Single cell multiomics and 3D genome architecture reveal novel pathways of human heart failure.

Heart failure is a leading cause of morbidity and mortality; yet gene regulatory mechanisms driving cell type-specific pathologic responses remain undefined. Here, we present the cell type-resolved transcriptomes, chromatin accessibility, histone modifications and chromatin organization of 36 non-failing and failing human hearts profiled from 776,479 cells spanning all cardiac chambers. Integrative analyses revealed dynamic changes in cell type composition, gene regulatory programs and chromatin organization, which expanded the annotation of cardiac -regulatory sequences by ten-fold and mapped cell type-specific enhancer-gene interactions.

The role of sphingolipids in heart failure.

Advanced heart failure (HF) is characterized by changes in the structure, function, and metabolism of cardiac muscle. As the disease progresses, cardiomyocytes shift their ATP production from fatty acid oxidation to glycolysis. This shift results in an accumulation of lipid metabolites, particularly sphingolipids, which can disrupt normal cellular function and contribute to cardiac dysfunction.

Peroxisome proliferator-activated receptor gamma ( )-mediated myocardial salvage in acute myocardial infarction managed with left ventricular unloading and coronary reperfusion.

Ischemic heart disease and acute myocardial infarction (AMI) is a leading cause of morbidity and mortality. Improvements have been made in coronary interventions to restore blood flow, but ischemia/reperfusion (I/R) injury significantly impacts clinical outcomes. We previously reported that activation of percutaneous mechanical unloading of the left ventricle (LV) with a transvalvular axial-flow device simultaneously with reperfusion improves myocardial salvage.

Direct mitochondrial import of lactate supports resilient carbohydrate oxidation.

Lactate is the highest turnover circulating metabolite in mammals. While traditionally viewed as a waste product, lactate is an important energy source for many organs, but first must be oxidized to pyruvate for entry into the tricarboxylic acid cycle (TCA cycle). This reaction is thought to occur in the cytosol, with pyruvate subsequently transported into mitochondria via the mitochondrial pyruvate carrier (MPC).

Enhancing mitochondrial pyruvate metabolism ameliorates ischemic reperfusion injury in the heart.

The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart; however, the rapid reintroduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the total myocardial damage, but there are no pharmacological interventions to reduce I/R.

Enhancing mitochondrial pyruvate metabolism ameliorates myocardial ischemic reperfusion injury.

The established clinical therapy for the treatment of acute myocardial infarction is primary percutaneous coronary intervention (PPCI) to restore blood flow to the ischemic myocardium. PPCI is effective at reperfusing the ischemic myocardium, however the rapid re-introduction of oxygenated blood also can cause ischemia-reperfusion (I/R) injury. Reperfusion injury is the culprit for up to half of the final myocardial damage, but there are no clinical interventions to reduce I/R injury.

Defining cardiac functional recovery in end-stage heart failure at single-cell resolution.

Recovery of cardiac function is the holy grail of heart failure therapy yet is infrequently observed and remains poorly understood. In this study, we performed single-nucleus RNA sequencing from patients with heart failure who recovered left ventricular systolic function after left ventricular assist device implantation, patients who did not recover and non-diseased donors. We identified cell-specific transcriptional signatures of recovery, most prominently in macrophages and fibroblasts.

Distinct Transcriptomic and Proteomic Profile Specifies Patients Who Have Heart Failure With Potential of Myocardial Recovery on Mechanical Unloading and Circulatory Support.

Background: Extensive evidence from single-center studies indicates that a subset of patients with chronic advanced heart failure (HF) undergoing left ventricular assist device (LVAD) support show significantly improved heart function and reverse structural remodeling (ie, termed "responders"). Furthermore, we recently published a multicenter prospective study, RESTAGE-HF (Remission from Stage D Heart Failure), demonstrating that LVAD support combined with standard HF medications induced remarkable cardiac structural and functional improvement, leading to high rates of LVAD weaning and excellent long-term outcomes. This intriguing phenomenon provides great translational and clinical promise, although the underlying molecular mechanisms driving this recovery are largely unknown.

Tumor-specific interendothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness.

Blood vessel abnormalization alters cancer cell metabolism and promotes cancer dissemination and metastasis. However, the biological features of the abnormalized blood vessels that facilitate cancer progression and whether they can be targeted therapeutically have not been fully investigated. Here, we found that an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), is expressed preferentially in abnormalized vessels of advanced colorectal cancers in humans and that its expression correlates negatively with long-term survival.

FGF21 (Fibroblast Growth Factor 21) Defines a Potential Cardiohepatic Signaling Circuit in End-Stage Heart Failure.

Background: Extrinsic control of cardiomyocyte metabolism is poorly understood in heart failure (HF). FGF21 (Fibroblast growth factor 21), a hormonal regulator of metabolism produced mainly in the liver and adipose tissue, is a prime candidate for such signaling.

Methods: To investigate this further, we examined blood and tissue obtained from human subjects with end-stage HF with reduced ejection fraction at the time of left ventricular assist device implantation and correlated serum FGF21 levels with cardiac gene expression, immunohistochemistry, and clinical parameters.

Cardiac-specific deletion of voltage dependent anion channel 2 leads to dilated cardiomyopathy by altering calcium homeostasis.

Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood.

Remodeling of t-system and proteins underlying excitation-contraction coupling in aging versus failing human heart.

It is well established that the aging heart progressively remodels towards a senescent phenotype, but alterations of cellular microstructure and their differences to chronic heart failure (HF) associated remodeling remain ill-defined. Here, we show that the transverse tubular system (t-system) and proteins underlying excitation-contraction coupling in cardiomyocytes are characteristically remodeled with age. We shed light on mechanisms of this remodeling and identified similarities and differences to chronic HF.

The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure.

The metabolic rewiring of cardiomyocytes is a widely accepted hallmark of heart failure (HF). These metabolic changes include a decrease in mitochondrial pyruvate oxidation and an increased export of lactate. We identify the mitochondrial pyruvate carrier (MPC) and the cellular lactate exporter monocarboxylate transporter 4 (MCT4) as pivotal nodes in this metabolic axis.

The Role of Nonglycolytic Glucose Metabolism in Myocardial Recovery Upon Mechanical Unloading and Circulatory Support in Chronic Heart Failure.

Background: Significant improvements in myocardial structure and function have been reported in some patients with advanced heart failure (termed responders [R]) following left ventricular assist device (LVAD)-induced mechanical unloading. This therapeutic strategy may alter myocardial energy metabolism in a manner that reverses the deleterious metabolic adaptations of the failing heart. Specifically, our previous work demonstrated a post-LVAD dissociation of glycolysis and oxidative-phosphorylation characterized by induction of glycolysis without subsequent increase in pyruvate oxidation through the tricarboxylic acid cycle.

Effect of Continuous-Flow Left Ventricular Assist Device Support on Coronary Artery Endothelial Function in Ischemic and Nonischemic Cardiomyopathy.

Background: The coronary vasculature encounters a reduction in pulsatility after implementing durable continuous-flow left ventricular assist device (CF-LVAD) circulatory support. Evidence exists that appropriate pulsatility is required to maintain endothelial cell homeostasis. We hypothesized that coronary artery endothelial function would be impaired after CF-LVAD intervention.

Placental labyrinth formation in mice requires endothelial FLRT2/UNC5B signaling.

The placental labyrinth is the interface for gas and nutrient exchange between the embryo and the mother; hence its proper development is essential for embryogenesis. However, the molecular mechanism underlying development of the placental labyrinth, particularly in terms of its endothelial organization, is not well understood. Here, we determined that fibronectin leucine-rich transmembrane protein 2 (FLRT2), a repulsive ligand of the UNC5 receptor family for neurons, is unexpectedly expressed in endothelial cells specifically in the placental labyrinth.

Evidence of Glycolysis Up-Regulation and Pyruvate Mitochondrial Oxidation Mismatch During Mechanical Unloading of the Failing Human Heart: Implications for Cardiac Reloading and Conditioning.

This study sought to investigate the effects of mechanical unloading on myocardial energetics and the metabolic perturbation of heart failure (HF) in an effort to identify potential new therapeutic targets that could enhance the unloading-induced cardiac recovery. The authors prospectively examined paired human myocardial tissue procured from 31 advanced HF patients at left ventricular assist device (LVAD) implant and at heart transplant plus tissue from 11 normal donors. They identified increased post-LVAD glycolytic metabolites without a coordinate increase in early, tricarboxylic acid (TCA) cycle intermediates.

Sheet-Like Remodeling of the Transverse Tubular System in Human Heart Failure Impairs Excitation-Contraction Coupling and Functional Recovery by Mechanical Unloading.

Background: Cardiac recovery in response to mechanical unloading by left ventricular assist devices (LVADs) has been demonstrated in subgroups of patients with chronic heart failure (HF). Hallmarks of HF are depletion and disorganization of the transverse tubular system (t-system) in cardiomyocytes. Here, we investigated remodeling of the t-system in human end-stage HF and its role in cardiac recovery.

Recovery Versus Remission: Clinical Insights.

Adverse myocardial remodeling can be reversed by medical, surgical, and device therapies leading to reduced heart failure (HF) morbidity and mortality and significant improvements in the structure and function of the failing heart. The growing population of HF patients who experience a degree of myocardial improvement should be better studied in terms of long-term outcomes and underlying biology to more clearly define the difference between recovery and remission. These investigations should also be focused in determining whether in chronic HF patients complete myocardial recovery is achievable at a meaningful rate and help us better understand, predict, and manipulate cardiac recovery.

UNC5B receptor deletion exacerbates tissue injury in response to AKI.

Netrin-1 regulates cell survival and apoptosis by activation of its receptors, including UNC5B. However, the in vivo role of UNC5B in cell survival during cellular stress and tissue injury is unknown. We investigated the role of UNC5B in cell survival in response to stress using mice heterozygously expressing the UNC5B gene (UNC5B(-/flox)) and mice with targeted homozygous deletion of UNC5B in kidney epithelial cells (UNC5B(-/flox/GGT-cre)).

The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases.

Cerebral cavernous malformation (CCM) is a common vascular dysplasia that affects both systemic and central nervous system blood vessels. Loss of function mutations in the CCM2 gene cause CCM. Here we show that targeted disruption of Ccm2 in mice results in failed lumen formation and early embryonic death through an endothelial cell autonomous mechanism.

The netrin receptor UNC5B promotes angiogenesis in specific vascular beds.

There is emerging evidence that the canonical neural guidance factor netrin can also direct the growth of blood vessels. We deleted the gene encoding UNC5B, a receptor for the netrin family of guidance molecules, specifically within the embryonic endothelium of mice. The result is a profound structural and functional deficiency in the arterioles of the placental labyrinth, which leads first to flow reversal in the umbilical artery and ultimately to embryonic death.