Primary graft dysfunction in heart transplantation: the challenge to survival.

Primary graft dysfunction (PGD) is a life-threatening clinical condition with a high mortality rate, presenting as left, right, or biventricular dysfunction within the initial 24 h following heart transplantation, in the absence of a discernible secondary cause. Given its intricate nature, definitive definition and diagnosis of PGD continues to pose a challenge. The pathophysiology of PGD encompasses numerous underlying mechanisms, some of which remain to be elucidated, including factors like myocardial damage, the release of proinflammatory mediators, and the occurrence of ischemia-reperfusion injury. The dynamic characteristics of both donors and recipients, coupled with the inclination towards marginal lists containing more risk factors, together contribute to the increased incidence of PGD. The augmentation of therapeutic strategies involving mechanical circulatory support accelerates myocardial recovery, thereby significantly contributing to survival. Nonetheless, a universally accepted treatment algorithm for the swift management of this clinical condition, which necessitates immediate intervention upon diagnosis, remains absent. This paper aims to review the existing literature and shed light on how diagnosis, pathophysiology, risk factors, treatment, and perioperative management affect the outcome of PGD.

Determinants of survival following heart transplantation in adults with congenital heart disease.

BACKGROUND: Adult patients surviving with congenital heart disease (ACHD) is growing. We examine the factors associated with heart transplant outcomes in this challenging population with complex anatomy requiring redo-surgeries. METHODS: We reviewed the United Network for Organ Sharing-Standard Transplant Analysis and Research database and analyzed 35,952 heart transplants from January 1st, 2000, to September 30th, 2018. We compared transplant characteristics for ischemic cardiomyopathy (ICM) (n = 14,236), nonischemic cardiomyopathy (NICM) (n = 20,676), and ACHD (n = 1040). Mean follow-up was 6.20 ± 4.84 years. Kaplan-Meier survival curves and Cox-proportional hazards analysis were used to analyze survival data. RESULTS: Multivariable analysis confirmed that ACHD was associated greater in-hospital death compared to ICM (HR = 0.54, P < 0.001) and NICM (HR = 0.46, P < 0.001). Notable factors associated with increased mortality were history of cerebrovascular disease (HR = 1.11, P = 0.026), prior history of malignancy (HR = 1.12, P = 0.006), pre-transplant biventricular support (HR = 1.12, P = 0.069), postoperative stroke (HR = 1.47, P < 0.001) and postoperative dialysis (HR = 1.71, P < 0.001). ACHD transplants had a longer donor heart ischemic time (P < 0.001) and trend towards more deaths from primary graft dysfunction (P = 0.07). In-hospital deaths were more likely with ACHD and use of mechanical support such as use of right ventricular assist device (HR = 2.20, P = 0.049), biventricular support (HR = 1.62, P < 0.001) and extracorporeal membrane oxygenation (HR = 2.36, P < 0.001). Conditional survival after censoring hospital deaths was significantly higher in ACHD (P < 0.001). CONCLUSION: Heart transplant in ACHD is associated with a higher post-operative mortality given anatomical complexity but a better long-term conditional survival. Normothermic donor heart perfusion may improve outcomes in the ACHD population by reducing the impact of longer ischemic times.

Case report: Facilitating right heart recovery after durable LVAD implantation through repair of atrioventricular valves and RVAD implantation using tunneled Dacron grafts.

Right ventricular assist device (RVAD) weaning is often an important goal for durable left ventricular assist device support. This may be facilitated by mitral and tricuspid repair as well as by minimizing the trauma of RVAD decannulation by using Dacron grafts.

Mitral Interventions in Heart Failure.

Patients with heart failure with reduced ejection fraction who have secondary mitral regurgitation (SMR) have poorer outcomes and quality of life than those without SMR. Guideline-directed medical therapy is the cornerstone of SMR treatment. Careful evaluation of landmark trials using mitral transcatheter edge-to-edge repair in SMR has led to an improved understanding of who will benefit from percutaneous interventions with emphasis on a multidisciplinary approach. The success with mitral transcatheter edge-to-edge repair in SMR has also spurred the evaluation of its role in populations that were not initially studied, such as end-stage heart failure and cardiogenic shock. A spectrum of transcatheter devices in development and clinical trials promise to further provide a growing array of management options for heart failure with reduced ejection fraction patients with symptomatic SMR.

Preoperative passive venous pressure-driven cardiac function determines left ventricular assist device outcomes.

BACKGROUND: Right heart output in heart failure can be compensated through increasing systemic venous pressure. We determined whether the magnitude of this "passive cardiac output" can predict LVAD outcomes. METHODS: This was a retrospective review of 383 patients who received a continuous-flow LVAD at the University of Michigan between 2012 and 2021. Pre-LVAD cardiac output driven by venous pressure was determined by dividing right atrial pressure by mean pulmonary artery pressure, multiplied by total cardiac output. Normalization to body surface area led to the passive cardiac index (PasCI). The Youden J statistic was used to identify the PasCI threshold, which predicted LVAD death by 2 years. RESULTS: Increased preoperative PasCI was associated with reduced survival (hazard ratio [HR], 2.27; P < .01), and increased risk of right ventricular failure (RVF) (HR, 3.46; P = .04). Youden analysis showed that a preoperative PasCI ≥0.5 (n = 226) predicted LVAD death (P = .10). Patients with PasCI ≥0.5 had poorer survival (P = .02), with a trend toward more heart failure readmission days (mean, 45.09 ± 67.64 vs 35.13 ± 45.02 days; P = .084) and increased gastrointestinal bleeding (29.2% vs 20.4%; P = .052). Additionally, of the 97 patients who experienced readmissions for heart failure, those with pre-LVAD implantation PasCI ≥0.5 were more likely to have more than 1 readmission (P = .05). CONCLUSIONS: Although right heart output can be augmented by raising venous pressure, this negatively impacts end-organ function and increases heart failure readmission days. Patients with a pre-LVAD PasCI ≥0.5 have worse post-LVAD survival and increased RVF. Using the PasCI metric in isolation or incorporated into a predictive model may improve the management of LVAD candidates with RV dysfunction.

Metabolic reprogramming by immune-responsive gene 1 up-regulation improves donor heart preservation and function.

Preservation quality of donor hearts is a key determinant of transplant success. Preservation duration beyond 4 hours is associated with primary graft dysfunction (PGD). Given transport time constraints, geographical limitations exist for donor-recipient matching, leading to donor heart underutilization. Here, we showed that metabolic reprogramming through up-regulation of the enzyme immune response gene 1 (IRG1) and its product itaconate improved heart function after prolonged preservation. Irg1 transcript induction was achieved by adding the histone deacetylase (HDAC) inhibitor valproic acid (VPA) to a histidine-tryptophan-ketoglutarate solution used for donor heart preservation. VPA increased acetylated H3K27 occupancy at the IRG1 enhancer and IRG1 transcript expression in human donor hearts. IRG1 converts aconitate to itaconate, which has both anti-inflammatory and antioxidant properties. Accordingly, our studies showed that Irg1 transcript up-regulation by VPA treatment increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in mice, which was accompanied by increased antioxidant protein expression [hemeoxygenase 1 (HO1) and superoxide dismutase 1 (SOD1)]. Deletion of Irg1 in mice (Irg1-/-) negated the antioxidant and cardioprotective effects of VPA. Consistent with itaconate's ability to inhibit succinate dehydrogenase, VPA treatment of human hearts increased itaconate availability and reduced succinate accumulation during preservation. VPA similarly increased IRG1 expression in pig donor hearts and improved its function in an ex vivo cardiac perfusion system both at the clinical 4-hour preservation threshold and at 10 hours. These results suggest that augmentation of cardioprotective immune-metabolomic pathways may be a promising therapeutic strategy for improving donor heart function in transplantation.

Defining the Sarcomeric Proteoform Landscape in Ischemic Cardiomyopathy by Top-Down Proteomics.

Ischemic cardiomyopathy (ICM) is a prominent form of heart failure, but the molecular mechanisms underlying ICM remain relatively understudied due to marked phenotypic heterogeneity. Alterations in post-translational modifications (PTMs) and isoform switches in sarcomeric proteins play important roles in cardiac pathophysiology. Thus, it is essential to define sarcomeric proteoform landscape to better understand ICM. Herein, we have implemented a top-down liquid chromatography (LC)-mass spectrometry (MS)-based proteomics method for the identification and quantification of sarcomeric proteoforms in the myocardia of donors without heart diseases (n = 16) compared to end-stage ICM patients (n = 16). Importantly, quantification of post-translational modifications (PTMs) and expression reveal significant changes in various sarcomeric proteins extracted from ICM tissues. Changes include altered phosphorylation and expression of cardiac troponin I (cTnI) and enigma homologue 2 (ENH2) as well as an increase in muscle LIM protein (MLP) and calsarcin-1 (Cal-1) phosphorylation in ICM hearts. Our results imply that the contractile apparatus of the sarcomere is severely dysregulated during ICM. Thus, this is the first study to uncover significant molecular changes to multiple sarcomeric proteins in the LV myocardia of the end-stage ICM patients using liquid chromatography-mass spectrometry (LC-MS)-based top-down proteomics. Raw data are available via the PRIDE repository with identifier PXD038066.

Mitral regurgitation severity at left ventricular assist device implantation is associated with distinct myocardial transcriptomic signatures.

OBJECTIVES: We examined for differences in pre-left ventricular assist device (LVAD) implantation myocardial transcriptome signatures among patients with different degrees of mitral regurgitation (MR). METHODS: Between January 2018 and October 2019, we collected left ventricular (LV) cores during durable LVAD implantation (n = 72). A retrospective chart review was performed. Total RNA was isolated from LV cores and used to construct cDNA sequence libraries. The libraries were sequenced with the NovaSeq system, and data were quantified using Kallisto. Gene Set Enrichment Analysis (GSEA) and Gene Ontology analyses were performed, with a false discovery rate <0.05 considered significant. RESULTS: Comparing patients with preoperative mild or less MR (n = 30) and those with moderate-severe MR (n = 42), the moderate-severe MR group weighted less (P = .004) and had more tricuspid valve repairs (P = .043), without differences in demographics or comorbidities. We then compared both groups with a group of human donor hearts without heart failure (n = 8). Compared with the donor hearts, there were 3985 differentially expressed genes (DEGs) for mild or less MR and 4587 DEGs for moderate-severe MR. Specifically altered genes included 448 DEGs for specific for mild or less MR and 1050 DEGs for moderate-severe MR. On GSEA, common regulated genes showed increased immune gene expression and reduced expression of contraction and energetic genes. Of the 1050 genes specific for moderate-severe MR, there were additional up-regulated genes related to inflammation and reduced expression of genes related to cellular proliferation. CONCLUSIONS: Patients undergoing durable LVAD implantation with moderate-severe MR had increased activation of genes related to inflammation and reduction of cellular proliferation genes. This may have important implications for myocardial recovery.

Role of the mitral valve in left ventricular assist device pathophysiology.

Functional mitral regurgitation (MR) in the setting of heart failure results from progressive dilatation of the left ventricle (LV) and mitral annulus. This leads to leaflet tethering with posterior displacement. Contrary to common assumptions, MR often does not resolve with LVAD decompression of the LV alone. The negative impact of significant (moderate-severe) mitral regurgitation in the LVAD setting is becoming better recognized in terms of its harmful effect on right heart function, pulmonary vascular resistance and hospital readmissions. However, controversies remain regarding the threshold for intervention and management. At present, there are no consensus indications for the repair of significant mitral regurgitation at the time of LVAD implantation due to the conflicting data regarding potential adverse effects of MR on clinical outcomes. In this review, we summarize the current understanding of MR pathophysiology in patients supported with LVAD and potential future management strategies.

Sex-based considerations for implementation of ventricular assist device therapy.

Women with advanced heart failure receive advanced surgical therapies such as durable left ventricular assist device (LVAD) implantation or heart transplantation at a rate much lower compared to males. Reasons for this discrepancy remain largely unknown. Much of what is understood reflects outcomes of those patients who ultimately receive device implant or heart transplantation. Females have been shown to have a higher mortality following LVAD implantation and experience higher rates of bleeding and clotting phenomena and right ventricular failure. Beyond outcomes, the literature is limited in the identification of pre-operative factors that drive lower than expected LVAD implant rates in this population. More focused research is needed to define the disparities in advance heart failure therapy delivery in women and other underserved populations.

Determining optimal donor heart ischemic times in adult cardiac transplantation.

OBJECTIVES: Unsupervised statistical determination of optimal allograft ischemic time (IT) on heart transplant outcomes among ABO donor heart types. METHODS: We identified 36,145 heart transplants (2000-2018) from the United Network for Organ Sharing database. Continuous and categorical variables were analyzed with parametric and nonparametric testing. Determination of IT cutoffs for survival analysis was performed using Contal and O'Quigley univariable method and Vito Muggeo multivariable segmented modeling. RESULTS: Univariable and multivariable IT threshold determination revealed a cutoff at about 3 h. The hourly increase in survival risk with ≥3 h IT is asymmetrically experienced at the early 90 days (hazard ratio [HR] = 1.29, p < .001) and up to 1-year time point (HR = 1.16, p < .001). Beyond 1 year the risk of prolonged IT is less impactful (HR = 1.04, p = .022). Longer IT was associated with more postoperative complications such as stroke (2.7% vs. 2.3, p = .042), dialysis (11.6% vs. 9.1%, p < .001) and death from primary graft dysfunction (1.8% vs. 1.2%, p < .001). O blood type donor hearts with IT ≥ 3 h has significantly increased hourly mortality risk at 90 days (HR = 1.27, p < .001), 90 days to 1 year (HR = 1.22, p < .001) and >1 year (HR = 1.05, p = .041). For non-O blood types with ≥3 h IT hourly mortality risk was increased at 90 days (HR = 1.33, p < .001), but not at 90 days to 1 year (HR = 1.09, p = .146) nor ≥1 year (HR = 1.08, p = .237). CONCLUSIONS: The donor heart IT threshold for survival determined from unbiased statistical modeling occurs at 3 h. With longer preservation times, transplantation with O donor hearts was associated with worse survival.

The role of surgery for secondary mitral regurgitation and heart failure in the era of transcatheter mitral valve therapies.

The approach to the management of mitral valve (MV) disease and heart failure (HF) has dramatically changed over the last decades. It is well recognized that severe mitral regurgitation secondary to ischemic or non-ischemic cardiomyopathy is associated with an excess risk of mortality. Understanding the impact of the surgical treatment modality on mortality outcomes has been difficult due to the broad spectrum of secondary mitral regurgitation (SMR) phenotypes and lack of randomized surgical clinical trials. Over the last 30 years, surgeons have failed to provide compelling evidence to convince the medical community of the need to treat SMR in patients with severe HF. Therefore, the surgical treatment of SMR has never gained uniform acceptance as a significant option among patients suffering from SMR. Recent evidence from randomized trials in a non-surgical eligible patients treated with transcatheter therapies, has provided a new perspective on SMR treatment. Recently published European and American guidelines confirm the key role of percutaneous treatment of SMR and in parallel, these guidelines reinforce the role of mitral valve surgery in patients who require surgical revascularization. Complex mitral valve repair combining subvalvular apparatus repair along with annuloplasty seems to be a promising approach in selected patients in selected centers. Meanwhile, mitral valve replacement has become the preferred surgical strategy in most patients with advanced heart failure and severe LV remodeling or high risk of recurrent mitral regurgitation. In this comprehensive review, we aimed to discuss the role of mitral surgery for SMR in patients with heart failure in the contemporary era and to provide a practical approach for its surgical management.

Impact of donor blood type on outcomes after prolonged allograft ischemic times.

OBJECTIVE: The study objective was to determine the influence of allograft ischemic time on heart transplant outcomes among ABO donor organ types given limited prior reports of its survival impact. METHODS: We identified 32,454 heart transplants (2000-2016) from the United Network for Organ Sharing database. Continuous and categoric variables were analyzed by parametric and nonparametric testing. Survival was determined using log-rank or Cox regression tests. Propensity matching adjusted for preoperative variables. RESULTS: By comparing allograft ischemic time less than 4 hours (n = 6579) with 4 hours or more (n = 25,875), the hazard ratios for death at 15 years after prolonged ischemic time (≥4 hours) for blood types O, A, B, and AB were 1.106 (P < .001), 1.062 (P < .001), 1.059 (P = .062), and 1.114 (P = .221), respectively. Unadjusted data demonstrated higher mortality for transplantation of O versus non-O donor hearts for ischemic time 4 hours or more (hazard ratio, 1.164; P < .001). After propensity matching, O donor hearts continued to have worse survival if preserved for 4 hours or more (hazard ratio, 1.137, P = .008), but not if ischemic time was less than 4 hours (hazard ratio, 1.042, P = .113). In a matched group with 4 hours or more of ischemic time, patients receiving O donor organs were more likely to experience death from primary graft dysfunction (2.5% vs 1.7%, P = .052) and chronic allograft rejection (1.9% vs 1.1%, P = .021). No difference in death from primary graft dysfunction or chronic allograft rejection was seen with less than 4 hours of ischemic time (P > .150). CONCLUSIONS: Compared with non-O donor hearts, transplantation with O donor hearts with ischemic time 4 hours or more leads to worse survival, with higher rates of primary graft dysfunction and chronic rejection. Caution should be practiced when considering donor hearts with the O blood type when anticipating extended cold ischemic times.