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OBJECTIVES: This study aimed to determine the safety and efficacy of combined low-dose everolimus and low-dose tacrolimus compared with standard-dose tacrolimus in attenuating left ventricular hypertrophy (LVH) after orthotopic heart transplantation (OHT). BACKGROUND: Calcineurin inhibitors (CNIs) such as tactrolimus are important in preventing cardiac allograft rejection and reducing mortality after OHT. However CNIs are causatively linked to the development of LVH, and are associated with nephrotoxicity and vasculopathy. CNI-sparing agents such as everolimus have been hypothesized to inhibit adverse effects of CNIs. METHODS: In this prospective, randomized, open-label study, OHT recipients were randomized at 12 weeks after OHT to a combination of low-dose everolimus and tacrolimus (the RADTAC group) or standard-dose tacrolimus (the TAC group), with both groups coadministered mycophenolate and prednisolone. The primary endpoint was LVH indexed as the change in left ventricular mass (DeltaLVM) by cardiovascular magnetic resonance (CMR) imaging from 12 to 52 weeks. Secondary endpoints included CMR-based myocardial performance, T1 fibrosis mapping, blood pressure, and renal function. Safety endpoints included episodes of allograft rejection and infection. RESULTS: Forty stable OHT recipients were randomized. Recipients in the RADTAC group had significantly lower tacrolimus levels compared with the TAC group (6.5 +/- 3.5 mug/l vs. 8.6 +/- 2.8 mug/l; p = 0.02). The mean everolimus level in the RADTAC group was 4.2 +/- 1.7 mug/l. A significant reduction in LVM was observed in the RADTAC group compared with an increase in LVM in the TAC group (DeltaLVM = -13.0 +/- 16.8 g vs. 2.1 +/- 8.4 g; p < 0.001). Significant differences were also noted in secondary endpoints measuring function and fibrosis (Delta circumferential strain = -2.9 +/- 2.8 vs. 2.1 +/- 2.3; p < 0.001; DeltaT1 mapping values = -32.7 +/- 51.3 ms vs. 26.3 +/- 90.4 ms; p = 0.003). No significant differences were observed in blood pressure (Delta mean arterial pressure = 4.2 +/- 18.8 mm Hg vs. 2.8 +/- 13.8 mm Hg; p = 0.77), renal function (Delta creatinine = 3.1 +/- 19.9 mumol/l vs. 9 +/- 21.8 mumol/l; p = 0.31), frequency of rejection episodes (p = 0.69), or frequency of infections (p = 0.67) between groups. CONCLUSIONS: The combination of low-dose everolimus and tacrolimus compared with standard-dose tacrolimus safely attenuates LVH in the first year after cardiac transplantation with an observed reduction in CMR-measured fibrosis and an improvement in myocardial strain.

Background Thirst is a common and troublesome symptom of patients with chronic heart failure (CHF). To date, there are no interventions to help alleviate thirst in this cohort. Chewing gum is a novel intervention, which has been tested in people undergoing haemodialysis, also prescribed with a fluid restricted therapy. The aim of this study was to determine the effect of chewing gum on the level of thirst in the short-term (average of 24 hours each day for 4 days) and in the longer-term (Days 7, 14 and 28) individuals with CHF. Methods Seventy-one (71) individuals with CHF on oral loop diuretics were randomised to chewing gum (n=36) or control (n=35) for 2 weeks. Both groups were assessed for their level of thirst at Days 1–4, 7, 14 and 28. Results Significant improvements in the level of thirst of those who received chewing gum compared to the control group at Day 4 (p=0.04) and Day 14 (p=0.02) were observed. Conclusion Chewing gum provided relief from thirst in the short-term and in the longer term. This trial provides important information to inform future clinical trials on ways to relieve thirst.

Background Transplantation of hearts retrieved from donation after circulatory death (DCD) donors is an evolving clinical practice. Objectives The purpose of this study is to provide an update on the authors’ Australian clinical program and discuss lessons learned since performing the world’s first series of distantly procured DCD heart transplants. Methods The authors report their experience of 23 DCD heart transplants from 45 DCD donor referrals since 2014. Donor details were collected using electronic donor records (Donate Life, Australia) and all recipient details were collected from clinical notes and electronic databases at St. Vincent’s Hospital. Results Hearts were retrieved from 33 of 45 DCD donors. A total of 12 donors did not progress to circulatory arrest within the pre-specified timeframe. Eight hearts failed to meet viability criteria during normothermic machine perfusion, and 2 hearts were declined due to machine malfunction. A total of 23 hearts were transplanted between July 2014 and April 2018. All recipients had successful implantation, with mechanical circulatory support utilized in 9 cases. One case requiring extracorporeal membrane oxygenation subsequently died on the sixth post-operative day, representing a mortality of 4.4% over 4 years with a total follow-up period of 15,500 days for the entire cohort. All surviving recipients had normal cardiac function on echocardiogram and no evidence of acute rejection on discharge. All surviving patients remain in New York Heart Association functional class I with normal biventricular function. Conclusions DCD heart transplant outcomes are excellent. Despite a higher requirement for mechanical circulatory support for delayed graft function, primarily in recipients with ventricular assist device support, overall survival and rejection episodes are comparable to outcomes from contemporary brain-dead donors.

BACKGROUND Despite advances in device technology and treatment strategies, infection remains a major cause of adverse events (AEs) in mechanical circulatory support (MCS) patients. To characterize the epidemiology of MCS infection, we examined the type, location, and timing of infection in the International Society for Heart and Lung Transplantation Registry (ISHLT) for Mechanically Assisted Circulatory Support (IMACS) over 3 years, 2013 to 2015. METHODS Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) definitions were used to categorize AE infections occurring in MCS patients within IMACS. The IMACS infection variables were mapped to ISHLT definitions for infection where feasible. Three categories of MCS infection were defined as ventricular assist device (VAD) specific, VAD related, and non-VAD. RESULTS There were 10,171 patients enrolled from January 2013 through December 2015. Infection was the most common AE, with 3,788 patients (37%) experiencing ≥ 1 infection, and 6,758 AE infections reported overall. Non-VAD infection was the largest category, 4,501: 34.0% pneumonias, 30.6% non-VAD-related bloodstream infections (BSIs), 24.15% urinary tract infections (UTIs), and 10.2% gastrointestinal infections. VAD-specific infection was the second largest category, 1,756: 82.9% driveline, 12.8% pocket, and 4.3% pump/or cannula infections. VAD-related infection was the smallest category, 501: 47.5% BSIs, 47.5% mediastinitis, and 5.0% mediastinitis/pocket infections. All 3 categories were more frequently reported ≤ 3 months after implant. CONCLUSIONS Non-VAD infection, including pneumonia, BSI, UTI, and gastrointestinal infection, was the leading category of infection in MCS patients and the most frequently reported ≤ 3 months after implant. These results provide evidence to support resourcing and strengthening infection prevention strategy early after implantation in MCS.

Objectives This is a systematic review summarizing the procedural characteristics and outcomes of ventricular assist device (VAD)–related ventricular tachycardia (VT) ablation. Background Drug-refractory VT refractory commonly develops post-VAD implantation. Procedural and outcome data come from small series or case reports. Methods An electronic search was performed using major databases. Primary outcomes were VT recurrence, mortality, and cardiac transplantation. Secondary endpoints were acute procedural success and procedural complications. Results Eighteen studies were included, with a total of 110 patients (mean age 59.6 ± 11 years, 89% men; VT storm 34%). Scar-related re-entry was the predominant mechanism of VT (90.3%) and cannula-related VT in 19.3% cases. Electroanatomical mapping interference occurred in 1.8% of cases; there were no reports of catheter entrapment. Noninducibility of clinical VT was achieved in 77.9%; procedural complications occurred in 9.4%. At a mean follow-up of 263.5 ± 267.0 days, VT recurred in 43.6%, 23.4% underwent cardiac transplant, and 48.1% died. There were no procedural-related deaths and no death was directly related to ventricular arrhythmia. In follow-up, there was a significant reduction in implantable cardioverter-defibrillator therapies or shocks (57.1% vs. 23.8%). Ablation allowed VT storm termination in 90% of patients. Conclusions VAD-related VT is predominantly related to pre-existing intrinsic myocardial scar rather than inflow cannula site insertion. Catheter ablation is a reasonable treatment strategy, albeit with expectedly high rate of recurrence, transplantation, and mortality related to severe underlying disease.

Purpose Hemolysis is an important complication of ventricular assist device (VAD) therapy. Several studies have postulated that chronic hemolysis may be a cause of adverse outcomes in patients with VADs, but consistent definitions and clinical outcome data are lacking. Methods We conducted a single-center retrospective cohort study examining survival to transplantation in patients who underwent VAD implantation from 2010-2020. Baseline demographics, renal function, echocardiographic, and cardiac catheterization data for the first 12 months of VAD therapy or until transplantation were collected. Additionally, all available lactate dehydrogenase (LDH) values were collected over this time frame and means were calculated for each patient. Results VADs were implanted in 166 patients, 19% female and 87% left-sided devices. Patients with mean LDH above the upper limit of normal for our laboratory's LDH assay of 440 units/liter (U/L) were more likely to die prior to transplantation compared to those with mean LDH Conclusion Mean LDH above the normal range was an independent and significant predictor of mortality in patients with VADs awaiting transplantation at our center over the last decade. While concomitant severe liver or RV dysfunction can raise LDH, chronic hemolysis is an important potential etiology for our observations. Further work is needed to define chronic hemolysis and its impact on outcomes in patients with VADs.

Purpose Extracorporeal membrane oxygenation (ECMO) is a life-saving therapy providing hemodynamic support to patients with advanced cardiorespiratory compromise. Following orthotopic heart transplantation (HTX), primary graft failure (PGF), especially wherein there is significant right ventricular dysfunction, can necessitate such intensive support to bridge to recovery or additional therapy. Marginal donors are used to increase the donor pool given the excess of candidates in most jurisdictions. Methods We conducted a single-center retrospective cohort study examining HTX from donation after brain death (DBD) donors that required post-operative ECMO for PGF from January 2008 - September 2020. Donor and recipient information were collected including demographics, renal function, echocardiographic measurements, biopsy data, and outcome measures. Marginal donor hearts were identified according to validated criteria including use of donor triiodothyronine (T3), donor left ventricular ejection fraction 60 years old, and donor ischemic time >6 hours or >4 hours if donor age >40 years old. Results Overall, 376 DBD HTX were performed, of which 126 involved marginal donor hearts (33.3%). ECMO was required in 81 (21.4%) of these patients, 42 (51.9%) of which involved marginal donor hearts. Thus, ECMO rates were 15.5% and 33.3% in non-marginal and marginal donor hearts, respectively. Overall, ECMO was successfully weaned in 75 (92.6%) and 62 (76.5%) survived their index HTX admission. Among patients who received non-marginal organs, 36 (92.3%) had ECMO weaned and 31 (79.5%) survived their index HTX admission versus 39 (92.9%) and 31 (73.8%) for these endpoints respectively among patients receiving marginal organs. Conclusion Our center's experience indicates that ECMO can provide satisfactory outcomes in HTX patients requiring advanced hemodynamic support post-operatively for PGF. Marginal donor hearts were more likely to require ECMO support post-operatively but had comparable and acceptable rates of index-admission survival compared to non-marginal cases. Further work is needed to evaluate outcome differences as efforts are made to expand the donor pool around the world.

Up to one-third of COVID-19 patients admitted to intensive care develop an acute cardiomyopathy, which may represent myocarditis or stress cardiomyopathy. Further, while mortality in older patients with COVID-19 appears related to multi-organ failure complicating acute respiratory distress syndrome (ARDS), the cause of death in younger patients may be related to acute heart failure. Cardiac involvement needs to be considered early on in critically ill COVID-19 patients, and even after the acute respiratory phase is passing. This Statement presents a screening algorithm to better identify COVID-19 patients at risk for severe heart failure and circulatory collapse, while balancing the need to protect health care workers and preserve personal protective equipment (PPE). The significance of serum troponin levels and the role of telemetry and targeted transthoracic echocardiography (TTE) in patient investigation and management are addressed, as are fundamental considerations in the management of acute heart failure in COVID-19 patients.

Purpose Left ventricular assist device (VAD) implantation via thoracotomy is a safe operation with potential advantages compared to conventional sternotomy. One proposed advantage is improved inflow cannula (IFC) positioning due to better visualisation. We investigated the difference in IFC angles for patients with HVADs implanted via these techniques and compared post-operative as well as long term outcomes. Methods 42 patients were retrospectively selected from our VAD database. 28 in the sternotomy group and 14 in the thoracotomy group. We included all thoracotomy implants performed at our centre and consecutive sternotomy implants from 2015-2019. Inclusion required a minimum support time of 30 days. Patients with concomitant procedures were excluded. The first post-operative CT chest scan was used to measure the angle between the IFC and mitral valve in axial and coronal planes. Results There was no significant difference in gender, INTERMACS score, BMI or age between the two groups. Median support time was not significantly different between the thoracotomy and sternotomy groups (328 vs 360 days, p=0.9). Median cardiopulmonary bypass (CPB) time was higher in the thoracotomy group (104 vs 78 minutes, p Conclusion In our sample size of 42 patients, the thoracotomy group had a slightly longer CPB time, however, there was no difference in IFC angle, pump thrombosis, GI bleeding, stroke or ICU length of stay. In saying this, there may be other benefits to the thoracotomy approach such as facilitating easier sternal entry upon transplantation.

Purpose Renal function following ventricular assist device (VAD) implantation is a key determinant of survival. The purpose of our study was to investigate whether the development of acute kidney injury (AKI) prior to, or following, VAD implantation influenced survival to transplant. We also sought to determine if the use of extra-corporeal membrane oxygenation (ECMO) or intra-aortic balloon pump (IABP) influenced AKI pre or post-VAD. Methods We undertook a single-centre retrospective cohort study examining outcomes in patients who underwent VAD implantation between 2010 and 2020. AKI was defined as per the KDIGO guidelines. The primary outcome was survival to transplant. Results 61% (96/158) of patients experienced pre-VAD AKI which predicted an increased risk of mortality (OR 2.32, p=0.032, CI 1.07 - 5.04). The incidence of post-VAD AKI was 54% (89/165) which was similarly associated with an increased risk of mortality (OR 2.49, p=0.012, CI 1.21 - 5.13). 67% (64/96) of patients who experienced pre-VAD AKI had post-VAD AKI. Patients who had both pre and post-VAD AKI had a significantly increased mortality prior to transplant with an OR of 3.5 (P=0.01, CI 1.3 - 9.41). Patients with pre-VAD AKI were more likely to require ECMO prior to VAD implantation (OR 2.94) however no difference was observed for IABP use. The use of ECMO or IABP prior to VAD implantation did not influence post-VAD AKI. Conclusion Acute kidney injury both pre and post-VAD implantation reduced likelihood of survival to transplant. Patients with AKI prior to VAD insertion were more likely to require ECMO, however the use of ECMO or IABP pre-VAD insertion did not appear to influence post-VAD AKI.

Background Left ventricular assist device (LVAD) support triggers adaptations within failing hearts. The HeartWare (HeartWare International, Inc., Framingham, MA) LVAD exhibits different flow profiles and afterload dependence compared with previous-generation devices, which may alter remodelling patterns. We sought to characterize myocardial adaptation to third-generation centrifugal-flow LVADs at a functional, hemodynamic, and structural level in addition to profiling transcriptomal changes using next-generation sequencing platforms. Methods We studied 37 patients supported with the HeartWare device with paired measurements of invasive hemodynamics, serial longitudinal left ventricular (LV) and right ventricular (RV) 3-dimensional echocardiography, and N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) measurements. Paired samples for comparison of histologic myocardial cellular size and transcriptomal profiling were performed on specimens taken at pump implant and transplantation. Results The mean support duration was 280 ± 163 days. Mechanical unloading after HeartWare support resulted in reduced filling pressures (mean pulmonary capillary wedge pressure 27.1 ± 6.6 to 14.8 ± 5.1 mm Hg, p 2 ( p = 0.02). LV and RV ejection fractions improved significantly (24% ± 8% to 35% ± 9% [ p p Conclusions Reverse remodelling is evident at multiple levels with chronic HeartWare support in the absence of changes in the microRNA transcriptome. Successful myocardial unloading is associated with a decrease in wall stress, regression of cardiomyocyte hypertrophy, and an improvement in LV and RV ejection fractions.

Purpose Aortic valve (AV) opening in patients supported with cfLVADS may be a marker of improved myocardial contractility. We aimed to study if status of aortic valve opening is influenced by right ventricular function, preload and afterload both at rest and exercise with pump speed titration. Methods Patients implanted with an isolated centrifugal cfLVAD undergoing routine right heart catheterisation were recruited. Mean arterial pressure (MAP), mean pulmonary capillary wedge pressure (PCWP) and pulmonary artery pressures were recorded. The pulmonary artery pressure index (PAPI) derived from formula was used as a surrogate for right ventricular function. Aortic valve status was determined by transthoracic echocardiography. Patients then performed graded exercise with supine bicycle ergometer until exhaustion (mean workload 40W) at both baseline and maximum pump speed with all measurements repeated. Patients were divided into two groups: closed or open AV. Results Thirteen patients were studied, mean age 37.4+/-7.4 yrs. Median NYHA class at time of study was II. Median pump speed at rest was 2600rpm (range 2500-2800). Echo derived baseline left ventricular ejection fraction was similar between both groups, closed AV valve 25+/-7.7, open 24.2+/-8.0%, p=0.86. At rest, there was no significant difference between closed AV and open AV for MAP 82.7+/-6.0 vs 85.2 +/-6.0mmHG, p=0.60, PCWP 14.7+/-0.2 vs 16.8+/-6.0mmHg, p=0.46 and PAPI 2.4+/-0.8 vs 2.9+/-0.9, p=0.33. Similarly, no significant difference was noted in these measures at maximum exercise and at maximum pump speed (median 2925rpm, range 2800-3210). Conclusion Aortic valve opening in patients supported by cfLVADs is not significantly influenced by afterload or preload at both rest and exercise. The contribution of intrinsic myocardial contractility derived by load independent methods on aortic valve opening is warranted.

Purpose Mechanical circulatory support (MCS) including left ventricular assist devices (LVADs) are increasingly important in managing patients with end-stage heart failure. Current generation LVADs, such as the HeartWare HVAD operate on a continuous flow basis. Many authors have identified the lack of physiological pulsatility as a limitation in these devices. We sought to test the feasibility of implementing physiological pulsatility using sino-atrial node (SAN) electrograms. Methods Three different rabbits had SAN tissue extracted, placed in a tissue bath and superfused with Krebs-Ringer solution. An extracellular fine metal electrode was placed into the tissue preparation for activity capture. The rate of spontaneous SAN activity was modulated by changing the temperature of the superfusing solution. Electrical activity was captured and identified using a data acquisition system and custom-made software. This was used to trigger a stepwise speed change in an HVAD running in a mock circulation loop. Signal capture was tested in three heart rate ranges (>120, 60-80 and ∼60 beats per minute). Results Unipolar electrogram signals were successfully recorded for all tissue extracts. To simulate physiological settings, we implemented a 100 ms delay between capture and effect, as well as a speed change duration of 30% per cycle (obtained from the beat-to-beat variation). HVAD motor speed was successfully increased from 2500 RPM to 2800 RPM in synchronicity with the firing of the SAN. Similarly, we were also able to achieve a reduction of speed from 2500 RPM to 2000 RPM in synchronicity with the firing of the SAN. Conclusion We were able to successfully capture electrical activity from the SAN for the purpose of introducing physiological pulsatility in all three of our rabbit experiments. This has the potential to change fundamental MCS flow hemodynamics.

Purpose LVAD implantation is often utilised as a bridge to transplantation or candidacy in those with pulmonary hypertension secondary to left heart disease (PHLHD). Pulmonary hypertension portends poorer outcomes post-transplant. We compared pre and post implantation haemodynamic response and outcomes in patients who normalise transpulmonary gradient (TPG) to those who do not. Methods Retrospective review of CF-LVAD patients was conducted for right heart catheter derived haemodynamic measurements and post-transplant outcomes from a single instituition. Results 219 CF-LVADs were implanted between October 2004 and September 2019. 48 patients had TPG greater than 12 prior to implantation. 1 patient was excluded for incomplete data. 28 patients normalised TPG (Gp 1) and 17 patients had elevated TPG (Gp 2) at first follow up. Table 1 describes the haemodynamic assessment of the two groups. At baseline, Gp 1 patient had significantly lower PVR, p=0.04. At follow-up, Gp 1 patients had significantly lower RAP, p Conclusion Baseline pulmonary vascular resistance may provide prognostic information in CF-LVAD patients with PHLHD. Early normalization in TPG is associated with favourable haemodynamic response.

Purpose An increasing number of end-stage heart failure patients are supported by continuous-flow Left Ventricular Assist Devices (cfLVADs) as a bridge to heart transplantation. Accurate assessment of arterial pulsatility remains a challenge because of diminished pulse pressure, which itself can be associated with adverse events such as gastrointestinal bleeding and stroke. Our study investigates the value of simultaneous arterial pressure and arterial blood velocity assessment in cfLVAD patients. Methods Brachial artery flow velocity (cm/s, Huntleigh) and brachial cuff oscillometry pressure (mmHg, Sphygmocor XCel) data were collected during outpatient visit. Velocity measurements obtained included peak, minimum, average velocity as well as pulsatility index. Pressure measurements obtained were systolic, diastolic as well as mean arterial pressure. Results Twelve velocity and pressure measurements were obtained from a total of nine VAD patients. Mean age was 57 years (Range 44-71). Mean device support duration was 187 days (Range 44-471). Mean brachial MAP was 92 mmHg (Range 74-112), whereas mean peak brachial artery velocity was 11 cm/s (Range 6-26). Mean pulsatility index was 3 (range 1-8). Correlation analysis using Spearman's rho demonstrated a significant inverse relationship between Brachial MAP and Peak velocity (Rho=-0.72, p=0.08). Conclusion Arterial flow measurements may provide incremental value over purely pressure-based assessment. Discrepancies between these modalities may provide further information regarding the arterial vasculature, specifically pertaining to the impact of higher MAP on blood flow.

Purpose Clinical trials of the HeartWare™ HVADTM System have demonstrated a low rate of post-implant severe right ventricular failure (RVF) requiring implantation of a right ventricular assist device (RVAD). In an analysis of the North American clinical trials of the HVAD System, including the ADVANCE BTT+CAP Trial (N=382), the ENDURANCE Trial (N=296), the ENDURANCE Supplemental Trial (N=308) and the Lateral Trial (N=144), RVADs were implanted in 2.7% of patients (31/1130) over 2 years of support. However, the overall percentage of patients in INTERMACS profile 1 at implant was only 4.2% and those with anticipated need for post-operative RVAD were excluded. We will present an analysis of severe RVF requiring an RVAD in the real-world post-approval study of the HVAD System when used in destination therapy patients (DT-PAS and Apogee International study). Methods The objective of this analysis is to examine the rate of RVAD use in the prospective DT PAS study (n=212) and the Apogee International study (n=46). At the time of presentation, we will have 258 patients with follow-up data through at least 6 months of support. Results Data is currently being collected from 50 centers in the US, EMEA, and Australia. Descriptive data and severe RVF data will be presented, and a comparison, accounting for baseline differences, to the HVAD clinical trials will be performed. Baseline parameters of the 258 patients includes mean age 58.3 years, with 15.4% INTERMACS profile 1 and 44.6% with ischemic etiology. Preliminary data from 212 patients in the US DT PAS cohort (with 16.3% INTERMACS 1) reveals an incidence of RVAD use of 6.1% over a mean time on support of 5 months. Data collection and analysis is ongoing. Conclusion Analyses of real-world use of the HVAD System reveals its increasing use in higher risk and more complex patients. Final data on RVAD use in 258 patients through 6 months will be available at the time of presentation.

Introduction Standard guideline-directed neurohumoral blocking therapy is often continued or initiated after left ventricular assist device (LVAD) implantation once haemodynamics are stabilised. Angiotensin/neprilysin inhibitors (ARNI) are well integrated into international guidelines, but the role of these agents in LVAD patients is unclear. In LVAD patients with high afterload sensitivity, small preload changes can lead to suboptimal LV filling and intermittent suction-mediated inflow cannula obstruction. Case Report We investigated the haemodynamic influence of ARNI on LVAD flow, as a surrogate marker of possible suction events, using the accessible logfile data from an in-vivo HeartWare(HW) device, which captures instantaneous power and derived flow every 15-minutes. We extracted the logfile data of a patient who, after stabilisation on ARNI therapy following LVAD implantation, ultimately ceased due to labile arterial pressures. Using the patient as their own control we calculated 1) the mean flow using a running average, 2) the pulsatility index (PI) from minimum/maximum flows, and 3) potential suction events (defined as outlier flow events two standard deviations from the mean). Mean flow was similar off (3.86±0.5l L/min) compared to on (3.78±0.7L/min) ARNI therapy. The PI was numerically higher on therapy (2.1±0.2 L/min) compared to no therapy (1.7±0.3 L/min). There were numerically many more outlier flow events with ARNI therapy (78) compared to no therapy (9), which may correlate with suction events, and suggests haemodynamic instability on therapy. Summary Whilst a few small studies have demonstrated general tolerability of ARNIs in LVAD patients, potent venodilatory and anti-hypertensive effects can cause unfavourable haemodynamics. We show evidence of increased haemodynamic instability evident from controller logfiles possibly due to a disproportionate reduction in preload relative to afterload with increased uncoupling of ventricular to arterial elastance.

Purpose BiVACOR is a novel total artificial heart utilising a single centrifugal magnetically levitated rotor with the ability to modulate pulsatile flow through speed variation. The device has been successfully tested in cattle with encouraging 90-day results. We sought to undertake a multicentre virtual and anatomical fitting study of the BiVACOR in patients undergoing heart transplantation. Methods 10 patients on the heart transplant waiting list were recruited (5 Females, 5 Males) across two heart transplant centres. A 1:1 titanium model of the device with correct port configuration (Aorta, Pulmonary Artery, Right Atrium, Left Atrium) was provided by BiVACOR. Chest size and major vessel measurements were recorded from preoperative CT Scans. The sterilised model was then inserted into the patient's chest cavity post heart explant, prior to implantation of the donor heart. The atrial ports (right and left) on the device were lined up with their native counterparts. Measurements were recorded in-situ. The Device was then removed. 3D reconstructions were also created to simulate a virtual fitting. Results Mean age was 53 years (Range 38-67). Mean BMI was 28 (Range 20-37). Aetiology was varied - 5 Patients had Ischaemic Cardiomyopathy, whereas 1 was restrictive, 1 was giant cell myocarditis and 3 were dilated cardiomyopathy. Four had re-do sternotomies and 3 of these involved a ventricular assist device explant. Mean Spine-to-Sternum distance at the level of T10 was 14cm (range 11-18). Mean Ao diameter was 3.1cm (range 2.5-3.8). Mean PA Diameter was 3.4cm (range 2.0-4.2). Mean Ao to Ao Port distance was 0.2cm (range 0-0.5). Mean PA to PA Port distance was 4.2cm (range 1-7). The device fit in all patients. There was no gross distortion to the geometry between native vessels/chambers and ports. Conclusion This study described the virtual and anatomical fitting of the BiVACOR total artificial heart. The device fit within the chest cavities of all 10 patients, who represented a variety of body morphologies and heart failure aetiology.

Purpose Rejection in heart transplant recipients is often diagnosed by surveillance biopsies as most patients are asymptomatic. Nevertheless, rejection, if left untreated, can produce progressive diastolic dysfunction followed by systolic heart failure. This in turn will cause an increase in central venous pressure due to decreased ventricular compliance. With this in mind we sought out to determine if elevated central venous pressures measured invasively at the time of the biopsy correlated with the presence of rejection. Methods Patients undergoing an endomyocardial biopsy between June and October 2020 were included. The invasive JVP was measured before and after the procedure by measuring the height of the blood column in the side port of the sheath open to the atmospheric pressure. The biopsy results were reported according to the 2004 ISHLT revision. Differences in median JVP for each biopsy result group (0, 1R, 2R, 3R) were compared using a Mann-Whitney test. The histogram density for each biopsy group was graphed using a Kernel density plot. Results Eighty-four patients underwent one or more endomyocardial biopsies, with a total of 374 biopsies performed. Of all procedures, 187 were grade 0 for rejection, 168 were grade 1R and 18 were grade 2R. One patient had Grade 3R rejection (not shown in illustration) The median JVP was not statistically different between the three groups and the numerical difference was not clinically meaningful (figure 1 A). The Kernel density plot (figure 1 B) demonstrates the similarities between the groups. The lack of correlation between invasive JVP and rejection persists if data from the first 2 weeks post heart transplant are excluded. Conclusion In our dataset, there was no clinical or statistical difference in median invasive JVP and rejection grade between the biopsy result groups. One limitation is that we only had one patient with severe rejection (3R). Overall, our findings reinforce the need for surveillance biopsies.

Purpose Mechanical Circulatory Support (MCS) devices such as ventricular assist devices (VADs) are increasingly important in managing patients with end-stage heart failure. Current generation VADs, such as the HVAD operate on a continuous flow basis. Many authors have identified the lack of pulsatility as a limitation. We tested the feasibility of using a signal from ex-vivo tissue of rabbit sinoatrial node (SAN) to induce pulsatility in an HVAD as well as the BiVACOR total artificial heart through synchronous speed variation. Methods Seven different rabbits had SAN tissue extracted, placed in a tissue bath and superfused with Krebs-Ringer solution. An extracellular fine metal electrode was placed into the tissue preparation for activity capture. The rate of spontaneous SAN activity was modulated by changing the temperature of the superfusing solution. Electrical activity was captured and identified using a data acquisition system and custom-made software. This was used to trigger a stepwise speed change in an HVAD as well as the BiVACOR running in a mock circulatory loop. Signal capture was tested across a range of heart rates. Results Electrogram signals were successfully recorded for all tissue extracts. To simulate physiological settings, we implemented a 100ms delay between capture and effect, as well as a speed change duration of 30% per cycle (obtained from beat-to-beat variation). HVAD motor speed was successfully increased from 2500RPM to 2800RPM in synchronicity with the firing of the SAN. We were also able to achieve a speed reduction from 2500RPM to 2000RPM in synchronicity with the firing of the SAN. The BIVACOR was similarly able to undergo motor speed increase and decrease in synchrony with the SAN at the lower heart rate setting. Conclusion We successfully captured electrical activity from the SAN, then relayed it to both an HVAD and the BiVACOR controller, in doing so we were able to induce pulsatility through speed variation in synchrony with SAN activity. This has the potential to change MCS haemodynamics.

Purpose Continuous flow left ventricular assist devices (LVADs) can change aortic valve (AoV) biomechanics, which can result in reduced or lack of AoV opening. This can increase the risk of thrombotic events, gastrointestinal bleeding and denovo aortic incompetence. Therefore, detection of AoV opening and adjusting pump speed corresponding to the AoV status play a vital role for heart failure (HF) patients with LVADs. Although current assessment of AoV rely on supine resting echocardiography, this method cannot be applied outside of hospital. This study presents a deep neural network model for noninvasive detection of AoV opening for Heartware patients in different patient states. Methods 18 patients supported by a continuous flow HeartWare HVAD underwent transthoracic echocardiography for parasternal M‐mode images of the AoV. A continuous recording of 2 minutes at rest, immediately following by 1-minute Valsalva maneuver and then followed by leg‐raising exercise for 1-minute. A deep neural network model was trained and validated through 10-fold cross validation to detect AoV status based on the 200 samples (four seconds) of pump flow. The developed model performance was assessed using several performance metrics such as accuracy, sensitivity, specificity and receiver operating characteristic (ROC) curve area (AUC). Results The deep neural networks model was able to detect AoV opening/closing accurately across 10-fold cross validation based on the pump flow. The results show the accuracy of 86.59 %, sensitivity 81.39 %, specificity of 89.55 % and AUC of 0.928. However, including more patients on training and validation process of deep neural networks model can improve these performance metrics. Conclusion The deep neural network model would be useful for real-time detection of AoV opening which can be employed to adjust pump speed in HF patients to promote at least intermittent AV opening. Implementation of the proposed AoV detection in real-time mode could be integrated into a “smart pump” control system to automatically adjust LVADs speed to ensure a desired frequency of AV opening.

Purpose Worsening renal function (WRF) in patients supported with ventricular assist devices (VAD) is associated with poor outcomes. Postulated mechanisms include right ventricular (RV) dysfunction, low pulsatility from continuous flow, and chronic haemolysis (CH). We aim to determine whether these predict WRF. Methods Consecutive VAD implants between 2010 - 2019 were analysed. Estimated glomerular filtration rate (eGFR - ml/min/m2), lactate dehydrogenase (LDH) and transthoracic echocardiogram (TTE) were collected until death/transplant to 12-months following implant. Demographics and medications 3-months post-implant were recorded. Adverse events included mortality, gastrointestinal (GI) bleed, ischaemic stroke, intracranial haemorrhage, pump thrombosis and driveline infection at any time until death/transplant.WRF was defined as drop in Kidney Disease Improving Global Outcomes Chronic Kidney Disease (KDIGO CKD) stage from baseline to last recorded eGFR. CH defined by elevated LDH. Pulsatility index (PI) derived from mean, peak and trough VAD flows at 1, 3 and 12 months. Results 173 patients included, WRF occurred in 49 patients. WRF was associated with increased GI bleed (odds ratio [OR] 4.41, p=0.02) and ischemic stroke (OR 5.05, p=0.018). WRF occurred less frequently in those on beta-blockers (OR 0.31, p = 0.009) and renin-angiotensin-system inhibitors (OR 0.31, p = 0.009). Although not statistically significant, those with WRF had median higher baseline eGFR (WRF vs. no WRF 68 vs 55, p=0.598). Less profound eGFR improvement at 1 month was seen in patients with WRF (1 vs. 25.5, p = 0.021), resulting in numerically lower eGFR at 1-month in those with WRF (77 vs. 83, p=0.119) respectively. WRF was not predicted by PI, CH or change in RV function on TTE. Conclusion WRF is associated with increased morbidity in patients supported with VAD, although the mechanism for this is unclear. Further studies are required to define CH and low pulsatility to determine their impact on WRF.

Purpose Left ventricular assist devices (LVADs) play a vital role for end-stage heart failure (HF) patients during destination therapy. However, the speed of LVADs are set at a constant speed mode which can result in insufficient perfusion and hazardous events such as ventricular suction and pulmonary congestion. A preload-based physiological control system, a “smart pump”, can be employed to adjust the LVAD speed automatically and therefore improve prefusion and deal with the hazardous events. Although most of these physiological control systems require direct measurement of preload, long-term implantation of a pressure sensor can lead to drift or thrombus formation. Preload can instead be estimated using pump intrinsic variables. This study presents a sensorless control of LVAD across different patient conditions without relying on any implantable sensors. Methods An adaptive preload-based physiological controller was employed to adjust the speed of HeartWare HVAD pump to handle interpatient and intrapatient variations using a computer simulation. A deep convolutional neural network (CNN) model was designed to estimated preload based on the 600 samples of pump flow in real-time mode. The proposed CNN model was trained and validated on 100 different patient conditions and tested over new 30 patient conditions and a range of changes to the cardiovascular system, including changes in PVR, SVR and rest to exercise. Finally, the physiological controller and preload estimator were combined to create a sesnorless preload-based physiological control system for LVADs. Results Preload was accurately estimated using the proposed deep convolutional neural network model, which was successfully trained, tested and validated using computer simulation data. The results for all scenarios show the correlation coefficient of 0.97 and RMSE of 0.84 (mmHg). Furthermore, the sesnorless preload-based physiological control was able to prevent ventricular suction and pulmonary congestions over new 30 patients. Conclusion The sesnorless preload-based physiological control can be useful for estimation of preload and control of LVAD speed in a real-time mode for HF patients without implantation of pressure sensors. This controller can improve the HF patients’ quality of lives and lifespan by increasing perfusion, preventing suction and congestion.

Hearts from older donors are increasingly being referred for transplantation. However, these hearts are more susceptible to ischemia-reperfusion injury (IRI), reflected in higher rates of primary graft dysfunction. We assessed a strategy of pharmacologic conditioning, supplementing Celsior (Genzyme, Naarden, The Netherlands) preservation solution with glyceryl trinitrate (GTN; Hospira Australia Pty, Ltd, Mulgrave, VIC, Australia), erythropoietin (EPO; Eprex; Janssen-Cilag, North Ryde, NSW, Australia), and zoniporide (ZON; Pfizer, Inc., Groton, CT), to protect older hearts against IRI and improve graft function.Wistar rats, aged 3, 12, and 18 months old, were used to represent adolescent, 30-year-old, and 45-year-old human donors, respectively. Animals were subjected to brain death (BD) and hearts stored for 6 hours at 2° to 3°C in Celsior or Celsior supplemented with GTN+EPO+ZON. Cardiac function and lactate dehydrogenase before and after storage were assessed during ex vivo perfusion. Western blots and histopathology were also analyzed.After BD, 18-month hearts demonstrated impaired aortic flow, coronary flow, and cardiac output compared with 3-month hearts (p0.001 to p0.0001). After storage in Celsior, the recovery of aortic flow, coronary flow, and cardiac output in 18-month BD hearts was further impaired (p0.01 vs 3-month hearts). Percentage functional recovery of 18-month BD hearts stored in Celsior supplemented with GTN+EPO+ZON was equivalent to that of 3-month hearts and significantly improved compared with 18-month hearts stored in Celsior alone (p0.01 to p0.001), with reduced lactate dehydrogenase release (p0.01) and myocardial edema (p0.05) and elevated phosphorylated extracellular signal-related kinase 1/2 (p0.05) and phosphorylated Akt (p0.01).Older hearts are more susceptible to IRI induced by BD and prolonged hypothermic storage. Supplemented Celsior activates cell survival signaling in older hearts, reduces IRI, and enhances donor heart preservation.

Truncating mutations in the TTN gene are the most common genetic cause of dilated cardiomyopathy in adults but their role in young patients is unknown. We studied 82 young dilated cardiomyopathy subjects and found that the prevalence of truncating TTN mutations in adolescents was similar to adults, but surprisingly few truncating TTN mutations were identified in affected children, including one confirmed de novo variant. In several cases, truncating TTN mutations in children with dilated cardiomyopathy had evidence of additional clinical or genetic risk factors. These findings have implications for genetic testing and suggest that single truncating TTN mutations are insufficient alone to cause pediatric-onset dilated cardiomyopathy.

Purpose Chronic thromboembolic pulmonary hypertension (CTEPH) is progressive condition characterised by fibro-thrombotic obstruction of pulmonary arteries, and is associated with significant mortality. Given techniques are evolving, there is still considerable variation in the literature regarding surgical and interventional outcomes. This study aims to determine outcomes for CTEPH patients undergoing pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) in specialist pulmonary hypertension unit with treatment modality determined by a multi-disciplinary heart team. Methods This is a retrospective cohort study of all patients undergoing PEA or BPA between 2002 and June 2018. A team of experienced cardiologists, surgeons and interventional radiologists made decisions regarding treatment modality. Both haemodynamic, clinical and procedural outcomes were measured, and comparison was made between treatment groups. Only patients who had available pre- and post intervention right heart catheter data were included in the haemodynamic analysis. Results A total of 92 patients were included between the PEA group (n=65, age 58 ± 16, m=32, f= 33) and BPA group (n=27, age 65 ± 17, m=15, F=12). For haemodynamic outcomes, a total 52 patients (42 PEA, 10 BPA) were included. There were statistically significant improvements in pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP), mean right atrial pressure and cardiac index. Though the reductions in mPAP (PEA 21 mmHg vs. BPA12.5 mmHg) and PVR (PEA 527 ± 350 dyn.s.cm−5 vs. BPA 304 dyn.s.cm−5) were more marked in the PEA group, there was no statistically significant difference between the groups. There were two deaths (3%) post PEA and one death (3.7%) encountered post-BPA. Conclusion We conclude, that with careful patient selection and experienced proceduralists, there is significant improvement in haemodynamic outcomes with both surgery and intervention, and an acceptable complication profile.

Purpose BiVACOR is a new and novel total artificial heart utilising a single centrifugal magnetically levitated motor featuring a pulsatile flow. The device has been successfully tested in cattle with encouraging 90-day results. We sought to undertake the first-in-man fitting of the device. Methods Six patients awaiting heart transplant were recruited (2 Females, 4 Males). Chest size, atria size, pulmonary artery (PA) and aortic (Ao) measurements were recorded from preoperative CT Scans and 3D reconstructions were created. We generated a 1:1 3D printed titanium prototype of the BiVACOR device. The sterilised prototype with correct port configuration (Aortic, Pulmonary Artery, Right Atrium, Left Atrium) was then inserted into the patient's chest cavity at surgery post heart explant and before implantation of the donor heart. The atrial ports (right and left) on the device were lined up with their native counterparts. Measurements were recorded in-vivo. The device was then removed and compared in size to the explanted heart. Results Mean age was 55 (SD 9) years. Mean BMI was 28 (SD 6) kg/m2. Aetiology was varied - 3 Patients had Ischaemic cardiomyopathy, 1 restrictive, 1 active giant cell and 1 idiopathic dilated cardiomyopathy. Two had re-do sternotomies and one of these was a ventricular assist device (HVAD) explant. Mean thoracic cage area was 377cm2 (range 343-413) at the level of the 5th rib. Mean Spine-to-Sternum distance was 13cm (range 11-16) measured between the 6th/7th ribs. Mean Ao diameter was 3.6cm (range 2.5-3.8). Mean PA diameter was 3.6cm (range 2.9-4.2). Mean Ao to Ao Port distance was 0.25cm (range 0-0.5). Mean PA to PA Port distance was 5.3cm (range 3.5-7). The device fit easily in all patients. There was no gross distortion to the geometry between native structures and ports. Conclusion This study described the first in man anatomical fitting of the BiVACOR total artificial heart. The device fit well within the chest cavities of all 6 patients, who represented a variety of body morphologies and heart failure etiology.

Purpose Vasoplegia post ventricular assist device (VAD) explant and heart transplantation is a well recognised phenomenon. One potential reason for this is the continuous flow nature of current generation VADs. We were interested in exploring the quantity of vasopressor requirement in patients undergoing heart transplantation between three groups - VAD explant (VE), Non-VAD implant previous sternotomy (PS) and no previous sternotomy (NPS). Methods We included 15 patients in each group for a total of 45 patients. Patients were retrospectively identified from our transplant database. We aimed to include our most recent transplants with 30-day outcome data available. Demographic, operative, and post-operative data was obtained from the medical records, operation reports and ICU charts. Statistical analysis was conducted using SPSS v25. Results There was no significant difference between the three groups in terms of Gender, Age, BMI, Pre-operative eGFR, Donor Ischaemic time, Donor Gender, Donor age or Donor BMI. Intraop blood transfusions were higher in the PS and VE groups compared to the NPS groups, p Conclusion From our data, we can conclude that the VE group had a higher vasopressor requirement than the NPS and PS groups at 48 Hours. Irrespective of these differences, there did not appear to be any difference in ICU length of stay and overall hospital length of stay amongst the three groups.

Purpose Stroke is considered one of the major hurdles in applying Left Ventricular Assist Device (LVAD) technology to a broader population, and remains a leading cause of mortality and morbidity despite advances in both technology and management. In the general population, incidence of stroke in African Americans (AA) has been reported to be twice that of their Caucasian counterparts, and the mortality following stroke higher in AA. We sought to assess the effect of race on both rate of stroke, as well as post stroke survival in the LVAD population. Methods Using the publically available NIH INTERMACS data, we identified and assessed stroke rates in a total of 14,573 patients support by continuous flow durable LVAD (cf-LVAD). We performed a univariate analysis based on gender and race, followed by a stepwise multivariate analysis adjusting for 20 commonly reported risk factors for stroke. We also applied Bayesian analyses to determine the significant variables impacting stroke in patients with and without self-reported Black ancestry Results There were 3916 patients with AA ancestry (26.8 %) and 3139 Females (21.5%). The overall stroke rate was 14.9%. There was no difference in the stroke rates between the AA and Caucasian CF-LVAD patients (15.3% vs. 14.7%, p=0.37), but there was an improved stroke free survival in the AA population (Figure 1,p Conclusion This study shows that patients with self-reported AA ancestry appears to be protected in regards to the time to first stroke, even when adjusted for gender. After a stroke occurs, AA patients also appear to have better survival when compared to Caucasians. This is paradoxical when compared to the non cf-LVAD population merits and avenue of further investigation into the mechanisms of stroke cf-LVAD patients.

Purpose Most heart failure patients undergoing ventricular assist device (VAD) implantation are managed with guideline-based therapy including the implantation of defibrillation capable device (ICD). Prior to surgery, programming allowing therapy with lower threshold could be lifesaving. After surgery, the defibrillator should be reprogrammed to protect the patient against painful, unnecessary shocks, as the circulation will be supported even in ventricular fibrillation. Difficulties in interrogation of ICD in patients with both HeartMate-II and HeartMate3 devices have been previously reported, related to the VAD-produced electromagnetic interference. Most cases result in a problem of communication between the ICD and the corresponding interrogating console. Methods An electronic search was performed to identify all articles and abstracts published on the topic until July 2019. To the list, we added one case from our clinical experience as well as manufacturer described cases of incompatibility. Results We identified 473 publications. Fourteen publications were ultimately included. Those publications described 22 patients with device interrogation issues post VAD implantation. To regain control of the device complete replacement of the ICD/CRT/PM was performed in 10 patients, and in one the implantation side was changed. In 11 cases a shielding technique was successfully utilized. From the data, we can extract the names of 14 devices with a documented communication problem. There were no reported cases of adverse interaction between HeartWare and ICDs. Conclusion Given the reported VAD-associated EMI interaction with ICD interrogation due to interruption of the handshake-signal to initiate ICD interrogation, it is likely all the variants of one specific ICD (1 lead, 2 lead, CRT) will also suffer from the same problem. More ex-vivo research is needed to better understand the phenomenon, and clinicians and patients with the listed ICDs need to be aware of the potential loss of ICD control with HM2 or HM3.