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Bid maintains mitochondrial cristae structure and function and protects against cardiac disease in an integrative genomics study.
Salisbury-Ruf CT, Bertram CC, Vergeade A, Lark DS, Shi Q, Heberling ML, Fortune NL, Okoye GD, Jerome WG, Wells QS, Fessel J, Moslehi J, Chen H, Roberts LJ, Boutaud O, Gamazon ER, Zinkel SS
(2018) Elife 7:
MeSH Terms: Animals, Apoptosis, BH3 Interacting Domain Death Agonist Protein, Beclin-1, Cell Respiration, Fibrosis, Gene Expression Regulation, Genome-Wide Association Study, Genomics, Heart Diseases, Heart Ventricles, Humans, Mice, Inbred C57BL, Mitochondria, Mitochondrial Proton-Translocating ATPases, Mutation, Myeloid Progenitor Cells, Myocardial Infarction, Myocytes, Cardiac, Polymorphism, Single Nucleotide, Protein Multimerization, Protein Structure, Secondary, Protein Subunits, Reactive Oxygen Species, Reproducibility of Results, Up-Regulation
Show Abstract · Added December 11, 2018
Bcl-2 family proteins reorganize mitochondrial membranes during apoptosis, to form pores and rearrange cristae. In vitro and in vivo analysis integrated with human genetics reveals a novel homeostatic mitochondrial function for Bcl-2 family protein Bid. Loss of full-length Bid results in apoptosis-independent, irregular cristae with decreased respiration. mice display stress-induced myocardial dysfunction and damage. A gene-based approach applied to a biobank, validated in two independent GWAS studies, reveals that decreased genetically determined BID expression associates with myocardial infarction (MI) susceptibility. Patients in the bottom 5% of the expression distribution exhibit >4 fold increased MI risk. Carrier status with nonsynonymous variation in Bid's membrane binding domain, Bid, associates with MI predisposition. Furthermore, Bid but not Bid associates with Mcl-1, previously implicated in cristae stability; decreased MCL-1 expression associates with MI. Our results identify a role for Bid in homeostatic mitochondrial cristae reorganization, that we link to human cardiac disease.
© 2018, Salisbury-Ruf et al.
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26 MeSH Terms
Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension.
Whitaker ME, Nair V, Sinari S, Dherange PA, Natarajan B, Trutter L, Brittain EL, Hemnes AR, Austin ED, Patel K, Black SM, Garcia JGN, Yuan Md PhD JX, Vanderpool RR, Rischard F, Makino A, Bedrick EJ, Desai AA
(2018) Am J Med 131: 702.e7-702.e13
MeSH Terms: Diabetes Mellitus, Female, Heart Ventricles, Humans, Hypertension, Pulmonary, Male, Pulmonary Artery, Retrospective Studies, Risk Factors, Ventricular Dysfunction, Right, Ventricular Remodeling
Show Abstract · Added June 7, 2018
BACKGROUND - Diabetes mellitus is associated with left ventricular hypertrophy and dysfunction. Parallel studies have also reported associations between diabetes mellitus and right ventricular dysfunction and reduced survival in patients with pulmonary arterial hypertension. However, the impact of diabetes mellitus on the pulmonary vasculature has not been well characterized. We hypothesized that diabetes mellitus and hyperglycemia could specifically influence right ventricular afterload and remodeling in patients with Group I pulmonary arterial hypertension, providing a link to their known susceptibility to right ventricular dysfunction.
METHODS - Using an adjusted model for age, sex, pulmonary vascular resistance, and medication use, associations of fasting blood glucose, glycated hemoglobin, and the presence of diabetes mellitus were evaluated with markers of disease severity in 162 patients with pulmonary arterial hypertension.
RESULTS - A surrogate measure of increased pulmonary artery stiffness, elevated pulmonary arterial elastance (P = .012), along with reduced log(pulmonary artery capacitance) (P = .006) were significantly associated with the presence of diabetes mellitus in patients with pulmonary arterial hypertension in a fully adjusted model. Similar associations between pulmonary arterial elastance and capacitance were noted with both fasting blood glucose and glycated hemoglobin. Furthermore, right ventricular wall thickness on echocardiography was greater in pulmonary arterial hypertension patients with diabetes, supporting the link between right ventricular remodeling and diabetes.
CONCLUSION - Cumulatively, these data demonstrate that an increase in right ventricular afterload, beyond pulmonary vascular resistance alone, may influence right ventricular remodeling and provide a mechanistic link between the susceptibility to right ventricular dysfunction in patients with both diabetes mellitus and pulmonary arterial hypertension.
Copyright © 2018 Elsevier Inc. All rights reserved.
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11 MeSH Terms
Dynamics of Zebrafish Heart Regeneration Using an HPLC-ESI-MS/MS Approach.
Ma D, Tu C, Sheng Q, Yang Y, Kan Z, Guo Y, Shyr Y, Scott IC, Lou X
(2018) J Proteome Res 17: 1300-1308
MeSH Terms: Animals, Chromatography, High Pressure Liquid, Fish Proteins, Gene Ontology, Heart Injuries, Heart Ventricles, Metabolic Networks and Pathways, Molecular Sequence Annotation, Myocardium, Proteomics, Real-Time Polymerase Chain Reaction, Regeneration, Spectrometry, Mass, Electrospray Ionization, Tumor Suppressor Protein p53, Zebrafish
Show Abstract · Added April 3, 2018
Failure to properly repair damaged due to myocardial infarction is a major cause of heart failure. In contrast with adult mammals, zebrafish hearts show remarkable regenerative capabilities after substantial damage. To characterize protein dynamics during heart regeneration, we employed an HPLC-ESI-MS/MS (mass spectrometry) approach. Myocardium tissues were taken from sham-operated fish and ventricle-resected sample at three different time points (2, 7, and 14 days); dynamics of protein expression were analyzed by an ion-current-based quantitative platform. More than 2000 protein groups were quantified in all 16 experiments. Two hundred and nine heart-regeneration-related protein groups were quantified and clustered into six time-course patterns. Functional analysis indicated that multiple molecular function and metabolic pathways were involved in heart regeneration. Interestingly, Ingenuity Pathway Analysis revealed that P53 signaling was inhibited during the heart regeneration, which was further verified by real-time quantitative polymerase chain reaction (Q-PCR). In summary, we applied systematic proteomics analysis on regenerating zebrafish heart, uncovered the dynamics of regenerative genes expression and regulatory pathways, and provided invaluable insight into design regenerative-based strategies in human hearts.
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15 MeSH Terms
Calmodulin Mutants Linked to Catecholaminergic Polymorphic Ventricular Tachycardia Fail to Inhibit Human RyR2 Channels.
Walweel K, Gomez-Hurtado N, Oo YW, Beard NA, Dos Remedios C, Johnson CN, Chazin WJ, van Helden DF, Knollmann BC, Laver DR
(2017) J Am Coll Cardiol 70: 115-117
MeSH Terms: Calmodulin, Heart Ventricles, Humans, In Vitro Techniques, Mutation, Phosphorylation, Ryanodine Receptor Calcium Release Channel, Tachycardia, Ventricular
Added March 24, 2018
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8 MeSH Terms
Neuregulin-1β induces proliferation, survival and paracrine signaling in normal human cardiac ventricular fibroblasts.
Kirabo A, Ryzhov S, Gupte M, Sengsayadeth S, Gumina RJ, Sawyer DB, Galindo CL
(2017) J Mol Cell Cardiol 105: 59-69
MeSH Terms: Calcium, Calcium Signaling, Cell Line, Cell Proliferation, Cell Survival, Heart Ventricles, Humans, Intracellular Space, Myofibroblasts, Neuregulin-1, Paracrine Communication, Sarcoplasmic Reticulum, Signal Transduction
Show Abstract · Added December 27, 2017
Neuregulin-1β (NRG-1β) is critical for cardiac development and repair, and recombinant forms are currently being assessed as possible therapeutics for systolic heart failure. We previously demonstrated that recombinant NRG-1β reduces cardiac fibrosis in an animal model of cardiac remodeling and heart failure, suggesting that there may be direct effects on cardiac fibroblasts. Here we show that NRG-1β receptors (ErbB2, ErbB3, and ErbB4) are expressed in normal human cardiac ventricular (NHCV) fibroblast cell lines. Treatment of NHCV fibroblasts with recombinant NRG-1β induced activation of the AKT pathway, which was phosphoinositide 3-kinase (PI3K)-dependent. Moreover, the NRG-1β-induced PI3K/AKT signaling in these cells required phosphorylation of both ErbB2 and ErbB3 receptors at tyrosine (Tyr)1248 and Tyr1289 respectively. RNASeq analysis of NRG-1β-treated cardiac fibroblasts obtained from three different individuals revealed a global gene expression signature consistent with cell growth and survival. We confirmed enhanced cellular proliferation and viability in NHCV fibroblasts in response to NRG-1β, which was abrogated by PI3K, ErbB2, and ErbB3 inhibitors. NRG-1β also induced production and secretion of cytokines (interleukin-1α and interferon-γ) and pro-reparative factors (angiopoietin-2, brain-derived neurotrophic factor, and crypto-1), suggesting a role in cardiac repair through the activation of paracrine signaling.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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13 MeSH Terms
Contrasting Nav1.8 Activity in Scn10a-/- Ventricular Myocytes and the Intact Heart.
Stroud DM, Yang T, Bersell K, Kryshtal DO, Nagao S, Shaffer C, Short L, Hall L, Atack TC, Zhang W, Knollmann BC, Baudenbacher F, Roden DM
(2016) J Am Heart Assoc 5:
MeSH Terms: Action Potentials, Animals, Electrocardiography, Heart, Heart Ventricles, Isolated Heart Preparation, Mice, Mice, Knockout, Myocardium, Myocytes, Cardiac, NAV1.8 Voltage-Gated Sodium Channel, Patch-Clamp Techniques, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added February 3, 2017
BACKGROUND - Genome-wide association studies have implicated variants in SCN10A, which encodes Nav1.8, as modulators of cardiac conduction. Follow-up work has indicated the SCN10A sequence includes an intronic enhancer for SCN5A. Yet the role of the Nav1.8 protein in the myocardium itself is still unclear. To investigate this, we use homozygous knockout mice (Scn10a) generated by disruption of exons 4 and 5, leaving the Scn5a enhancer intact.
METHODS AND RESULTS - We previously reported that pharmacologic blockade of Nav1.8 in wild-type animals blunts action potential prolongation by ATX-II at slow drive rates (≤1 Hz). Here we present evidence of the same blunting in Scn10a compared to wild-type ventricular myocytes, supporting the conclusion that Nav1.8 contributes to late sodium current at slow rates. In contrast to earlier studies, we found no differences in electrocardiographic parameters between genotypes. Low-dose ATX-II exposure in lightly anesthetized animals and Langendorff-perfused hearts prolonged QTc and generated arrhythmias to the same extent in wild-type and Scn10a. RNA sequencing failed to identify full-length Scn10a transcripts in wild-type or knockout isolated ventricular myocytes. However, loss of late current in Scn10a myocytes was replicated independently in a blinded set of experiments.
CONCLUSIONS - While Scn10a transcripts are not detectible in ventricular cardiomyocytes, gene deletion results in reproducible loss of late sodium current under extreme experimental conditions. However, there are no identifiable consequences of this Scn10a deletion in the intact mouse heart at usual rates. These findings argue that common variants in SCN10A that affect ventricular conduction do so by modulating SCN5A.
© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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14 MeSH Terms
Transcription factor ETV1 is essential for rapid conduction in the heart.
Shekhar A, Lin X, Liu FY, Zhang J, Mo H, Bastarache L, Denny JC, Cox NJ, Delmar M, Roden DM, Fishman GI, Park DS
(2016) J Clin Invest 126: 4444-4459
MeSH Terms: Animals, DNA-Binding Proteins, Heart Atria, Heart Conduction System, Heart Ventricles, Homeobox Protein Nkx-2.5, Humans, Mice, Mice, Transgenic, Myocardium, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel, Transcription Factors
Show Abstract · Added March 14, 2018
Rapid impulse propagation in the heart is a defining property of pectinated atrial myocardium (PAM) and the ventricular conduction system (VCS) and is essential for maintaining normal cardiac rhythm and optimal cardiac output. Conduction defects in these tissues produce a disproportionate burden of arrhythmic disease and are major predictors of mortality in heart failure patients. Despite the clinical importance, little is known about the gene regulatory network that dictates the fast conduction phenotype. Here, we have used signal transduction and transcriptional profiling screens to identify a genetic pathway that converges on the NRG1-responsive transcription factor ETV1 as a critical regulator of fast conduction physiology for PAM and VCS cardiomyocytes. Etv1 was highly expressed in murine PAM and VCS cardiomyocytes, where it regulates expression of Nkx2-5, Gja5, and Scn5a, key cardiac genes required for rapid conduction. Mice deficient in Etv1 exhibited marked cardiac conduction defects coupled with developmental abnormalities of the VCS. Loss of Etv1 resulted in a complete disruption of the normal sodium current heterogeneity that exists between atrial, VCS, and ventricular myocytes. Lastly, a phenome-wide association study identified a link between ETV1 and bundle branch block and heart block in humans. Together, these results identify ETV1 as a critical factor in determining fast conduction physiology in the heart.
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13 MeSH Terms
Transitions in Metabolic Risk and Long-Term Cardiovascular Health: Coronary Artery Risk Development in Young Adults (CARDIA) Study.
Murthy VL, Abbasi SA, Siddique J, Colangelo LA, Reis J, Venkatesh BA, Carr JJ, Terry JG, Camhi SM, Jerosch-Herold M, de Ferranti S, Das S, Freedman J, Carnethon MR, Lewis CE, Lima JA, Shah RV
(2016) J Am Heart Assoc 5:
MeSH Terms: Adolescent, Adult, Blood Glucose, Blood Pressure, Body Mass Index, Cardiovascular Diseases, Cholesterol, HDL, Cohort Studies, Coronary Artery Disease, Diabetes Mellitus, Disease Progression, Echocardiography, Female, Follow-Up Studies, Heart Ventricles, Humans, Hypertension, Logistic Models, Longitudinal Studies, Male, Metabolic Syndrome, Organ Size, Risk Factors, Tomography, X-Ray Computed, Triglycerides, United States, Vascular Calcification, Waist Circumference, Young Adult
Show Abstract · Added September 11, 2017
BACKGROUND - Despite evidence suggesting that early metabolic dysfunction impacts cardiovascular disease risk, current guidelines focus on risk assessments later in life, missing early transitions in metabolic risk that may represent opportunities for averting the development of cardiovascular disease.
METHODS AND RESULTS - In 4420 young adults in the Coronary Artery Risk Development in Young Adults (CARDIA) study, we defined a "metabolic" risk score based on components of the Third Report of the Adult Treatment Panel's definition of metabolic syndrome. Using latent class trajectory analysis adjusted for sex, race, and time-dependent body mass index, we identified 6 distinct metabolic trajectories over time, specified by initial and final risk: low-stable, low-worsening, high-stable, intermediate-worsening, intermediate-stable, and high-worsening. Overall, individuals gained weight over time in CARDIA with statistically but not clinically different body mass index trend over time. Dysglycemia and dyslipidemia over time were highest in initially high or worsening trajectory groups. Divergence in metabolic trajectories occurred in early adulthood (before age 40), with 2 of 3 individuals experiencing an increase in metabolic risk over time. Membership in a higher-risk trajectory (defined as initially high or worsening over time) was associated with greater prevalence and extent of coronary artery calcification, left ventricular mass, and decreased left ventricular strain at year 25. Importantly, despite similar rise in body mass index across trajectories over 25 years, coronary artery calcification and left ventricular structure and function more closely tracked risk factor trajectories.
CONCLUSIONS - Transitions in metabolic risk occur early in life. Obesity-related metabolic dysfunction is related to subclinical cardiovascular phenotypes independent of evolution in body mass index, including coronary artery calcification and myocardial hypertrophy and dysfunction.
© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
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29 MeSH Terms
Evaluating the Utility of Baseline Cardiac Function Screening in Early-Stage Breast Cancer Treatment.
Truong SR, Barry WT, Moslehi JJ, Baker EL, Mayer EL, Partridge AH
(2016) Oncologist 21: 666-70
MeSH Terms: Adult, Aged, Aged, 80 and over, Breast Neoplasms, Echocardiography, Female, Heart, Heart Ventricles, Humans, Middle Aged, Neoplasm Staging, Retrospective Studies, Ventricular Function, Left
Show Abstract · Added March 26, 2017
BACKGROUND - Cardiotoxicity can be a complication of anthracycline- or trastuzumab-based therapy for breast cancer patients. Screening echocardiograms (ECHOs) and radionuclide ventriculograms (RVGs) are often performed before administration of these agents to evaluate cardiac function. Limited evidence for the clinical utility of these screening tests is available.
METHODS - Early-stage breast cancer patients diagnosed from 2006 to 2011 (n = 1,067) with baseline ECHOs/RVGs were identified in a single institution prospective registry. Medical record review was performed to obtain pre- and post-ECHO/RVG treatment plans, baseline ECHO/RVG results, cardiac risk factors, and cardiac events. Patients with cardiac history were excluded. ECHO/RVG abnormalities were defined as ejection fraction (EF) <55%, valvular disease, left ventricular hypertrophy, and diastolic dysfunction. Cardiac events were defined as heart failure, myocardial infarction, arrhythmia, valvular disease, or angina during or after chemotherapy.
RESULTS - Among 600 eligible patients, abnormal ECHO/RVG results were observed in 13 (2.2%, 1.2%-3.7%), including 9 with baseline EF <55%. There were no detected changes in treatment plans, although more frequent cardiac monitoring was recommended for 2 patients. There were no significant differences in age, race, menopausal status, smoking history, alcohol use, body mass index, or medical comorbidities between patients with abnormal and normal results. In follow-up (mean, 4.0 years; range, 0-8.3), 15 patients developed cardiac events (none of whom had had abnormal baseline ECHOs/RVGs).
CONCLUSION - Baseline ECHO/RVG in patients without prior cardiac history rarely yields an abnormality that prompts change in planned anthracycline- and/or trastuzumab-based treatment. Moreover, few cardiac events developed in this screened population in follow-up.
IMPLICATIONS FOR PRACTICE - Baseline cardiac function screening with echocardiograms or radionuclide ventriculograms is frequently performed before administration of anthracycline- or trastuzumab-based chemotherapy in breast cancer patients due to the relatively low cost and risk to patients and the concern for potential cardiotoxicity. However, at a population level, these tests can take up time and can add up to significant costs for both patients and the health care system. This study finds that in patients with no history of cardiac disease, baseline cardiac function screening rarely identifies abnormalities that change treatment plans. Moreover, few cardiac events develop in an average of 4 years of follow-up, including none in patients with abnormal baseline cardiac function screening results. This suggests that baseline cardiac function screening may have limited utility in chemotherapy planning in young breast cancer patients with no history of cardiac disease.
©AlphaMed Press.
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13 MeSH Terms
Mechanisms of Lipid Accumulation in the Bone Morphogenetic Protein Receptor Type 2 Mutant Right Ventricle.
Talati MH, Brittain EL, Fessel JP, Penner N, Atkinson J, Funke M, Grueter C, Jerome WG, Freeman M, Newman JH, West J, Hemnes AR
(2016) Am J Respir Crit Care Med 194: 719-28
MeSH Terms: Animals, Bone Morphogenetic Protein Receptors, Type II, Cell Line, Disease Models, Animal, Fatty Acids, Heart Ventricles, Hypertension, Pulmonary, Lipid Metabolism, Lipids, Metabolomics, Mice, Mice, Transgenic, Microscopy, Electron, Myocytes, Cardiac
Show Abstract · Added April 22, 2016
RATIONALE - In heritable pulmonary arterial hypertension with germline mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene, right ventricle (RV) dysfunction is associated with RV lipotoxicity; however, the underlying mechanism for lipid accumulation is not known.
OBJECTIVES - We hypothesized that lipid accumulation in cardiomyocytes with BMPR2 mutation occurs owing to alterations in lipid transport and impaired fatty acid oxidation (FAO), which is exacerbated by a high-lipid (Western) diet (WD).
METHODS - We used a transgenic mouse model of pulmonary arterial hypertension with mutant BMPR2 and generated a cardiomyocyte cell line with BMPR2 mutation. Electron microscopy and metabolomic analysis were performed on mouse RVs.
MEASUREMENTS AND MAIN RESULTS - By metabolomics analysis, we found an increase in long-chain fatty acids in BMPR2 mutant mouse RVs compared with controls, which correlated with cardiac index. BMPR2-mutant cardiomyocytes had increased lipid compared with controls. Direct measurement of FAO in the WD-fed BMPR2-mutant RV showed impaired palmitate-linked oxygen consumption, and metabolomics analysis showed reduced indices of FAO. Using both mutant BMPR2 mouse RVs and cardiomyocytes, we found an increase in the uptake of (14)C-palmitate and fatty acid transporter CD36 that was further exacerbated by WD.
CONCLUSIONS - Taken together, our data suggest that impaired FAO and increased expression of the lipid transporter CD36 are key mechanisms underlying lipid deposition in the BMPR2-mutant RV, which are exacerbated in the presence of dietary lipids. These findings suggest important features leading to RV lipotoxicity in pulmonary arterial hypertension and may point to novel areas of therapeutic intervention.
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14 MeSH Terms