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.

How do mechanical circulatory support patients die? Autopsy findings for left-ventricular assist device/total artificial heart nonsurvivors.

BACKGROUND: Although life saving for end-stage heart failure patients, permanent mechanical circulatory support (MCS) is often the proximate cause of death in those that do not survive to transplant. Autopsy remains the gold standard for diagnosing causes of death and a vital tool for better understanding underlying pathology of nonsurvivors. The aim of this study was to determine the frequency and outcomes of autopsy investigations and compare these with premortem clinical assessment. METHODS: The autopsy findings and medical records of all patients who underwent left ventricular assist device (LVAD) or total artificial heart (TAH) insertion between June 1994 and April 2022 as a bridge to transplant, but subsequently died pre-heart transplantation were reviewed. RESULTS: A total of 203 patients had a LVAD or TAH implanted during the study period. Seventy-eight patients (M=59, F=19) died prior to transplantation (age 55 [14] years, INTERMACS=2). Autopsies were conducted in 26 of 78 patients (33%). Three were limited studies. The leading contributor to cause of death was respiratory (14/26), either nosocomial infection or associated with multiorgan failure. Intracranial hemorrhage was the second most common cause of death (8/26). There was a major discrepancy rate of 17% and a minor discrepancy rate of 43%. Autopsy study added a total of 14 additional contributors of death beyond clinical assessment alone (Graphical Abstract). CONCLUSIONS: Over an observational period of 26years, the frequency of autopsy was low. To improve LVAD/TAH patient survival to transplant, better understanding as to cause of death is required. Patients with MCS have complex physiology and are at high risk of infection and bleeding complications.

Tricuspid Regurgitation After Heart Transplantation: The Cause or the Result of Graft Dysfunction?

BACKGROUND: Tricuspid regurgitation (TR) is common following heart transplantation and has been shown to adversely influence patient outcomes. The aim of this study was to identify causes of progression to moderate-severe TR in the first 2 y after transplantation. METHODS: This was a retrospective, single-center study of all patients who underwent heart transplantation over a 6-y period. Transthoracic echocardiogram (TTE) was performed at month 0, between 6 and 12 mo, and 1-2 y postoperatively to determine the presence and severity of TR. RESULTS: A total of 163 patients were included, of whom 142 underwent TTE before first endomyocardial biopsy. At month 0, 127 (78%) patients had nil-mild TR before first biopsy, whereas 36 (22%) had moderate-severe TR. In patients with nil-mild TR, 9 (7%) progressed to moderate-severe TR by 6 mo and 1 underwent tricuspid valve (TV) surgery. Of patients with moderate-severe TR before first biopsy, by 2 y, 3 had undergone TV surgery. The use of postoperative extracorporeal membrane oxygenation (ECMO) in the latter group was significant (78%; P < 0.05) as was rejection profile ( P = 0.02). Patients with late progressive moderate-severe TR had a significantly higher 2-y mortality than those who had moderate-severe TR immediately. CONCLUSIONS: Overall, our study has shown that in the 2 main groups of interest (early moderate-severe TR and progression from nil-mild to moderate-severe TR), TR is more likely to be the result of significant underling graft dysfunction rather than the cause of it.

Rapid triage and transition to telehealth for heart transplant patients in the COVID-19 pandemic setting.

BACKGROUND: In the setting of the COVID-19 pandemic, a rapid uptake of telehealth services was instituted with the aim of reducing the spread of disease to vulnerable patient populations including heart transplant recipients. METHODS: Single-center, cohort study of all heart transplant patients seen by our institution's transplant program during the first 6 weeks of transition from in-person consultation to telehealth (23 March - 5 June 2020). RESULTS: Face-to-face consultation allocation strongly favored patients in the early post-operative period (34 vs. 242 weeks post-transplant; p < 0.001). Telehealth consultation dramatically reduced patient travel and wait times (80 min per visit saved in telehealth patients). No apparent excess re-hospitalization or mortality was seen in telehealth patients. CONCLUSIONS: With appropriate triage, telehealth was feasible in heart transplant recipients, with videoconferencing being the preferred modality. Patients seen face-to-face were those triaged to be higher acuity based on time since transplant and overall clinical status. These patients have the expected higher rates of hospital re-admission, and therefore should continue to be seen in person.

Impact of frailty on mortality and morbidity in bridge to transplant recipients of contemporary durable mechanical circulatory support.

BACKGROUND: Frailty is associated with adverse outcomes in advanced heart failure. We studied the impact of frailty on postoperative outcomes in bridge to transplant (BTT) durable mechanical circulatory support (MCS) recipients. METHODS: Patients undergoing left ventricular assist device (LVAD, n = 96) or biventricular support (BiV, n = 11) as BTT underwent frailty assessment. Frailty was defined as ≥ 3 physical domains of the Fried's Frailty Phenotype (FFP) or ≥ 2 physical domains of the FFP plus cognitive impairment on the Montreal Cognitive Assessment (MoCA). RESULTS: No difference in mortality at 360 days was observed in frail (n = 6/38, 15.8%) vs non-frail (n = 4/58, 6.9%) LVAD supported patients, p = 0.19. However, there was a significant excess mortality in frail BiV (n = 4/5) vs non-frail BiV (n = 0/6) supported patients, p = 0.013. In all patients, frail patients compared to non-frail patients experienced longer intensive care unit stay, 12 vs 6 days (p < 0.0001) and hospital length of stay, 48 vs 27 days (p < 0.0001). There was no difference in hemocompatibility and infection related adverse events. The majority (n = 22/29, 75.9%) of frail patients became non-frail following MCS; contrastingly, a minority (n = 3/42, 7.1%) became frail from being non-frail (p = 0.0003). CONCLUSIONS: Abnormal markers of frailty are common in patients undergoing BTT-MCS support and those used herein predict mortality in BiV-supported patients, but not in LVAD patients. These findings may help us better identify patients who will benefit most from BiV-BTT therapy.

Validation of Cognitive Impairment in Combination With Physical Frailty as a Predictor of Mortality in Patients With Advanced Heart Failure Referred for Heart Transplantation.

BACKGROUND: The aim of this study was to validate our previous finding that frailty predicts early mortality in patients with advanced heart failure (AHF) and that including cognition in the frailty assessment enhances the prediction of mortality. METHODS: Patients with AHF referred to our Transplant Unit between November 2015 and April 2020 underwent physical frailty assessment using the modified Fried physical frailty (PF) phenotype as well as cognitive assessment using the Montreal Cognitive Assessment to identify patients who were cognitively frail (CogF). We assessed the predictive value of the 2 frailty measures (PF ≥ 3 of 5 = frail; CogF ≥ 3 of 6 = frail) for pretransplant mortality. RESULTS: Three hundred thirteen patients (233 male and 80 female; age 53 ± 13 y) were assessed. Of these, 224 patients (72%) were nonfrail and 89 (28%) were frail using the PF. The CogF assessment identified an additional 30 patients as frail: 119 (38%). Frail patients had significantly increased mortality as compared to nonfrail patients. Ventricular assist device and heart transplant-censored survival at 12 mo was 92 ± 2 % for nonfrail and 69 ± 5% for frail patients (P < 0.0001) using the CogF instrument. CONCLUSIONS: This study validates our previously published findings that frailty is prevalent in patients with AHF referred for heart transplantation. PF predicts early mortality. The addition of cognitive assessment to the physical assessment of frailty identifies an additional cohort of patients with a similarly poor prognosis.

Heart transplantation following donation after circulatory death: Expanding the donor pool.

Heart transplantation from donation after circulatory death (DCD) donors is a rapidly expanding practice. In this review, we describe the history and challenges of DCD heart transplantation and overview the procurement protocols and methods of limiting ischemic injury, current outcomes, and future directions. There are now at least three protocols that permit resuscitation and viability assessment of the DCD heart either in situ or ex situ. While the retrieval protocol for hearts from DCD donors will depend on local regulations, the outcomes of DCD heart transplant recipients reported to date are excellent regardless of the retrieval protocol and are comparable to the outcomes of heart transplant recipients from donation after brain death (DBD) donors. In the two centers with the largest published experience, DCD heart transplantation now accounts for one third of their heart transplant activity. With international trends indicating that there is an increasing utilisation of the DCD pathway, it is expected that DCD donors will become a major source of heart donation worldwide.

The impact of frailty on mortality after heart transplantation.

BACKGROUND: Frailty is prevalent in the patients with advanced heart failure; however, its impact on clinical outcomes after heart transplantation (HTx) is unclear. The aim of this study was to assess the impact of pre-transplant frailty on mortality and the duration of hospitalization after HTx. METHODS: We retrospectively reviewed the post-transplant outcomes of 140 patients with advanced heart failure who had undergone frailty assessment within the 6-month interval before HTx: 43 of them were frail (F) and 97 were non-frail (NF). RESULTS: Post-transplant survival rates for the NF cohort at 1 and 12 months were 97% (93-100) and 95% (91-99) (95% CI), respectively. In contrast, post-transplant survival rates for the F cohort at the same time points were 86% (76-96) and 74% (60-84) (p < 0.0008 vs NF cohort), respectively. The Cox proportional hazards regression analysis demonstrated that pre-transplant frailty was an independent predictor of post-transplant mortality with a hazard ratio of 3.8 (95% CI: 1.4-10.5). Intensive care unit and hospital length of stay were 2 and 7 days longer in the F cohort (both p < 0.05), respectively, than in the NF cohort. CONCLUSIONS: Frailty within 6 months before HTx is independently associated with increased mortality and prolonged hospitalization after transplantation. Future research should focus on the development of strategies to mitigate the adverse effects of pre-transplant frailty.

Valvular Regurgitation in a Biventricular Mock Circulatory Loop.

Aortic regurgitation (AR), mitral regurgitation (MR), and tricuspid regurgitation (TR) after continuous-flow left ventricular assist device (LVAD) are common and may increase with prolonged LVAD support. The aim of this study was to simulate severe valvular regurgitation (AR, MR, and TR) within a 4-elemental pulsatile mock circulatory loop (MCL) and observe their impact on isolated LVAD and biventricular assist device (BiVAD) with HeartWare HVAD. Aortic regurgitation, MR, and TR were achieved via the removal of one leaflet from bileaflet mechanical valve from the appropriate valves of the left or right ventricles. The impact of alteration of LVAD pump speed (LVAD 2200-4000 RPM, right ventricular assist device [RVAD] 2400 RPM) and altered LVAD preload (10-25 mm Hg) was assessed. With each of the regurgitant valve lesions, there was a decrease in isolated LVAD pump flow pulsatility. Isolated LVAD provided sufficient support in the setting of severe MR or TR compared with control, and flows were enhanced with BiVAD support. In severe AR, there was no benefit of BiVAD support over isolated LVAD, and actual loop flows remained low. High LVAD flows combined with low RVAD flows and dampened aortic pressures are good indicators of AR. The 4-elemental MCL successfully simulated several control and abnormal valvular conditions using various pump speeds. Current findings are consistent with conservative management of MR and TR in the setting of mechanical support, but emphasize the importance of the correction of AR.

Right Ventricular Failure Post LVAD Implantation Corrected with Biventricular Support: An In Vitro Model.

Right ventricular failure after left ventricular assist device (LVAD) implantation is associated with high mortality. Management remains limited to pharmacologic therapy and temporary mechanical support. Delayed right ventricular assist device (RVAD) support after LVAD implantation is associated with poorer outcomes. With the advent of miniaturized, durable, continuous flow ventricular assist device systems, chronic RVAD and biventricular assist device (BiVAD) support has been used with some success. The purpose of this study was to assess combined BiVAD and LVAD with delayed RVAD support within a four-elemental mock circulatory loop (MCL) simulating the human cardiovascular system. Our hypothesis was that delayed continuous flow RVAD (RVAD) would produce similar hemodynamic and flow parameters to those of initial BiVAD support. Using the MCL, baseline biventricular heart failure with elevated right and left filling pressures with low cardiac output was simulated. The addition of LVAD within a biventricular configuration improved cardiac output somewhat, but was associated with persistent right heart failure with elevated right-sided filling pressures. The addition of an RVAD significantly improved LVAD outputs and returned filling pressures to normal throughout the circulation. In conclusion, RVAD support successfully restored hemodynamics and flow parameters of biventricular failure supported with isolated LVAD with persistent elevated right atrial pressure.

Biventricular mechanical support devices--clinical perspectives.

Cardiac transplantation remains the optimal treatment for end stage heart failure in selected patients. However, the shortage of donor hearts, rigorous eligibility criteria and long waiting lists have increased the demand for alternative treatment strategies such as mechanical circulatory support. While many patients are adequately supported with left ventricular assist devices, frequently there is right heart failure or involvement of the right ventricle, requiring biventricular support. Pulsatile flow biventricular devices and total artificial hearts approved for temporary biventricular support have limitations including size, high rates of adverse events and restricted mobility which makes them unsuitable for long term support. A number of centres have reported dual continuous flow left ventricular assist devices as a means of supporting the left and right heart. This review will summarise the literature on the outcomes and complications from current biventricular support devices and assess the role of dual continuous flow VAD therapy, and the new continuous flow total heart replacement devices.

Long-term biventricular HeartWare ventricular assist device support--Case series of right atrial and right ventricular implantation outcomes.

BACKGROUND: There is limited information on outcomes using the HeartWare ventricular assist device (HVAD; HeartWare, Framington, MA) as a biventricular assist device, especially with respect to site of right ventricular assist device (RVAD) implantation. METHODS: Outcomes in 13 patients with dilated cardiomyopathy and severe biventricular failure who underwent dual HVAD implantation as bridge to transplantation between August 2011 and October 2014 were reviewed. RESULTS: Of 13 patients, 10 were Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Level 1, and 3 were INTERMACS Level 2. Mean age was 45 ± 11 years, and mean body mass index was 26 ± 4 kg/m(2). There were 7 patients on temporary mechanical support pre-operatively (extracorporeal life support, n = 5; intra-aortic balloon pump, n = 2). The median hospital length of stay was 53 days (interquartile range [IQR] 33-70 days) with a median intensive care unit length of stay of 14 days (IQR 8-36 days). The median length of support on device was 269 days (IQR 93-426 days). The right HVAD was implanted in the right ventricular (RV) free wall in 6 patients and in the right atrial (RA) free wall in 7 patients. Transplantation was successfully performed in 5 patients, and overall survival for the entire cohort was 54%. RVAD pump thrombosis occurred in 3 of 6 RV pumps and 1 of 7 RA pumps. No left ventricular assist device pump thrombosis was observed. Bleeding tended to be higher in the RV implantation group (3 of 6 vs 0 of 7). During follow up, 6 patients died (4 of 7 in the RA group vs 2 of 6 in the RV group). Cause of death was multiple-organ failure in 3 patients, sepsis in 2 patients, and intracerebral hemorrhage in 1 patient. CONCLUSIONS: Critically ill patients who require biventricular support can be successfully bridged to transplant using 2 HVADs. RA implantation may allow right heart support with lower pump thrombosis and bleeding complications, although this was at the expense of a higher mortality in this cohort.

Impact of Implantable Cardioverter Defibrillators on Survival of Patients with Centrifugal Left Ventricular Assist Devices.

BACKGROUND: Both implantable cardioverter defibrillators (ICDs) and left ventricular assist devices (LVADs) have a positive impact on survival in the heart failure population. We sought to determine whether these positive effects on survival are additive or whether LVAD therapy supersedes ICD therapy. METHOD: We analyzed survival data of patients implanted with nonpulsatile LVADs between October 2004 and March 2013. Survival in patients with ICDs (n = 64) was compared to those without ICDs (n = 36). Patients exited the study at the time of heart transplantation or death. RESULTS: A total of 100 patients underwent LVAD implantation during this time. Patients had a mean follow-up time of 364 ± 295 days. Death occurred in 15 (38%) patients in the no ICD group versus 18 (30%) in the ICD group. Univariate analysis demonstrated a marginal early survival benefit at up to 1 year post-LVAD implant in the ICD cohort; however, at time points greater than 1 year there was no statistically significant benefit in ICD therapy in LVAD patients (P = 0.56). Multivariate analysis did not show any significant predictor of survival. There were no patients who died of sudden cardiac death. There was no significant difference in the time to heart transplantation (443 days ± 251 no ICD vs 372 days ± 277 ICD, P = 0.37). CONCLUSION: The benefit of ICD therapy in the setting of continuous flow LVAD therapy is uncertain. Although prolonged ventricular arrhythmias (VAs) may potentially impact on patient survival, LVAD therapy is beneficial in prevention of sudden cardiac death due to VAs.

Cardiac surgery is successful in heart transplant recipients.

BACKGROUND: Improved survival of heart transplant (HTx) recipients and increased acceptance of higher risk donors allows development of late pathology. However, there are few data to guide surgical options. We evaluated short-term outcomes and mortality to guide pre-operative assessment, planning, and post-operative care. METHODS: Single centre, retrospective review of 912 patients who underwent HTx from February 1984 - June 2012, identified 22 patients who underwent subsequent cardiac surgery. Data are presented as median (IQR). RESULTS: Indications for surgery were coronary allograft vasculopathy (CAV) (n=10), valvular disease (n=6), infection (n=3), ascending aortic aneurysm (n=1), and constrictive pericarditis (n=2). There was one intraoperative death (myocardial infarction). Hospital stay was 10 (8-21) days. Four patients (18%) returned to theatre for complications. After cardiac surgery, survival at one, five and 10 years was 91±6%, 79±10% and 59±15% with a follow-up of 4.6 (1.7-10.2) years. High pre-operative creatinine was a univariate risk factor for mortality, HR=1.028, (95%CI 1.00-1.056; p=0.05). A time dependent Cox proportional hazards model of the risk of cardiac surgery post-HTx showed no significant hazard; HR=0.87 (95%CI 0.37-2.00; p=0.74). CONCLUSIONS: Our experience shows cardiac surgery post-HTx is associated with low mortality, and confirms that cardiac surgery is appropriate for selected HTx recipients.

Enhanced preservation of the rat heart after prolonged hypothermic ischemia with erythropoietin-supplemented Celsior solution.

BACKGROUND: The cardioprotective efficacy of erythropoietin (EPO) has been widely documented in rodent models of acute coronary syndrome. We sought to evaluate its cardioprotective potential as an adjunct to Celsior cardioplegia in a rodent model of prolonged hypothermic global ischemia-reperfusion injury. METHODS: Isolated working rat hearts were subjected to 6 or 10 hours of hypothermic ischemic storage in Celsior cardioplegic solution. Celsior was supplemented with EPO over a dose range of 0 to 5 units/ml, as well as with glyceryl trinitrate (0.1 mg/ml) and zoniporide (1 µmol/liter). Myocardial functional recovery was determined after 45 minutes of reperfusion, then left ventricular tissue was prepared for Western blotting. RESULTS: The presence of EPO in Celsior dose-dependently improved recovery of myocardial function after 6 hours ischemic storage time (cardiac output recovery: 52.5 ± 11.3% vs 2.5 ± 0.4%; EPO: 5 units/ml vs 0 units/ml; p < 0.05). This functional benefit was associated with decreased lactate dehydrogenase released into coronary effluent and enhanced phosphorylation of STAT3, all of which were completely abrogated by pre-treatment with stattic, a selective inhibitor of STAT3 activation. When the ischemic storage time was extended to 10 hours, additive beneficial effects on myocardial function were seen when EPO was used in combination with the cardioprotective agents glyceryl trinitrate and zoniporide. CONCLUSIONS: EPO has demonstrated cardioprotective efficacy in a rodent model of ischemia-reperfusion injury simulating cardiac allograft preservation, which appears to be mediated via activation of the SAFE cytoprotective signaling pathway.