furthermore, we found no indication of differences in most outcomes between extracorporeal circuit types. In the case of redo-CABG, MiECC could provide an alternative strategy.

Clinicopathological correlations in heart transplantation recipients complicated by death or re-transplantation.

Purpose: This study aimed to identify and correlate pathological findings with clinical outcomes in patients after orthotopic heart transplantation (OHT) who either died or underwent a re-transplantation. Methodology and study design: Single-center retrospective analysis of primary OHT patients who died or were re-transplanted between October 2012 and July 2021. Clinical data were matched with corresponding pathological findings from endomyocardial biopsies on antibody-mediated rejection, cellular rejection, and cardiac allograft vasculopathy. Re-assessment of available tissue samples was performed to investigate acute myocardial injury (AMI) as a distinct phenomenon. These were correlated with clinical outcomes, which included severe primary graft dysfunction. Patients were grouped according to the presence of AMI and compared. Results: We identified 47 patients with truncated outcomes after the first OHT. The median age was 59 years, 36 patients (76%) were male, 25 patients (53%) had a prior history of cardiac operation, and 21 patients (45%) were supported with a durable assist device before OHT. Of those, AMI was identified in 22 (47%) patients (AMI group), and 25 patients had no AMI (non-AMI group). Groups were comparable in baseline and perioperative data. Histopathological observations in AMI group included a non-significant higher incidence of antibody-mediated rejection Grade 1 or higher (pAMR ≥ 1) (32% vs. 12%, P = 0.154), and non-significant lower incidence of severe acute cellular rejection (ACR ≥ 2R) (32% vs. 40%, P = 0.762). Clinical observations in the AMI group found a significantly higher occurrence of severe primary graft dysfunction (68% vs. 20%, P = 0.001) and a highly significant shorter duration from transplantation to death or re-transplantation (42 days [IQR 26, 120] vs. 1,133 days [711-1,664], P < 0.0001). Those patients had a significantly higher occurrence of cardiac-related deaths (64% vs. 24%, P = 0.020). No difference was observed in other outcomes. Conclusion: In heart transplant recipients with a truncated postoperative course leading to either death or re-transplantation, AMI in endomyocardial biopsies was a common pathological phenomenon, which correlated with the clinical occurrence of severe primary graft dysfunction. Those patients had significantly shorter survival times and higher cardiac-related deaths. The presence of AMI suggests a truncated course after OHT.

Concomitant tricuspid valve repair in left ventricular assist device implantation may increase the risk for temporary right ventricular support but does not impact overall outcomes.

OBJECTIVES: Tricuspid valve repair in left ventricular assist device implantation continues to pose a challenge and may impact the occurrence of early and late right heart failure. We investigated the effects of concomitant tricuspid repair on clinical outcomes. METHODS: A retrospective, multicentre study enrolled adult patients who received continuous-flow left ventricular assist devices between 2005 and 2017 and compared those who received concomitant tricuspid valve repair to those who did not. Primary outcomes were early right heart failure necessitating temporary ventricular assist devices and right heart failure-related rehospitalizations requiring inotropic or diuretic treatment. RESULTS: Out of 526 patients who underwent left ventricular assist device implantation, 110 (21%) received a concomitant tricuspid valve repair. Those patients were sicker, and most had moderate or severe tricuspid regurgitation. A significantly higher incidence of temporary right ventricular assist devices was observed in the group with concomitant tricupid valve repair (18% vs. 11%, P = 0.049), with a significantly elevated risk for temporary right heart assist device (sHR 1.68, 95% CI 1.04-2.72; P = 0.037). After adjusting for confounders, no significant differences were found in the incidence of and risk for most clinical outcomes, including right heart failure-related rehospitalizations (P = 0.891) and death (P = 0.563). CONCLUSIONS: Concomitant tricuspid valve repair, when deemed necessary in left ventricular assist device implantation, may increase the risk of early right heart failure requiring a temporary right ventricular assist device but does not impact the incidence or risk of death or rehospitalizations due to late right heart failure.

Third-generation continuous-flow left ventricular assist devices: a comparative outcome analysis by device type.

AIMS: Continuous-flow left ventricular assist devices (CF-LVADs) have become a standard of care in end-stage heart failure. Limited data exist comparing outcomes of HeartMate3 (HM3) and HeartWare HVAD (HW). We aimed to compare midterm outcomes of these devices. METHODS AND RESULTS: Investigator-initiated retrospective-observational comparative analysis of all patients who underwent primary LVAD implantation of either HM3 or HW at our centre between January 2010 and December 2020. Data were derived from a prospective registry. Primary endpoints were all-cause mortality and heart transplantation. Secondary endpoints included device-related major adverse cardiac and cerebrovascular events, which included major bleeding, major neurological dysfunction (defined as persisting neurological impairment for ≥24 h), device-related major infection (excluding driveline infections), major device malfunctions leading to re-intervention or partial device exchange (pump failure, outflow-graft twist or failure, controller failure, battery failure, patient cable failure, but excluding pump thrombosis), and pump thrombosis. Further secondary endpoints included right heart failure, gastrointestinal bleeding, driveline infections, and surgical re-interventions. The secondary outcomes were analysed not only for the first event but also for recurrent events. The analysis included competing risks analysis and recurrent event regression analysis, with adjustment for confounders age, gender, body mass index (BMI), and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level. Out of 106 primary CF-LVAD implantations, 36 (34%) received HM3 and 70 (66%) received HW. Median follow-up was 1.48 years [interquartile range 0.67, 2.41]. HM3 was more often implanted in men (91.7% vs. 72.9%, P = 0.024); patients were older (median 61 years [54, 66.5] vs. 52.5 years [43, 60], P < 0.001), had a higher BMI (median 26.7 kg/m2 [23.4, 29.0] vs. 24.3 kg/m2 [20.7, 27.4], P = 0.013), had more comorbidities, and were more likely targeted for destination therapy (36.1% vs. 14.3%, P = 0.010). Death occurred in 33.3% of HM3 patients, compared with 22.9% of HW patients, P = 0.247 (probability of survival at 4 years, 54.7% vs. 74.1%, P = 0.296). After adjustment for confounders, we observed a significant six-fold risk increase in device malfunctions for HW [hazard ratio (HR) 6.49, 95% confidence interval (CI) [1.89, 22.32], P = 0.003], but no significant differences in pump thrombosis (P = 0.173) or overall survival (P = 0.801). CONCLUSIONS: Comparing midterm outcomes between HM3 and HW for LVAD support from a prospective registry, HW patients had a significantly higher risk of device malfunctions. No significant differences were evident between devices in overall survival and in respect to most outcomes.

Many steps can be taken to enhance recovery after thoracic surgery.

Our letter to the editor comments on issues raised in the May 14, 2020, article by Budacan et al. addressing the development of enhanced recovery after thoracic surgery. In the United Kingdom and Ireland, a nationwide survey identified issues. Here, we expand on the authors' findings.

Indoleamine-2,3-Dioxygenase as a Perioperative Marker of the Immune System.

Indoleamine-2,3-dioxygenase (IDO) is the "rate-limiting" enzyme in the kynurenine (Kyn) pathway of the tryptophan (Trp) catabolism. By its immune-modulatory effect, IDO initiates changes to the physiologically balanced immune state and plays a key role in the pathogenesis of various diseases, as well as in the perioperative setting during surgery. In autoimmune processes, highly malignant cancers such as glioblastoma or organ transplantation, IDO's involvement has been studied extensively. However, in severe systemic infections, as present in sepsis, it is not yet completely understood. Hereafter, in this narrative review, we present the current knowledge of IDO's implication on such complex immune-related processes. Moreover, we address the role of IDO as a predictive biomarker as well as a therapeutic target for immune-mediated diseases. Finally, we discuss IDO in the setting of surgical trauma-induced stress and highlight its promising use as a biomarker in the pre-operative setting for all disciplines involved in the decision-making process and treatment of patients undergoing surgery.

Hemolysis After Transcatheter Mitral Valve Implantation Resolved by Valve Retensioning.

Transcatheter mitral valve implantation is an emerging technology for the treatment of inoperable or high-risk patients with symptomatic severe mitral regurgitation. Known technical issues are obstruction of the left ventricular outflow tract, paravalvular leakage, and hemolysis. We report a case of valve retensioning successfully resolving paravalvular leakage and hemolysis. (Level of Difficulty: Intermediate.).