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1.
Diabetes Obes Metab ; 24(9): 1762-1769, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35546449

RESUMO

AIM: To investigate whether an increased bolus: basal insulin ratio (BBR) with liver-targeted bolus insulin (BoI) would increase BoI use and decrease hypoglycaemic events (HEv). PATIENT POPULATION AND METHODS: We enrolled 52 persons (HbA1c 6.9% ± 0.12%, mean ± SEM) with type 1 diabetes using multiple daily injections. Hepatic-directed vesicle (HDV) was used to deliver 1% of peripheral injected BoI to the liver. A 90-day run-in period was used to introduce subjects to unblinded continuous glucose monitoring and optimize standard basal insulin (BaI) (degludec) and BoI (lispro) dosing. At 90 days, BoI was changed to HDV-insulin lispro and subjects were randomized to an immediate 10% or 40% decrease in BaI dose. RESULTS: At 90 days postrandomization, total insulin dosing was increased by ~7% in both cohorts. The -10% and -40% BaI cohorts were on 7.7% and 13% greater BoI with 6.9% and 30% (P = .02) increases in BBR, respectively. Compared with baseline at randomization, nocturnal level 2 HEv were reduced by 21% and 43%, with 54% and 59% reductions in patient-reported HEv in the -10% and -40% BaI cohorts, respectively. CONCLUSIONS: Our study shows that liver-targeted BoI safely decreases HEv and symptoms without compromising glucose control. We further show that with initiation of liver-targeted BoI, the BBR can be safely increased by significantly lowering BaI dosing, leading to greater BoI usage.


Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Hipoglicemia , Glicemia , Automonitorização da Glicemia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Insulina Glargina , Insulina Lispro/uso terapêutico , Insulina de Ação Prolongada , Insulina Regular Humana , Fígado/química
2.
Circ Res ; 122(3): 479-488, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29208679

RESUMO

RATIONALE: The TIME trial (Timing in Myocardial Infarction Evaluation) was the first cell therapy trial sufficiently powered to determine if timing of cell delivery after ST-segment-elevation myocardial infarction affects recovery of left ventricular (LV) function. OBJECTIVE: To report the 2-year clinical and cardiac magnetic resonance imaging results and their modification by microvascular obstruction. METHODS AND RESULTS: TIME was a randomized, double-blind, placebo-controlled trial comparing 150 million bone marrow mononuclear cells versus placebo in 120 patients with anterior ST-segment-elevation myocardial infarctions resulting in LV dysfunction. Primary end points included changes in global (LV ejection fraction) and regional (infarct and border zone) function. Secondary end points included changes in LV volumes, infarct size, and major adverse cardiac events. Here, we analyzed the continued trajectory of these measures out to 2 years and the influence of microvascular obstruction present at baseline on these long-term outcomes. At 2 years (n=85), LV ejection fraction was similar in the bone marrow mononuclear cells (48.7%) and placebo groups (51.6%) with no difference in regional LV function. Infarct size and LV mass decreased ≥30% in each group at 6 months and declined gradually to 2 years. LV volumes increased ≈10% at 6 months and remained stable to 2 years. Microvascular obstruction was present in 48 patients at baseline and was associated with significantly larger infarct size (56.5 versus 36.2 g), greater adverse LV remodeling, and marked reduction in LV ejection fraction recovery (0.2% versus 6.2%). CONCLUSIONS: In one of the longest serial cardiac magnetic resonance imaging analyses of patients with large anterior ST-segment-elevation myocardial infarctions, bone marrow mononuclear cells administration did not improve recovery of LV function over 2 years. Microvascular obstruction was associated with reduced recovery of LV function, greater adverse LV remodeling, and more device implantations. The use of cardiac magnetic resonance imaging leads to greater dropout of patients over time because of device implantation in patients with more severe LV dysfunction resulting in overestimation of clinical stability of the cohort. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684021.


Assuntos
Transplante de Medula Óssea/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Disfunção Ventricular Esquerda/terapia , Adulto , Idoso , Método Duplo-Cego , Feminino , Seguimentos , Ventrículos do Coração/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Microcirculação , Pessoa de Meia-Idade , Tamanho do Órgão , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Volume Sistólico , Fatores de Tempo , Disfunção Ventricular Esquerda/etiologia
3.
Int Urogynecol J ; 31(1): 107-115, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30666428

RESUMO

INTRODUCTION AND HYPOTHESIS: SDF-1 chemokine enhances tissue regeneration through stem cell chemotaxis, neovascularization and neuronal regeneration. We hypothesized that non-viral delivery of human plasmids that express SDF-1 (pSDF-1) may represent a novel regenerative therapy for stress urinary incontinence (SUI). METHODS: Seventy-six female rats underwent vaginal distention (VD). They were then divided into four groups according to treatment: pSDF-1 (n = 42), sham (n = 30), PBS (n = 1) and luciferase-tagged pSDF-1 (n = 3). Immediately after VD, the pSDF-1 group underwent immediate periurethral injection of pSDF-1, and the sham group received a vehicle injection followed by leak point pressure (LPP) measurement at the 4th, 7th and 14th days. Urogenital tissues were collected for histology. H&E and trichrome slides were analyzed for vascularity and collagen/muscle components of the sphincter. For the luciferase-tagged pSDF-1 group, bioluminescence scans (BLIs) were obtained on the 3rd, 7th and 14th days following injections. Statistical analysis was conducted using ANOVA with post hoc LSD tests. The Mann-Whitney U test was employed to make pair-wise comparisons between the treated and sham groups. We used IBM SPSS, version 22, for statistical analyses. RESULTS: BLI showed high expression of luciferase-tagged pSDF-1 in the pelvic area over time. VD resulted in a decline of LPP at the 4th day in both groups. The pSDF1-treated group demonstrated accelerated recovery that was significantly higher than that of the sham-treated group at the 7th day (22.64 cmH2O versus 13.99 cmH2O, p < 0.001). Functional improvement persisted until the 14th day (30.51 cmH2O versus 24.11 cmH2O, p = 0.067). Vascularity density in the pSDF-1-treated group was higher than in the sham group at the 7th and 14th days (p < 0.05). The muscle density/sphincter area increased significantly from the 4th to 14th day only in the pSDF-1 group. CONCLUSIONS: Periurethral injection of pSDF-1 after simulated childbirth accelerated the recovery of continence and regeneration of the urethral sphincter in a rat SUI model. This intervention can potentially be translated to the treatment of post-partum urinary incontinence.


Assuntos
Quimiocina CXCL12/genética , Terapia Genética/métodos , Transtornos Puerperais/prevenção & controle , Incontinência Urinária por Estresse/prevenção & controle , Animais , Modelos Animais de Doenças , Injeções , Plasmídeos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
4.
Clin Chem ; 65(2): 282-290, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30463841

RESUMO

BACKGROUND: Cholesterol efflux capacity (CEC) is a measure of HDL function that, in cell-based studies, has demonstrated an inverse association with cardiovascular disease. The cell-based measure of CEC is complex and low-throughput. We hypothesized that assessment of the lipoprotein proteome would allow for precise, high-throughput CEC prediction. METHODS: After isolating lipoprotein particles from serum, we used LC-MS/MS to quantify 21 lipoprotein-associated proteins. A bioinformatic pipeline was used to identify proteins with univariate correlation to cell-based CEC measurements and generate a multivariate algorithm for CEC prediction (pCE). Using logistic regression, protein coefficients in the pCE model were reweighted to yield a new algorithm predicting coronary artery disease (pCAD). RESULTS: Discovery using targeted LC-MS/MS analysis of 105 training and test samples yielded a pCE model comprising 5 proteins (Spearman r = 0.86). Evaluation of pCE in a case-control study of 231 specimens from healthy individuals and patients with coronary artery disease revealed lower pCE in cases (P = 0.03). Derived within this same study, the pCAD model significantly improved classification (P < 0.0001). Following analytical validation of the multiplexed proteomic method, we conducted a case-control study of myocardial infarction in 137 postmenopausal women that confirmed significant separation of specimen cohorts in both the pCE (P = 0.015) and pCAD (P = 0.001) models. CONCLUSIONS: Development of a proteomic pCE provides a reproducible high-throughput alternative to traditional cell-based CEC assays. The pCAD model improves stratification of case and control cohorts and, with further studies to establish clinical validity, presents a new opportunity for the assessment of cardiovascular health.


Assuntos
Apolipoproteína A-I/sangue , Colesterol/metabolismo , Doença da Artéria Coronariana/patologia , Lipoproteínas/sangue , Proteoma/análise , Espectrometria de Massas em Tandem/métodos , Área Sob a Curva , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Doença da Artéria Coronariana/sangue , Feminino , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/patologia , Curva ROC , Estudos de Validação como Assunto
5.
Am J Physiol Heart Circ Physiol ; 310(1): H20-8, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26519029

RESUMO

The stromal cell-derived factor-1 (SDF-1):CXCR4 is important in myocardial repair. In this study we tested the hypothesis that early upregulation of cardiomyocyte CXCR4 (CM-CXCR4) at a time of high myocardial SDF-1 expression could be a strategy to engage the SDF-1:CXCR4 axis and improve cardiac repair. The effects of the hypoxia inducible factor (HIF) hydroxylase inhibitor dimethyloxalylglycine (DMOG) on CXCR4 expression was tested on H9c2 cells. In mice a myocardial infarction (MI) was produced in CM-CXCR4 null and wild-type controls. Mice were randomized to receive injection of DMOG (DMOG group) or saline (Saline group) into the border zone after MI. Protein and mRNA expression of CM-CXCR4 were quantified. Echocardiography was used to assess cardiac function. During hypoxia, DMOG treatment increased CXCR4 expression of H9c2 cells by 29 and 42% at 15 and 24 h, respectively. In vivo DMOG treatment increased CM-CXCR4 expression at 15 h post-MI in control mice but not in CM-CXCR4 null mice. DMOG resulted in increased ejection fraction in control mice but not in CM-CXCR4 null mice 21 days after MI. Consistent with greater cardiomyocyte survival with DMOG treatment, we observed a significant increase in cardiac myosin-positive area within the infarct zone after DMOG treatment in control mice, but no increase in CM-CXCR4 null mice. Inhibition of cardiomyocyte death in MI through the stabilization of HIF-1α requires downstream CM-CXCR4 expression. These data suggest that engagement of the SDF-1:CXCR4 axis through the early upregulation of CM-CXCR4 is a strategy for improving cardiac repair after MI.


Assuntos
Aminoácidos Dicarboxílicos/farmacologia , Cardiotônicos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Receptores CXCR4/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular , Linhagem Celular , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Ratos , Receptores CXCR4/deficiência , Receptores CXCR4/genética , Recuperação de Função Fisiológica , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Volume Sistólico/efeitos dos fármacos , Fatores de Tempo , Regulação para Cima
6.
Eur Heart J ; 36(33): 2228-38, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26056125

RESUMO

BACKGROUND: Stromal cell-derived factor-1 (SDF-1) promotes tissue repair through mechanisms of cell survival, endogenous stem cell recruitment, and vasculogenesis. Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure (STOP-HF) is a Phase II, double-blind, randomized, placebo-controlled trial to evaluate safety and efficacy of a single treatment of plasmid stromal cell-derived factor-1 (pSDF-1) delivered via endomyocardial injection to patients with ischaemic heart failure (IHF). METHODS: Ninety-three subjects with IHF on stable guideline-based medical therapy and left ventricular ejection fraction (LVEF) ≤40%, completed Minnesota Living with Heart Failure Questionnaire (MLWHFQ) and 6-min walk distance (6 MWD), were randomized 1 : 1 : 1 to receive a single treatment of either a 15 or 30 mg dose of pSDF-1 or placebo via endomyocardial injections. Safety and efficacy parameters were assessed at 4 and 12 months after injection. Left ventricular functional and structural measures were assessed by contrast echocardiography and quantified by a blinded independent core laboratory. Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure was powered based on change in 6 MWD and MLWHFQ at 4 months. RESULTS: Subject profiles at baseline were (mean ± SD): age 65 ± 9 years, LVEF 28 ± 7%, left ventricular end-systolic volume (LVESV) 167 ± 66 mL, N-terminal pro brain natriuretic peptide (BNP) (NTproBNP) 1120 ± 1084 pg/mL, MLWHFQ 50 ± 20 points, and 6 MWD 289 ± 99 m. Patients were 11 ± 9 years post most recent myocardial infarction. Study injections were delivered without serious adverse events in all subjects. Sixty-two patients received drug with no unanticipated serious product-related adverse events. The primary endpoint was a composite of change in 6 MWD and MLWHFQ from baseline to 4 months follow-up. The primary endpoint was not met (P = 0.89). For the patients treated with pSDF-1, there was a trend toward an improvement in LVEF at 12 months (placebo vs. 15 mg vs. 30 mg ΔLVEF: -2 vs. -0.5 vs. 1.5%, P = 0.20). A pre-specified analysis of the effects of pSDF-1 based on tertiles of LVEF at entry revealed improvements in EF and LVESV from lowest-to-highest LVEF. Patients in the first tertile of EF (<26%) that received 30 mg of pSDF-1 demonstrated a 7% increase in EF compared with a 4% decrease in placebo (ΔLVEF = 11%, P = 0.01) at 12 months. There was also a trend towards improvement in LVESV, with treated patients demonstrating an 18.5 mL decrease compared with a 15 mL increase for placebo at 12 months (ΔLVESV = 33.5 mL, P = 0.12). The change in end-diastolic and end-systolic volume equated to a 14 mL increase in stroke volume in the patients treated with 30 mg of pSDF-1 compared with a decrease of -11 mL in the placebo group (ΔSV = 25 mL, P = 0.09). In addition, the 30 mg-treated cohort exhibited a trend towards improvement in NTproBNP compared with placebo at 12 months (-784 pg/mL, P = 0.23). CONCLUSIONS: The blinded placebo-controlled STOP-HF trial demonstrated the safety of a single endocardial administration of pSDF-1 but failed to demonstrate its primary endpoint of improved composite score at 4 months after treatment. Through a pre-specified analysis the STOP-HF trial demonstrates the potential for attenuating LV remodelling and improving EF in high-risk ischaemic cardiomyopathy. The safety profile supports repeat dosing with pSDF-1 and the degree of left ventricular remodelling suggests the potential for improved outcomes in larger future trials.


Assuntos
Quimiocina CXCL12/administração & dosagem , Terapia Genética/métodos , Insuficiência Cardíaca/terapia , Isquemia Miocárdica/terapia , Idoso , Análise de Variância , Quimiocina CXCL12/efeitos adversos , Quimiocina CXCL12/genética , Doença Crônica , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/patologia , Humanos , Injeções Intralesionais , Masculino , Isquemia Miocárdica/patologia , Volume Sistólico/fisiologia , Resultado do Tratamento , Remodelação Ventricular/fisiologia
7.
Am J Physiol Renal Physiol ; 308(2): F92-F100, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25377914

RESUMO

Childbirth injures muscles and nerves responsible for urinary continence. Mesenchymal stem cells (MSCs) or their secretome given systemically could provide therapeutic benefit for this complex multisite injury. We investigated whether MSCs or their secretome, as collected from cell culture, facilitate recovery from simulated childbirth injury. Age-matched female Sprague-Dawley rats received pudendal nerve crush and vaginal distension (PNC+VD) and a single intravenous (iv) injection of 2 million MSCs or saline. Controls received sham injury and iv saline. Additional rats received PNC+VD and a single intraperitoneal (ip) injection of concentrated media conditioned by MSCs (CCM) or concentrated control media (CM). Controls received a sham injury and ip CM. Urethral and nerve function were assessed with leak point pressure (LPP) and pudendal nerve sensory branch potential (PNSBP) recordings 3 wk after injury. Urethral and pudendal nerve anatomy were assessed qualitatively by blinded investigators. Quantitative data were analyzed using one-way ANOVA and Holm-Sidak post hoc tests with P < 0.05 indicating significant differences. Both LPP and PNSBP were significantly decreased 3 wk after PNC+VD with saline or CM compared with sham-injured rats, but not with MSC or CCM. Elastic fiber density in the urethra increased and changed in orientation after PNC+VD, with a greater increase in elastic fibers with MSC or CCM. Pudendal nerve fascicles were less dense and irregularly shaped after PNC+VD and had reduced pathology with MSC or CCM. MSC and CCM provide similar protective effects after PNC+VD, suggesting that MSCs act via their secretions in this dual muscle and nerve injury.


Assuntos
Transplante de Células-Tronco Mesenquimais , Nervo Pudendo/fisiologia , Uretra/fisiologia , Incontinência Urinária por Estresse/prevenção & controle , Animais , Meios de Cultivo Condicionados , Feminino , Injeções Intraperitoneais , Injeções Intravenosas , Células-Tronco Mesenquimais/metabolismo , Parto , Nervo Pudendo/lesões , Ratos Sprague-Dawley , Uretra/lesões , Incontinência Urinária por Estresse/etiologia
8.
Circ Res ; 112(5): 816-25, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23429605

RESUMO

RATIONALE: Preclinical studies indicate that adult stem cells induce tissue repair by activating endogenous stem cells through the stromal cell-derived factor-1:chemokine receptor type 4 axis. JVS-100 is a DNA plasmid encoding human stromal cell-derived factor-1. OBJECTIVE: We tested in a phase 1, open-label, dose-escalation study with 12 months of follow-up in subjects with ischemic cardiomyopathy to see if JVS-100 improves clinical parameters. METHODS AND RESULTS: Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction ≤40% on stable medical therapy, were enrolled to receive 5, 15, or 30 mg of JVS-100 via endomyocardial injection. The primary end points for safety and efficacy were at 1 and 4 months, respectively. The primary safety end point was a major adverse cardiac event. Efficacy end points were change in quality of life, New York Heart Association class, 6-minute walk distance, single photon emission computed tomography, N-terminal pro-brain natruretic peptide, and echocardiography at 4 and 12 months. The primary safety end point was met. At 4 months, all of the cohorts demonstrated improvements in 6-minute walk distance, quality of life, and New York Heart Association class. Subjects in the 15- and 30-mg dose groups exhibited improvements in 6-minute walk distance (15 mg: median [range]: 41 minutes [3-61 minutes]; 30 mg: 31 minutes [22-74 minutes]) and quality of life (15 mg: -16 points [+1 to -32 points]; 30 mg: -24 points [+17 to -38 points]) over baseline. At 12 months, improvements in symptoms were maintained. CONCLUSIONS: These data highlight the importance of defining the molecular mechanisms of stem cell-based tissue repair and suggest that overexpression of stromal cell-derived factor-1 via gene therapy is a strategy for improving heart failure symptoms in patients with ischemic cardiomyopathy.


Assuntos
Quimiocina CXCL12/genética , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Insuficiência Cardíaca/terapia , Plasmídeos , Idoso , Quimiocina CXCL12/metabolismo , Estudos de Coortes , Relação Dose-Resposta a Droga , Ecocardiografia , Tolerância ao Exercício , Feminino , Seguimentos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Miocárdio/patologia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Tomografia por Emissão de Pósitrons , Qualidade de Vida , Resultado do Tratamento
9.
Int J Neurosci ; 125(6): 424-32, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25029671

RESUMO

PURPOSE/AIM: Heart failure patients often require assistance with activities of daily living, including driving. Recent work shows heart failure patients commit more errors on a simulated driving task relative to controls and cognitive dysfunction contributed to these errors. We sought to extend these findings by examining whether structural magnetic resonance imaging indices correlate with driving independence and performance in heart failure. MATERIALS AND METHODS: Forty-nine heart failure patients underwent brain magnetic resonance imaging and performed a battery assessing attention/executive function and memory. A self-report instrument was used to assess independence in transportation. A subset of heart failure participants (N = 8) completed a validated driving simulator scenario. RESULTS: Among the larger sample (N = 49), reduced gray matter correlated with greater dependence in transportation and worse attention/executive function; in turn, worse attention/executive function predicted greater assistance with transportation (p < 0.05). Among the subset that completed the driving simulator (N = 8), reduced gray matter correlated with more stop signs missed and increased white matter hyperintensities correlated with greater collisions, centerline crossings and time out of lane (p < 0.05). Poorer attention/executive function was also associated with more time over the speed limit on the driving simulation (p < 0.05). Follow-up analyses showed the above effects were largely independent of age. CONCLUSIONS: Reduced structural brain integrity is associated with poorer reported and simulated driving in persons with heart failure. Larger prospective studies that employ on-road testing are needed to clarify brain changes and risk for unsafe driving in heart failure.


Assuntos
Condução de Veículo , Encéfalo/patologia , Transtornos Cognitivos/etiologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/patologia , Desempenho Psicomotor/fisiologia , Atividades Cotidianas , Idoso , Atenção/fisiologia , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Autorrelato , Estatística como Assunto
10.
Am J Occup Ther ; 69(2): 6902260010p1-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26122681

RESUMO

OBJECTIVE: Reduced physical fitness secondary to heart failure (HF) may contribute to poor driving; reduced physical fitness is a known correlate of cognitive impairment and has been associated with decreased independence in driving. No study has examined the associations among physical fitness, cognition, and driving performance in people with HF. METHOD: Eighteen people with HF completed a physical fitness assessment, a cognitive test battery, and a validated driving simulator scenario. RESULTS: Partial correlations showed that poorer physical fitness was correlated with more collisions and stop signs missed and lower scores on a composite score of attention, executive function, and psychomotor speed. Cognitive dysfunction predicted reduced driving simulation performance. CONCLUSION: Reduced physical fitness in participants with HF was associated with worse simulated driving, possibly because of cognitive dysfunction. Larger studies using on-road testing are needed to confirm our findings and identify clinical interventions to maximize safe driving.


Assuntos
Condução de Veículo/psicologia , Transtornos Cognitivos/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Aptidão Física/fisiologia , Idoso , Atenção/fisiologia , Transtornos Cognitivos/complicações , Transtornos Cognitivos/psicologia , Estudos de Coortes , Estudos Transversais , Função Executiva/fisiologia , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/psicologia , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Aptidão Física/psicologia , Desempenho Psicomotor/fisiologia , Fatores de Risco
11.
Cytokine ; 69(2): 277-83, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25034237

RESUMO

Chemotactic factors direct the migration of immune cells, multipotent stem cells, and progenitor cells under physiologic and pathologic conditions. Chemokine ligand 12 and chemokine ligand 7 have been identified and investigated in multiple studies for their role in cellular trafficking in the setting of tissue regeneration. Recent early phase clinical trials have suggested that these molecules may lead to clinical benefit in patients with chronic disease. Importantly, these two proteins may play additional significant roles in directing the migration of multipotent cells, such as mesenchymal stem cells and hematopoietic progenitor cells. This article reviews the functions of these two chemokines, focusing on recruitment to sites of injury, immune function modulation, and contributions to embryonic development. Additional research would provide valuable insight into the potential clinical application of these two proteins in stem cell therapy.


Assuntos
Quimiocina CCL7/metabolismo , Quimiocina CXCL12/metabolismo , Desenvolvimento Embrionário , Imunidade , Regeneração , Animais , Humanos , Ferimentos e Lesões/patologia
12.
J Nutr ; 144(7): 1030-6, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24759932

RESUMO

HDL and apolipoprotein A1 (apoA1) concentrations inversely correlate with risk of death from ischemic heart disease; however, the role of apoA1 in the myocardial response to ischemia has not been well defined. To test whether apoA1, the primary HDL apolipoprotein, has an acute anti-inflammatory role in ischemic heart disease, we induced myocardial infarction via direct left anterior descending coronary artery ligation in apoA1 null (apoA1(-/-)) and apoA1 heterozygous (apoA1(+/-)) mice. We observed that apoA1(+/-) and apoA1(-/-) mice had a 52% and 125% increase in infarct size as a percentage of area at risk, respectively, compared with wild-type (WT) C57BL/6 mice. Mitochondrial oxidation contributes to tissue damage in ischemia-reperfusion injury. A substantial defect was present at baseline in the electron transport chain of cardiac myocytes from apoA1(-/-) mice localized to the coenzyme Q (CoQ) pool with impaired electron transfer (67% decrease) from complex II to complex III. Administration of coenzyme Q10 (CoQ10) to apoA1 null mice normalized the cardiac mitochondrial CoQ pool and reduced infarct size to that observed in WT mice. CoQ10 administration did not significantly alter infarct size in WT mice. These data identify CoQ pool content leading to impaired mitochondrial function as major contributors to infarct size in the setting of low HDL/apoA1. These data suggest a previously unappreciated mechanism for myocardial stunning, cardiac dysfunction, and muscle pain associated with low HDL and low apoA1 concentrations that can be corrected by CoQ10 supplementation and suggest populations of patients that may benefit particularly from CoQ10 supplementation.


Assuntos
Antioxidantes/metabolismo , Apolipoproteína A-I/metabolismo , Modelos Animais de Doenças , Mitocôndrias Cardíacas/metabolismo , Infarto do Miocárdio/terapia , Miocárdio/metabolismo , Ubiquinona/análogos & derivados , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacocinética , Antioxidantes/uso terapêutico , Apolipoproteína A-I/sangue , Apolipoproteína A-I/genética , Cardiotônicos/administração & dosagem , Cardiotônicos/metabolismo , Cardiotônicos/farmacocinética , Cardiotônicos/uso terapêutico , Suplementos Nutricionais , Transporte de Elétrons/efeitos dos fármacos , Complexo II de Transporte de Elétrons/química , Complexo II de Transporte de Elétrons/metabolismo , Complexo III da Cadeia de Transporte de Elétrons/química , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Coração/efeitos dos fármacos , Hipoalfalipoproteinemias/fisiopatologia , Injeções Intraperitoneais , Absorção Intestinal , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/enzimologia , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/enzimologia , Miocárdio/patologia , Distribuição Tecidual , Ubiquinona/administração & dosagem , Ubiquinona/metabolismo , Ubiquinona/farmacocinética , Ubiquinona/uso terapêutico
14.
Circ Res ; 110(2): 304-11, 2012 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-22052917

RESUMO

RATIONALE: MultiStem is an allogeneic bone marrow-derived adherent adult stem cell product that has shown efficacy in preclinical models of acute myocardial infarction (AMI). In this phase I clinical trial in patients with first ST-elevation-myocardial infarction (STEMI), we combine first-in-man delivery of MultiStem with a first-in-coronary adventitial delivery system to determine the effects of this system on left ventricular function at 4 months after AMI. OBJECTIVE: Test the effects of adventitial delivery of Multistem in the peri-infarct period in patients with first STEMI. METHODS AND RESULTS: This study was a phase I, open-label, dose-escalating registry control group study. Nineteen patients received MultiStem (20 million, n=6; 50 million, n=7; or 100 million, n=6) and 6 subjects were assigned to the registry control group. Two to 5 days after AMI, we delivered MultiStem to the adventitia of the infarct-related vessel in patients with first-time STEMI. All patients underwent primary percutaneous coronary intervention with resulting Thrombolysis In Myocardial Infarction grade 3 flow and with ejection fraction (EF) ≤45% as determined by echocardiogram or left ventriculogram within 12 hours of primary percutaneous coronary intervention. The cell product (20 million, 50 million, or 100 million) was well tolerated, and no serious adverse events were deemed related to MultiStem. There was no increase in creatine kinase-MB or troponin associated with the adventitial delivery of MultiStem. In patients with EF determined to be ≤45% by a core laboratory within 24 hours before the MultiStem injection, we observed a 0.9 (n=4), 3.9 (n=4), 13.5 (n=5), and 10.9 (n=2) percent absolute increases in EF in the registry, 20 million, 50 million, and 100 million dose groups, respectively. The increases in EF in the 50 million and 100 million groups were accompanied by 25.4 and 8.4 mL increases in left ventricular stroke volume. CONCLUSIONS: In this study, the delivery of MultiStem to the myocardium in patients with recent STEMI was well tolerated and safe. In patients who exhibited significant myocardial damage, the delivery of ≥50 million MultiStem resulted in improved EF and stroke volume 4 months later. These findings support further development of MultiStem in patients with AMI and they validate the potential of a system for delivery of adult stem cells at any time after primary percutaneous coronary intervention.


Assuntos
Células-Tronco Adultas/transplante , Angioplastia Coronária com Balão , Transplante de Medula Óssea , Infarto do Miocárdio/terapia , Células-Tronco Adultas/imunologia , Idoso , Transplante de Medula Óssea/efeitos adversos , Terapia Combinada , Tecido Conjuntivo , Feminino , Humanos , Masculino , Microinjeções , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/cirurgia , Miocárdio/patologia , Recuperação de Função Fisiológica , Sistema de Registros , Volume Sistólico , Fatores de Tempo , Transplante Homólogo , Resultado do Tratamento , Estados Unidos , Função Ventricular Esquerda
15.
Circulation ; 126(3): 314-24, 2012 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-22685115

RESUMO

BACKGROUND: Overexpression of stromal cell-derived factor-1 in injured tissue leads to improved end-organ function. In this study, we quantify the local trophic effects of mesenchymal stem cell (MSC) stromal cell-derived factor-1 release on the effects of MSC engraftment in the myocardium after acute myocardial infarction. METHODS AND RESULTS: Conditional cardiac myocyte CXCR4 (CM-CXCR4) null mice were generated by use of tamoxifen-inducible cardiac-specific cre by crossing CXCR4 floxed with MCM-cre mouse. Studies were performed in littermates with (CM-CXCR4 null) or without (control) tamoxifen injection 3 weeks before acute myocardial infarction. One day after acute myocardial infarction, mice received 100,000 MSC or saline via tail vein. We show α-myosin heavy chain MerCreMer and the MLC-2v promoters are active in cardiac progenitor cells. MSC engraftment in wild-type mice decreased terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling positive CM (-44%, P<0.01), increased cardiac progenitor cell recruitment (100.9%, P<0.01), and increased cardiac myosin-positive area (39%, P<0.05) at 4, 7, and 21 days after acute myocardial infarction, respectively. MSC in wild-type mice resulted in 107.4% (P<0.05) increase in ejection fraction in comparison with 25.9% (P=NS) increase in CM-CXCR4 null mice. These differences occurred despite equivalent increases (16%) in vascular density in response to MSC infusion in wild-type and CM-CXCR4 null mice. CONCLUSIONS: These data demonstrate that the local trophic effects of MSC require cardiac progenitor cell and CM-CXCR4 expression and are mediated by MSC stromal cell-derived factor-1 secretion. Our results further demonstrate and quantify for the first time a specific paracrine mechanism of MSC engraftment. In the absence of CM-CXCR4 expression, there is a significant loss of functional benefit in MSC-mediated repair despite equal increases in vascular density.


Assuntos
Quimiocina CXCL12/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/terapia , Receptores CXCR4/genética , Animais , Apoptose/fisiologia , Movimento Celular/fisiologia , Circulação Coronária/fisiologia , Expressão Gênica/fisiologia , Proteínas de Fluorescência Verde/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miocárdio/citologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/fisiologia , Comunicação Parácrina/fisiologia , Receptores CXCR4/metabolismo , Remodelação Ventricular/fisiologia
16.
J Urol ; 189(4): 1588-94, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23022009

RESUMO

PURPOSE: Human childbirth simulated by vaginal distention is known to increase the expression of chemokines and receptors involved in stem cell homing and tissue repair. We hypothesized that pregnancy and parturition in rats contributes to the expression of chemokines and receptors after vaginal distention. MATERIALS AND METHODS: We used 72 age matched female Lewis rats, including virgin rats with and without vaginal distention, and delivered rats with and without vaginal distention. Each rat was sacrificed immediately, or 3 or 7 days after vaginal distention and/or parturition, and the urethra was harvested. Relative expression of chemokines and receptors was determined by real-time polymerase chain reaction. Mixed models were used with the Bonferroni correction for multiple comparisons. RESULTS: Vaginal distention up-regulated urethral expression of CCL7 immediately after injury in virgin and postpartum rats. Hypoxia inducible factor-1α and vascular endothelial growth factor were up-regulated only in virgin rats immediately after vaginal distention. CD191 expression was immediately up-regulated in postpartum rats without vaginal distention compared to virgin rats without vaginal distention. CD195 was up-regulated in virgin rats 3 days after vaginal distention compared to virgin rats without vaginal distention. CD193 and CXCR4 showed delayed up-regulation in virgin rats 7 days after vaginal distention. CXCL12 was up-regulated in virgin rats 3 days after vaginal distention compared to immediately after vaginal distention. Interleukin-8 and CD192 showed no differential expression. CONCLUSIONS: Vaginal distention results in up-regulation of the chemokines and receptors expressed during tissue injury, which may facilitate the spontaneous functional recovery previously noted. Pregnancy and delivery up-regulated CD191 and attenuated the expression of hypoxia inducible factor-1α and vascular endothelial growth factor in the setting of vaginal distention, likely by decreasing hypoxia.


Assuntos
Quimiocinas/biossíntese , Parto , Receptores de Quimiocinas/biossíntese , Incontinência Urinária por Estresse/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Ratos , Ratos Wistar , Vagina
17.
J Gen Intern Med ; 28(10): 1353-63, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23771782

RESUMO

Coronary artery disease is the leading cause of death in Americans. After myocardial infarction, significant ventricular damage persists despite timely reperfusion and pharmacological management. Treatment is limited, as current modalities do not cure this damage. In the past decade, stem cell therapy has emerged as a promising therapeutic solution to restore myocardial function. Clinical trials have demonstrated safety and beneficial effects in patients suffering from acute myocardial infarction, heart failure, and dilated cardiomyopathy. These benefits include improved ventricular function, increased ejection fraction, and decreased infarct size. Mechanisms of therapy are still not clearly understood. However, it is believed that paracrine factors, including stromal cell-derived factor-1, contribute significantly to stem cell benefits. The purpose of this article is to provide medical professionals with an overview on stem cell therapy for the heart and to discuss potential future directions.


Assuntos
Cardiopatias/terapia , Transplante de Células-Tronco/métodos , Ensaios Clínicos como Assunto , Sobrevivência de Enxerto , Cardiopatias/fisiopatologia , Insuficiência Cardíaca/terapia , Humanos , Infarto do Miocárdio/terapia , Comunicação Parácrina/fisiologia
18.
FASEB J ; 26(6): 2363-73, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22362893

RESUMO

Thrombospondin-4 (TSP-4) expression increases dramatically in hypertrophic and failing hearts in rodent models and in humans. The aim of this study was to address the function of TSP-4 in the heart. TSP-4-knockout (Thbs4(-/-)) and wild-type (WT) mice were subjected to transverse aortic constriction (TAC) to increase left ventricle load. After 2 wk, Thbs4(-/-) mice had a significantly higher heart weight/body weight ratio than WT mice. The additional increase in the heart weight in TAC Thbs4(-/-) mice was due to increased deposition of extracellular matrix (ECM). The levels of interstitial collagens were higher in the knockout mice, but the size of cardiomyocytes and apoptosis in the myocardium was unaffected by TSP-4 deficiency, suggesting that increased reactive fibrosis was the primary cause of the higher heart weight. The increased ECM deposition in Thbs4(-/-) mice was accompanied by changes in functional parameters of the heart and decreased vessel density. The expression of inflammatory and fibrotic genes known to be influential in myocardial remodeling changed as a result of TSP-4 deficiency in vivo and as a result of incubation of cells with recombinant TSP-4 in vitro. Thus, TSP-4 is involved in regulating the adaptive responses of the heart to pressure overload, suggesting its important role in myocardial remodeling. Our study showed a direct influence of TSP-4 on heart function and to identify the mechanism of its effects on heart remodeling.


Assuntos
Cardiomegalia/fisiopatologia , Miocárdio/patologia , Trombospondinas/deficiência , Remodelação Ventricular/fisiologia , Animais , Aorta/patologia , Colágeno/biossíntese , Constrição Patológica/fisiopatologia , Matriz Extracelular/metabolismo , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/patologia , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Miócitos Cardíacos/patologia , Trombospondinas/fisiologia
20.
PLoS One ; 18(7): e0288712, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37471318

RESUMO

BACKGROUND: Levels of free myeloperoxidase (MPO), a cardiovascular risk marker, have been reported to decline with standard care. Whether such declines signify decreased risk of mortality remains unknown. DESIGN: Cox proportional hazard models were generated using data from a retrospective cohort study of prospectively collected measures. PARTICIPANTS: Patients (3,658) who had MPO measurements and LDL-C ≥ 90 mg/dL during 2011-2015 were selected based on a stratified random sampling on MPO risk level. Baseline MPO was either low (<470 pmol/L), moderate (470-539 pmol/L), or high (≥540 pmol/L). MAIN OUTCOMES AND MEASURES: First occurrence of MACE (myocardial infarction, stroke, coronary revascularization, or all-cause death). RESULTS: Mean age was 66.5 years, and 64.7% were women. During a mean 6.5-year follow-up, crude incidence per 1000 patient years was driven by death. The incidence and all-cause death was highest for patients with high MPO (21.2; 95% CI, 19.0-23.7), then moderate (14.6; 95% CI, 11.5-18.5) and low (2.3; 95% CI, 1.2-4.6) MPO. After adjusting for age, sex, and cardiovascular risk factors, risk of cardiovascular death did not differ significantly between patients with high and low MPO (HR, 1.57; 95% CI, 0.56-4.39), but patients with high MPO had greater risk of non-cardiovascular (HR, 6.15; 95% CI, 2.27-16.64) and all-cause (HR, 3.83; 95% CI, 1.88-7.78) death. During follow-up, a 100 pmol/L decrease in MPO correlated with a 5% reduction in mortality (HR, 0.95; 95% CI, 0.93-0.97) over 5 years. CONCLUSIONS: Free circulating MPO is a strong marker of risk of mortality. Monitoring changes in MPO levels over time may provide insight into changes in physiology that mark a patient for increased risk of mortality.


Assuntos
Doenças Cardiovasculares , Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Feminino , Idoso , Masculino , Estudos Retrospectivos , Ativação de Neutrófilo , Fatores de Risco
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