Publications by authors named "Douglas B Sawyer"

152 Publications

Decreased expression of ErbB2 on left ventricular epicardial cells in patients with diabetes mellitus.

Cell Signal 2022 May 21:110360. Epub 2022 May 21.

Tufts Medical Center, Boston, MA, United States of America. Electronic address:

We investigated the cell surface expression of ErbB receptors on left ventricular (LV) epicardial endothelial cells and CD105 cells obtained from cardiac biopsies of patients undergoing coronary artery bypass grafting surgery (CABG). Endothelial cells and CD105 non-endothelial cells were freshly isolated from LV epicardial biopsies obtained from 15 subjects with diabetes mellitus (DM) and 8 controls. The expression of ErbB receptors was examined using flow cytometry. We found that diabetes mellitus (DM) and high levels of hemoglobin A1C are associated with reduced expression of ErbB2. To determine if the expression of ErbB2 receptors is regulated by glucose levels, we examined the effect of high Glucose in human microvascular endothelial cells (HMEC-1) and CD105 non-endothelial cells, using a novel flow cytometric approach to simultaneously determine the total level, cell surface expression, and phosphorylation of ErbB2. Incubation of cells in the presence of 25 mM d-glucose resulted in decreased cell surface but not total levels of ErbB2. The level of ErbB2 at the cell surface is controlled by disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) that is expressed on LV epicardial cells. Inhibition of ADAM10 prevented the high glucose-dependent decrease in the cell surface expression of ErbB2. We suggest that high Glucose depresses ErbB receptor signaling in endothelial cells and cardiac progenitor cells via the promotion of ADAM10-dependent cleavage of ErbB2 at the cell surface, thus contributing to vascular dysfunction and adverse remodeling seen in diabetic patients.
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http://dx.doi.org/10.1016/j.cellsig.2022.110360DOI Listing
May 2022

The number of circulating CD26 expressing cells is decreased in critical COVID-19 illness.

Cytometry A 2022 Mar 4. Epub 2022 Mar 4.

Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, Maine, USA.

We evaluated the number of CD26 expressing cells in peripheral blood of patients with COVID-19 within 72 h of admission and on day 4 and day 7 after enrollment. The majority of CD26 expressing cells were presented by CD3 CD4 lymphocytes. A low number of CD26 expressing cells were found to be associated with critical-severity COVID-19 disease. Conversely, increasing numbers of CD26 expressing T cells over the first week of standard treatment was associated with good outcomes. Clinically, the number of circulating CD26 cells might be a marker of recovery or the therapeutic efficacy of anti-COVID-19 treatment. New therapies aimed at preserving and increasing the level of CD26 expressing T cells may prove useful in the treatment of COVID-19 disease.
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http://dx.doi.org/10.1002/cyto.a.24547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9087143PMC
March 2022

DEspR neutrophils are associated with critical illness in COVID-19.

Sci Rep 2021 11 17;11(1):22463. Epub 2021 Nov 17.

Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME, 04074, USA.

SARS-CoV-2 infection results in a spectrum of outcomes from no symptoms to widely varying degrees of illness to death. A better understanding of the immune response to SARS-CoV-2 infection and subsequent, often excessive, inflammation may inform treatment decisions and reveal opportunities for therapy. We studied immune cell subpopulations and their associations with clinical parameters in a cohort of 26 patients with COVID-19. Following informed consent, we collected blood samples from hospitalized patients with COVID-19 within 72 h of admission. Flow cytometry was used to analyze white blood cell subpopulations. Plasma levels of cytokines and chemokines were measured using ELISA. Neutrophils undergoing neutrophil extracellular traps (NET) formation were evaluated in blood smears. We examined the immunophenotype of patients with COVID-19 in comparison to that of SARS-CoV-2 negative controls. A novel subset of pro-inflammatory neutrophils expressing a high level of dual endothelin-1 and VEGF signal peptide-activated receptor (DEspR) at the cell surface was found to be associated with elevated circulating CCL23, increased NETosis, and critical-severity COVID-19 illness. The potential to target this subpopulation of neutrophils to reduce secondary tissue damage caused by SARS-CoV-2 infection warrants further investigation.
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http://dx.doi.org/10.1038/s41598-021-01943-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599677PMC
November 2021

Anthracycline-Induced Vascular Dysfunction: Is MitoQ the Answer?

Authors:
Douglas B Sawyer

JACC CardioOncol 2020 Sep 15;2(3):489-490. Epub 2020 Sep 15.

Maine Medical Center, Tufts University School of Medicine, Portland, Maine, USA.

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http://dx.doi.org/10.1016/j.jaccao.2020.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352173PMC
September 2020

Circulating growth factors and cardiac remodeling in the community: The Framingham Heart Study.

Int J Cardiol 2021 04 7;329:217-224. Epub 2021 Jan 7.

Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA; Boston University's and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.. Electronic address:

Background And Aims: Cardiac and vascular growth factors (GF) may influence myocardial remodeling through cardiac growth and angiogenic effects. We hypothesized that concentrations of circulating GF are associated with cardiac remodeling traits.

Methods: We related blood concentrations of vascular endothelial GF (VEGF), VEGFR-1 (sFlt1), angiopoietin 2 (Ang-2), soluble angiopoietin type-2 receptor (sTie2), hepatocyte GF (HGF), insulin-like GF (IGF)-1, IGF binding protein (IGFBP)-3, and growth differentiation factor-15 (GDF-15) to echocardiographic traits in 3151 Framingham Study participants (mean age 40 years, 55% women). We evaluated the following measures: left ventricular (LV) mass index (LVMi), LV ejection fraction (LVEF), global longitudinal strain (GLS), mitral E/e', and aortic root diameter (AoR). All biomarker values were sex-standardized.

Results: In multivariable-adjusted analyses, higher GDF-15 concentrations were associated with higher log-LVMi (β = 0.009 per SD, P = 0.01). Similarly, sTie2 concentrations were positively associated with log-E/e' (β = 0.011 per SD, P = 0.04). IGF-1 and Ang-2 concentrations were positively and negatively associated with GLS, respectively (β = 0.16 per SD and β = -0.15 per SD, both P < 0.05), whereas higher sFlt1 and Ang-2 levels were associated with smaller log-AoR (β = -0.004 per SD and β  = -0.005 per SD, respectively; P < 0.05).

Conclusion: In our large community-based sample, we observed patterns of associations between several circulating vascular GF and cardiac remodeling indices that are consistent with the known biological effects of these pro- and anti-angiogenic factors on the myocardium and conduit arteries. Additional studies are warranted to replicate our findings and assess their prognostic significance.
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http://dx.doi.org/10.1016/j.ijcard.2020.12.088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940564PMC
April 2021

Modification of ventriculo-arterial coupling by spironolactone in nonischemic dilated cardiomyopathy.

ESC Heart Fail 2021 04 5;8(2):1156-1166. Epub 2021 Jan 5.

VA Tennessee Valley Health Care System, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.

Aims: We sought to clarify the role of ventriculo-arterial (V-A) coupling in the treatment of nonischemic dilated cardiomyopathy (NIDCM) by adding a mineralocorticoid receptor antagonist (MRA) to conventional anti-failure therapy.

Methods And Results: We employed cardiac magnetic resonance imaging to quantify left ventricular (LV) contractility and V-A coupling in normal subjects at rest (n = 11) and in patients with NIDCM (n = 12) before and after long term anti-failure therapy, in which MRA was added to conventional anti-failure therapy. After ≥6 months' treatment in NIDCM patients, LV volumes and mass decreased, and the LV ejection fraction increased from a median of 24% (17, 27) (interquartile range IQR) to 47 (42, 52) (P < 0.002), with a marked reduction in arterial elastance (Ea) from 2.89 mmHg/mL (2.34, 4.0) to 1.50 (1.29, 1.95) (P < 0.002), similar to Ea of normal subjects, 1.53 (1.34, 1.67) (P > 0.05). The V-A coupling ratio, Ea/end-systolic elastance (single-beat method), decreased by -1.08 (-1.96, -0.55), (P = 0.003), as did Ea/end-systolic pressure/end-systolic pressure ratio, -0.54 (0.35, 0.87), (P = 0.002). The preload recruitable stroke work (PRSW) increased as did PRSW indexed for Ea (both P = 0.002), which reflected 'total circulatory performance'.

Conclusions: In NIDCM, adding MRA to conventional anti-failure therapy markedly improved LV ejection fraction and reduced peripheral vascular resistance, due to both improved LV contractility and especially to enhanced V-A coupling, as Ea decreased to normal. Total circulatory performance was a sensitive indicator of both LV pump performance and the arterial loading conditions.
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http://dx.doi.org/10.1002/ehf2.13161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006677PMC
April 2021

Protective role of ErbB3 signaling in myeloid cells during adaptation to cardiac pressure overload.

J Mol Cell Cardiol 2021 03 28;152:1-16. Epub 2020 Nov 28.

Maine Medical Center Research Institute, Scarborough, ME, United States of America. Electronic address:

Background: Myeloid cells play an important role in a wide variety of cardiovascular disorders, including both ischemic and non-ischemic cardiomyopathies. Neuregulin-1 (NRG-1)/ErbB signaling has recently emerged as an important factor contributing to the control of inflammatory activation of myeloid cells after an ischemic injury. However, the role of ErbB signaling in myeloid cells in non-ischemic cardiomyopathy is not fully understood. This study investigated the role of ErbB3 receptors in the regulation of early adaptive response using a mouse model of transverse aortic constriction (TAC) for non-ischemic cardiomyopathy.

Methods And Results: TAC surgery was performed in groups of age- and sex-matched myeloid cell-specific ErbB3-deficient mice (ErbB3) and control animals (ErbB3). The number of cardiac CD45 immune cells, CD11b myeloid cells, Ly6G neutrophils, and Ly6C monocytes was determined using flow cytometric analysis. Five days after TAC, survival was dramatically reduced in male but not female ErbB3 mice or control animals. The examination of lung weight to body weight ratio suggested that acute pulmonary edema was present in ErbB3 male mice after TAC. To determine the cellular and molecular mechanisms involved in the increased mortality in ErbB3 male mice, cardiac cell populations were examined at day 3 post-TAC using flow cytometry. Myeloid cells accumulated in control but not in ErbB3 male mouse hearts. This was accompanied by increased proliferation of Sca-1 positive non-immune cells (endothelial cells and fibroblasts) in control but not ErbB3 male mice. No significant differences in intramyocardial accumulation of myeloid cells or proliferation of Sca-1 cells were found between the groups of ErbB3 and ErbB3 female mice. An antibody-based protein array analysis revealed that IGF-1 expression was significantly downregulated only in ErbB3 mice hearts compared to control animals after TAC.

Conclusion: Our data demonstrate the crucial role of myeloid cell-specific ErbB3 signaling in the cardiac accumulation of myeloid cells, which contributes to the activation of cardiac endothelial cells and fibroblasts and development of an early adaptive response to cardiac pressure overload in male mice.
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http://dx.doi.org/10.1016/j.yjmcc.2020.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981250PMC
March 2021

Neuregulins: protective and reparative growth factors in multiple forms of cardiovascular disease.

Clin Sci (Lond) 2020 10;134(19):2623-2643

Maine Medical Center, Portland, Maine, USA.

Neuregulins (NRGs) are protein ligands that act through ErbB receptor tyrosine kinases to regulate tissue morphogenesis, plasticity, and adaptive responses to physiologic needs in multiple tissues, including the heart and circulatory system. The role of NRG/ErbB signaling in cardiovascular biology, and how it responds to physiologic and pathologic stresses is a rapidly evolving field. While initial concepts focused on the role that NRG may play in regulating cardiac myocyte responses, including cell survival, growth, adaptation to stress, and proliferation, emerging data support a broader role for NRGs in the regulation of metabolism, inflammation, and fibrosis in response to injury. The constellation of effects modulated by NRGs may account for the findings that two distinct forms of recombinant NRG-1 have beneficial effects on cardiac function in humans with systolic heart failure. NRG-4 has recently emerged as an adipokine with similar potential to regulate cardiovascular responses to inflammation and injury. Beyond systolic heart failure, NRGs appear to have beneficial effects in diastolic heart failure, prevention of atherosclerosis, preventing adverse effects on diabetes on the heart and vasculature, including atherosclerosis, as well as the cardiac dysfunction associated with sepsis. Collectively, this literature supports the further examination of how this developmentally critical signaling system functions and how it might be leveraged to treat cardiovascular disease.
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http://dx.doi.org/10.1042/CS20200230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557502PMC
October 2020

What is Quality End-of-Life Care for Patients With Heart Failure? A Qualitative Study With Physicians.

J Am Heart Assoc 2020 09 31;9(18):e016505. Epub 2020 Aug 31.

Center for Outcomes Research and Evaluation Maine Medical Center Portland ME.

Background Advanced heart failure (AHF) carries a morbidity and mortality that are similar or worse than many advanced cancers. Despite this, there are no accepted quality metrics for end-of-life (EOL) care for patients with AHF. Methods and Results As a first step toward identifying quality measures, we performed a qualitative study with 23 physicians who care for patients with AHF. Individual, in-depth, semistructured interviews explored physicians' perceptions of characteristics of high-quality EOL care and the barriers encountered. Interviews were analyzed using software-assisted line-by-line coding in order to identify emergent themes. Although some elements and barriers of high-quality EOL care for AHF were similar to those described for other diseases, we identified several unique features. We found a competing desire to avoid overly aggressive care at EOL alongside a need to ensure that life-prolonging interventions were exhausted. We also identified several barriers related to identifying EOL including greater prognostic uncertainty, inadequate recognition of AHF as a terminal disease and dependence of symptom control on disease-modifying therapies. Conclusions Our findings support quality metrics that prioritize receipt of goal-concordant care over utilization measures as well as a need for more inclusive payment models that appropriately reflect the dual nature of many AHF therapies.
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http://dx.doi.org/10.1161/JAHA.120.016505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727006PMC
September 2020

High ErbB3 activating activity in human blood is not due to circulating neuregulin-1 beta.

Life Sci 2020 Jun 3;251:117634. Epub 2020 Apr 3.

Maine Medical Center Research Institute, Scarborough, ME, United States of America. Electronic address:

Neuregulin-1β (NRG-1) is a membrane-bound or secreted growth and differentiation factor that mediates its action by binding to ErbB receptors. Circulating levels of NRG-1 are characterized by large inter-individual variability with the range of absolute values covering two orders of magnitude, from hundreds to tens of thousands of picograms per milliliter of blood. NRG-1 signaling via ErbB receptors contributes to the cell survival and downregulation of the inflammatory response. A higher level of circulating NRG-1 may indicate increased shedding of membrane-bound NRG-1, which in turn can contribute to better protection against cardiovascular stress or injury. However, it is unknown whether circulating NRG-1 can induce activation of ErbB receptors. In the current study, we performed an analysis of circulating NRG-1 functional activity using a cell-based ELISA measuring phosphorylation of ErbB3 induced by blood plasma obtained from healthy donors. We found high levels of ErbB3 activating activity in human plasma. No correlations were found between the levels of circulating NRG-1 and plasma ErbB3 activating activity. To determine the direct effect of circulating NRG-1, we incubated plasma with neutralizing antibody, which prevented the stimulatory effect of recombinant NRG-1 on activation of ErbB3. No effect of the neutralizing antibody was found on plasma-induced phosphorylation of ErbB3. We also found that a significant portion of circulating NRG-1 is comprised of full-length NRG-1 associated with large extracellular vesicles. Our results demonstrate that circulating NRG-1 does not contribute to plasma-induced ErbB3 activating activity and emphasizes the importance of functional testing of NRG-1 proteins in biological samples.
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http://dx.doi.org/10.1016/j.lfs.2020.117634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233313PMC
June 2020

Prolonged Cardiopulmonary Bypass is Associated With Endothelial Glycocalyx Degradation.

J Surg Res 2020 07 30;251:287-295. Epub 2020 Apr 30.

Maine Medical Center Cardiovascular Institute, Portland, Maine; Maine Medical Center Research Institute, Scarborough, Maine. Electronic address:

Background: The endothelial glycocalyx (EG) is involved in critical regulatory mechanisms that maintain endothelial vascular integrity. We hypothesized that prolonged cardiopulmonary bypass (CPB) may be associated with EG degradation. We performed an analysis of soluble syndecan-1 levels in relation to duration of CPB, as well as factors associated with cell stress and damage, such as mitochondrial DNA (mtDNA) and inflammation.

Methods: Blood samples from subjects undergoing cardiac surgery with CPB (n = 54) were obtained before and during surgery, 4-8 h and 24 h after completion of CPB, and on postoperative day 4. Flow cytometry was used to determine subpopulations of white blood cells. Plasma levels of mtDNA were determined using quantitative polymerase chain reaction and plasma content of shed syndecan-1 was measured. To determine whether syndecan-1 was signaling white blood cells, the effect of recombinant syndecan-1 on mobilization of neutrophils from bone marrow was tested in mice.

Results: CPB is associated with increased mtDNA during surgery, increased syndecan-1 blood levels at 4-8 h, and increased white blood cell count at 4-8 h and 24 h. Correlation analysis revealed significant positive associations between time on CPB and syndecan-1 (r = 0.488, P < 0.001) and level of syndecan-1 and neutrophil count (r = 0.351, P = 0.038) at 4-8 h. Intravenous administration of recombinant syndecan-1 in mice resulted in a 2.5-fold increase in the number of circulating neutrophils, concurrent with decreased bone marrow neutrophil number.

Conclusions: Longer duration of CPB is associated with increased plasma levels of soluble syndecan-1, a signal for EG degradation, which can induce neutrophil egress from the bone marrow. Development of therapy targeting EG shedding may be beneficial in patients with prolonged CPB.
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http://dx.doi.org/10.1016/j.jss.2020.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247933PMC
July 2020

Systemic and cardiac susceptibility of immune compromised mice to doxorubicin.

Cardiooncology 2019 25;5. Epub 2019 Apr 25.

1Maine Medical Center Research Institute, Center for Molecular Medicine, 81 Research Drive, Scarborough, ME 04074 USA.

Background: Anthracycline chemotherapy is an effective and widely used treatment for solid tumors and hematological malignancies regardless of its known cardiotoxicity. The mechanisms of the cardiotoxicity are not fully understood and methods to protect the heart during or following anthracycline chemotherapy are currently unclear. In order to examine the efficacy of human cell based therapy in anthracycline-induced injury, we characterized a mouse model using an immune compromised strain of mice capable of accepting human cells.

Methods: Immune compromised mice (NOD.Cg-Prkdc Il2rg/SzJ) were repeatedly exposed to pharmaceutical grade doxorubicin (0.5 mg/kg - 4 mg/kg). Cardiotoxicity was assessed by echocardiography and μCT imaging of the coronary vascular bed as well as by flow cytometry and by histological assessments of anthracycline-induced cardiac tissue damage.

Results: The immune compromised mice were highly susceptible to doxorubicin treatment. Doxorubicin induced both systemic and cardiac toxicities. Gastrointestinal and hepatic injury occurred at 4 mg/kg and 1.5 mg/kg dosing while mice receiving 0.5 mg/kg weekly only displayed hepatic damage. Repeated exposure to 0.5 mg/kg anthracyclines resulted in cardiac toxicity. Flow cytometric analysis of hearts indicated a loss in endothelial and cardiac progenitor cells after doxorubicin treatment. This endothelial loss is corroborated by the lack of small vessels detected by μCT in the hearts of mice exposed to doxorubicin. Histological assessment shows no overt cardiomyocyte injury but livers from mice treated with doxorubicin show marked hepatic plate atrophy with intracytoplasmic and canalicular cholestasis, rare pericentral hepatocellular necrosis and significant zone 3 iron accumulation, likely an indication of metabolic injury due to doxorubicin toxicity.

Conclusions: Immune compromised mice are sensitive to doxorubicin therapy resulting in systemic complications in addition to cardiovascular toxicity. Anthracycline-induced cardiotoxicity is observed at very low doses in NOD.Cg-Prkdc Il2rg/SzJ mice.
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http://dx.doi.org/10.1186/s40959-019-0037-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048100PMC
April 2019

3D Co-culture of hiPSC-Derived Cardiomyocytes With Cardiac Fibroblasts Improves Tissue-Like Features of Cardiac Spheroids.

Front Mol Biosci 2020 14;7:14. Epub 2020 Feb 14.

Cardiology Department, DBMR MEM C812, Bern University Hospital, Bern, Switzerland.

Both cardiomyocytes and cardiac fibroblasts (CF) play essential roles in cardiac development, function, and remodeling. Properties of 3D co-cultures are incompletely understood. Hence, 3D co-culture of cardiomyocytes and CF was characterized, and selected features compared with single-type and 2D culture conditions. Human cardiomyocytes derived from induced-pluripotent stem cells (hiPSC-CMs) were obtained from Cellular Dynamics or Ncardia, and primary human cardiac fibroblasts from ScienCell. Cardiac spheroids were investigated using cryosections and whole-mount confocal microscopy, video motion analysis, scanning-, and transmission-electron microscopy (SEM, TEM), action potential recording, and quantitative PCR (qPCR). Spheroids formed in hanging drops or in non-adhesive wells showed spontaneous contractions for at least 1 month with frequent media changes. SEM of mechanically opened spheroids revealed a dense inner structure and no signs of blebbing. TEM of co-culture spheroids at 1 month showed myofibrils, intercalated disc-like structures and mitochondria. Ultrastructural features were comparable to fetal human myocardium. We then assessed immunostained 2D cultures, cryosections of spheroids, and whole-mount preparations by confocal microscopy. CF in co-culture spheroids assumed a small size and shape similar to the situation in ventricular tissue. Spheroids made only of CF and cultured for 3 weeks showed no stress fibers and strongly reduced amounts of alpha smooth muscle actin compared to early spheroids and 2D cultures as shown by confocal microscopy, western blotting, and qPCR. The addition of CF to cardiac spheroids did not lead to arrhythmogenic effects as measured by sharp-electrode electrophysiology. Video motion analysis showed a faster spontaneous contraction rate in co-culture spheroids compared to pure hiPSC-CMs, but similar contraction amplitudes and kinetics. Spontaneous contraction rates were not dependent on spheroid size. Applying increasing pacing frequencies resulted in decreasing contraction amplitudes without positive staircase effect. Gene expression analysis of selected cytoskeleton and myofibrillar proteins showed more tissue-like expression patterns in co-culture spheroids than with cardiomyocytes alone or in 2D culture. We demonstrate that the use of 3D co-culture of hiPSC-CMs and CF is superior over 2D culture conditions for co-culture models and more closely mimicking the native state of the myocardium with relevance to drug development as well as for personalized medicine.
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http://dx.doi.org/10.3389/fmolb.2020.00014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033479PMC
February 2020

Number of Circulating CD 73-Expressing Lymphocytes Correlates With Survival After Cardiac Arrest.

J Am Heart Assoc 2019 07 25;8(13):e010874. Epub 2019 Jun 25.

1 Maine Medical Center Research Institute Scarborough ME.

Background Patients resuscitated from cardiac arrest ( CA ) have highly variable neurological, circulatory, and systemic ischemia-reperfusion injuries. After the initial hypoxic-ischemic insult, a cascade of immune and inflammatory responses develops and is often fatal. The role of the immune response in pathophysiological characteristics and recovery is not well understood. We studied immune cell activity and its association with outcomes in a cohort of CA survivors. Methods and Results After informed consent, we collected blood samples at intervals over a week after resuscitation from CA . We examined the expression of CD 39 and CD 73 (alias 5'-nucleotidase), production of tumor necrosis factor-α, generation of reactive oxygen species, and secretion of vascular endothelial growth factor by circulating myeloid and lymphoid cells, in comparison to cells obtained from control subjects before coronary artery bypass grafting surgery. The number of circulating total and CD 73-expressing lymphocytes correlated with survival after CA . Incubation of immune cells, obtained from post- CA subjects, with AMP , a substrate for CD 73, resulted in inhibition of tumor necrosis factor-α production and generation of reactive oxygen species. This effect was blocked by adenosine 5'-(α, β-methylene) diphosphate, a specific inhibitor of CD 73 and ZM 241385, an A2 adenosine receptor antagonist. We also found that AMP -dependent activation of CD 73 induces production of vascular endothelial growth factor. Conclusions CD 73-expressing lymphocytes mediate cellular protection from inflammation after CA through inhibition of proinflammatory activation of myeloid cells and promotion of vascular endothelial growth factor secretion. The contribution of CD 73 lymphocytes in the regulation of acute inflammation and tissue injury after CA warrants further study.
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http://dx.doi.org/10.1161/JAHA.118.010874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662342PMC
July 2019

Anthracycline and Peripartum Cardiomyopathies.

Circ Res 2019 05;124(11):1633-1646

From the Department of Cardiovascular Medicine, Maine Medical Center, Portland.

Anthracycline-associated cardiomyopathy and peripartum cardiomyopathy are nonischemic cardiomyopathies that often afflict previously healthy young patients; both diseases have been well described since at least the 1970s and both occur in the settings of predictable stressors (ie, cancer treatment and pregnancy). Despite this, the precise mechanisms and the ability to reliably predict who exactly will go on to develop cardiomyopathy and heart failure in the face of anthracycline exposure or childbirth have proven elusive. For both cardiomyopathies, recent advances in basic and molecular sciences have illuminated the complex balance between cardiomyocyte and endothelial homeostasis via 3 broad pathways: reactive oxidative stress, interference in apoptosis/growth/metabolism, and angiogenic imbalance. These advances have already shown potential for specific, disease-altering therapies, and as our mechanistic knowledge continues to evolve, further clinical successes are expected to follow.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.313577DOI Listing
May 2019

Endothelial Cells Regulate Physiological Cardiomyocyte Growth via VEGFR2-Mediated Paracrine Signaling.

Circulation 2019 05 29;139(22):2570-2584. Epub 2019 Mar 29.

Wihuri Research Institute, Helsinki, Finland and Translational Cancer Biology Program, Research Programs Unit, Faculty of Medicine, University of Helsinki, Finland (R.K., K.A.H., M.R., K.A.).

Background: Heart failure, which is a major global health problem, is often preceded by pathological cardiac hypertrophy. The expansion of the cardiac vasculature, to maintain adequate supply of oxygen and nutrients, is a key determinant of whether the heart grows in a physiological compensated manner or a pathological decompensated manner. Bidirectional endothelial cell (EC)-cardiomyocyte (CMC) cross talk via cardiokine and angiocrine signaling plays an essential role in the regulation of cardiac growth and homeostasis. Currently, the mechanisms involved in the EC-CMC interaction are not fully understood, and very little is known about the EC-derived signals involved. Understanding how an excess of angiogenesis induces cardiac hypertrophy and how ECs regulate CMC homeostasis could provide novel therapeutic targets for heart failure.

Methods: Genetic mouse models were used to delete vascular endothelial growth factor (VEGF) receptors, adeno-associated viral vectors to transduce the myocardium, and pharmacological inhibitors to block VEGF and ErbB signaling in vivo. Cell culture experiments were used for mechanistic studies, and quantitative polymerase chain reaction, microarrays, ELISA, and immunohistochemistry were used to analyze the cardiac phenotypes.

Results: Both EC deletion of VEGF receptor (VEGFR)-1 and adeno-associated viral vector-mediated delivery of the VEGFR1-specific ligands VEGF-B or placental growth factor into the myocardium increased the coronary vasculature and induced CMC hypertrophy in adult mice. The resulting cardiac hypertrophy was physiological, as indicated by preserved cardiac function and exercise capacity and lack of pathological gene activation. These changes were mediated by increased VEGF signaling via endothelial VEGFR2, because the effects of VEGF-B and placental growth factor on both angiogenesis and CMC growth were fully inhibited by treatment with antibodies blocking VEGFR2 or by endothelial deletion of VEGFR2. To identify activated pathways downstream of VEGFR2, whole-genome transcriptomics and secretome analyses were performed, and the Notch and ErbB pathways were shown to be involved in transducing signals for EC-CMC cross talk in response to angiogenesis. Pharmacological or genetic blocking of ErbB signaling also inhibited part of the VEGF-B-induced effects in the heart.

Conclusions: This study reveals that cross talk between the EC VEGFR2 and CMC ErbB signaling pathways coordinates CMC hypertrophy with angiogenesis, contributing to physiological cardiac growth.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.036099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553980PMC
May 2019

Successful rebuilding after disaster, even in the heart, starts with infrastructure.

J Thorac Dis 2018 Nov;10(Suppl 33):S4165-S4167

Maine Medical Center, Cardiovascular Institute, Portland, ME, USA.

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http://dx.doi.org/10.21037/jtd.2018.10.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297528PMC
November 2018

Timing of Left Ventricular Remodeling in Nonischemic Dilated Cardiomyopathy.

Am J Med Sci 2018 09 8;356(3):262-267. Epub 2018 Jun 8.

Division of Cardiovascular Medicine and. Electronic address:

Background: Mineralocorticoid receptor antagonist (MRA) treatment produces beneficial left ventricular (LV) remodeling in nonischemic dilated cardiomyopathy (NIDCM). This study addressed the timing of maximal beneficial LV remodeling in NIDCM when adding MRA.

Materials And Methods: We studied 12 patients with NIDCM on stable β-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor-blocking therapy who underwent cardiac magnetic resonance imaging before and after 6-31 months of continuous MRA therapy.

Results: At baseline, the LV ejection fraction (LVEF) was 24% (19-27); median [interquartile range]. The LV end-systolic volume index (LVESVI) was 63 ml (57-76) and the LV stroke volume index (LVSVI) was 19 ml (14-21), all depressed. After adding MRA to the HF regimen, the LVEF increased to 47% (42-52), with a decrease in LVESVI to 36 ml (33-45) and increase in LVSVI to 36 ml (28-39) (for each, P  < 0 .0001). Using generalized least squares analysis, the maximal beneficial remodeling (defined by maximal increase in LVEF, the maximal decrease in LVESVI and maximal increase in LVSVI) was achieved after approximately 12-16 months of MRA treatment.

Conclusions: Adding MRA to a standard medical regimen for NIDCM resulted in beneficial LV remodeling. The maximal beneficial remodeling was achieved with 12-16 months of MRA therapy. These results have implications for the timing of other advanced therapies, such as placing internal cardioverter-defibrillators.
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http://dx.doi.org/10.1016/j.amjms.2018.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388723PMC
September 2018

Intensity of Glycemic Control Affects Long-Term Survival After Coronary Artery Bypass Graft Surgery.

Ann Thorac Surg 2019 02 28;107(2):477-484. Epub 2018 Sep 28.

Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.

Background: A patient's hemoglobin (Hb) A level, regardless of diabetic status, is a measure of glycemic control. Studies have found it is an independent predictor of short-term death in patients undergoing coronary artery bypass grafting (CABG). In this study, we used preoperative HbA to assess whether levels are associated with short-term and long-term survival after CABG.

Methods: From a regional registry of consecutive cases, we identified 6,415 patients undergoing on-pump isolated CABG from 2008 to 2015 with documented preoperative HbA level. We defined four HbA groups: less than 5.7% (n = 1,713), 5.7% to 6.4% (n = 2,505), 6.5% to 8.0% (n = 1,377), and more than 8% (n = 820). Relationship to in-hospital outcomes and long-term survival was assessed. Outcome rates and hazard ratios were adjusted for patient and disease risk factors using multivariable logistic regression and Cox models.

Results: The study included 3,740 patients (58%) not diagnosed as having diabetes and 2,674 with diabetes. Prediabetes (HbA 5.7% to 6.4%) was documented in 52% (n = 1,933) of nondiabetic patients. Higher HbA values were associated with younger age, female sex, greater body mass index, more comorbid diseases, lower ejection fraction, more 3-vessel coronary disease, and recent myocardial infarction (p < 0.05 trend for all). After adjustment for patient risk, greater HbA values were not associated with higher rates of in-hospital death or morbidity. Long-term survival was significantly worse as HbA increased. Risk of death increased by 13% for every unit increase in HbA (adjusted hazard ratio, 1.13; 95% confidence interval, 1.07 to 1.19; p < 0.001).

Conclusions: Preadmission glycemic control, as assessed by HbA, is predictive of long-term survival, with higher levels associated with poorer prognosis. Whether this risk can be modified by better glycemic control postoperatively remains to be determined.
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http://dx.doi.org/10.1016/j.athoracsur.2018.07.078DOI Listing
February 2019

Anthracycline Cardiomyopathy: The Plot Gets Thinner.

Circ Heart Fail 2018 07;11(7):e005194

Maine Medical Center, Portland (D.B.S., S.A.F.).

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.118.005194DOI Listing
July 2018

Effects of endogenous serum neuregulin-1β on morbidity and mortality in patients with heart failure and left ventricular systolic dysfunction.

Biomarkers 2018 Nov 17;23(7):704-708. Epub 2018 Aug 17.

g Cardiovascular Division , Washington University in St. Louis , St. Louis , MO , USA.

Context: Improved left ventricular ejection fraction (LVEF) following administration of recombinant human Neuregulin-1β (NRG), epidermal growth factor (EGF) involved in cardiomyocyte repair/survival, has been observed in patients with systolic heart failure (HF).

Methods: Serum NRG was measured by ELISA in 248 patients with NYHA class I-IV HF.

Results: NRG exhibited a marginally significant effect on LVEF trajectory over 11 months (p = 0.07). There is no apparent level of NRG that predicts improved survival.

Conclusions: There is a potential relationship between serum NRG and improved LVEF, indicating the need to investigate the utility of NRG in predicting HF outcomes, including LVEF maintenance.
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http://dx.doi.org/10.1080/1354750X.2018.1485054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291851PMC
November 2018

Increased Number of Circulating CD8/CD26 T Cells in the Blood of Duchenne Muscular Dystrophy Patients Is Associated with Augmented Binding of Adenosine Deaminase and Higher Muscular Strength Scores.

Front Pharmacol 2017 18;8:914. Epub 2017 Dec 18.

Maine Medical Center Research Institute, Scarborough, ME, United States.

Duchenne muscular dystrophy (DMD) is an X-linked disorder that leads to cardiac and skeletal myopathy. The complex immune activation in boys with DMD is incompletely understood. To better understand the contribution of the immune system into the progression of DMD, we performed a systematic characterization of immune cell subpopulations obtained from peripheral blood of DMD subjects and control donors. We found that the number of CD8 cells expressing CD26 (also known as adenosine deaminase complexing protein 2) was increased in DMD subjects compared to control. No differences, however, were found in the levels of circulating factors associated with pro-inflammatory activation of CD8/CD26 cells, such as tumor necrosis factor-α (TNFα), granzyme B, and interferon-γ (IFNγ). The number of CD8/CD26 cells correlated directly with quantitative muscle testing (QMT) in DMD subjects. Since CD26 mediates binding of adenosine deaminase (ADA) to the T cell surface, we tested ADA-binding capacity of CD8/CD26 cells and the activity of bound ADA. We found that mononuclear cells (MNC) obtained from DMD subjects with an increased number of CD8/CD26 T cells had a greater capacity to bind ADA. In addition, these MNC demonstrated increased hydrolytic deamination of adenosine to inosine. Altogether, our data demonstrated that (1) an increased number of circulating CD8/CD26 T cells is associated with preservation of muscle strength in DMD subjects, and (2) CD8/CD26 T cells from DMD subjects mediated degradation of adenosine by adenosine deaminase. These results support a role for T cells in slowing the decline in skeletal muscle function, and a need for further investigation into contribution of CD8/CD26 T cells in the regulation of chronic inflammation associated with DMD.
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http://dx.doi.org/10.3389/fphar.2017.00914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741593PMC
December 2017

ErbB2 promotes endothelial phenotype of human left ventricular epicardial highly proliferative cells (eHiPC).

J Mol Cell Cardiol 2018 02 29;115:39-50. Epub 2017 Dec 29.

Maine Medical Center Research Institute, Scarborough, ME, United States; Maine Medical Center, Portland, ME, United States. Electronic address:

The adult human heart contains a subpopulation of highly proliferative cells. The role of ErbB receptors in these cells has not been studied. From human left ventricular (LV) epicardial biopsies, we isolated highly proliferative cells (eHiPC) to characterize the cell surface expression and function of ErbB receptors in the regulation of cell proliferation and phenotype. We found that human LV eHiPC express all four ErbB receptor subtypes. However, the expression of ErbB receptors varied widely among eHiPC isolated from different subjects. eHiPC with higher cell surface expression of ErbB2 reproduced the phenotype of endothelial cells and were characterized by endothelial cell-like functional properties. We also found that EGF/ErbB1 induces VEGFR2 expression, while ligands for both ErbB1 and ErbB3/4 induce expression of Tie2. The number of CD31CD45 endothelial cells is higher in LV biopsies from subjects with high ErbB2 (ErbB2) eHiPC compared to low ErbB2 (ErbB2) eHiPC. These findings have important implications for potential strategies to increase the efficacy of cell-based revascularization of the injured heart, through promotion of an endothelial phenotype in cardiac highly proliferative cells.
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http://dx.doi.org/10.1016/j.yjmcc.2017.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5926239PMC
February 2018

Altered ADAMTS5 Expression and Versican Proteolysis: A Possible Molecular Mechanism in Barlow's Disease.

Ann Thorac Surg 2018 04 15;105(4):1144-1151. Epub 2017 Dec 15.

Department of Cardiac Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: We hypothesized that gene expression profiles of mitral valve (MV) leaflets from patients with Barlow's disease (BD) are distinct from those with fibroelastic deficiency (FED).

Methods: MVs were obtained from patients with BD (7 men, 3 women; 61.4 ± 12.7 years old) or FED (6 men, 5 women; 54.5 ± 6.0 years old) undergoing operations for severe mitral regurgitation (MR). Normal MVs were obtained from 6 donor hearts unmatched for transplant (3 men, 3 women; 58.3 ± 7.5 years old), and gene expression was assessed using cDNA microarrays. Select transcripts were validated by quantitative reverse-transcription polymerase chain reaction, followed by an assessment of protein levels by immunostaining.

Results: The global gene expression profile for BD was clearly distinct from normal and FED groups. A total of 4,684 genes were significantly differential (fold-difference >1.5, p < 0.05) among the three groups, 1,363 of which were commonly altered in BD and FED compared with healthy individuals (eg TGFβ2 [transforming growth factor β2] and TGFβ3 were equally upregulated in BD and FED). Most interesting were 329 BD-specific genes, including ADAMTS5 (a disintegrin-like and metalloprotease domain with thrombospondin-type 5), which was uniquely downregulated in BD based on microarrays and quantitative reverse-transcription polymerase chain reaction. Consistent with this finding, the ADAMTS5 substrate versican was increased in BD and conversely lower in FED.

Conclusions: MV leaflets in BD and FED exhibit distinct gene expression patterns, suggesting different pathophysiologic mechanisms are involved in leaflet remodeling. Moreover, downregulation of ADAMTS5 in BD, along with the accumulation of its substrate versican in the valvular extracellular matrix, might contribute to leaflet thickening and enlargement.
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http://dx.doi.org/10.1016/j.athoracsur.2017.11.035DOI Listing
April 2018

Chronic Neuregulin-1β Treatment Mitigates the Progression of Postmyocardial Infarction Heart Failure in the Setting of Type 1 Diabetes Mellitus by Suppressing Myocardial Apoptosis, Fibrosis, and Key Oxidant-Producing Enzymes.

J Card Fail 2017 Dec 4;23(12):887-899. Epub 2017 Sep 4.

Department of Professional and Medical Education, Meharry Medical College, Nashville, Tennessee. Electronic address:

Background: Type 1 diabetes mellitus (DM) patients surviving myocardial infarction (MI) have substantially higher cardiovascular morbidity and mortality compared to their nondiabetic counterparts owing to the more frequent development of subsequent heart failure (HF). Neuregulin (NRG)-1β is released from cardiac microvascular endothelial cells and acts as a paracrine factor via the ErbB family of tyrosine kinase receptors expressed in cardiac myocytes to regulate cardiac development and stress responses. Because myocardial NRG-1/ErbB signaling has been documented to be impaired during HF associated with type 1 DM, we examined whether enhancement of NRG-1β signaling via exogenous administration of recombinant NRG-1β could exert beneficial effects against post-MI HF in the type 1 diabetic heart.

Methods And Results: Type 1 DM was induced in male Sprague Dawley rats by a single injection of streptozotocin (STZ) (65 mg/kg). Two weeks after induction of type 1 DM, rats underwent left coronary artery ligation to induce MI. STZ-diabetic rats were treated with saline or NRG-1β (100 µg/kg) twice per week for 7 weeks, starting 2 weeks before experimental MI. Residual left ventricular function was significantly greater in the NRG-1β-treated STZ-diabetic MI group compared with the vehicle-treated STZ-diabetic MI group 5 weeks after MI as assessed by high-resolution echocardiography. NRG-1β treatment of STZ-diabetic MI rats was associated with reduced myocardial fibrosis and apoptosis as well as decreased gene expression of key oxidant-producing enzymes.

Conclusions: These results suggest that recombinant NRG-1β may be a promising therapeutic for HF post-MI in the setting of type 1 DM.
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http://dx.doi.org/10.1016/j.cardfail.2017.08.456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716474PMC
December 2017

Species-specific effects of neuregulin-1β (cimaglermin alfa) on glucose handling in animal models and humans with heart failure.

Toxicol Appl Pharmacol 2017 10 2;332:92-99. Epub 2017 Aug 2.

Acorda Therapeutics, Inc., 420 Saw Mill River Rd, Ardsley, NY 10502, USA. Electronic address:

Neuregulin-1β is a member of the neuregulin family of growth factors and is critically important for normal development and functioning of the heart and brain. A recombinant version of neuregulin-1β, cimaglermin alfa (also known as glial growth factor 2 or GGF2) is being investigated as a possible therapy for heart failure. Previous studies suggest that neuregulin-1β stimulation of skeletal muscle increases glucose uptake and, specifically, sufficient doses of cimaglermin alfa acutely produce hypoglycemia in pigs. Since acute hypoglycemia could be a safety concern, blood glucose changes in the above pig study were further investigated. In addition, basal glucose and glucose disposal were investigated in mice. Finally, as part of standard clinical chemistry profiling in a single ascending-dose human safety study, blood glucose levels were evaluated in patients with heart failure after cimaglermin alfa treatment. A single intravenous injection of cimaglermin alfa at doses of 0.8mg/kg and 2.6mg/kg in mice resulted in a transient reduction of blood glucose concentrations of approximately 20% and 34%, respectively, at 2h after the treatment compared to pre-treatment levels. Similar results were observed in diabetic mice. Treatment with cimaglermin alfa also increased blood glucose disposal following oral challenge in mice. However, no significant alterations in blood glucose concentrations were found in human heart failure patients at 0.5 and 2h after treatment with cimaglermin alfa over an equivalent human dose range, based on body surface area. Taken together, these data indicate strong species differences in blood glucose handling after cimaglermin alfa treatment, and particularly do not indicate that this phenomenon should affect human subjects.
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http://dx.doi.org/10.1016/j.taap.2017.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684703PMC
October 2017

Gradient release of cardiac morphogens by photo-responsive polymer micelles for gradient-mediated variation of embryoid body differentiation.

J Mater Chem B 2017 Jul 16;5(26):5206-5217. Epub 2017 Jun 16.

Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.

Retinoic acid (RA) is a well-known morphogen in human development. However, how an RA gradient distribution influences cardiac development remains obscure due to the lack of appropriate experimental apparatus. To address this issue, a polymeric micelle system with covalently attached RA was engineered to deliver gradient quantities of RA upon photo-irradiation. A photo-degradable polymeric nanoparticle (NP) composed of an amphiphilic methoxy(polyethylene glycol)-b-poly(ε-caprolactone)-co-poly(azido-ε-caprolactone-g-ortho nitrobenzyl retinoic ester) copolymer was synthesized, and hanging RA was covalently attached through a photo-sensitive o-nitrobenzyl (ONB) linker. The ONB linker was efficiently cleaved when exposed to a light (365 nm)-gradient, and the consequent gradient release of RA from the micelles was demonstrated. The efficacy of the photo-gradient-mediated RA release was validated across different concentrations of polymer micelles over varied irradiation periods. It was confirmed that polymer micelles demonstrated minimal cytotoxicity when exposed to mouse embryoid bodies (EBs). Finally, when the photo-gradient release of polymer micelles was applied, GFP-cardiac troponin T reporter mouse EBs demonstrated a concurrent gradient-like pattern of cardiac differentiation, verifying the utility of our novel photo-gradient approach to study morphogen gradients not only for cardiac development but also for other potential biological microenvironments subject to morphogen presentation with highly defined spatial and temporal geometries.
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http://dx.doi.org/10.1039/c7tb00880eDOI Listing
July 2017

GRMD cardiac and skeletal muscle metabolism gene profiles are distinct.

BMC Med Genomics 2017 04 8;10(1):21. Epub 2017 Apr 8.

Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2200 Pierce Avenue, 359A Preston Research Building, Nashville, TN, 37232, USA.

Background: Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which codes for the dystrophin protein. While progress has been made in defining the molecular basis and pathogenesis of DMD, major gaps remain in understanding mechanisms that contribute to the marked delay in cardiac compared to skeletal muscle dysfunction.

Methods: To address this question, we analyzed cardiac and skeletal muscle tissue microarrays from golden retriever muscular dystrophy (GRMD) dogs, a genetically and clinically homologous model for DMD. A total of 15 dogs, 3 each GRMD and controls at 6 and 12 months plus 3 older (47-93 months) GRMD dogs, were assessed.

Results: GRMD dogs exhibited tissue- and age-specific transcriptional profiles and enriched functions in skeletal but not cardiac muscle, consistent with a "metabolic crisis" seen with DMD microarray studies. Most notably, dozens of energy production-associated molecules, including all of the TCA cycle enzymes and multiple electron transport components, were down regulated. Glycolytic and glycolysis shunt pathway-associated enzymes, such as those of the anabolic pentose phosphate pathway, were also altered, in keeping with gene expression in other forms of muscle atrophy. On the other hand, GRMD cardiac muscle genes were enriched in nucleotide metabolism and pathways that are critical for neuromuscular junction maintenance, synaptic function and conduction.

Conclusions: These findings suggest differential metabolic dysfunction may contribute to distinct pathological phenotypes in skeletal and cardiac muscle.
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http://dx.doi.org/10.1186/s12920-017-0257-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385041PMC
April 2017

Cardio-Oncology-A Rapidly Evolving and Expanding Field of Medicine.

Heart Fail Clin 2017 Apr;13(2):xiii

Maine Medical Center Cardiovascular Institute, 22 Bramhall Street, Portland, ME 04102, USA. Electronic address:

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http://dx.doi.org/10.1016/j.hfc.2017.01.001DOI Listing
April 2017

Neuregulin-1β induces proliferation, survival and paracrine signaling in normal human cardiac ventricular fibroblasts.

J Mol Cell Cardiol 2017 04 3;105:59-69. Epub 2017 Mar 3.

Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN 37232, United States. Electronic address:

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.
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http://dx.doi.org/10.1016/j.yjmcc.2017.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715731PMC
April 2017
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