cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism.

Beta-adrenergic agonists stimulate cardiac contractility and simultaneously blunt this response by coactivating NO synthase (NOS3) to enhance cGMP synthesis and activate protein kinase G (PKG-1). cGMP is also catabolically regulated by phosphodiesterase 5A (PDE5A). PDE5A inhibition by sildenafil (Viagra) increases cGMP and is used widely to treat erectile dysfunction; however, its role in the heart and its interaction with beta-adrenergic and NOS3/cGMP stimulation is largely unknown.

Short-term effects of right-left heart sequential cardiac resynchronization in patients with heart failure, chronic atrial fibrillation, and atrioventricular nodal block.

Background: Single-site ventricular pacing in patients with heart failure, atrial fibrillation, and severe atrioventricular (AV) nodal block risks the generation of discoordinate contraction. Whether altering the site of stimulation can offset this detrimental effect and what role sequential right ventricular-left ventricular (RV-LV) stimulation might play in such patients remain unknown.

Methods And Results: Nine subjects with heart failure (ejection fraction, 14% to 30%), atrial fibrillation, and AV block were studied by pressure-volume analysis.

Computer-aided detection in diagnostic mammography: detection of clinically unsuspected cancers.

Objective: We had two objectives: to determine the percentage of women presenting with clinical findings whose diagnostic mammogram led to detection of a breast cancer at a site distant from the original clinical complaint and to assess the performance of computer-aided detection (CAD) on diagnostic mammography.

Materials And Methods: Three institutions contributed consecutive cases in which a mammogram was obtained to evaluate a clinical finding, after which a histologic diagnosis of breast cancer was made. Clinical data and the mammograms were reviewed to determine the nature of the clinical findings and to document the location and characteristics of 212 biopsy-proven cancers in 197 patients who met the study criteria.

Novel model of constrictive pericarditis associated with autoimmune heart disease in interferon-gamma-knockout mice.

Background: Constrictive pericarditis represents a serious hemodynamic syndrome that may lead to heart failure. Studies of its pathophysiological mechanisms have been impeded by the lack of an animal model.

Methods And Results: Cardiac myosin-induced experimental autoimmune myocarditis in interferon (IFN)-gamma-knockout (KO) mice results in increased cardiac inflammation and development of severe grossly detectable pericarditis.

Developing a comprehensive pesticide health effects tracking system for an urban setting: New York City's approach.

In recent years, there have been substantial investments and improvements in federal and state surveillance systems to track the health effects from pesticide exposure. These surveillance systems help to identify risk factors for occupational exposure to pesticides, patterns in poisonings, clusters of disease, and populations at risk of exposure from pesticide use. Data from pesticide use registries and recent epidemiologic evidence pointing to health risks from urban residential pesticide use make a strong case for understanding better the sale, application, and use of pesticides in cities.

Age and gender affect ventricular-vascular coupling during aerobic exercise.

Objectives: The goal of this study was to examine the age-associated differences in ventricular-vascular coupling, defined by the ratio of arterial elastance (EaI) to left ventricular systolic elastance (E(LV)I), and its components, at rest and during exercise.

Background: Ejection fraction (EF) increases during exercise, but the EF reserve decreases with aging. Ejection fraction is inversely related to EaI/E(LV)I, an index of the interaction between arterial and ventricular properties, which is an important determinant of cardiac performance.

Mechanisms underlying conduction slowing and arrhythmogenesis in nonischemic dilated cardiomyopathy.

Heart Failure (HF) is associated with an increased risk of sudden death caused by ventricular tachyarrhythmias. Recent studies have implicated repolarization abnormalities and, in particular, exaggerated heterogeneity of transmural repolarization in the genesis of polymorphic ventricular tachycardia in a canine model of nonischemic dilated cardiomyopathy. The presence and degree to which conduction abnormalities play a role in arrhythmogenesis in this model are uncertain.

Evolution of a hypervariable region of the low density lipoprotein receptor (LDLR) gene in humans and other hominoids.

Alu repeats in primates have been shown to evolve at a neutral mutation rate, as anticipated for non-coding autosomal loci. However, we have identified Alu elements within the 3' untranslated region (UTR) of the low density lipoprotein receptor (LDLR) gene that exhibited highly accelerated rates of evolution. In humans, a 100- and 25-fold increase in average divergence, for an upstream Alu (Alu U) and a downstream Alu (Alu D) respectively, was estimated based on sequence analysis among eight individuals of diverse ethnic backgrounds.

What mechanisms underlie diastolic dysfunction in heart failure?

Abnormalities of diastolic function are common to virtually all forms of cardiac failure. However, their underlying mechanisms, precise role in the generation and phenotypic expression of heart failure, and value as specific therapeutic targets remain poorly understood. A growing proportion of heart failure patients, particularly among the elderly, have apparently preserved systolic function, and this is fueling interest for better understanding and treating diastolic abnormalities.

Access to health care for the uninsured on Long Island: a case study.

Sixteen percent of people living on Long Island have no health insurance. They do not receive health insurance at their place of employment and are too poor to pay for it on their own. Most are too young to qualify for Medicare and fall between the cracks of the Medicaid system.

Molecular, forensic and haplotypic inconsistencies regarding the identity of the Ekaterinburg remains.

Background: A set of human remains unearthed near Ekaterinburg, Russia has been attributed to the Romanov Imperial Family of Russia and their physician and servants. That conclusion was officially accepted by the Russian government following publication of DNA tests that were widely publicized. The published study included no discussion of major forensic discrepancies and the information regarding the burial site and remains included irregularities.

Advanced glycation end product cross-linking: pathophysiologic role and therapeutic target in cardiovascular disease.

Advanced glycation end products (AGEs) form by a nonenzymatic reaction between reducing sugars and biological proteins. These stable compounds accumulate slowly throughout the life span and contribute to structural and physiologic changes in the cardiovascular system such as increased vascular and myocardial stiffness, endothelial dysfunction, altered vascular injury responses, and atherosclerotic plaque formation. Mechanisms underlying these alterations include AGE cross-linking of collagen and AGE interactions with circulating proteins and AGE receptors.

Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure.

Background: We tested the hypothesis that prophylactic cardiac-resynchronization therapy in the form of biventricular stimulation with a pacemaker with or without a defibrillator would reduce the risk of death and hospitalization among patients with advanced chronic heart failure and intraventricular conduction delays.

Methods: A total of 1520 patients who had advanced heart failure (New York Heart Association class III or IV) due to ischemic or nonischemic cardiomyopathies and a QRS interval of at least 120 msec were randomly assigned in a 1:2:2 ratio to receive optimal pharmacologic therapy (diuretics, angiotensin-converting-enzyme inhibitors, beta-blockers, and spironolactone) alone or in combination with cardiac-resynchronization therapy with either a pacemaker or a pacemaker-defibrillator. The primary composite end point was the time to death from or hospitalization for any cause.

Role of cardiac myosin binding protein C in sustaining left ventricular systolic stiffening.

Despite advances in the molecular biology of cardiac myosin binding protein-C (cMyBP-C), little is understood about its precise role in muscle contraction, particularly in the intact heart. We tested the hypothesis that cMyBP-C is central to the time course and magnitude of left ventricular systolic elastance (chamber stiffening), and assessed mechanisms for this influence in intact hearts, trabeculae, and skinned fibers from wild-type (+/+) and homozygous truncated cMyBP-C (t/t) male mice. cMyBP-C protein was not detected by gel electrophoresis or Western blot in t/t myocardium.

Quantitative analysis of myocardial inflammation by flow cytometry in murine autoimmune myocarditis: correlation with cardiac function.

Inflammation has been increasingly recognized as an important pathological component of heart failure. Existing methods of assessing myocardial infiltrate are labor-intensive and provide data that are difficult to quantify and not representative of the whole heart. As a result, little effort has been made to systematically assess the components of myocardial inflammation.

Advanced glycation endproduct crosslinking in the cardiovascular system: potential therapeutic target for cardiovascular disease.

Advanced glycation endproducts (AGEs) are formed by a reaction between reducing sugars and biological amines. Because of their marked stability, glycated proteins accumulate slowly over a person's lifespan, and can contribute to age-associated structural and physiological changes in the cardiovascular system such as increased vascular and myocardial stiffness, endothelial dysfunction, altered vascular injury responses and atherosclerotic plaque formation. The mechanisms by which AGEs affect the cardiovascular system include collagen crosslinking, alteration of low-density lipoprotein molecules and impairment of cellular nitric oxide signalling through their interaction with AGE receptors (RAGEs).

Modulation of in vivo cardiac function by myocyte-specific nitric oxide synthase-3.

Nitric oxide (NO) functions principally as a diffusible paracrine effector. The exception is in cardiomyocytes where both NO synthases (NOS) and target proteins coexist, allowing NO to work in an autocrine/intracrine fashion. However, the most abundant myocyte isoform (NOS3) is far more expressed in vascular endothelium; thus, the in vivo contribution of myocyte-NOS3 remains less clear.

Frequency- and afterload-dependent cardiac modulation in vivo by troponin I with constitutively active protein kinase A phosphorylation sites.

Acute beta-adrenergic stimulation enhances cardiac contractility, accelerates muscle relaxation, and amplifies the inotropic and lusitropic response to increased stimulation frequency. These effects are modulated by phosphorylation of calcium handling and myofilament proteins such as troponin I (TnI) by protein kinase A (PKA). To more directly delineate the role of TnI PKA phosphorylation, transgenic mice were generated that overexpress cardiac TnI in which the serine residues normally targeted by PKA are mutated to aspartic acid to mimic constitutive phosphorylation (TnIDD22,23).

Augmented systolic response to the calcium sensitizer EMD-57033 in a transgenic model with troponin I truncation.

Myocardial stunning is a form of acute reversible cardiac dysfunction that occurs after brief periods of ischemia and reperfusion. In several animal models, stunning is associated with proteolytic truncation of troponin I (TnI). Mice expressing the same proteolytic TnI fragment [TnI-(1-193)] demonstrate cardiac depression with a decreased maximal calcium-activated tension.

Robust adenoviral and adeno-associated viral gene transfer to the in vivo murine heart: application to study of phospholamban physiology.

Background: Viral gene transfer to the whole heart in vivo has been achieved in several mammalian species but remained difficult to accomplish in murine hearts. We postulated that a key impediment derives from the use of proximal aortic occlusion during virus injection, because this eliminates coronary perfusion gradients in mice as aortic root and left ventricle pressures equalize.

Methods And Results: Pressure-volume analysis confirmed these mechanics.