RESUMO
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.
Assuntos
Parada Cardíaca , Humanos , Camundongos , Animais , Parada Cardíaca/complicações , Quimiocinas , Quimiocinas CCRESUMO
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.
Assuntos
COVID-19 , Dipeptidil Peptidase 4 , Humanos , LinfócitosRESUMO
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.
Assuntos
Doenças Cardiovasculares , Metanfetamina , Anfetamina , Cálcio , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Catecolaminas , Humanos , Metanfetamina/efeitos adversos , Espécies Reativas de OxigênioRESUMO
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.
Assuntos
Adaptação Fisiológica , Cardiomegalia/prevenção & controle , Modelos Animais de Doenças , Hipertrofia Ventricular Esquerda/prevenção & controle , Células Mieloides/imunologia , Receptor ErbB-3/fisiologia , Animais , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Feminino , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Masculino , Camundongos , Camundongos Knockout , Células Mieloides/metabolismoRESUMO
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.
Assuntos
Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Cardiomiopatias/induzido quimicamente , Células Endoteliais/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Complicações na Gravidez/etiologia , Animais , Sobreviventes de Câncer , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Cardiomiopatias/prevenção & controle , Cardiotoxicidade , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Humanos , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Período Periparto , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/metabolismo , Complicações na Gravidez/fisiopatologia , Prognóstico , Fatores de Risco , Transdução de SinaisRESUMO
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.
Assuntos
Cardiomegalia/metabolismo , Células Endoteliais/metabolismo , Miócitos Cardíacos/metabolismo , Neovascularização Fisiológica , Comunicação Parácrina , Transdução de Sinais , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/patologia , Receptores ErbB/metabolismo , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/patologia , Receptor Cross-Talk , Receptores Notch/metabolismo , Fator B de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
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.
Assuntos
Cardiotônicos/metabolismo , Doenças Cardiovasculares/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neurregulinas/metabolismo , Animais , Doenças Cardiovasculares/sangue , Ensaios Clínicos como Assunto , Humanos , Neovascularização Fisiológica , Neurregulinas/sangueRESUMO
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.
Assuntos
Ponte Cardiopulmonar/efeitos adversos , Endotélio/ultraestrutura , Glicocálix/fisiologia , Duração da Cirurgia , Idoso , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Ponte Cardiopulmonar/métodos , DNA Mitocondrial/sangue , Feminino , Humanos , Interleucina-6/sangue , Contagem de Leucócitos , Masculino , Camundongos , Pessoa de Meia-Idade , Neutrófilos/patologia , Proteínas Recombinantes/farmacologia , Sindecana-1/sangue , Sindecana-1/farmacologiaRESUMO
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.
Assuntos
Células Endoteliais/citologia , Células Endoteliais/metabolismo , Ventrículos do Coração/citologia , Pericárdio/citologia , Receptor ErbB-2/metabolismo , Animais , Biomarcadores/metabolismo , Biópsia , Contagem de Células , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular , Proliferação de Células , Fator de Crescimento Epidérmico/metabolismo , Feminino , Humanos , Ligantes , Masculino , Pessoa de Meia-Idade , Fenótipo , Ratos , Transdução de Sinais , Regulação para CimaRESUMO
Through the success of basic and disease-specific research, cancer survivors are one of the largest growing subsets of individuals accessing the healthcare system. Interestingly, cardiovascular disease is the second leading cause of morbidity and mortality in cancer survivors after recurrent malignancy. This recognition has helped stimulate a collaboration between oncology and cardiology practitioners and researchers, and the portmanteau cardio-oncology (also known as onco-cardiology) can now be found in many medical centers. This collaboration promises new insights into how cancer therapies impact cardiovascular homeostasis and long-term effects on cancer survivors. In this review, we will discuss the most recent views on the cardiotoxicity related to various classes of chemotherapy agents and radiation. We will also discuss broadly the current strategies for treating and preventing cardiovascular effects of cancer therapy.
Assuntos
Antineoplásicos/efeitos adversos , Cardiotoxicidade/epidemiologia , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Neoplasias/epidemiologia , Animais , Cardiotoxicidade/diagnóstico , Doenças Cardiovasculares/diagnóstico , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/patologia , Humanos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Resultado do TratamentoRESUMO
CONTEXT: Improved left ventricular ejection fraction (LVEF) following administration of recombinant human Neuregulin-1ß (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.
Assuntos
Insuficiência Cardíaca/diagnóstico , Neuregulina-1/sangue , Disfunção Ventricular Esquerda/diagnóstico , Fator de Crescimento Epidérmico/sangue , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Neurregulinas/sangue , Valor Preditivo dos Testes , Prognóstico , Volume Sistólico , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/mortalidadeRESUMO
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.
Assuntos
Miofibroblastos/metabolismo , Neuregulina-1/metabolismo , Comunicação Parácrina , Transdução de Sinais , Cálcio/metabolismo , Sinalização do Cálcio , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , Ventrículos do Coração/metabolismo , Humanos , Espaço Intracelular/metabolismo , Retículo Sarcoplasmático/metabolismoRESUMO
Immune activation in chronic systolic heart failure (HF) correlates with disease severity and prognosis. Recombinant neuregulin-1 (rNRG-1) is being developed as a possible therapy for HF, based on the activation of ERBB receptors in cardiac cells. Work in animal models of HF led us to hypothesize that there may be direct effects of NRG-1 on immune system activation and inflammation. We investigated the expression of ERBB receptors and the effect of rNRG-1 isoform glial growth factor 2 (GGF2) in subpopulations of peripheral blood mononuclear cells (PB MNCs) in subjects with HF. We found that human monocytes express both ERBB2 and ERBB3 receptors, with high interindividual variability among subjects. Monocyte surface ERBB3 and TNF-α mRNA expression were inversely correlated in subjects with HF but not in human subjects without HF. GGF2 activation of ERBB signaling ex vivo inhibited LPS-induced TNF-α production, specifically in the CD14lowCD16+ population of monocytes in a phosphoinositide 3-kinase-dependent manner. GGF2 suppression of TNF-α correlated directly with the expression of ERBB3. In vivo, a single dose of intravenous GGF2 reduced TNF-α expression in PB MNCs of HF subjects participating in a phase I safety study of GGF2. These results support a role for ERBB3 signaling in the regulation of TNF-α production from CD14lowCD16+ monocytes and a need for further investigation into the clinical significance of NRG-1/ERBB signaling as a modulator of immune system function.NEW & NOTEWORTHY This study identified a novel role of neuregulin-1 (NRG-1)/ERBB signaling in the control of proinflammatory activation of monocytes. These results further improve our fundamental understanding of cardioprotective effects of NRG-1 in patients with heart failure.
Assuntos
Receptores ErbB/biossíntese , Inflamação/fisiopatologia , Monócitos , Transdução de Sinais , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/genética , Feminino , Humanos , Técnicas In Vitro , Ativação de Macrófagos , Masculino , Pessoa de Meia-Idade , Neuregulina-1/metabolismo , Neuregulina-1/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Receptor ErbB-3/biossíntese , Receptor ErbB-3/genética , Proteínas Recombinantes/metabolismo , Fator de Necrose Tumoral alfa/biossínteseRESUMO
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)-1ß 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-1ß signaling via exogenous administration of recombinant NRG-1ß 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-1ß (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-1ß-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-1ß 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-1ß may be a promising therapeutic for HF post-MI in the setting of type 1 DM.
Assuntos
Apoptose/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Neuregulina-1/administração & dosagem , Oxidantes/antagonistas & inibidores , Animais , Antioxidantes/administração & dosagem , Apoptose/fisiologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Progressão da Doença , Esquema de Medicação , Fibrose , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Oxidantes/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: The myocardial longitudinal relaxation time (T1) on cardiac magnetic resonance imaging (CMR) can quantify myocardial fibrosis in the presence or absence of visually detectable late gadolinium (Gd) enhancement (LGE). Mineralocorticoid receptor antagonist (MRA) treatment produces beneficial remodeling in nonischemic dilated cardiomyopathy (NIDCM). We assessed the hypothesis that interstitial myocardial fibrosis measured with the use of CMR predicts left ventricular (LV) beneficial remodeling in NIDCM after heart failure (HF) treatment including MRAs. METHODS AND RESULTS: Twelve patients with NIDCM, on stable beta-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor-blocking therapy, were studied before and after 6-29 months of treatment with MRAs, by means of CMR assessment of LV structure, function, and T1 from standard Look-Locker sequences (T1LL). All patients had depressed cardiac function, dilated left ventricles, and no visual LGE. After adding MRA to HF treatment, the LV ejection fraction increased and the LV end-systolic volume index (LV end-systolic volume/m2) decreased in all patients (P < .0001). This this was inversely proportional to the baseline myocardial T1LL (r = -0.65; P = .02). CONCLUSION: Myocardial T1LL, in the absence of visually detectable LGE, was quantitatively related to the degree of beneficial LV remodeling achieved in response to adding MRA to a HF regimen.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/diagnóstico , Imagem Cinética por Ressonância Magnética/métodos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Miocárdio/patologia , Remodelação Ventricular/fisiologia , Adulto , Quimioterapia Combinada , Feminino , Seguimentos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de TempoRESUMO
Neuregulin-1ß 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-1ß, 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-1ß 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.
Assuntos
Glicemia/metabolismo , Insuficiência Cardíaca/sangue , Neuregulina-1/farmacologia , Adolescente , Adulto , Idoso , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Humanos , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Modelos Animais , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Especificidade da Espécie , Suínos , Adulto JovemRESUMO
To determine whether hepatic depletion of vitamin A (VA) stores has an effect on the postnatal heart, studies were carried out with mice lacking liver retinyl ester stores fed either a VA-sufficient (LRVAS) or VA-deficient (LRVAD) diet (to deplete circulating retinol and extrahepatic stores of retinyl esters). There were no observable differences in the weights or gross morphology of hearts from LRVAS or LRVAD mice relative to sex-matched, age-matched, and genetically matched wild-type (WT) controls fed the VAS diet (WTVAS), but changes in the transcription of functionally relevant genes were consistent with a state of VAD in LRVAS and LRVAD ventricles. In silico analysis revealed that 58/67 differentially expressed transcripts identified in a microarray screen are products of genes that have DNA retinoic acid response elements. Flow cytometric analysis revealed a significant and cell-specific increase in the number of proliferating Sca-1 cardiac progenitor cells in LRVAS animals relative to WTVAS controls. Before myocardial infarction, LRVAS and WTVAS mice had similar cardiac systolic function and structure, as measured by echocardiography, but, unexpectedly, repeat echocardiography demonstrated that LRVAS mice had less adverse remodeling by 1 wk after myocardial infarction. Overall, the results demonstrate that the adult heart is responsive to retinoids, and, most notably, reducing hepatic VA stores (while maintaining circulating levels of VA) impacts ventricular gene expression profiles, progenitor cell numbers, and response to injury.
Assuntos
Fígado/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Receptores do Ácido Retinoico/metabolismo , Retinoides/metabolismo , Deficiência de Vitamina A/metabolismo , Aciltransferases/genética , Aciltransferases/metabolismo , Animais , Ecocardiografia , Coração/fisiopatologia , Camundongos , Camundongos Knockout , Infarto do Miocárdio/fisiopatologia , Deficiência de Vitamina A/genética , Deficiência de Vitamina A/fisiopatologia , Receptor gama de Ácido RetinoicoRESUMO
Management approaches for patients in the emergency department (ED) who present with acute heart failure (AHF) have largely focused on intravenous diuretics. Yet, the primary pathophysiologic derangement underlying AHF in many patients is not solely volume overload. Patients with hypertensive AHF (H-AHF) represent a clinical phenotype with distinct pathophysiologic mechanisms that result in elevated ventricular filling pressures. To optimize treatment response and minimize adverse events in this subgroup, we propose that clinical management be tailored to a conceptual model of disease based on these mechanisms. This consensus statement reviews the relevant pathophysiology, clinical characteristics, approach to therapy, and considerations for clinical trials in ED patients with H-AHF.
Assuntos
Pesquisa Biomédica , Consenso , Gerenciamento Clínico , Medicina de Emergência/métodos , Insuficiência Cardíaca/terapia , Hipertensão/terapia , Sociedades Médicas , Doença Aguda , Insuficiência Cardíaca/complicações , Humanos , Hipertensão/complicações , Estados UnidosRESUMO
BACKGROUND: In Duchenne muscular dystrophy (DMD), abnormal cardiac function is typically preceded by a decade of skeletal muscle disease. Molecular reasons for differences in onset and progression of these muscle groups are unknown. Human biomarkers are lacking. METHODS: We analyzed cardiac and skeletal muscle microarrays from normal and golden retriever muscular dystrophy (GRMD) dogs (ages 6, 12, or 47+ mo) to gain insight into muscle dysfunction and to identify putative DMD biomarkers. These biomarkers were then measured using human DMD blood samples. RESULTS: We identified GRMD candidate genes that might contribute to the disparity between cardiac and skeletal muscle disease, focusing on brain-derived neurotropic factor (BDNF) and osteopontin (OPN/SPP1, hereafter indicated as SPP1). BDNF was elevated in cardiac muscle of younger GRMD but was unaltered in skeletal muscle, while SPP1 was increased only in GRMD skeletal muscle. In human DMD, circulating levels of BDNF were inversely correlated with ventricular function and fibrosis, while SPP1 levels correlated with skeletal muscle function. CONCLUSION: These results highlight gene expression patterns that could account for differences in cardiac and skeletal disease in GRMD. Most notably, animal model-derived data were translated to DMD and support use of BDNF and SPP1 as biomarkers for cardiac and skeletal muscle involvement, respectively.
Assuntos
Biomarcadores/metabolismo , Coração/fisiopatologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Análise de Sequência com Séries de Oligonucleotídeos , Animais , Estudos de Casos e Controles , Estudos de Coortes , Cães , Humanos , Distrofia Muscular de Duchenne/genéticaRESUMO
BACKGROUND: Duchenne muscular dystrophy (DMD) cardiomyopathy is a progressive disease for which there is no cure. Disease-specific therapies are needed that can be initiated before irreversible myocardial damage ensues. In order to evaluate therapeutic efficacy, surrogate endpoints other than ejection fraction must be found. The hypothesis of this study is that T1 and extracellular volume fraction (ECV) mapping using cardiovascular magnetic resonance (CMR) can detect diffuse extracellular matrix expansion in DMD patients with normal left ventricular ejection fraction (LVEF) and without myocardial late gadolinium enhancement (LGE). METHODS: Thirty-one DMD and 11 healthy control participants were prospectively enrolled. CMR using a modified Look-Locker (MOLLI) sequence was performed in all participants before and after contrast administration. T1 and ECV maps of the mid left ventricular myocardium were generated and regions of interest were contoured using the standard 6-segment AHA model. Global and segmental values were compared between DMD and controls using a Wilcoxon rank-sum test. RESULTS: The DMD participants had significantly higher mean native T1 compared with controls (1045 ms vs. 988 ms, p = 0.001). DMD participants with normal LVEF and without evidence of LGE also demonstrated elevated mean native T1 (1039 ms vs. 988 ms, p = 0.002, and 1038 ms vs. 988 ms, p = 0.011). DMD participants had a significantly greater mean ECV than controls (0.31 vs. 0.24, p < 0.001), even in the settings of normal LVEF (0.28 vs. 0.24, p < 0.001) and negative LGE (0.29 vs. 0.24, p = 0.001). CONCLUSIONS: DMD participants have elevated LV myocardial native T1 and ECV, even in the setting of normal LVEF and in the absence of LGE. T1 and ECV mapping in DMD have potential to serve as surrogate cardiomyopathy outcome measures for clinical trials.