Treprostinil Effectiveness in Higher-Risk Pediatric Patients With Idiopathic and Heritable Pulmonary Arterial Hypertension.

Background: Little is known about the effectiveness of treprostinil in higher-risk paediatric patients with various pulmonary arterial hypertension genotypes. This study was designed to investigate the prognosis of higher-risk paediatric patients with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH) after treprostinil therapy.

Methods: Children with IPAH/HPAH who were stratified as higher risk and treated with treprostinil in our centre were included as the study cohort.

Right Heart Catheterization in Pediatric Pulmonary Arterial Hypertension: Insights and Outcome from a Large Tertiary Center.

Aim: To define the clinical characteristics, hemodynamics, and adverse events for pediatric patients with pulmonary arterial hypertension (PAH) undergoing right heart catheterization (RHC). Methods: The large referral single center data of 591 diagnostic RHC procedures performed between 2005 and 2020 on pediatric PAH patients was retrospectively collected and analyzed. Results: A total of 591 RHC procedures performed on 469 patients with congenital heart disease (CHD)-PAH (median age 8.

Isolated Coarctation of the Aorta: Current Concepts and Perspectives.

Current management of isolated CoA, localized narrowing of the aortic arch in the absence of other congenital heart disease, is a success story with improved prenatal diagnosis, high survival and improved understanding of long-term complication. Isolated CoA has heterogenous presentations, complex etiologic mechanisms, and progressive pathophysiologic changes that influence outcome. End-to-end or extended end-to-end anastomosis are the favored surgical approaches for isolated CoA in infants and transcatheter intervention is favored for children and adults.

Pulmonary hypertensive crisis in children with pulmonary arterial hypertension undergoing cardiac catheterization.

Pediatric patients with pulmonary arterial hypertension (PAH) are considered to be at risk for pulmonary hypertensive crisis (PHC) or even death during right heart catheterization (RHC). This retrospective study was designed to identify the risks and clinical characteristics associated with PHC in pediatric PAH patients. We included 163 consecutive procedures from 147 pediatric patients diagnosed with PAH who underwent diagnostic RHC in Beijing Anzhen Hospital between January 2007 and December 2020.

Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane AMPK/NRF2 pathways.

Herein, we define the role of ferroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) by examining the expression of key regulators of ferroptosis in mice with DCM and a new DCM model. Advanced glycation end-products (AGEs), an important pathogenic factor of DCM, were found to induce ferroptosis in engineered cardiac tissues (ECTs), as reflected through increased levels of and lipid peroxides and decreased ferritin and SLC7A11 levels. Typical morphological changes of ferroptosis in cardiomyocytes were observed using transmission electron microscopy.

Sulforaphane Does Not Protect Right Ventricular Systolic and Diastolic Functions in Nrf2 Knockout Pulmonary Artery Hypertension Mice.

Purpose: Nrf2 is a nuclear transcription factor and plays an important role in the regulation of oxidative stress and inflammation. We recently demonstrated that sulforaphane (SFN) protected mice from developing pulmonary arterial hypertension (PAH) and right ventricular (RV) dysfunction by elevating cardiac Nrf2 expression and function. Here we further investigate Nrf2 dependence for SFN-mediated prevention of PAH and RV dysfunction in an Nrf2 knockout mouse model.

Better Outcomes in Pulmonary Arterial Hypertension After Repair of Congenital Heart Disease, Compared With Idiopathic Pulmonary Arterial Hypertension.

Background: Pulmonary vascular changes in postoperative pulmonary artery hypertension (PAH) are similar to those seen in idiopathic PAH. Data are sparse on direct comparative midterm outcomes for these 2 high-risk populations.

Methods: Patients with idiopathic or postoperative PAH referred to a large tertiary hospital between June 2005 and July 2019 were retrospectively evaluated.

Emerging roles of microRNA-208a in cardiology and reverse cardio-oncology.

Cardiovascular diseases (CVDs) and cancer, which are the leading causes of mortality globally, have been viewed as two distinct diseases. However, the fact that cancer and CVDs may coincide has been noted by cardiologists when taking care of patients with CVDs caused by cancer chemotherapy; this entity is designated cardio-oncology. More recently, patients with CVDs have also been found to have increased risk of cancers, termed reverse cardio-oncology.

Engineered cardiac tissues: a novel in vitro model to investigate the pathophysiology of mouse diabetic cardiomyopathy.

Rodent diabetic models, used to understand the pathophysiology of diabetic cardiomyopathy (DCM), remain several limitations. Engineered cardiac tissues (ECTs) have emerged as robust 3D in vitro models to investigate structure-function relationships as well as cardiac injury and repair. Advanced glycation end-products (AGEs), produced through glycation of proteins or lipids in response to hyperglycemia, are important pathogenic factor for the development of DCM.

Chronic Optogenetic Pacing of Human-Induced Pluripotent Stem Cell-Derived Engineered Cardiac Tissues.

The delivery of cells into damaged myocardium induces limited cardiac regeneration due to extensive cell death. In an effort to limit cell death, our lab formulates three-dimensional matrices as a delivery system for cell therapy. Our primary work has been focused on the formation of engineered cardiac tissues (ECTs) from human-induced pluripotent stem cell-derived engineered cardiac cells.

Preparation of Mesh-Shaped Engineered Cardiac Tissues Derived from Human iPS Cells for In Vivo Myocardial Repair.

The current protocol describes methods to generate scalable, mesh-shaped engineered cardiac tissues (ECTs) composed of cardiovascular cells derived from human induced pluripotent stem cells (hiPSCs), which are developed towards the goal of clinical use. HiPSC-derived cardiomyocytes, endothelial cells, and vascular mural cells are mixed with gel matrix and then poured into a polydimethylsiloxane (PDMS) tissue mold with rectangular internal staggered posts. By culture day 14 ECTs mature into a 1.

Validating the Paradigm That Biomechanical Forces Regulate Embryonic Cardiovascular Morphogenesis and Are Fundamental in the Etiology of Congenital Heart Disease.

The goal of this review is to provide a broad overview of the biomechanical maturation and regulation of vertebrate cardiovascular (CV) morphogenesis and the evidence for mechanistic relationships between function and form relevant to the origins of congenital heart disease (CHD). The embryonic heart has been investigated for over a century, initially focusing on the chick embryo due to the opportunity to isolate and investigate myocardial electromechanical maturation, the ability to directly instrument and measure normal cardiac function, intervene to alter ventricular loading conditions, and then investigate changes in functional and structural maturation to deduce mechanism. The paradigm of "Develop and validate quantitative techniques, describe normal, perturb the system, describe abnormal, then deduce mechanisms" was taught to many young investigators by Dr.

Zinc as a countermeasure for cadmium toxicity.

Cadmium (Cd) is an important environmental pollutant and long-term Cd exposure is closely related to autoimmune diseases, cancer, cardiovascular diseases (CVD), and hepatic dysfunction. Zinc (Zn) is an essential metal that plays key roles in protein structure, catalysis, and regulation of their function. Numerous studies have shown that Zn can reduce Cd toxicity; however, the underlying mechanisms have not been extensively explored.

Sulforaphane prevents right ventricular injury and reduces pulmonary vascular remodeling in pulmonary arterial hypertension.

Right ventricular (RV) dysfunction is the main determinant of mortality in patients with pulmonary arterial hypertension (PAH) and while inflammation is pathogenic in PAH, there is limited information on the role of RV inflammation in PAH. Sulforaphane (SFN), a potent Nrf2 activator, has significant anti-inflammatory effects and facilitates cardiac protection in preclinical diabetic models. Therefore, we hypothesized that SFN might play a comparable role in reducing RV and pulmonary inflammation and injury in a murine PAH model.

Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: preclinical and clinical evidence.

The pathogenesis and clinical features of diabetic cardiomyopathy have been well-studied in the past decade, but effective approaches to prevent and treat this disease are limited. Diabetic cardiomyopathy occurs as a result of the dysregulated glucose and lipid metabolism associated with diabetes mellitus, which leads to increased oxidative stress and the activation of multiple inflammatory pathways that mediate cellular and extracellular injury, pathological cardiac remodelling, and diastolic and systolic dysfunction. Preclinical studies in animal models of diabetes have identified multiple intracellular pathways involved in the pathogenesis of diabetic cardiomyopathy and potential cardioprotective strategies to prevent and treat the disease, including antifibrotic agents, anti-inflammatory agents and antioxidants.

Zinc protects against cadmium-induced toxicity in neonatal murine engineered cardiac tissues via metallothionein-dependent and independent mechanisms.

Cadmium (Cd) is a nonessential heavy metal and a prevalent environmental toxin that has been shown to induce significant cardiomyocyte apoptosis in neonatal murine engineered cardiac tissues (ECTs). In contrast, zinc (Zn) is a potent metallothionein (MT) inducer, which plays an important role in protection against Cd toxicity. In this study, we investigated the protective effects of Zn against Cd toxicity in ECTs and explore the underlying mechanisms.

Neonatal murine engineered cardiac tissue toxicology model: Impact of dexrazoxane on doxorubicin induced injury.

Doxorubicin (DOX) induced cardiotoxicity is a life-threatening side effect of chemotherapy and decreased cardiac function can present years after treatment. Despite the investigation of a broad range of pharmacologic interventions, to date the only drug shown to reduce DOX-related cardiotoxicity in preclinical studies and limited clinical trials is the iron chelating agent, dexrazoxane (DRZ), although the mechanisms responsible for DRZ mediated protection from DOX related cardiotoxicity remain unclear. Engineered cardiac tissues (ECTs) can be used for tissue repair strategies and as in vitro surrogate models to test cardiac toxicities and preventative countermeasures.

Nrf2: Redox and Metabolic Regulator of Stem Cell State and Function.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is ubiquitously expressed in most eukaryotic cells and functions to induce a broad range of cellular defenses against exogenous and endogenous stresses, including oxidants, xenobiotics, and excessive nutrient/metabolite supply. Because the production and fate of stem cells are often modulated by cellular redox and metabolic homeostasis, important roles of Nrf2 have emerged in the regulation of stem cell quiescence, survival, self-renewal, proliferation, senescence, and differentiation. In a rapidly advancing field, this review summarizes Nrf2 signaling in the context of stem cell state and function and provides a rationale for Nrf2 as a therapeutic target in stem cell-based regenerative medicine.

Chronic optical pacing conditioning of h-iPSC engineered cardiac tissues.

The immaturity of human induced pluripotent stem cell derived engineered cardiac tissues limits their ability to regenerate damaged myocardium and to serve as robust models for human disease and drug toxicity studies. Several chronic biomimetic conditioning protocols, including mechanical stretch, perfusion, and/or electrical stimulation promote engineered cardiac tissue maturation but have significant technical limitations. Non-contacting chronic optical stimulation using heterologously expressed channelrhodopsin light-gated ion channels, termed optogenetics, may be an advantageous alternative to chronic invasive electrical stimulation for engineered cardiac tissue conditioning.

Utilizing Contrast-Enhanced Ultrasound Imaging for Evaluating Fatty Liver Disease Progression in Pre-clinical Mouse Models.

We developed a protocol to investigate and optimize the application of contrast-enhanced ultrasound (CEUS) to non-invasive diagnosis of progressing fatty liver disease in mouse models. Eighteen 4-wk-old male C57 L/J mice were randomly assigned to one of the three groups and placed on a control diet, high-fat diet or non-alcoholic steatohepatitis diet for the next 10 wk. After 14 wk, B-mode imaging and CEUS imaging using a VisualSonics Vevo2100 system were performed.

Asymmetry in Mechanosensitive Gene Expression during Aortic Arch Morphogenesis.

Embryonic aortic arches (AA) are initially bilaterally paired, transitional vessels and failures in remodeling based on hemodynamic and growth-related adaptations cause a spectrum of congenital heart disease (CHD) anatomies. Identifying regulatory mechanisms and cross-talk between the genetic elements of these vessels are critical to understand the ethiology of CHD and refine predictive computational models. This study aims to screen expression profiles of fundamental biological pathways in AA at early stages of chick embryo morphogenesis and correlate them with our current understanding of growth and mechanical loading.

Right ventricular dysfunction and remodeling in diabetic cardiomyopathy.

The increasing prevalence of diabetic cardiomyopathy (DCM) is an important threat to health worldwide. While left ventricular (LV) dysfunction in DCM is well recognized, the accurate detection, diagnosis, and treatment of changes in right ventricular (RV) structure and function have not been well characterized. The pathophysiology of RV dysfunction in DCM may share features with LV diastolic and systolic dysfunction, including pathways related to insulin resistance and oxidant injury, although the RV has a unique cellular origin and composition and unique biomechanical properties and is coupled to the lower-impedance pulmonary vascular bed.

Adipose-derived cells improve left ventricular diastolic function and increase microvascular perfusion in advanced age.

An early manifestation of coronary artery disease in advanced age is the development of microvascular dysfunction leading to deficits in diastolic function. Our lab has previously shown that epicardial treatment with adipose-derived stromal vascular fraction (SVF) preserves microvascular function following coronary ischemia in a young rodent model. Follow-up studies showed intravenous (i.

Neonatal Murine Engineered Cardiac Tissue Toxicology Model: Impact of Metallothionein Overexpression on Cadmium-Induced Injury.

Engineered cardiac tissues (ECTs) serve as robust in vitro models to study human cardiac diseases including cardiac toxicity assays due to rapid structural and functional maturation and the ability to vary ECT composition. Metallothionein (MT) has been shown to be cardioprotective for environmental toxicants including heavy metals. To date, studies on the role of cardiomyocyte (CM)-specific MT expression and function have occurred in dissociated single cell assays or expensive in vivo small animal models.