Dynamin-related protein 1 is a critical regulator of mitochondrial calcium homeostasis during myocardial ischemia/reperfusion injury.

Dynamin-related protein 1 (Drp1) is a cytosolic GTPase protein that when activated translocates to the mitochondria, meditating mitochondrial fission and increasing reactive oxygen species (ROS) in cardiomyocytes. Drp1 has shown promise as a therapeutic target for reducing cardiac ischemia/reperfusion (IR) injury; however, the lack of specificity of some small molecule Drp1 inhibitors and the reliance on the use of Drp1 haploinsufficient hearts from older mice have left the role of Drp1 in IR in question. Here, we address these concerns using two approaches, using: (a) short-term (3 weeks), conditional, cardiomyocyte-specific, Drp1 knockout (KO) and (b) a novel, highly specific Drp1 GTPase inhibitor, Drpitor1a.

Microglial Activation and Neurological Outcomes in a Murine Model of Cardiac Arrest.

Background: Neurological injury following successful resuscitation from sudden cardiac arrest (CA) is common. The pathophysiological basis of this injury remains poorly understood, and treatment options are limited. Microglial activation and neuroinflammation are established contributors to many neuropathologies, such as Alzheimer disease and traumatic brain injury, but their potential role in post-CA injury has only recently been recognized.

Assessment of Brain Glucose Metabolism Following Cardiac Arrest by [F]FDG Positron Emission Tomography.

Background: Cardiac arrest (CA) patients who survived by cardiopulmonary resuscitation (CPR) can present different levels of neurological deficits ranging from minor cognitive impairments to persistent vegetative state and brain death. The pathophysiology of the resulting brain injury is poorly understood, and whether changes in post-CA brain metabolism contribute to the injury are unknown. Here we utilized [F]fluorodeoxyglucose (FDG)-Positron emission tomography (PET) to study in vivo cerebral glucose metabolism 72 h following CA in a murine CA model.

Suppression of Superoxide-Hydrogen Peroxide Production at Site IQ of Mitochondrial Complex I Attenuates Myocardial Stunning and Improves Postcardiac Arrest Outcomes.

Objectives: Cardiogenic shock following cardiopulmonary resuscitation for sudden cardiac arrest is common, occurring even in the absence of acute coronary artery occlusion, and contributes to high rates of postcardiopulmonary resuscitation mortality. The pathophysiology of this shock is unclear, and effective therapies for improving clinical outcomes are lacking.

Design: Laboratory investigation.

Enhanced pyruvate dehydrogenase activity improves cardiac outcomes in a murine model of cardiac arrest.

Rationale: Post-ischemic changes in cellular metabolism alter myocardial and neurological function. Pyruvate dehydrogenase (PDH), the limiting step in mitochondrial glucose oxidation, is inhibited by increased expression of PDH kinase (PDK) during ischemia/reperfusion injury. This results in decreased utilization of glucose to generate cellular ATP.

Honokiol, an activator of Sirtuin-3 (SIRT3) preserves mitochondria and protects the heart from doxorubicin-induced cardiomyopathy in mice.

Doxorubicin is the chemotherapeutic drug of choice for a wide variety of cancers, and cardiotoxicity is one of the major side effects of doxorubicin treatment. One of the main cellular targets of doxorubicin in the heart is mitochondria. Mitochondrial sirtuin, SIRT3 has been shown to protect against doxorubicin-induced cardiotoxicity.

Inhibition of the mitochondrial fission protein dynamin-related protein 1 improves survival in a murine cardiac arrest model.

Objectives: Survival following sudden cardiac arrest is poor despite advances in cardiopulmonary resuscitation and the use of therapeutic hypothermia. Dynamin-related protein 1, a regulator of mitochondrial fission, is an important determinant of reactive oxygen species generation, myocardial necrosis, and left ventricular function following ischemia/reperfusion injury, but its role in cardiac arrest is unknown. We hypothesized that dynamin-related protein 1 inhibition would improve survival, cardiac hemodynamics, and mitochondrial function in an in vivo model of cardiac arrest.

Differential regeneration of myocardial infarction depending on the progression of disease and the composition of biomimetic hydrogel.

Hydrogel has been used for regenerating myocardial infraction (MI) as a delivery vehicle for cells and growth factors. This study showed that injectable hyaluronic acid (HA)-based hydrogels alone would effectively regenerate the damaged infarcted heart tissue. We found that there are two major factors of regeneration in MI.

Dynamin-related protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission.

Mitochondrial fission, regulated by dynamin-related protein-1 (Drp1), is a newly recognized determinant of mitochondrial function, but its contribution to left ventricular (LV) impairment following ischemia-reperfusion (IR) injury is unknown. We report that Drp1 activation during IR results in LV dysfunction and that Drp1 inhibition is beneficial. In both isolated neonatal murine cardiomyocytes and adult rat hearts (Langendorff preparation) mitochondrial fragmentation and swelling occurred within 30 min of IR.

Cardiac glutaminolysis: a maladaptive cancer metabolism pathway in the right ventricle in pulmonary hypertension.

Unlabelled: The rapid growth of cancer cells is permitted by metabolic changes, notably increased aerobic glycolysis and increased glutaminolysis. Aerobic glycolysis is also evident in the hypertrophying myocytes in right ventricular hypertrophy (RVH), particularly in association with pulmonary arterial hypertension (PAH). It is unknown whether glutaminolysis occurs in the heart.

Metabolism and bioenergetics in the right ventricle and pulmonary vasculature in pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a syndrome in which pulmonary vascular cross sectional area and compliance are reduced by vasoconstriction, vascular remodeling, and inflammation. Vascular remodeling results in part from increased proliferation and impaired apoptosis of vascular cells. The resulting increase in afterload promotes right ventricular hypertrophy (RVH) and RV failure.

PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is a lethal, female-predominant, vascular disease. Pathologic changes in PA smooth muscle cells (PASMC) include excessive proliferation, apoptosis-resistance, and mitochondrial fragmentation. Activation of dynamin-related protein increases mitotic fission and promotes this proliferation-apoptosis imbalance.

FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate.

Pyruvate dehydrogenase kinase (PDK) is activated in right ventricular hypertrophy (RVH), causing an increase in glycolysis relative to glucose oxidation that impairs right ventricular function. The stimulus for PDK upregulation, its isoform specificity, and the long-term effects of PDK inhibition are unknown. We hypothesize that FOXO1-mediated PDK4 upregulation causes bioenergetic impairment and RV dysfunction, which can be reversed by dichloroacetate.

GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension.

Background: The cause and consequences of impaired adrenergic signaling in right ventricular failure/hypertrophy (RVH) are poorly understood. We hypothesized that G protein-coupled receptor kinase-2 (GRK2)-mediated uncoupling of β-adrenergic receptor signaling impairs inotropic reserve. The implications of right ventricular (RV) adrenergic remodeling for inotrope selection and the therapeutic benefit of interrupting Gβγ-GRK2 interaction, using gallein, were tested.

Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by pulmonary vascular obstruction caused, in part, by pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Mitochondrial fragmentation and normoxic activation of hypoxia-inducible factor-1α (HIF-1α) have been observed in PAH PASMCs; however, their relationship and relevance to the development of PAH are unknown. Dynamin-related protein-1 (DRP1) is a GTPase that, when activated by kinases that phosphorylate serine 616, causes mitochondrial fission.

Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle's cycle.

Right ventricular hypertrophy (RVH) and RV failure are major determinants of prognosis in pulmonary hypertension and congenital heart disease. In RVH, there is a metabolic shift from glucose oxidation (GO) to glycolysis. Directly increasing GO improves RV function, demonstrating the susceptibility of RVH to metabolic intervention.

A central role for CD68(+) macrophages in hepatopulmonary syndrome. Reversal by macrophage depletion.

Rationale: The etiology of hepatopulmonary syndrome (HPS), a common complication of cirrhosis, is unknown. Inflammation and macrophage accumulation occur in HPS; however, their importance is unclear. Common bile duct ligation (CBDL) creates an accepted model of HPS, allowing us to investigate the cause of HPS.

Validation of high-resolution echocardiography and magnetic resonance imaging vs. high-fidelity catheterization in experimental pulmonary hypertension.

High-frequency echocardiography and high-field-strength magnetic resonance imaging (MRI) are new noninvasive methods for quantifying pulmonary arterial hypertension (PAH) and right ventricular (RV) hypertrophy (RVH). We compared these noninvasive methods of assessing the pulmonary circulation to the gold standard, cardiac catheterization (micromanometer-tipped catheters), in rats with monocrotaline-induced PAH and normal controls. Closed-chest, Sprague-Dawley rats were anesthetized with inhaled isoflurane (25 monocrotaline, 6 age-matched controls).

Evaluation of the hemodynamics of a tissue-engineered hybrid graft.

We evaluated the hemodynamics of tissue-engineered hybrid graft in vivo. The hybrid expanded polytetrafluoroethylene (ePTFE) scaffold was fabricated by coating the ePTFE graft with poly (lactide-co-glycolide) (PLGA) solution. This scaffold was turned into an engineered hybrid graft by culturing smooth muscle cells on its surface.

The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle.

Right ventricular hypertrophy (RVH) and RV failure contribute to morbidity and mortality in pulmonary arterial hypertension (PAH). The cause of RV dysfunction and the feasibility of therapeutically targeting the RV are uncertain. We hypothesized that RV dysfunction and electrical remodeling in RVH result, in part, from a glycolytic shift in the myocyte, caused by activation of pyruvate dehydrogenase kinase (PDK).

Development of a closed air loop electropneumatic actuator for driving a pneumatic blood pump.

In this study, we developed a small pneumatic actuator that can be used as an extracorporeal biventricular assist device. It incorporated a bellows-transforming mechanism to generate blood-pumping pressure. The cylindrical unit is 88 +/- 0.

Regeneration of ischemic heart using hyaluronic acid-based injectable hydrogel.

An injectable hydrogel was applied to regenerate a myocardial infarction and functional recovery of the heart. A myocardial infarction was induced in rat by circumflex artery ligation. A hyaluronic acid-based hydrogel was injected into the epicardium of the infarcted area.

Both Purkinje cells and left ventricular posteroseptal reentry contribute to the maintenance of ventricular fibrillation in open-chest dogs and swine: effects of catheter ablation and the ventricular cut-and-sew operation.

Background: Radiofrequency catheter ablation (RFCA) targeting the left ventricular posteroseptum (LVPS) and posterior papillary muscle (PPM) terminates or prevents ventricular fibrillation (VF) in rabbit and dog hearts. However, whether the mechanism of VF maintenance is reentry or focal Purkinje firing is unclear.

Methods And Results: In the present study the effects of RFCA (endocardial ablation of PPM+LVPS in 7 dogs and 7 swine), left ventricular anterolateral wall ablation (LVAL in 7 dogs), and the cut-and-sew operation (CSO: along the left ventricular posterior wall (LVPW) beside PPM in 7 swine) on VF inducibility were compared.

Ventricular assist device implantation using a right thoracotomy.

Most patients needing implantation of a ventricular assist device (VAD) require repeated sternotomy; some after cardiac surgery, and others later for heart transplantation. The purpose of this study was to establish the right thoracotomy technique as an alternative for VAD implantation to reduce repeated sternotomy-related morbidity and mortality. We performed a right thoracotomy in animals, preclinical cadaver fitting tests, and a clinical case.