Ferroptosis Inhibition Combats Metabolic Derangements and Improves Cardiac Function in Pulmonary Artery Banded Pigs.

Right heart failure (RHF) is a leading cause of mortality in multiple cardiovascular diseases and preclinical and human data suggest impaired metabolism is a significant contributor to right-sided cardiac dysfunction. Ferroptosis is a nonapopotic form of cell death driven by impaired metabolism. Rodent data suggests ferroptosis inhibition can restore mitochondrial electron transport chain function and enhance cardiac contractility in left heart failure models, but the effects of ferroptosis inhibition in translational large animal models of RHF are unknown.

Ferroptosis-Mediated Inflammation Promotes Pulmonary Hypertension.

Background: Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species generation, results in lipid peroxidation and ferroptosis. Ferroptosis is an inflammatory mode of cell death that promotes complement activation and macrophage recruitment. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells exhibit cellular phenotypes that promote ferroptosis.

Restructures the Micro/Mycobiome to Combat Glycoprotein-130 Associated Microtubule Remodeling and Right Ventricular Dysfunction in Pulmonary Arterial Hypertension.

Emerging data demonstrate systemic and local inflammation regulate right ventricular (RV) adaption in preclinical and human pulmonary arterial hypertension (PAH). Pathological RV inflammation is targetable as antagonism of glycoprotein-130 (GP130) signaling counteracts pathological microtubule remodeling and improves RV function in rodents. Microtubules control several aspects of cardiomyocyte biology including cellular and nuclear size/structure, t-tubule homeostasis, and the proper localization of connexin-43.

Pathophysiology of the right ventricle and its pulmonary vascular interaction.

The right ventricle and its stress response is perhaps the most important arbiter of survival in patients with pulmonary hypertension of many causes. The physiology of the cardiopulmonary unit and definition of right heart failure proposed in the 2018 World Symposium on Pulmonary Hypertension have proven useful constructs in subsequent years. Here, we review updated knowledge of basic mechanisms that drive right ventricular function in health and disease, and which may be useful for therapeutic intervention in the future.

Ketone bodies in right ventricular failure: A unique therapeutic opportunity.

Background: Ketone bodies are pleotropic metabolites that play important roles in multiple biological processes ranging from bioenergetics to inflammation regulation via suppression of the NLRP3 inflammasome, and epigenetic modifications. Ketone bodies are elevated in left ventricular failure (LVF) and multiple approaches that increase ketone concentrations exert advantageous cardiac effects in rodents and humans. However, the relationships between ketone bodies and right ventricular failure (RVF) are relatively unexplored.

Multi-omic and multispecies analysis of right ventricular dysfunction.

Background: Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking.

Sex differences in right ventricular function between Groups 1 and 3 pulmonary hypertension.

Group 3 pulmonary hypertension (PH) patients have disproportionate right ventricular dysfunction (RVD) compared to pulmonary arterial hypertension. We evaluated how sex and PH etiology modulated RVD. Strain echocardiography showed no intrasex differences between PH types.

Effect of Combination of Balloon Pulmonary Angioplasty and Medical Therapy on Reverse Right Ventricular Remodeling and Hemodynamics in Chronic Thromboembolic Pulmonary Hypertension.

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive and debilitating disorder that results from incomplete resolution of vascular obstructions resulting in pulmonary hypertension. Surgical pulmonary thromboendarterectomy (PTE) is the treatment of choice for CTEPH. Unfortunately, many CTEPH patients are ineligible for PTE or do not have access to an expert surgical center.

Ketone Bodies in Right Ventricular Failure: A Unique Therapeutic Opportunity.

Ketone bodies are pleotropic metabolites that play important roles in multiple biological processes ranging from bioenergetics to inflammation regulation via suppression of the NLRP3 inflammasome, and epigenetic modifications. Ketone bodies are elevated in left ventricular failure (LVF) and multiple approaches that increase ketone concentrations exert advantageous cardiac effects in rodents and humans. However, the relationships between ketone bodies and right ventricular failure (RVF) are relatively unexplored.

Intermittent Fasting Activates AMP-Kinase to Restructure Right Ventricular Lipid Metabolism and Microtubules.

Intermittent fasting (IF) extends life span via pleotropic mechanisms, but one important molecular mediator is adenosine monophosphate-activated protein kinase (AMPK). AMPK enhances lipid metabolism and modulates microtubule dynamics. Dysregulation of these molecular pathways causes right ventricular (RV) failure in patients with pulmonary arterial hypertension.

Effect of Chronic Digoxin Use on Mortality and Heart Failure Hospitalization in Pulmonary Arterial Hypertension.

Background Digoxin acutely increases cardiac output in patients with pulmonary arterial hypertension (PAH) and right ventricular failure; however, the effects of chronic digoxin use in PAH are unclear. Methods and Results Data from the Minnesota Pulmonary Hypertension Repository were used. The primary analysis used likelihood of digoxin prescription.

Junctophilin-2 Regulates Mitochondrial Metabolism.

Right ventricular dysfunction (RVD) is a risk factor for mortality in multiple cardiovascular diseases, but approaches to combat RVD are lacking. Therapies used for left heart failure are largely ineffective in RVD, and thus the identification of molecules that augment RV function could improve outcomes in a wide-array of cardiac limitations. Junctophilin-2 (JPH2) is an essential protein that plays important roles in cardiomyocytes, including calcium handling/maintenance of t-tubule structure and gene transcription.

A Multi-omic and Multi-Species Analysis of Right Ventricular Failure.

Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no approved treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking.

Ferroptosis Integrates Mitochondrial Derangements and Pathological Inflammation to Promote Pulmonary Hypertension.

Background: Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species (ROS) generation, results in lipid peroxidation and ferroptosis. Ferroptosis is an inflammatory mode of cell death that promotes complement activation and macrophage recruitment. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells (PAEC) exhibit cellular phenotypes that promote ferroptosis.

An integrated proteomic and transcriptomic signature of the failing right ventricle in monocrotaline induced pulmonary arterial hypertension in male rats.

Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy that results in death from right ventricular failure (RVF). There is limited understanding of the molecular mechanisms of RVF in PAH. In a PAH-RVF model induced by injection of adult male rats with monocrotaline (MCT; 60 mg/kg), we performed mass spectrometry to identify proteins that change in the RV as a consequence of PAH induced RVF.