- An internationally respected physician-scientist who has made major contributions to our understanding of the pathobi... moreAn internationally respected physician-scientist who has made major contributions to our understanding of the pathobiology of the failing heart. Most recently, his interests have focused on the use of gene replacement therapy to treat mono-genetic cardiomyopathies, specifically individuals with truncations or large deletions in the BAG3 gene.edit
Research Interests: Clinical Trial, Heart Failure, Humans, Congestive Heart Failure, Female, and 15 moreRegression Analysis, Potassium, Aged, Middle Aged, Older Women, Elderly Women, Coronary Artery Disease, Quinolines, Aspartate Aminotransferase, Confidence Interval, Relative Risk, Coronary artery, Multicenter Studies as Topic, Randomized Controlled Trials as Topic, and Cardiovascular medicine and haematology
Background—Cardiac resynchronization therapy (CRT) alone or combined with an implantable defibrillator (CRT-D) has been shown to improve exercise capacity and quality of life and to reduce heart failure (HF) hospitalizations and mortality... more
Background—Cardiac resynchronization therapy (CRT) alone or combined with an implantable defibrillator (CRT-D) has been shown to improve exercise capacity and quality of life and to reduce heart failure (HF) hospitalizations and mortality in patients with New York Heart Association (NYHA) class III and IV HF. There is concern that the device procedure may destabilize these very ill class IV patients.
We evaluated whether phospholemman (PLM) regulates L-type Ca(2+) current (ICa) in mouse ventricular myocytes. Expression of α1-subunit of L-type Ca(2+) channels between wild-type (WT) and PLM knockout (KO) hearts was similar. Compared to... more
We evaluated whether phospholemman (PLM) regulates L-type Ca(2+) current (ICa) in mouse ventricular myocytes. Expression of α1-subunit of L-type Ca(2+) channels between wild-type (WT) and PLM knockout (KO) hearts was similar. Compared to WT myocytes, peak ICa (at -10mV) from KO myocytes was ~41% larger, the inactivation time constant (τinact) of ICa was ~39% longer, but deactivation time constant (τdeact) was similar. In the presence of isoproterenol (1μM), peak ICa was ~48% larger and τinact was ~144% higher in KO myocytes. With Ba(2+) as the permeant ion, PLM enhanced voltage-dependent inactivation but had no effect on τdeact. To dissect the molecular determinants by which PLM regulated ICa, we expressed PLM mutants by adenovirus-mediated gene transfer in cultured KO myocytes. After 24h in culture, KO myocytes expressing green fluorescent protein (GFP) had significantly larger peak ICa and longer τinact than KO myocytes expressing WT PLM; thereby independently confirming the obser...
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The higher performance of fine-line fabrication processes has allowed CMOS ICs to be used in communication applications previously dominated by compound semiconductor devices, thus enabling the integration of increased functionality on a... more
The higher performance of fine-line fabrication processes has allowed CMOS ICs to be used in communication applications previously dominated by compound semiconductor devices, thus enabling the integration of increased functionality on a single IC. This paper presents a ...
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Aeluros, Mountain View, CA The rapid growth in the deployment of 10Gb/s Ethernet switches for the enterprise market has created a need for low-cost short-reach optical modules in small form-factors such as XENPAK, X2, and XPAK. Recent... more
Aeluros, Mountain View, CA The rapid growth in the deployment of 10Gb/s Ethernet switches for the enterprise market has created a need for low-cost short-reach optical modules in small form-factors such as XENPAK, X2, and XPAK. Recent advances in manufacturing have ...
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Objectives and Background: We evaluated the ability of 23 genetic variants to provide prognostic information in patients enrolled in the Genetic Substudy of the Surgical Treatment for Ischemic Heart Failure (STICH) trials. Methods:... more
Objectives and Background: We evaluated the ability of 23 genetic variants to provide prognostic information in patients enrolled in the Genetic Substudy of the Surgical Treatment for Ischemic Heart Failure (STICH) trials. Methods: Patients assigned to STICH Hypothesis 1 were randomized to medical therapy with or without coronary artery bypass grafting (CABG). Those assigned to STICH Hypothesis 2 were randomized to CABG or CABG with left ventricular reconstruction. Results: In patients assigned to STICH Hypothesis 2 (n = 714), no genetic variant met the prespecified Bonferroni-adjusted threshold for statistical significance (p < 0.002); however, several variants met nominal prognostic significance: variants in the β2-adrenergic receptor gene (β2-AR Gln27Glu) and in the A1-adenosine receptor gene (A1-717 T/G) were associated with an increased risk of a subject dying or being hospitalized for a cardiac problem (p = 0.027 and 0.031, respectively). These relationships remained nomina...
Research Interests: Cardiology, Treatment Outcome, Multivariate Analysis, Heart Failure, Humans, and 14 moreHospitalization, Female, Male, Risk factors, Left Ventricular Dysfunction, Aged, Middle Aged, Genotype, Prognosis, Risk Factors, Coronary Artery Disease, Coronary artery bypass surgery, Genetic Markers, and Cohort Studies
Transplantation: Endorsed by the Heart Rhythm Society College of Chest Physicians and the International Society for Heart and Lung Management of Heart Failure): Developed in Collaboration With the American (Writing Committee to Update the 2001 Guidelines for the Evaluation and Cardiology/American...more
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Transplantation: Endorsed by the Heart Rhythm Society College of Chest Physicians and the International Society for Heart and Lung Management of Heart Failure): Developed in Collaboration With the American (Writing Committee to Update the 2001 Guidelines for the Evaluation and of Cardiology/Ameri...more
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Research Interests: Cardiology, Health Care, Survival Analysis, Treatment Outcome, Public Health, and 50 moreApplied Economics, Sweden, Finland, Greece, Heart Failure, Denmark, Prospective studies, Humans, Markov chains, Computer Simulation, Human Resources for Health, Int, Europe, Hospitalization, Hospital costs, United States, Female, Male, Follow-up studies, Cost effectiveness, Incidence, Discount Rate, Risk factors, Left Ventricular Dysfunction, Clinical Sciences, Aged, Middle Aged, HF, Quality adjusted life years, Health Care System, Public health systems and services research, Chronic Heart Failure, Analytical Model, Survival Rate, Willingness to Pay, Economic Models, Cost Benefit Analysis, Clinical Cardiology, Gauche, Risk Factors, Public Health System, Implantable defibrillators-cardioverters, Ventricular Remodeling, Health Care Costs, Cardiac-Resynchronization-Therapy-Devices-Market, Resource Utilization, Monte Carlo Method, Ly, QALY, and Pharmaceutical preparations
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miR-146a is a microRNA whose transcript levels are induced in the heart upon activation of NF-κB, a transcription factor induced by pro-inflammatory molecules strongly related to the pathogenesis of cardiac disorders. The main goal of... more
miR-146a is a microRNA whose transcript levels are induced in the heart upon activation of NF-κB, a transcription factor induced by pro-inflammatory molecules strongly related to the pathogenesis of cardiac disorders. The main goal of this study consisted in studying new roles of miR-146a in cardiac pathological processes caused by the pro-inflammatory cytokine TNF-α. Our results demonstrate that miR-146a transcript levels were sharply increased in cardiac ventricular tissue of transgenic mice with specific overexpression of TNF-α in the heart, and also in a cardiomyocyte cell line of human origin (AC16) exposed to TNF-α. Among all the in silico predicted miR-146a target genes, c-Fos mRNA and protein levels notably decreased after TNF-α treatment or miR-146a overexpression. These changes correlated with a diminution in the DNA-binding activity of AP-1, the c-Fos-containing transcription factor complex. Interestingly, AP-1 inhibition was accompanied by a reduction in matrix metallopr...
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Background—Left ventricular assist device (LVAD) support of the failing heart induces salutary changes in myocardial structure and function. Matrix metalloproteinases (MMPs) are increased in the failing heart and are induced by stretch in... more
Background—Left ventricular assist device (LVAD) support of the failing heart induces salutary changes in myocardial structure and function. Matrix metalloproteinases (MMPs) are increased in the failing heart and are induced by stretch in cardiac cells in vitro. We hypothesized that mechanical unloading may affect LV plasticity by regulating MMPs and their substrates. Methods and Results—LV samples were collected from patients
Research Interests: Immunohistochemistry, Western blotting, Heart Failure, Protein Structure and Function, Humans, and 19 moreCollagen, Left Ventricular Assist Device, Left Ventricular Dysfunction, Dilated cardiomyopathy, Clinical Sciences, Middle Aged, Adult, Myocardium, Functional Recovery, Public health systems and services research, Western blot, Circulation, Matrix Metalloproteinases, Continuous Flow Heart Assist Devices, Enzyme Linked Immunosorbent Assay, Cardiac Transplantation, Matrix Metalloproteinase, Down-Regulation, and Assistive Device
We evaluated whether phospholemman (PLM) regulates L-type Ca(2+) current (ICa) in mouse ventricular myocytes. Expression of α1-subunit of L-type Ca(2+) channels between wild-type (WT) and PLM knockout (KO) hearts was similar. Compared to... more
We evaluated whether phospholemman (PLM) regulates L-type Ca(2+) current (ICa) in mouse ventricular myocytes. Expression of α1-subunit of L-type Ca(2+) channels between wild-type (WT) and PLM knockout (KO) hearts was similar. Compared to WT myocytes, peak ICa (at -10mV) from KO myocytes was ~41% larger, the inactivation time constant (τinact) of ICa was ~39% longer, but deactivation time constant (τdeact) was similar. In the presence of isoproterenol (1μM), peak ICa was ~48% larger and τinact was ~144% higher in KO myocytes. With Ba(2+) as the permeant ion, PLM enhanced voltage-dependent inactivation but had no effect on τdeact. To dissect the molecular determinants by which PLM regulated ICa, we expressed PLM mutants by adenovirus-mediated gene transfer in cultured KO myocytes. After 24h in culture, KO myocytes expressing green fluorescent protein (GFP) had significantly larger peak ICa and longer τinact than KO myocytes expressing WT PLM; thereby independently confirming the obser...
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Heart failure (HF) is a disease of epidemic proportion and is associated with exceedingly high health care costs. G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) kinase 2 (GRK2), which is up-regulated... more
Heart failure (HF) is a disease of epidemic proportion and is associated with exceedingly high health care costs. G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) kinase 2 (GRK2), which is up-regulated in the failing human heart, appears to play a critical role in HF progression in part because enhanced GRK2 activity promotes dysfunctional adrenergic signaling and myocyte death. Recently, we found that the selective serotonin reuptake inhibitor (SSRI) paroxetine could inhibit GRK2 with selectivity over other GRKs. Wild-type mice were treated for 4 weeks with paroxetine starting at 2 weeks after myocardial infarction (MI). These mice were compared with mice treated with fluoxetine, which does not inhibit GRK2, to control for the SSRI effects of paroxetine. All mice exhibited similar left ventricular (LV) dysfunction before treatment; however, although the control and fluoxetine groups had continued degradation of function, the paroxetine group had...
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The most common cause of dilated cardiomyopathy and heart failure (HF) is ischemic heart disease; however, in a third of all patients the cause remains undefined and patients are diagnosed as having idiopathic dilated cardiomyopathy... more
The most common cause of dilated cardiomyopathy and heart failure (HF) is ischemic heart disease; however, in a third of all patients the cause remains undefined and patients are diagnosed as having idiopathic dilated cardiomyopathy (IDC). Recent studies suggest that many patients with IDC have a family history of HF and rare genetic variants in over 35 genes have been shown to be causative of disease. We employed whole-exome sequencing to identify the causative variant in a large family with autosomal dominant transmission of dilated cardiomyopathy. Sequencing and subsequent informatics revealed a novel 10-nucleotide deletion in the BCL2-associated athanogene 3 (BAG3) gene (Ch10:del 121436332_12143641: del. 1266_1275 [NM 004281]) that segregated with all affected individuals. The deletion predicted a shift in the reading frame with the resultant deletion of 135 amino acids from the C-terminal end of the protein. Consistent with genetic variants in genes encoding other sarcomeric pr...
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Enhanced arginine vasopressin levels are associated with increased mortality during end-stage human heart failure, and cardiac arginine vasopressin type 1A receptor (V1AR) expression becomes increased. Additionally, mice with... more
Enhanced arginine vasopressin levels are associated with increased mortality during end-stage human heart failure, and cardiac arginine vasopressin type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted V1AR overexpression develop cardiomyopathy and decreased β-adrenergic receptor (βAR) responsiveness. This led us to hypothesize that V1AR signaling regulates βAR responsiveness and in doing so contributes to development of heart failure. Transaortic constriction resulted in decreased cardiac function and βAR density and increased cardiac V1AR expression, effects reversed by a V1AR-selective antagonist. Molecularly, V1AR stimulation led to decreased βAR ligand affinity, as well as βAR-induced Ca(2+) mobilization and cAMP generation in isolated adult cardiomyocytes, effects recapitulated via ex vivo Langendorff analysis. V1AR-mediated regulation of βAR responsiveness was demonstrated to occur in a previously unrecognized Gq protein-independent/...
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ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of H...more
Background—In the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial, 1520 patients with advanced heart failure were assigned in a 1:2:2 ratio to optimal pharmacological therapy or optimal... more
Background—In the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial, 1520 patients with advanced heart failure were assigned in a 1:2:2 ratio to optimal pharmacological therapy or optimal pharmacological therapy plus cardiac resynchronization therapy (CRT-P) or CRT with defibrillator (CRT-D). Use of CRT-P and CRT-D was associated with a significant reduction in combined risk of death
Research Interests: Treatment, Recurrent Events Models, Comparative Study, Heart Failure, Humans, and 17 moreDiabetes mellitus, Hospitalization, Female, Male, Risk factors, Clinical Sciences, Aged, Middle Aged, Risk Factor, Adult, Public health systems and services research, Circulation, Risk Factors, Implantable defibrillators-cardioverters, Cardiac-Resynchronization-Therapy-Devices-Market, Proportional Hazards Models, and Right-censoring
Transplantation: Endorsed by the Heart Rhythm Society College of Chest Physicians and the International Society for Heart and Lung Management of Heart Failure): Developed in Collaboration With the American (Writing Committee to Update the 2001 Guidelines for the Evaluation and of Cardiology/Ameri...more
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Recent studies have focused their attention on the role of the proinflammatory cytokine tumor necrosis factor (TNF) in the development of heart failure. First recognized as an endotoxin-induced serum factor that caused necrosis of tumors... more
Recent studies have focused their attention on the role of the proinflammatory cytokine tumor necrosis factor (TNF) in the development of heart failure. First recognized as an endotoxin-induced serum factor that caused necrosis of tumors and cachexia, it is now recognized that TNF participates in the pathophysiology of a group of inflammatory diseases including rheumatoid arthritis and Crohn&amp;amp;#39;s disease. The normal heart does not express TNF; however, the failing heart produces robust quantities. Furthermore, there is a direct relationship between the level of TNF expression and the severity of disease. In addition, both in vivo and in vitro studies demonstrate that TNF effects cellular and biochemical changes that mirror those seen in patients with congestive heart failure. Furthermore, in animal models, the development of the heart failure phenotype can be abrogated at least in part by anticytokine therapy. Based on information from experimental studies, investigators are now evaluating the clinical efficacy of novel anticytokine and anti-TNF strategies in patients with heart failure; one such strategy is the use of a recombinantly produced chimeric TNF alpha soluble receptor. Thus, in view of the emerging importance of proinflammatory cytokines in the pathogenesis of heart disease, we review the biology of TNF, its role in inflammatory diseases, the effects of TNF on the physiology of the heart and the development of clinical strategies that target the cytokine pathways.
Research Interests: Cardiology, Rheumatoid Arthritis, Heart Failure, Humans, Congestive Heart Failure, and 16 moreAnimals, Heart, Animal Model, Experimental Study, Dilated cardiomyopathy, Inflammatory disease, Heart Disease, Myocardium, Public health systems and services research, Tumor necrosis factor-alpha, Basic Research, Biological markers, In Vitro Studies, Angiotensin II, Tumor Necrosis Factor–α (TNF), and The American
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Research Interests: Immunology, Multiple sclerosis, Gene expression, Neuroimmunology, Humans, and 13 moreNatural Killer cells, Female, Antigen Presentation, Quinolones, Middle Aged, Pathway Analysis, Adult, Very high throughput, Healthy Subjects, Cell Survival, Neurosciences, Gene Expression Regulation, and Gene expression profiling
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Human heart failure is associated with a diminished contractile response to beta-adrenergic agonists. We hypothesized that alterations in the activity of a guanine nucleotide-binding regulatory protein (G protein) might be partially... more
Human heart failure is associated with a diminished contractile response to beta-adrenergic agonists. We hypothesized that alterations in the activity of a guanine nucleotide-binding regulatory protein (G protein) might be partially responsible for this abnormality. We therefore measured the activity of G proteins in failing human myocardium utilizing bacterial toxin-catalyzed ADP ribosylation. The activity of a 40,000-mol wt pertussis toxin substrate (alpha G40) was increased by 36% in failing human hearts when compared with nonfailing controls. In contrast, there was no change in the level of the stimulatory regulatory subunit (Gs). The increased activity in alpha G40 was associated with a 30% decrease in basal as well as 5&#39;-guanylyl imidodiphosphate-stimulated adenylate cyclase activity. These data suggest that increased alpha G40 activity is a new marker for failing myocardium and may account at least in part for the diminished responsiveness to beta 1-adrenergic agonists in the failing human heart.
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We characterized the effects of ethanol on the activators of adenylate cyclase complex that act through the receptor site, the stimulatory guanine nucleotide-binding regulatory protein (Gs), or the catalytic unit. Ethanol had no effect on... more
We characterized the effects of ethanol on the activators of adenylate cyclase complex that act through the receptor site, the stimulatory guanine nucleotide-binding regulatory protein (Gs), or the catalytic unit. Ethanol had no effect on adenylate cyclase activity stimulated by Mn2+, a selective activator of the catalytic unit, whereas high concentrations of ethanol inhibited both basal and isoproterenol-stimulated adenylate cyclase. In contrast, in the presence of nonhydrolyzable GTP analogs, ethanol potentiated substantial increases in adenylate cyclase activity. In the presence of these GTP analogs, ethanol increased the Vmax without altering the affinity of adenylate cyclase for ATP. Ethanol also increased adenylate cyclase activity in membranes in which Gs had been preactivated with isoproterenol plus a nonhydrolyzable GTP analog, suggesting that ethanol enhanced the interaction between activated Gs and the catalytic unit. Paradoxically, the ability of cholera toxin and NAD+ to augment adenylate cyclase activity through an effect on Gs was attenuated by increasing concentrations of ethanol. These results suggest that acute exposure to ethanol has multiple effects on cardiac membrane adenylate cyclase.