Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function.

Parvalbumin-positive (PV ) fast-spiking interneurons are essential to control the firing activity of principal neuron ensembles, thereby regulating cognitive processes. The high firing frequency activity of PV interneurons imposes high-energy demands on their metabolism that must be supplied by distinctive machinery for energy generation. Exploring single-cell transcriptomic data for the mouse cortex, we identified a metabolism-associated gene with highly restricted expression to PV interneurons: Cox6a2, which codes for an isoform of a cytochrome c oxidase subunit.

Fuchs' Endothelial Corneal Dystrophy and RNA Foci in Patients With Myotonic Dystrophy.

Purpose: The most common cause of Fuchs' endothelial corneal dystrophy (FECD) is an intronic CTG repeat expansion in TCF4. Expanded CUG repeat RNA colocalize with splicing factor, muscleblind-like 1 (MBNL1), in nuclear foci in endothelium as a molecular hallmark. Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG repeat expansion in the 3'-untranslated region (UTR) of DMPK.

Bendopnea and risk of adverse clinical outcomes in ambulatory patients with systolic heart failure.

Background: Recently, the symptom of bendopnea, that is, shortness of breath when bending forwards such as when putting on shoes, has been described in heart failure patients and found to be associated with higher ventricular filling pressures, particularly in the setting of low cardiac index. However, it is not known whether bendopnea is associated with clinical outcomes.

Methods: In a prospective convenience sample of 179 patients followed in our heart failure disease management clinic, we determined the presence of bendopnea at the time of enrollment and ascertained clinical outcomes through 1 year of follow-up.

Human ventricular unloading induces cardiomyocyte proliferation.

Background: The adult mammalian heart is incapable of meaningful regeneration after substantial cardiomyocyte loss, primarily due to the inability of adult cardiomyocytes to divide. Our group recently showed that mitochondria-mediated oxidative DNA damage is an important regulator of postnatal cardiomyocyte cell cycle arrest. However, it is not known whether mechanical load also plays a role in this process.

Variation of heart transplant rates in the United States during holidays.

Background: Some cardiac transplant programs may upgrade listed patients to United Network for Organ Sharing (UNOS) 1A-status during the holidays. Whether more transplants actually occur during holidays is unknown.

Methods: We assessed rates of single-organ heart transplantation from 2001 to 2010 for recipients age ≥18 yr using the UNOS database.

High-sensitivity cardiac troponin I assay to screen for acute rejection in patients with heart transplant.

Background: A noninvasive biomarker that could accurately diagnose acute rejection (AR) in heart transplant recipients could obviate the need for surveillance endomyocardial biopsies. We assessed the performance metrics of a novel high-sensitivity cardiac troponin I (cTnI) assay for this purpose.

Methods And Results: Stored serum samples were retrospectively matched to endomyocardial biopsies in 98 cardiac transplant recipients, who survived ≥3 months after transplant.

Characterization of a novel symptom of advanced heart failure: bendopnea.

Objectives: This study sought to examine the frequency and hemodynamic correlates of shortness of breath when bending forward, a symptom we have termed "bendopnea."

Background: Many heart failure patients describe bendopnea such as when putting on their shoes. This symptom has not previously been characterized.

Cytoglobin modulates myogenic progenitor cell viability and muscle regeneration.

Mammalian skeletal muscle can remodel, repair, and regenerate itself by mobilizing satellite cells, a resident population of myogenic progenitor cells. Muscle injury and subsequent activation of myogenic progenitor cells is associated with oxidative stress. Cytoglobin is a hemoprotein expressed in response to oxidative stress in a variety of tissues, including striated muscle.

Tolerability of sirolimus: a decade of experience at a single cardiac transplant center.

Sirolimus is used in cardiac transplant recipients to prevent rejection, progression of cardiac allograft vasculopathy, and renal dysfunction. However, sirolimus has many potential side effects and its tolerability when used outside of clinical trials is not well established. We describe a decade of experience with sirolimus in cardiac transplant recipients at our institution.

Pulmonary veins in the normal lung and pulmonary hypertension due to left heart disease.

Despite the importance of pulmonary veins in normal lung physiology and the pathobiology of pulmonary hypertension with left heart disease (PH-LHD), pulmonary veins remain largely understudied. Difficult to identify histologically, lung venous endothelium or smooth muscle cells display no unique characteristic functional and structural markers that distinguish them from pulmonary arteries. To address these challenges, we undertook a search for unique molecular markers in pulmonary veins.

Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity and insulin resistance.

Oxidative phosphorylation in mitochondria is responsible for 90% of ATP synthesis in most cells. This essential housekeeping function is mediated by nuclear and mitochondrial genes encoding subunits of complex I to V of the respiratory chain. Although complex IV is the best studied of these complexes, the exact function of the striated muscle-specific subunit COX6A2 is still poorly understood.

Relationship of right- to left-sided ventricular filling pressures in advanced heart failure: insights from the ESCAPE trial.

Background: Although right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP) are correlated in heart failure, in a sizeable minority of patients, the RAP and PCWP are not tightly coupled. The basis of this variability in the RAP/PCWP ratio, and whether it conveys prognostic value, is not known.

Methods And Results: We analyzed the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial database.

Regulation of neonatal and adult mammalian heart regeneration by the miR-15 family.

We recently identified a brief time period during postnatal development when the mammalian heart retains significant regenerative potential after amputation of the ventricular apex. However, one major unresolved question is whether the neonatal mouse heart can also regenerate in response to myocardial ischemia, the most common antecedent of heart failure in humans. Here, we induced ischemic myocardial infarction (MI) in 1-d-old mice and found that this results in extensive myocardial necrosis and systolic dysfunction.

The natural history of new-onset heart failure with a severely depressed left ventricular ejection fraction: implications for timing of implantable cardioverter-defibrillator implantation.

Background: Guidelines recommend that patients with new-onset systolic heart failure (HF) receive a trial of medical therapy before an implantable cardiac defibrillator (ICD). This strategy allows for improvement of left ventricular ejection fraction (LVEF), thereby avoiding an ICD, but exposes patients to risk of potentially preventable sudden cardiac death during the trial of medical therapy.

Methods: We reviewed a consecutive series of patients with HF of <6 months duration with a severely depressed LVEF (<30%) evaluated in a HF clinic (N = 224).

Sirolimus use and incidence of venous thromboembolism in cardiac transplant recipients.

Sirolimus is an immunosuppressive agent increasingly used in cardiac transplant recipients in the setting of allograft vasculopathy or worsening renal function. Recently, sirolimus has been associated with increased risk of venous thromboembolism (VTE) in lung transplant recipients. To investigate whether this association is also present in cardiac transplant recipients, we retrospectively reviewed the charts of 67 cardiac transplant recipients whose immunosuppressive regimen included sirolimus and 134 matched cardiac transplant recipients whose regimen did not include sirolimus.

IIIB or not IIIB: a previously unanswered question.

The term New York Heart Association (NYHA) class IIIB has been used increasingly in clinical medicine, including as an inclusion criteria for many clinical trials assessing left ventricular assist devices (LVADs). Indeed, NYHA class IIIB is incorporated in the Food and Drug Administration's approved indication for the Heartmate II. However, on review of the medical literature, we found that there is no consensus definition of NYHA class IIIB.

Regulation of myoglobin expression.

Myoglobin is a well-characterized, cytoplasmic hemoprotein that is expressed primarily in cardiomyocytes and oxidative skeletal muscle fibers. However, recent studies also suggest low-level myoglobin expression in various non-muscle tissues. Prior studies incorporating molecular, pharmacological, physiological and transgenic technologies have demonstrated that myoglobin is an essential oxygen-storage hemoprotein capable of facilitating oxygen transport and modulating nitric oxide homeostasis within cardiac and skeletal myocytes.

Concentric left ventricular hypertrophy as assessed by cardiac magnetic resonance imaging and risk of death in cardiac transplant recipients.

Background: Although risk factors for left ventricular (LV) hypertrophy in the native heart are well known, as is its association with increased risk of adverse outcomes, such information is poorly defined in heart transplant (HTx) recipients. We determined whether increased LV mass and concentricity (mass/volume) were associated with death in patients after HTx.

Methods: Between May 2003 and May 2006, 140 HTx recipients underwent cardiac magnetic resonance imaging (MRI).

Clinical outcomes after cardiac transplantation in muscular dystrophy patients.

Background: Patients with muscular dystrophy are at risk of developing a dilated cardiomyopathy and can progress to advanced heart failure. At present, it is not known whether such patients can safely undergo cardiac transplantation.

Methods: This was a retrospective review of the Cardiac Transplant Research Database, a multi-institutional registry of 29 transplant centers in the United States, from the years 1990 to 2005.

Association of cystatin C with left ventricular structure and function: the Dallas Heart Study.

Background: Cystatin C, a novel marker of renal function, has been associated with heart failure and cardiovascular mortality in older individuals. We tested the hypothesis that cystatin C is associated with preclinical cardiac structural and functional abnormalities in a younger population-based sample.

Methods And Results: The study included participants in the Dallas Heart Study (ages 30 to 65 years) who had measurements of cystatin C and cardiac MRI.

Pancreatic gout masquerading as pancreatic cancer in a heart transplant candidate.

In this report, a case is presented of a patient with advanced heart failure who had asymptomatic pancreatic gout, which masqueraded as metastatic pancreatic cancer. This unusual presentation of gout was important to recognize, as the presence of a pancreatic cancer would have precluded cardiac transplantation in an otherwise suitable candidate.

Utility of routine immunofluorescence staining for C4d in cardiac transplant recipients.

Background: Immunofluorescence staining of endomyocardial biopsy (EMB) specimens to detect the complement fragment C4d is used to diagnose antibody-mediated rejection. However, data are limited regarding the utility of routine staining for C4d in clinical care.

Methods: This study retrospectively reviewed the clinical course of adult cardiac transplant recipients who underwent > or = 2 EMBs with immunofluorescence C4d staining at the University of Texas Southwestern Medical Center since September 2006.

Calcineurin activates cytoglobin transcription in hypoxic myocytes.

Cardiac hypertrophy develops in response to a variety of cardiovascular stresses and results in activation of numerous signaling cascades and proteins. In the present study, we demonstrate that cytoglobin is a stress-responsive hemoprotein in the hypoxia-induced hypertrophic myocardium and it is transcriptionally regulated by calcineurin-dependent transcription factors. The cytoglobin transcript level is abundantly expressed in the adult heart and in response to hypoxia cytoglobin expression is markedly up-regulated within the hypoxia-induced hypertrophic heart.