Dynamic Metabolic Changes During Prolonged Ex Situ Heart Perfusion Are Associated With Myocardial Functional Decline.

Ex situ heart perfusion (ESHP) was developed to preserve and evaluate donated hearts in a perfused beating state. However, myocardial function declines during ESHP, which limits the duration of perfusion and the potential to expand the donor pool. In this research, we combine a novel, minimally-invasive sampling approach with comparative global metabolite profiling to evaluate changes in the metabolomic patterns associated with declines in myocardial function during ESHP. Biocompatible solid-phase microextraction (SPME) microprobes serving as chemical biopsy were used to sample heart tissue and perfusate in a translational porcine ESHP model and a small cohort of clinical cases. In addition, six core-needle biopsies of the left ventricular wall were collected to compare the performance of our SPME sampling method against that of traditional tissue-collection. Our state-of-the-art metabolomics platform allowed us to identify a large number of significantly altered metabolites and lipid species that presented comparable profile of alterations to conventional biopsies. However, significant discrepancies in the pool of identified analytes using two sampling methods (SPME vs. biopsy) were also identified concerning mainly compounds susceptible to dynamic biotransformation and most likely being a result of low-invasive nature of SPME. Overall, our results revealed striking metabolic alterations during prolonged 8h-ESHP associated with uncontrolled inflammation not counterbalanced by resolution, endothelial injury, accelerated mitochondrial oxidative stress, the disruption of mitochondrial bioenergetics, and the accumulation of harmful lipid species. In conclusion, the combination of perfusion parameters and metabolomics can uncover various mechanisms of organ injury and recovery, which can help differentiate between donor hearts that are transplantable from those that should be discarded.

Echocardiographic assessment of left ventricular function in ex situ heart perfusion using pump-supported and passive afterload working mode: a pilot study.

Ex situ heart perfusion (ESHP) has been developed to decrease cold ischemia time and allow metabolic assessment of donor hearts prior to transplantation. Current clinical ESHP systems preserve the heart in an unloaded condition and only evaluate the cardiac metabolic profile. In this pilot study we performed echocardiographic functional assessment using two alternative systems for left ventricular (LV) loading: pump supported afterload working mode (SAM) and passive afterload working modes (PAM). Six hearts were procured from male Yorkshire pigs. During cold ischemia, hearts were mounted on our custom made ESHP circuit and a 3D-printed enclosure for the performance of echocardiography with a standard TEE probe. Following perfusion with Langherdorf mode of the unloaded heart, the system was switched into different working modes to allow LV loading and functional assessment: pump supported (SAM) and passive (PAM). Echocardiographic assessment of left ventricular function in the donor hearts was performed in vivo and at 1 h of ESHP with SAM, after 4.5 h with PAM and after 5.5 h with SAM. We obtained good quality epicardial echocardiographic images at all time points allowing a comprehensive LV systolic assessment. All indices showed a decrease in LV systolic function throughout the trial with the biggest drop after heart harvesting. We demonstrated the feasibility of echocardiographic functional assessment during ESHP and two different working modes. The expected LV systolic dysfunction consisted of a reduction in EF, FAC, FS, and strain throughout the experiment with the most significant decrease after harvesting.

Redo sternotomy versus left ventricular assist device explant as risk factors for early mortality following heart transplantation.

OBJECTIVES: There is an increasing proportion of patients with a previous sternotomy (PS) or durable left ventricular assist device (LVAD) undergoing heart transplantation (HT). We hypothesized that patients with LVAD support at the time of HT have a lower risk than patients with PS and may have a comparable risk to patients with a virgin chest (VC). METHODS: This is a single-centre retrospective cohort study of all adults who underwent primary single-organ HT between 2002 and 2017. Multivariable Cox regression analyses were performed to compare 30-day and 1-year mortality between transplanted patients with a VC (VC-HT), a PS (PS-HT) or an LVAD explant (LVAD-HT). RESULTS: Three hundred seventy-nine patients were analysed (VC-HT: 196, PS-HT: 94, LVAD-HT: 89). A larger proportion of patients in the LVAD-HT group were males (83%), had blood group O (52%), non-ischaemic aetiology (70%) and sensitization (67%). The PS-HT group had a higher frequency of patients with congenital heart disease (30%) and PSs compared to LVAD-HT patients (P < 0.001). PS-HT and LVAD-HT patients required a longer bypass time (P < 0.001) and showed a greater estimated blood loss (P < 0.001). Postoperatively, LVAD-HT required haemodialysis more frequently than the VC-HT group (P = 0.031). Multivariable analyses found that PS-HT patients had increased 30-day mortality compared to VC-HT [hazard ratio (HR) 2.63, 95% confidence interval (CI) 1.15-6.01; P = 0.022] while LVAD-HT did not (HR 2.17, 95% CI 0.96-4.93; P = 0.064). At 1-year, neither PS-HT nor LVAD-HT groups were significantly associated with increased mortality compared to VC-HT. CONCLUSIONS: Transplants in recipients with PS-HT demonstrated increased early mortality compared to VC-HT patients. Although LVAD explant is often technically challenging, this population demonstrated similar mortality compared to those VC-HT patients. The chronic and perioperative support provided by the LVAD may play a favourable role in early patient outcomes compared to other redo sternotomy patients.

Comparing Donor Heart Assessment Strategies During Ex Situ Heart Perfusion to Better Estimate Posttransplant Cardiac Function.

BACKGROUND: Ex situ heart perfusion (ESHP) limits ischemic periods and enables continuous monitoring of donated hearts; however, a validated assessment method to predict cardiac performance has yet to be established. We compare biventricular contractile and metabolic parameters measured during ESHP to determine the best evaluation strategy to estimate cardiac function following transplantation. METHODS: Donor pigs were assigned to undergo beating-heart donation (n = 9) or donation after circulatory death (n = 8) induced by hypoxia. Hearts were preserved for 4 hours with ESHP while invasive and noninvasive (NI) biventricular contractile, and metabolic assessments were performed. Following transplantation, hearts were evaluated at 3 hours of reperfusion. Spearman correlation was used to determine the relationship between ESHP parameters and posttransplant function. RESULTS: We performed 17 transplants; 14 successfully weaned from bypass (beating-heart donation versus donation after circulatory death; P = 0.580). Left ventricular invasive preload recruitable stroke work (PRSW) (r = 0.770; P = 0.009), NI PRSW (r = 0.730; P = 0.001), and NI maximum elastance (r = 0.706; P = 0.002) strongly correlated with cardiac index (CI) following transplantation. Right ventricular NI PRSW moderately correlated to CI following transplantation (r = 0.688; P = 0.003). Lactate levels were weakly correlated with CI following transplantation (r = -0.495; P = 0.043). None of the echocardiography measurements correlated with cardiac function following transplantation. CONCLUSIONS: Left ventricular functional parameters, especially ventricular work and reserve, provided the best estimation of myocardial performance following transplantation. Furthermore, simple NI estimates of ventricular function proved useful in this setting. Right ventricular and metabolic measurements were limited in their ability to correlate with myocardial recovery. This emphasizes the need for an ESHP platform capable of assessing myocardial contractility and suggests that metabolic parameters alone do not provide a reliable evaluation.