Delayed CCL23 response is associated with poor outcomes after cardiac arrest.

Chemokines, a family of chemotactic cytokines, mediate leukocyte migration to and entrance into inflamed tissue, contributing to the intensity of local inflammation. We performed an analysis of chemokine and immune cell responses to cardiac arrest (CA). Forty-two patients resuscitated from cardiac arrest were analyzed, and twenty-two patients who underwent coronary artery bypass grafting (CABG) surgery were enrolled. Quantitative antibody array, chemokines, and endotoxin quantification were performed using the patients blood. Analysis of CCL23 production in neutrophils obtained from CA patients and injected into immunodeficient mice after CA and cardiopulmonary resuscitation (CPR) were done using flow cytometry. The levels of CCL2, CCL4, and CCL23 are increased in CA patients. Temporal dynamics were different for each chemokine, with early increases in CCL2 and CCL4, followed by a delayed elevation in CCL23 at forty-eight hours after CA. A high level of CCL23 was associated with an increased number of neutrophils, neuron-specific enolase (NSE), worse cerebral performance category (CPC) score, and higher mortality. To investigate the role of neutrophil activation locally in injured brain tissue, we used a mouse model of CA/CPR. CCL23 production was increased in human neutrophils that infiltrated mouse brains compared to those in the peripheral circulation. It is known that an early intense inflammatory response (within hours) is associated with poor outcomes after CA. Our data indicate that late activation of neutrophils in brain tissue may also promote ongoing injury via the production of CCL23 and impair recovery after cardiac arrest.

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

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.

Cardiovascular disease associated with methamphetamine use: a review.

Methamphetamine abuse is a global epidemic associated with a wide-ranging array of adverse effects on the cardiovascular system including dilated cardiomyopathy, malignant and benign arrhythmias, coronary vasospasm, and atherosclerotic coronary artery disease. While the acute behavioral manifestations of amphetamine abuse are the most easily clinically identified, cardiovascular toxicity is common in this patient population and should be considered in this setting due to its high morbidity and mortality. The specific mechanisms for amphetamine cardiotoxicity have not been fully established, but new research implicates activation of several cellular targets including Sigma-1 receptors and trace amine-associated receptor 1 (TAAR1) leading to a myriad of negative downstream effects including increased reactive oxygenating species (ROS), mitochondrial dysfunction, and modulations of intracellular calcium. Additional pathologic effects are mediated by increased circulating catecholamines, which when chronically activated have well-established adverse effects on the cardiovascular system. In this article, we present a case report followed by a current review of the epidemiology, pathophysiology, diagnosis, and treatment modalities of amphetamine-induced cardiovascular disease.

Neuregulin (NRG-1ß) Is Pro-Myogenic and Anti-Cachectic in Respiratory Muscles of Post-Myocardial Infarcted Swine.

Neuregulin-1ß (NRG-1ß) is a growth and differentiation factor with pleiotropic systemic effects. Because NRG-1ß has therapeutic potential for heart failure and has known growth effects in skeletal muscle, we hypothesized that it might affect heart failure-associated cachexia, a severe co-morbidity characterized by a loss of muscle mass. We therefore assessed NRG-1ß's effect on intercostal skeletal muscle gene expression in a swine model of heart failure using recombinant glial growth factor 2 (USAN-cimaglermin alfa), a version of NRG-1ß that has been tested in humans with systolic heart failure. Animals received one of two intravenous doses (0.67 or 2 mg/kg) of NRG-1ß bi-weekly for 4 weeks, beginning one week after infarct. Based on paired-end RNA sequencing, NRG-1ß treatment altered the intercostal muscle gene expression of 581 transcripts, including genes required for myofiber growth, maintenance and survival, such as MYH3, MYHC, MYL6B, KY and HES1. Importantly, NRG-1ß altered the directionality of at least 85 genes associated with cachexia, including myostatin, which negatively regulates myoblast differentiation by down-regulating MyoD expression. Consistent with this, MyoD was increased in NRG-1ß-treated animals. In vitro experiments with myoblast cell lines confirmed that NRG-1ß induces ERBB-dependent differentiation. These findings suggest a NRG-1ß-mediated anti-atrophic, anti-cachexia effect that may provide additional benefits to this potential therapy in heart failure.

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

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.

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

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 (ß = 0.009 per SD, P = 0.01). Similarly, sTie2 concentrations were positively associated with log-E/e' (ß = 0.011 per SD, P = 0.04). IGF-1 and Ang-2 concentrations were positively and negatively associated with GLS, respectively (ßIGF-1 = 0.16 per SD and ßAng-2 = -0.15 per SD, both P < 0.05), whereas higher sFlt1 and Ang-2 levels were associated with smaller log-AoR (ßsFlt1 = -0.004 per SD and ß Ang-2 = -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.

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

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 (ErbB3MyeKO) and control animals (ErbB3MyeWT). 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 ErbB3MyeKO mice or control animals. The examination of lung weight to body weight ratio suggested that acute pulmonary edema was present in ErbB3MyeKO male mice after TAC. To determine the cellular and molecular mechanisms involved in the increased mortality in ErbB3MyeKO male mice, cardiac cell populations were examined at day 3 post-TAC using flow cytometry. Myeloid cells accumulated in control but not in ErbB3MyeKO male mouse hearts. This was accompanied by increased proliferation of Sca-1 positive non-immune cells (endothelial cells and fibroblasts) in control but not ErbB3MyeKO male mice. No significant differences in intramyocardial accumulation of myeloid cells or proliferation of Sca-1 cells were found between the groups of ErbB3MyeKO and ErbB3MyeWT female mice. An antibody-based protein array analysis revealed that IGF-1 expression was significantly downregulated only in ErbB3MyeKO 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.

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

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.

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

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.

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

Neuregulin-1ß (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.

Prolonged Cardiopulmonary Bypass is Associated With Endothelial Glycocalyx Degradation.

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 (rs = 0.488, P < 0.001) and level of syndecan-1 and neutrophil count (rs = 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.

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

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, ß-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.

Anthracycline and Peripartum Cardiomyopathies.

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.

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

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.

Systemic and cardiac susceptibility of immune compromised mice to doxorubicin.

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-Prkdcscid Il2rgtm1Wjl/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-Prkdcscid Il2rgtm1Wjl/SzJ mice.

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

BACKGROUND: A patient's hemoglobin (Hb) A1c 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 HbA1c 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 HbA1c level. We defined four HbA1c 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 (HbA1c 5.7% to 6.4%) was documented in 52% (n = 1,933) of nondiabetic patients. Higher HbA1c 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 HbA1c values were not associated with higher rates of in-hospital death or morbidity. Long-term survival was significantly worse as HbA1c increased. Risk of death increased by 13% for every unit increase in HbA1c (adjusted hazard ratio, 1.13; 95% confidence interval, 1.07 to 1.19; p < 0.001). CONCLUSIONS: Preadmission glycemic control, as assessed by HbA1c, 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.

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

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 CD31posCD45neg endothelial cells is higher in LV biopsies from subjects with high ErbB2 (ErbB2high) eHiPC compared to low ErbB2 (ErbB2low) 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.

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

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 TGFß2 [transforming growth factor ß2] and TGFß3 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.

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

Neuregulin-1ß (NRG-1ß) 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-1ß 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-1ß receptors (ErbB2, ErbB3, and ErbB4) are expressed in normal human cardiac ventricular (NHCV) fibroblast cell lines. Treatment of NHCV fibroblasts with recombinant NRG-1ß induced activation of the AKT pathway, which was phosphoinositide 3-kinase (PI3K)-dependent. Moreover, the NRG-1ß-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-1ß-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-1ß, which was abrogated by PI3K, ErbB2, and ErbB3 inhibitors. NRG-1ß 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.