Characteristics and Outcomes of a Single-Centre Cohort of Adult Congenital Heart Disease Patients Referred for Heart Transplant.

BACKGROUND: Adult congenital heart disease (ACHD) services increasingly encounter heart failure (HF) in the ageing ACHD population. Optimal timing of referral for heart transplant (HTx) evaluation in this heterogeneous population is complex and ill-defined. We aim to outline the characteristics and outcomes of ACHD patients referred for HTx from a large Australian ACHD centre. METHOD: Retrospective review of ACHD patients referred for HTx from a primary ACHD centre (1992-2021). Database analysis of patient demographics, characteristics, wait-listing, and transplantation outcomes was performed. RESULTS: A total of 45 patients (mean age 37±9.9 years old; 69% male) were referred for HTx with a mean follow-up of 5.9±6.3 years. Of these, 22 of 45 (49%) were listed and transplanted, including one heart-lung transplant. The commonest diagnosis was dextro-transposition of the great arteries (13/45, 29%). Most patients, 33 of 45 (73.3%) had undergone at least one cardiac surgery in childhood. Indications for HTx referral included HF in 34 of 45 (75%), followed by pulmonary hypertension in 7 of 45 (11%). Median transplant wait-list time was 145 days (interquartile range, 112-256). Of the 23 patients not wait-listed, the reasons included clinical stability in 13 of 45 (29%), psychosocial factors in 2 of 45 (4.4%) and prohibitive surgical risk, including multiorgan dysfunction, in 8 of 45 (17.7%). Transplant was of a single organ in most, 21 of 22 (95.5%). Overall mortality was 5 of 22 (22.7%) in those after HTx, and 14 of 23 (60.9%) in those not listed (p=0.0156). CONCLUSIONS: Increasingly, ACHD patients demonstrate the need for advanced HF treatments. HTx decision-making is complex, and increased mortality is seen in those not wait-listed. Ultimately, the referral of ACHD patients for HTx is underpinned by local decision-making and experience, wait-list times and outcomes.

HeartMate 3 implantation with an emphasis on the biventricular configuration.

OBJECTIVES: Right ventricular failure following implantation of a durable left ventricular assist device (LVAD) is a major driver of mortality. Reported survival following biventricular (BiVAD) or total artificial heart (TAH) implantation remains substantially inferior to LVAD alone. We report our outcomes with LVAD and BiVAD HeartMate 3 (HM3). METHODS: Consecutive patients undergoing implantation of an HM3 LVAD between November 2014 and December 2021, at The Alfred, Australia were included in the study. Comparison was made between the BiVAD and LVAD alone groups. RESULTS: A total of 86 patients, 65 patients with LVAD alone and 21 in a BiVAD configuration underwent implantation. The median age of the LVAD and BiVAD groups was 56 years (Interquartile range 46-62) and 49 years (Interquartile range 37-55), respectively. By 4 years after implantation, 54% of LVAD patients and 43% of BiVAD patients had undergone cardiac transplantation. The incidence of stroke in the entire experience was 3.5% and pump thrombosis 5% (all in the RVAD). There were 14 deaths in the LVAD group and 1 in the BiVAD group. The actuarial survival for LVAD patients at 1 year was 85% and BiVAD patients at 1 year was 95%. CONCLUSIONS: The application of HM 3 BiVAD support in selected patients appears to offer a satisfactory solution to patients requiring biventricular support.

Impact of postoperative hyperlactatemia in orthotopic heart transplantation.

BACKGROUND: Hyperlactatemia (HL) is a common phenomenon after cardiac surgery which is related to tissue hypoperfusion and hypoxia and associated with poor outcomes. It is also often seen in the postoperative period after orthotopic heart transplantation (OHTx), but the association between HL and outcomes after OHTx is not well known. We evaluated the incidence and outcome of HL after OHTx. METHODS: This was a retrospective study of 209 patients who underwent OHTx between January 2011 and December 2020. Patients were classified into 3 groups according to their peak lactate levels within the first 72 h postoperatively: group 1, normal to mild hyperlactatemia (<5 mmol/L, n = 42); group 2, moderate hyperlactatemia (5-10 mmol/L, n = 110); and group 3, severe hyperlactatemia (>10 mmol/L, n = 57). The primary composite endpoint was all-cause mortality or postoperative initiation of veno-arterial extracorporeal membrane oxygenation (VA ECMO) within 30 days. Secondary endpoints included duration of mechanical ventilation, intensive care unit length of stay, and hospital length of stay. RESULTS: Patients with higher postoperative peak lactate levels were more commonly transplanted from left ventricular assist device support (33.3 % vs 50.9 % vs 64.9, p < 0.01) and had longer cardiopulmonary bypass time [127 min (109-148) vs 141 min (116-186) vs 153 min (127-182), p = 0.02]. Composite primary endpoint was met in 18 patients (8.6 %) and was significantly more common in patients with higher postoperative peak lactate levels (0.0 % vs 6.4 % vs 19.3 %, p < 0.01). CONCLUSIONS: Severe hyperlactatemia following orthotopic heart transplant was associated with an increased risk of post-transplant VA ECMO initiation and mortality at 30 days.

Effect of RVAD Cannulation Length on Right Ventricular Thrombosis Risk: An In Silico Investigation.

Left ventricular assist devices (LVADs) have been used off-label as long-term support of the right heart due to the lack of a clinically approved durable right VAD (RVAD). Whilst various techniques to reduce RVAD inflow cannula protrusion have been described, the implication of the protrusion length on right heart blood flow and subsequent risk of thrombosis remains poorly understood. This study investigates the influence of RVAD diaphragmatic cannulation length on right ventricular thrombosis risk using a patient-specific right ventricle in silico model validated with particle image velocimetry. Four cannulation lengths (5, 10, 15 and 25 mm) were evaluated in a one-way fluid-structure interaction simulation with boundary conditions generated from a lumped parameter model, simulating a biventricular supported condition. Simulation results demonstrated that the 25-mm cannulation length exhibited a lower thrombosis risk compared to 5-, 10- and 15-mm cannulation lengths due to improved flow energy distribution (25.2%, 24.4% and 17.8% increased), reduced stagnation volume (72%, 68% and 49% reduction), better washout rate (13.0%, 11.6% and 9.1% faster) and lower blood residence time (6% reduction). In the simulated scenario, our findings suggest that a longer RVAD diaphragmatic cannulation length may be beneficial in lowering thrombosis risk; however, further clinical studies are warranted.

Clinical and economic impact of ventricular assist device infections: a real-world claims analysis.

BACKGROUND: VAD therapy has revolutionized the treatment of end-stage heart failure, but infections remain an important complication. The objective of this study was to characterize the clinical and economic impacts of VAD-specific infections. METHODS: A retrospective analysis of a United States claims database identified members ≥ 18 years with a claim for a VAD implant procedure, at least 6 months of pre-implant baseline data, and 12 months of follow-up between 1 June 2016 and 31 December 2019. Cumulative incidence of infection was calculated. Infection and non-infection cohorts were compared regarding mortality, healthcare utilization, and total cost. Regression models were used to identify risk factors associated with infections and mortality. RESULTS: A total of 2,259 patients with a VAD implant were included, with 369 experiencing infection (12-month cumulative incidence 16.1%). Patients with infection were 2.1 times more likely to die (p < 0.001, 95% CI [1.5-2.9]). The mean 12-month total cost per US patient was $354,339 for the non-infection cohort and $397,546 for the infection cohort, a difference of $43,207 (p < 0.0001). CONCLUSIONS: VAD infections were associated with higher mortality, more healthcare utilization, and higher total cost. Strategies to minimize VAD-specific infections could lead to improved clinical and economic outcomes.

Hypothermic oxygenated perfusion (HOPE) safely and effectively extends acceptable donor heart preservation times: Results of the Australian and New Zealand trial.

BACKGROUND: Cold static storage preservation of donor hearts for periods longer than 4 hours increases the risk of primary graft dysfunction (PGD). The aim of the study was to determine if hypothermic oxygenated perfusion (HOPE) could safely prolong the preservation time of donor hearts. METHODS: We conducted a nonrandomized, single arm, multicenter investigation of the effect of HOPE using the XVIVO Heart Preservation System on donor hearts with a projected preservation time of 6 to 8 hours on 30-day recipient survival and allograft function post-transplant. Each center completed 1 or 2 short preservation time followed by long preservation time cases. PGD was classified as occurring in the first 24 hours after transplantation or secondary graft dysfunction (SGD) occurring at any time with a clearly defined cause. Trial survival was compared with a comparator group based on data from the International Society of Heart and Lung Transplantation (ISHLT) Registry. RESULTS: We performed heart transplants using 7 short and 29 long preservation time donor hearts placed on the HOPE system. The mean preservation time for the long preservation time cases was 414 minutes, the longest being 8 hours and 47 minutes. There was 100% survival at 30 days. One long preservation time recipient developed PGD, and 1 developed SGD. One short preservation time patient developed SGD. Thirty day survival was superior to the ISHLT comparator group despite substantially longer preservation times in the trial patients. CONCLUSIONS: HOPE provides effective preservation out to preservation times of nearly 9 hours allowing retrieval from remote geographic locations.

Getting out of the box: the future of the UK donation after circulatory determination of death heart programme.

Heart failure imposes a significant burden on all health care systems and has a 5-year mortality of 50%. Heart transplantation and ventricular assist device (VAD) implantation are the definitive therapies for end stage heart disease, although transplantation appears to offer superior long-term survival and quality of life over VAD implantation. Transplantation is limited by a shortage in donor hearts, resulting in considerable waiting list mortality. Donation after circulatory determination of death (DCD) offers a significant uplift in the number of donors for heart transplantation. The outcomes both from the UK and internationally have been exciting, with outcomes at least as good as conventional donation after brain death (DBD) transplantation. Currently, DCD hearts are reperfused using ex-situ machine perfusion (ESMP). Whilst ESMP has enabled the development of DCD transplantation, it comes at significant cost, with the per run cost of approximately GBP £90,000. In-situ perfusion of the heart, otherwise known as thoraco-abdominal normothermic regional perfusion (taNRP) is cheaper, but there are ethical concerns regarding the potential to restore cerebral perfusion in the donor. We must determine whether there is any cerebral circulation during in-situ perfusion of the heart to ensure that it does not invalidate the diagnosis of death and potentially violate the dead donor rule. Besides this, there is a need for a randomised controlled trial to definitively determine whether taNRP offers any clinical advantages over ex-situ machine perfusion. This viewpoint article explores these issues in more detail.

Candida causes recurrent vulvovaginal candidiasis by forming morphologically disparate biofilms on the human vaginal epithelium.

Background: Recurrent vulvovaginal candidiasis (RVVC) is a recalcitrant medical condition that affects many women of reproductive age. The importance of biofilm formation by Candida in RVVC has been recently questioned. This study aimed to elucidate the fundamental growth modes of Candida in the vagina of patients with RVVC or sporadic vulvovaginal candidiasis (VVC) and to assess their roles in the persistence of RVVC. Methods: Vaginal tissues were sampled from twelve patients clinically and microbiologically diagnosed as RVVC or VVC at a post-antifungal-treatment and asymptomatic period. High-resolution scanning electron microscopy, fluorescence in situ hybridization in combination with Candida-specific 18S rRNA probes and viable fungal burden were used to qualitatively and quantitatively evaluate Candida growth in the human vagina. The presence of Candida biofilm extracellular polymeric substances was examined using confocal laser scanning microscopy and biopsy sections pre-stained with Concanavalin A. Histopathological analysis was carried out on infected vaginal tissues stained with hematoxylin and eosin. Lastly, the susceptibility of epithelium-associated Candida biofilms to fluconazole at the peak serum concentration was evaluated. Results: Candida species grew on the vaginal epithelium of RVVC patients as morphologically disparate biofilms including monolayers, microcolonies, and macro-colonies, in addition to sporadic adherent cells. Candida biofilm growth on the vaginal epithelium was associated with mild lymphocytic infiltration of the vaginal mucosa. These epithelium-based Candida biofilms presented an important characteristic contributing to the persistence of RVVC that is the high tolerance to fluconazole. Conclusions: In summary, our study provides direct evidence to support the presence of Candida biofilms in RVVC and an important role of biofilm formation in disease persistence.

Impact of early pericardial fluid chymase activation after cardiac surgery.

Introduction: Chymase is a highly destructive serine protease rapidly neutralized in the circulation by protease inhibitors. Here we test whether pericardial fluid (PCF) chymase activation and other inflammatory biomarkers determine intensive care unit length of stay, and explore mechanisms of chymase delivery by extracellular vesicles to the heart. Methods: PCF was collected from adult patients (17 on-pump; 13 off-pump) 4 h after cardiac surgery. Extracellular vesicles (EVs) containing chymase were injected into Sprague-Dawley rats to test for their ability to deliver chymase to the heart. Results: The mean intensive care unit (ICU) stay and mean total length of stay was 2.17 ± 3.8 days and 6.41 ± 1.3 days respectively. Chymase activity and 32 inflammatory markers did not differ in on-pump vs. off-pump cardiac surgery. Society of Thoracic Surgeons Predicted Risk of Morbidity and Mortality Score (STS-PROM), 4-hour post-surgery PCF chymase activity and C-X-C motif chemokine ligand 6 (CXCL6) were all independent predictors of ICU and total hospital length of stay by univariate analysis. Mass spectrometry of baseline PCF shows the presence of serine protease inhibitors that neutralize chymase activity. The compartmentalization of chymase within and on the surface of PCF EVs was visualized by immunogold labeling and transmission electron microscopy. A chymase inhibitor prevented EV chymase activity (0.28 fmol/mg/min vs. 14.14 fmol/mg/min). Intravenous injection of PCF EVs obtained 24 h after surgery into Sprague Dawley rats shows diffuse human chymase uptake in the heart with extensive cardiomyocyte damage 4 h after injection. Discussion: Early postoperative PCF chymase activation underscores its potential role in cardiac damage soon after on- or off-pump cardiac surgery. In addition, chymase in extracellular vesicles provides a protected delivery mechanism from neutralization by circulating serine protease inhibitors.

Anti-infective characteristics of a new Carbothane ventricular assist device driveline.

Objectives: Driveline infections are a major complication of ventricular assist device (VAD) therapy. A newly introduced Carbothane driveline has preliminarily demonstrated anti-infective potential against driveline infections. This study aimed to comprehensively assess the anti-biofilm capability of the Carbothane driveline and explore its physicochemical characteristics. Methods: We assessed the Carbothane driveline against biofilm formation of leading microorganisms causing VAD driveline infections, including Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa and Candida albicans, using novel in vitro biofilm assays mimicking different infection micro-environments. The importance of physicochemical properties of the Carbothane driveline in microorganism-device interactions were analyzed, particularly focusing on the surface chemistry. The role of micro-gaps in driveline tunnels on biofilm migration was also examined. Results: All organisms were able to attach to the smooth and velour sections of the Carbothane driveline. Early microbial adherence, at least for S. aureus and S. epidermidis, did not proceed to the formation of mature biofilms in a drip-flow biofilm reactor mimicking the driveline exit site environment. The presence of a driveline tunnel however, promoted staphylococcal biofilm formation on the Carbothane driveline. Physicochemical analysis of the Carbothane driveline revealed surface characteristics that may have contributed to its anti-biofilm activity, such as the aliphatic nature of its surface. The presence of micro-gaps in the tunnel facilitated biofilm migration of the studied bacterial species. Conclusion: This study provides experimental evidence to support the anti-biofilm activity of the Carbothane driveline and uncovered specific physicochemical features that may explain its ability to inhibit biofilm formation.

Donor heart ischemic time can be extended beyond 9 hours using hypothermic machine perfusion in sheep.

BACKGROUND: The global shortage of donor hearts available for transplantation is a major problem for the treatment of end-stage heart failure. The ischemic time for donor hearts using traditional preservation by standard static cold storage (SCS) is limited to approximately 4 hours, beyond which the risk for primary graft dysfunction (PGD) significantly increases. Hypothermic machine perfusion (HMP) of donor hearts has been proposed to safely extend ischemic time without increasing the risk of PGD. METHODS: Using our sheep model of 24 hours brain death (BD) followed by orthotopic heart transplantation (HTx), we examined post-transplant outcomes in recipients following donor heart preservation by HMP for 8 hours, compared to donor heart preservation for 2 hours by either SCS or HMP. RESULTS: Following HTx, all HMP recipients (both 2 hours and 8 hours groups) survived to the end of the study (6 hours after transplantation and successful weaning from cardiopulmonary bypass), required less vasoactive support for hemodynamic stability, and exhibited superior metabolic, fluid status and inflammatory profiles compared to SCS recipients. Contractile function and cardiac damage (troponin I release and histological assessment) was comparable between groups. CONCLUSIONS: Overall, compared to current clinical SCS, recipient outcomes following transplantation are not adversely impacted by extending HMP to 8 hours. These results have important implications for clinical transplantation where longer ischemic times may be required (e.g., complex surgical cases, transport across long distances). Additionally, HMP may allow safe preservation of "marginal" donor hearts that are more susceptible to myocardial injury and facilitate increased utilization of these hearts for transplantation.

Impact of Concomitant Mitral Regurgitation on the Hemodynamic Indicators of Aortic Stenosis.

Background In patients with aortic stenosis (AS), the presence of mitral regurgitation (MR) can lead to underestimation of AS severity and worse clinical outcomes. The objective of this study was to characterize the magnitude of the effects of concomitant MR on hemodynamic indicators of AS severity using clinical data and a computational cardiovascular simulation. Methods and Results Echocardiographic data from 1427 patients with severe AS were used to inform a computational cardiovascular system model, and varying degrees of MR and AS were simulated. Hemodynamic data, including left ventricular and aortic pressure waveforms, were generated for all simulations. Simulated reduction in mean transaortic pressure gradient (MPG) associated with MR was then used to calculate the adjusted MPG in the clinical cohort. MR was present in 861 (60%) patients. Compared with patients without MR, patients with MR had a lower aortic-valve area (0.83±0.2 cm2 versus 0.75±0.2; P<0.001) and were more likely to have a low-gradient pattern (MPG <40 mm Hg) (45% versus 54%; P<0.001). Simulations showed that the presence of concomitant mild, moderate, and severe MR with AS was accompanied by a mean reduction in MPG of 10%, 29%, and 40%, respectively. For patients with MR, their calculated adjusted MPG was on average 24% higher than their MPG (52±22 versus 42±16 mm Hg). Of the 467 patients with low-gradient AS and MR, 240 (51%) would reclassify as high gradient based on their adjusted MPG. Conclusions Concomitant MR results in lower MPG and reduced forward flow compared with isolated AS. Careful quantitation of MR should be factored into the assessment of AS severity to mitigate for potential underestimation.

Heart-Lung Transplantation: Technical Modifications to Simplify the Procedure.

Heart-lung transplantation is a mature therapy but has perioperative complications, such as phrenic nerve dysfunction and mediastinal bleeding. We report our technical modifications to simplify the procedure.

Extracorporeal Membrane Oxygenation as a Bridge to Surgical Repair of Postinfarct Ventricular Septal Defect.

Postinfarct ventricular septal defect (PIVSD) is associated with high mortality and the management of these patients has been a challenge with little improvement in outcomes. We commenced a protocol of veno-arterial extracorporeal membrane oxygenation (VA ECMO) for those patients who present in cardiogenic shock with the aim to improve end-organ function before definitive surgical repair to reduce postoperative mortality. This study reviewed the results of this strategy. This was a single-center, retrospective review of all patients who were admitted to our institution with PIVSD in cardiogenic shock from September 2015 to November 2019. Clinical and investigative data were evaluated. Eight patients were referred with PIVSD during this period in cardiogenic shock. One patient had an anterior PIVSD and the other seven had inferior PIVSD. Six patients underwent surgical repair at a median (interquartile range, IQR) of 7 (5-8) days after initiation of VA ECMO. Two patients did not undergo surgical repair. Five patients survived after surgery and one patient died postoperatively due to multiorgan failure. Preoperative use of VA ECMO is a feasible strategy for PIVSD and may improve the results of repair.

In silico Prediction of Thrombosis Risk in a Ventricular Assist Device Supported Right Heart: The Impact of Cannulation Site.

Right ventricular assist device (RVAD) associated thrombosis is a serious complication that may arise due to unfavorable blood flow dynamics (blood stasis) caused by RVAD cannula protrusion within the chambers. This study aims to investigate the thrombosis risk of cannulation via the right atrium (RA) and right ventricle (RV) (diaphragmatic) under full RVAD support using computational fluid dynamics. A HeartWare HVAD inflow cannula was virtually implanted in either the RA or RV of a rigid-walled right heart geometry (including RA, RV, superior, and inferior vena cava) extracted from computed tomography data of a biventricular support patient. Transient simulations, validated with particle image velocimetry, were performed with constant inflow. Thrombosis risk was predicted by analyzing the time-averaged blood velocity, blood stagnation volume, washout rate, and blood residence time (BRT). Results showed that RA cannulation disturbed the physiological swirling flow structure which can be found in an uncannulated RA. This led to a large low-velocity recirculation flow in the RV, increasing the thrombosis risk. Contrarily, RV diaphragmatic cannulation showed better preservation of swirling flow in the RA and flow ejection into the RV. Consequently, RV diaphragmatic cannulation exhibited a better washout rate (99% vs. 57% of old blood was replaced in 12 s), lower blood stagnation volume (0.13 ml vs. 32.85 ml), and BRT (4.2 s vs. 7.1 s) than the RA cannulation in this simulated non-pulsatile case. Our findings suggest that RV diaphragmatic cannulation had a lower thrombosis risk and might be more favorable in a full RVAD-supported setting.

Survival and left ventricular dysfunction post lung transplantation for pulmonary arterial hypertension.

PURPOSE: Bilateral lung transplantation for end-stage pulmonary arterial hypertension (PAH) is traditionally associated with higher early post-transplant mortality when compared with other indications. Changes in perioperative management, including the growing use of perioperative extracorporeal membrane oxygenation (ECMO) and an increased awareness of postoperative left ventricular dysfunction (LVD), have resulted in outcomes that are uncertain. MATERIALS AND METHODS: We conducted a single-center, retrospective observational study at a lung transplantation center in Melbourne, Australia, from 2006 to 2019. ECMO use was categorized as preoperative, prophylactic, or rescue. Postoperative LVD was defined as a reduction in left ventricular function on echocardiography or using strict clinical criteria. RESULTS: 50 patients underwent lung transplantation for PAH. 12-month survival was 48/50 (96%). ECMO was used in 26 (52%) patients, and the use of prophylactic VA-ECMO increased over the study period. Postoperative LVD was diagnosed in 21 (42%) patients. 12-month survival and left ventricular function was no different between LVD and non-LVD groups. CONCLUSIONS: This study showed that high survival rates can be achieved following lung transplantation for PAH. We found that ECMO utilization was common, and indications have changed over time. LVD was common but did not impact 12-month survival.

In vivo evaluation of skin integration with ventricular assist device drivelines.

BACKGROUND: Ventricular assist device (VAD) driveline exit site infection is a common complication. 3D scaffolds manufactured with highly homogeneous pores via melt electro-writing (MEW) may generate an improved skin-driveline interface which permits cellular in-growth and creates a barrier to prevent bacterial migration along the driveline tissue tunnel. This study investigated skin integration on segments of Heartmate 3 driveline: smooth polyurethane, velour, and on a custom MEW scaffold in a small animal model. METHODS: Drivelines with surfaces consisting of smooth polyurethane, velour bonded to smooth polyurethane, and smooth polyurethane with a MEW scaffold sleeve were implanted percutaneously in the dorsum of 42 rats. Each rat was implanted with 2 pieces of driveline of 2 cm in length. Skin integration was assessed after 7 and 14 days. RESULTS: Macroscopically, velour and MEW scaffold surfaces were anchored at the driveline-skin interface while smooth polyurethane samples were not attached. The histology analyses showed epidermal migration throughout the thickness of the velour and MEW scaffold groups. Evident tissue growth around single MEW scaffold fibers resulted in full coverage of the pores, while areas of compacted fibers were apparent in the velour group. Tissue ingrowth was significantly higher in the MEW group compared to the velour group after 7 (p < 0.0001) and 14 days (p < 0.0001). Marsupialization was observed in the smooth polyurethane samples. Mechanical pull-out forces were similar between velour and MEW scaffold groups at 7 and 14 days (p > 0.05). CONCLUSIONS: Velour and MEW scaffolds promoted epidermal integration while smooth polyurethane drivelines did not. Fine control of MEW scaffold structure production resulted in full cellular coverage and may reduce driveline infection.