Mineralocorticoid Receptor Antagonism Reduces Atrial Arrhythmias Post-Cardiac Surgery and Attenuates Atrial Stress Responses to Cardioplegic Arrest.

Background: New postoperative atrial fibrillation (POAF) occurs in about 40% after cardiac surgery. Mineralocorticoid receptor antagonists (MRA) are known to reduce chronic atrial fibrillation (AF) development and burden. We examined the impact of preoperative MRA use on POAF and also examine the atrial cell type impacted by MRA treatment during cold cardiac preservation.

The origin, progress, and application of cell-based cardiac regeneration therapy.

Cardiovascular disease (CVD) has become a severe threat to human health, with morbidity and mortality increasing yearly and gradually becoming younger. When the disease progresses to the middle and late stages, the loss of a large number of cardiomyocytes is irreparable to the body itself, and clinical drug therapy and mechanical support therapy cannot reverse the development of the disease. To explore the source of regenerated myocardium in model animals with the ability of heart regeneration through lineage tracing and other methods, and develop a new alternative therapy for CVDs, namely cell therapy.

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.

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.

Assessment of Ex Vivo Murine Biventricular Function in a Langendorff Model.

Primary graft dysfunction (PGD) remains the leading cause of early death following heart transplantation. Prolonged ischemic time during cold preservation is an important risk factor for PGD, and reliable evaluation of cardiac function is essential to study the functional responses of the donor heart after cold preservation. The accompanying video describes a technique to assess murine right and left ventricular function using ex vivo perfusion based in a Langendorff model after cold preservation for different durations.

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.

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.

Acetyl-CoA production by specific metabolites promotes cardiac repair after myocardial infarction via histone acetylation.

Myocardial infarction (MI) is accompanied by severe energy deprivation and extensive epigenetic changes. However, how energy metabolism and chromatin modifications are interlinked during MI and heart repair has been poorly explored. Here, we examined the effect of different carbon sources that are involved in the major metabolic pathways of acetyl-CoA synthesis on myocardial infarction and found that elevation of acetyl-CoA by sodium octanoate (8C) significantly improved heart function in ischemia reperfusion (I/R) rats.

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.

Untargeted metabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysm and dissection.

Aims: Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with no effective cure. Macrophages play an important role in the development of AAD. As succinate triggers inflammatory changes in macrophages, we investigated the significance of succinate in the pathogenesis of AAD and its clinical relevance.

Differential inflammatory responses of the native left and right ventricle associated with donor heart preservation.

Background: Dysfunction and inflammation of hearts subjected to cold ischemic preservation may differ between left and right ventricles, suggesting distinct strategies for amelioration.

Methods And Results: Explanted murine hearts subjected to cold ischemia for 0, 4, or 8 h in preservation solution were assessed for function during 60 min of warm perfusion and then analyzed for cell death and inflammation by immunohistochemistry and western blotting and total RNA sequencing. Increased cold ischemic times led to greater left ventricle (LV) dysfunction compared to right ventricle (RV).

Risk factors for heart transplant survival with greater than 5 h of donor heart ischemic time.

Objective: Implantation of donor hearts with prolonged ischemic times is associated with worse survival. We sought to identify risk factors that modulate the effects of prolonged preservation.

Methods: Retrospective review of the United Network for Organ Sharing database (2000-2018) to identify transplants with >5 (n = 1526) or ≤5 h (n = 35,733) of donor heart preservation.

"The Secret Life of Human Donor Hearts": An Examination of Transcriptomic Events During Cold Storage.

Background: Ischemic tolerance of donor hearts has a major impact on the efficiency in utilization and clinical outcomes. Molecular events during storage may influence the severity of ischemic injury.

Methods: RNA sequencing was used to study the transcriptional profile of the human left ventricle (LV, n=4) and right ventricle (RV, n=4) after 0, 4, and 8 hours of cold storage in histidine-tryptophan-ketoglutarate preservation solution.

SWI/SNF Component BAF250a Coordinates OCT4 and WNT Signaling Pathway to Control Cardiac Lineage Differentiation.

Dissecting epigenetic mechanisms controlling early cardiac differentiation will provide insights into heart regeneration and heart disease treatment. SWI/SNF complexes remodel nucleosomes to regulate gene expression and play a key role in organogenesis. Here, we reported a unique function of BAF250a in regulating the physical interaction of OCT4 and β-CATENIN during cardiac lineage differentiation from human ESCs.

Histidine-Tryptophan-Ketoglutarate Solution for Donor Heart Preservation Is Safe for Transplantation.

Background: Various solutions are used for donor heart preservation. We examined the outcomes in our heart transplant population where histidine-tryptophan-ketoglutarate (HTK) solution has been used for heart preservation since 2004.

Methods: This was a retrospective review of the United Network for Organ Sharing (UNOS) database (2004-2016) comparing our heart transplant outcomes with other national centers.

Chemical suppression of specific C-C chemokine signaling pathways enhances cardiac reprogramming.

Reprogramming of fibroblasts into induced cardiomyocytes (iCMs) is a potentially promising strategy for regenerating a damaged heart. However, low fibroblast-cardiomyocyte conversion rates remain a major challenge in this reprogramming. To this end, here we conducted a chemical screen and identified four agents, insulin-like growth factor-1, Mll1 inhibitor MM589, transforming growth factor-β inhibitor A83-01, and Bmi1 inhibitor PTC-209, termed IMAP, which coordinately enhanced reprogramming efficiency.

Chromatin remodeling mediated by ARID1A is indispensable for normal hematopoiesis in mice.

Precise regulation of chromatin architecture is vital to physiological processes including hematopoiesis. ARID1A is a core component of the mammalian SWI/SNF complex, which is one of the ATP-dependent chromatin remodeling complexes. To uncover the role of ARID1A in hematopoietic development, we utilized hematopoietic cell-specific deletion of Arid1a in mice.