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1.
Cell Physiol Biochem ; 53(3): 465-479, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31464387

RESUMO

BACKGROUND/AIMS: Cyclophilin D (CypD) mediates the mitochondrial permeability transition pore (mPTP) opening that contributes to mitochondrial dysfunction. CypD is regulated by its acetylation/deacetylation state that depends on Sirtuin-3 (SIRT3) mitochondrial deacetylase. Since obesity and metabolic syndrome decrease SIRT3 activity and expression, we tested the hypothesis that CypD hyperacetylation promotes mitochondrial dysfunction under this pathophysiological state, which is associated with ventricular dysfunction and heart failure. METHODS: Myocardial tissue samples from patients with left ventricular heart failure, with either obesity or normal weight, were processed for the expression of SIRT3 and acetylation profile by Western Blot (WB). In addition, a rat model of obesity and metabolic syndrome induced by 30% (w/v) of sucrose was conducted. The WB analysis was used to determine the levels of mitochondrial expression of SIRT3, Adenine Nucleotide Translocator (ANT), CypD and the acetylation profile, as well as immunoprecipitation to establish the acetylation levels of CypD. Mitochondrial function was assessed by oxygen consumption analysis and maximum Ca2+ retention capacity. Oxidative stress was assessed by aconitase activity, protein carbonyl and thiol groups content. RESULTS: SIRT3 expression in the biopsies of the failing human hearts showed a 46% decrease in the expression levels of obese patients in comparison to the non-obese patients (p=0.0219). Remarkably, body mass index was associated with protein acetylation (0.627; p = 0.035), suggesting that the acetylation profiles of the failing hearts of obese patients are partly mediated by a reduction in SIRT3, which is also associated with higher BNP levels, indicating a more severe ventricular dysfunction (-0.636; p = 0.043). Accordingly, obese rats demonstrated a SIRT3 mitochondrial expression decrease of 22% concomitantly with a hyperacetylated mitochondrial profile, including CypD. Cardiac mitochondria from obese animals were 2.5-fold more prone to mPTP opening than the controls. CONCLUSION: Our results indicate that obesity reduces SIRT3 expression and that CypD hyperacetylation increases mPTP opening, suggesting that the activation of SIRT3 might be a potential target to decrease ventricular dysfunction and slow the progression of heart failure.

2.
Circ Res ; 124(11): 1568-1583, 2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31120823

RESUMO

Myocarditis is generally a mild and self-limited consequence of systemic infection of cardiotropic viruses. However, patients can develop a temporary or permanent impairment of cardiac function including acute cardiomyopathy with hemodynamic compromise or severe arrhythmias. In this setting, specific causes of inflammation are associated with variable risks of death and transplantation. Recent translational studies suggest that treatments tailored to specific causes of myocarditis may impact clinical outcomes when added to guideline-directed medical care. This review summarizes recent advances in translational research that influence the utility of endomyocardial biopsy for the management of inflammatory cardiomyopathies. Emerging therapies for myocarditis based on these mechanistic hypotheses are entering clinical trials and may add to the benefits of established heart failure treatment.

3.
BMJ Open ; 9(3): e022826, 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30918029

RESUMO

INTRODUCTION: Chronic heart failure with reduced ejection fraction (HFrEF) treatment targets neurohormonal inhibition; however, our experimental observations and the recent clinical evidence in myocardial infarction and heart transplant patients support the anti-inflammatory pathway as a potential novel therapeutic target. Therefore, we aimed to assess the safety of human monoclonal antibody-CD20 (rituximab) in patients with HFrEF. METHODS AND ANALYSIS: We designed this protocol according to the Standard Protocol Items: Recommendations for Interventional Trials guidelines as a phase II, single-centred, single group and prospective clinical trial. We hypothesise that the use of a monoclonal antibody, rituximab, could be a potentially safe new agent in HFrEF management. We will include patients with EF≤40%, New York Heart Association functional class III/IV and unresponsive to standard treatment. We will use a dosing regimen (1000 mg) previously applied to post-transplant patients and patients with rheumatoid arthritis with favourable results, aiming to provide supplementary evidence of safety in patients with HFrEF. We designed strategies tailored to preserving the integrity of patient safety. The date of study initiation will be 29th of May 2019. ETHICS AND DISSEMINATION: The following protocol was approved by IRB committees, and as a requirement, all patients need to sign an informed consent form before being subjected to any procedure prior to the initiation of the study. We are aware that the trial will be run in patients who due to their cardiovascular functional class, have reserved prognosis, with no known therapy that leads to improvement. Hence, this trial searches to establish the safety of an alternative strategy in ameliorating prognosis. Regardless of the study outcomes, whether favourable or not, they will be published. If a favourable outcome is evidenced, it will prompt performing a phase III, efficacy-based study. TRIAL REGISTRATION NUMBER: The trial was approved by the IRB (CONBIOÉTICA-19-CEI-011-20161017 and COFEPRIS-17-CI-19-039-003), and registered at Clinicaltrials.gov (NCT03332888; Pre-Results).

4.
Int J Mol Sci ; 19(12)2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30467294

RESUMO

Heart failure (HF) is a cardiovascular syndrome characterized by maladaptive changes with an underlying inflammatory mediated pathogenesis. Nevertheless, current therapy is aimed at the heart workload and neurohormonal axis; thus, prognosis remains poor. To continue improving treatment, we rely on murine models for a better understanding of HF pathophysiology. Among them, pressure overload HF (PO-HF) animal models are a common strategy. Development of PO-HF is characterized by monocyte infiltration, which orchestrates a cascade of events leading to sustained inflammation and maladaptive changes. Here, we divide the PO-HF model progression into four phases and describe the inflammatory, structural, and gene expression profiles. This division is relevant due to its similarities with clinical hypertensive heart disease progression to HF. Evidence shows improvement in hemodynamic and other local parameters by altering the inflammatory response in a specific immune response at a specific point of time. Thus, it is relevant to focus on the time-dependent immune response interaction in order to provide more effective therapy. This review summarizes the pathogenesis of PO-HF murine models, highlighting the inflammatory events in a time frame view. By this approach, we expect to provide researchers with a better understanding of the intertwining time-dependent events that occur in PO-HF.

5.
BMJ Open ; 8(10): e022562, 2018 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-30337314

RESUMO

OBJECTIVE: To define and compare the reference interval of B-type natriuretic peptide (BNP) in healthy newborns (HN) from healthy mothers and with severe pre-eclampsia. DESIGN: Prospective, multicentre, cross-sectional study. SETTING: Four obstetric wards of second-level academic hospitals. PARTICIPANTS: 167 HN, from 146 healthy and 21 severe pre-eclamptic women. We included newborns from healthy mothers with full-term pregnancies (38 to 42 gestational weeks), who received adequate prenatal care and who had Apgar scores ≥7 at 0 and 5 min. Newborns with chromosomopathies identified during prenatal consultations, those with respiratory distress and those with cardiac or pulmonary disease detected in the first paediatric evaluation were excluded from this study. In the group of pre-eclamptic women, we considered the same inclusion criteria, but the patients also had to meet the diagnostic criteria for pre-eclampsia with severity features, according to the American College of Obstetricians and Gynaecologists guidelines. The same exclusion criteria used for the healthy group were applied to the pre-eclampsia-associated newborn. INTERVENTIONS: A single blood sample from the umbilical cord artery after delivery (vaginal or caesarean section). PRIMARY OUTCOME: Reference level of BNP in HN. RESULTS: In the HN group, the median BNP was 12.15 pg/mL (IQR 7.7-16.8 pg/mL) and in the pre-eclamptic group 20.8 pg/mL (IQR 5.8-46.5 pg/mL). The reference interval for BNP in HN was 5pg/mL (95% CI 5 to 5) to 34 pg/mL (95% CI 28.4 to 38.8). We identified higher expression of BNP in newborns from pre-eclamptic women overall (p=0.037, r=0.16) and in newborns exposed to stress conditions, such as complications during labour and delivery (p=0.004, r=0.33). CONCLUSIONS: In HN, BNP concentrations at birth were lower than reported in other similar populations. In neonates with stress conditions, the higher expression of this biomarker establishes another possible link between stress and the cardiovascular response. TRIAL REGISTRATION NUMBER: NCT02574806; Pre-results.

7.
ASAIO J ; 64(2): 196-202, 2018 Mar/Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28885379

RESUMO

Patients bridged to transplant (BTT) with continuous-flow left ventricular assist devices (CF-LVADs) have increased in the past decade. Decision support tools for these patients are limited. We developed a risk score to estimate prognosis and guide decision-making. We included heart transplant recipients bridged with CF-LVADs from the United Network for Organ Sharing (UNOS) database and divided them into development (2,522 patients) and validation cohorts (1,681 patients). Univariate and multivariate Cox proportional hazards models were performed. Variables that independently predicted outcomes (age, African American race, recipient body mass index [BMI], intravenous [IV] antibiotic use, pretransplant dialysis, and total bilirubin) were assigned weight using linear transformation, and risk scores were derived. Patients were grouped by predicted posttransplant mortality: low risk (≤ 38 points), medium risk (38-41 points), and high risk (≥ 42 points). We performed Cox proportional hazards analysis on wait-listed CF-LVAD patients who were not transplanted. Score significantly discriminated survival among the groups in the development cohort (6.7, 12.9, 20.7; p = 0.001), validation cohort (6.4, 10.1, 13.6; p < 0.001), and ambulatory cohort (6.4, 11.5, 17.2; p < 0.001). We derived a left ventricular assist device (LVAD) BTT risk score that effectively identifies CF-LVAD patients who are at higher risk for worse outcomes after heart transplant. This score may help physicians weigh the risks of transplantation in patients with CF-LVAD.

8.
Eur J Heart Fail ; 20(2): 317-322, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28871621

RESUMO

AIMS: Changes in systolic blood pressure (SBP) during an admission for acute heart failure (AHF), especially those leading to hypotension, have been suggested to increase the risk for adverse outcomes. METHODS AND RESULTS: We analysed associations of SBP decrease during the first 24 h from randomization with serum creatinine changes at the last time-point available (72 h), using linear regression, and with 30- and 180-day outcomes, using Cox regression, in 1257 patients in the VERITAS study. After multivariable adjustment for baseline SBP, greater SBP decrease at 24 h from randomization was associated with greater creatinine increase at 72 h and greater risk for 30-day all-cause death, worsening heart failure (HF) or HF readmission. The hazard ratio (HR) for each 1 mmHg decrease in SBP at 24 h for 30-day death, worsening HF or HF rehospitalization was 1.01 [95% confidence interval (CI) 1.00-1.02; P = 0.021]. Similarly, the HR for each 1 mmHg decrease in SBP at 24 h for 180-day all-cause mortality was 1.01 (95% CI 1.00-1.03; P = 0.038). The associations between SBP decrease and outcomes did not differ by tezosentan treatment group, although tezosentan treatment was associated with a greater SBP decrease at 24 h. CONCLUSIONS: In the current post hoc analysis, SBP decrease during the first 24 h was associated with increased renal impairment and adverse outcomes at 30 and 180 days. Caution, with special attention to blood pressure monitoring, should be exercised when vasodilating agents are given to AHF patients.

9.
Arch Med Res ; 48(1): 1-11, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28577862

RESUMO

Heart failure (HF) is considered the endpoint of a variety of cardiac diseases, which are the leading cause of death in adults and considered a growing pandemic worldwide. Independent of the initial form of cardiac injury, there is evidence linking the involvement of the immune system. In HF there is evidence of the participation of TH1, and TH17 cells, which account for sustained pathological chronic inflammation, cell migration, and the induction of specific pathological phenotypes of mononuclear cells. Of equal or even higher relevance are the B lymphocyte activation mechanisms that include production of pro-inflammatory cytokines, chemokines, and cardiac autoantibodies with or without activation of the complement proteins. Both of these unbalanced T- and B-cell pathways of the adaptive immune system are associated with cardiomyocyte death and tissue remodeling by fibrosis leading to a dysfunctional heart. At this time, therapy with neutralizing antibodies and the use of anti-cytokine immunomodulators to counteract the immune system effects have reached a plateau of mixed results in clinical trials. Nevertheless, recent evidence showed promising results in animal models that suggest that modulation of the adaptive immune system cells more than some of their effector molecules could have benefits in HF patients. This review summarizes the role of the adaptive immunity cells in HF, considering the sustained activation of adaptive immune system as a potential contributor to disease progression in humans and experimental models where its regulation provides a new therapeutic target.


Assuntos
Imunidade Adaptativa , Insuficiência Cardíaca/imunologia , Animais , Autoanticorpos/imunologia , Linfócitos B/imunologia , Morte Celular , Citocinas/metabolismo , Progressão da Doença , Fibrose , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/terapia , Humanos , Inflamação/imunologia , Inflamação/patologia , Miocárdio/imunologia , Miocárdio/patologia
10.
ASAIO J ; 63(6): 704-712, 2017 Nov/Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28504984

RESUMO

The model for end-stage liver disease (MELD) has been used as a predictor of mortality after left ventricular assist device (LVAD) placement. However, improvement or worsening of MELD and how those changes affect outcomes is unknown. We performed a retrospective analysis of 244 patients implanted with a continuous flow (CF) LVAD. Patients were dichotomized at admission into low- or high-risk categories using a cutoff of MELD ≥ 19, and they were reclassified at day of implant forming four groups: Group LL (low to low, remained low risk), LH (low to high, worsened to high risk), HH (high to high, remained high risk), and HL (high to low, improved to low risk). Patients who improved to a low risk (group HL) had the same 1 year survival as those that remained low risk (group LL; 80% vs. 77%; p = 0.6). However, patients who were initially classified as low risk and worsened to a high risk (group LH) had a survival that was worse than those that were consistently high risk (group HH; 55% vs. 10%; p = 0.01). Model for end-stage liver disease reclassification after adjusting for commonly attributed risk factors remained an independent predictor for mortality, including patients classified as Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) 1 and 2. In conclusion, our MELD score reclassification is an independent and powerful predictor of mortality in patients undergoing LVAD implantation.


Assuntos
Insuficiência Cardíaca/classificação , Insuficiência Cardíaca/cirurgia , Coração Auxiliar , Adulto , Feminino , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
11.
Int J Pharm ; 524(1-2): 257-267, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28359821

RESUMO

Vascular remodeling resulting from pulmonary arterial hypertension (PAH) leads to endothelial fenestrations. This feature can be exploited by nanoparticles (NP), allowing them to extravasate from circulation and accumulate in remodeled pulmonary vessels. Hyperactivation of the mTOR pathway in PAH drives pulmonary arterial smooth muscle cell proliferation. We hypothesized that rapamycin (RAP)-loaded NPs, an mTOR inhibitor, would accumulate in diseased lungs, selectively targeting vascular mTOR and preventing PAH progression. RAP poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) NPs were fabricated. NP accumulation and efficacy were examined in a rat monocrotaline model of PAH. Following intravenous (IV) administration, NP accumulation in diseased lungs was verified via LC/MS analysis and confocal imaging. Pulmonary arteriole thickness, right ventricular systolic pressures, and ventricular remodeling were determined to assess the therapeutic potential of RAP NPs. Monocrotaline-exposed rats showed increased NP accumulation within lungs compared to healthy controls, with NPs present to a high extent within pulmonary perivascular regions. RAP, in both free and NP form, attenuated PAH development, with histological analysis revealing minimal changes in pulmonary arteriole thickness and no ventricular remodeling. Importantly, NP-treated rats showed reduced systemic side effects compared to free RAP. This study demonstrates the potential for nanoparticles to significantly impact PAH through site-specific delivery of therapeutics.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Pulmão/efeitos dos fármacos , Nanopartículas/administração & dosagem , Sirolimo/farmacologia , Administração Intravenosa , Animais , Modelos Animais de Doenças , Pulmão/patologia , Ratos , Ratos Sprague-Dawley , Sirolimo/administração & dosagem
12.
Eur J Heart Fail ; 19(6): 739-747, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28296139

RESUMO

OBJECTIVE: Plasma concentrations of B-type natriuretic peptide (BNP) and troponin are often measured for diagnostic purposes when patients are admitted with heart failure, but their prognostic value when measured soon after admission is uncertain. We aimed to investigate the added prognostic value of admission measurements of BNP and troponins in patients with acute heart failure. METHODS AND RESULTS: Multivariable prognostic models for death or any worsening heart failure (WHF) or rehospitalization for WHF by 30 days, 30-day death or rehospitalization for WHF, and 90-day mortality were constructed using baseline data from the Value of Endothelin Receptor Inhibition with Tezosentan in Acute heart failure Studies (VERITAS) including BNP and troponin I. Of 1347 patients, the median (interquartile range) value of BNP was 422 (156-945) pg/mL and 855 (63%) had measurable troponin I. By 30 days, 432 patients had died or experienced WHF. Clinical variables had only moderate predictive performance that was not substantially improved by BNP or troponin I (c-indices 0.6528 and 0.6595, respectively). By 30 days, 150 patients died or were rehospitalized for WHF. The c-index using clinical variables (0.6855) was not improved by adding biomarkers. By 90 days, 135 patients had died. The c-index for mortality was somewhat better than for composite outcomes (0.7394) but improved little with biomarkers (0.7461). CONCLUSION: Routine clinical data recorded at the time of admission in patients with acute heart failure are poor at predicting recurrent admissions but somewhat better at predicting mortality. Neither BNP nor troponin measured at admission improved predictions; measurement closer to discharge, or of other novel biomarkers, might perform differently.


Assuntos
Insuficiência Cardíaca/sangue , Peptídeo Natriurético Encefálico/sangue , Admissão do Paciente , Piridinas/administração & dosagem , Receptores de Endotelina/efeitos dos fármacos , Tetrazóis/administração & dosagem , Troponina I/sangue , Doença Aguda , Idoso , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Mortalidade Hospitalar/tendências , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Alta do Paciente/tendências , Prognóstico , Receptores de Endotelina/sangue , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo , Estados Unidos/epidemiologia , Vasodilatadores/administração & dosagem
13.
Oxid Med Cell Longev ; 2017: 5750897, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28337252

RESUMO

Intracellular Ca2+ mishandling is an underlying mechanism in hypoxia/reoxygenation (H/R) injury that results in mitochondrial dysfunction and cardiomyocytes death. These events are mediated by mitochondrial Ca2+ (mCa2+) overload that is facilitated by the mitochondrial calcium uniporter (MCU) channel. Along this line, we evaluated the effect of siRNA-targeting MCU in cardiomyocytes subjected to H/R injury. First, cardiomyocytes treated with siRNA demonstrated a reduction of MCU expression by 67%, which resulted in significant decrease in mitochondrial Ca2+ transport. siRNA treated cardiomyocytes showed decreased mitochondrial permeability pore opening and oxidative stress trigger by Ca2+ overload. Furthermore, after H/R injury MCU silencing decreased necrosis and apoptosis levels by 30% and 50%, respectively, and resulted in reduction in caspases 3/7, 9, and 8 activity. Our findings are consistent with previous conclusions that demonstrate that MCU activity is partly responsible for cellular injury induced by H/R and support the concept of utilizing siRNA-targeting MCU as a potential therapeutic strategy.


Assuntos
Canais de Cálcio/metabolismo , Cálcio/metabolismo , RNA Interferente Pequeno/metabolismo , Animais , Apoptose , Canais de Cálcio/química , Canais de Cálcio/genética , Hipóxia Celular , Linhagem Celular , Sobrevivência Celular , Ciclosporina/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Interferência de RNA , RNA Mensageiro/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo
14.
Cardiovasc Ther ; 35(3)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28238219

RESUMO

AIM: To determine the prevalence of in-hospital nonsteroidal antiinflammatory drug (NSAID) exposure and associated outcomes in patients admitted with a primary diagnosis of heart failure. METHODS: We performed a propensity-matched cohort analysis of patients admitted to Houston Methodist Hospital System with a primary diagnosis of heart failure according to the International Classification of Diseases-9-Clinical Modification (ICD-9-CM) from January 1, 2011 to December 31, 2014. RESULTS: Of the 9742 patients admitted with a primary diagnosis of heart failure, 384 patients (3.9%) were exposed to NSAID. After applying propensity scores we matched 305 NSAID exposed with 915 unexposed patients. Patients with in-hospital NSAID exposure had a longer length of stay (7.0±8.8 days vs 6.1±8.5; P=.003) and increased prevalence of worsening renal function (34.4% vs 27.9%; P=.030). There were not statically significant differences in in-hospital mortality rate or 30-day all-cause readmission rate. CONCLUSION: Exposure to NSAID in patients admitted with a primary diagnosis of heart failure was low but was associated with adverse outcomes including longer length of stay and higher prevalence or worsening renal function.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Insuficiência Cardíaca/diagnóstico , Hospitalização , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/administração & dosagem , Distribuição de Qui-Quadrado , Esquema de Medicação , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Mortalidade Hospitalar , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Prognóstico , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Texas , Fatores de Tempo
15.
Am J Physiol Heart Circ Physiol ; 312(4): H645-H661, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28130337

RESUMO

Recent evidence has shown that nanoparticles that have been used to improve or create new functional properties for common products may pose potential risks to human health. Silicon dioxide (SiO2) has emerged as a promising therapy vector for the heart. However, its potential toxicity and mechanisms of damage remain poorly understood. This study provides the first exploration of SiO2-induced toxicity in cultured cardiomyocytes exposed to 7- or 670-nm SiO2 particles. We evaluated the mechanism of cell death in isolated adult cardiomyocytes exposed to 24-h incubation. The SiO2 cell membrane association and internalization were analyzed. SiO2 showed a dose-dependent cytotoxic effect with a half-maximal inhibitory concentration for the 7 nm (99.5 ± 12.4 µg/ml) and 670 nm (>1,500 µg/ml) particles, which indicates size-dependent toxicity. We evaluated cardiomyocyte shortening and intracellular Ca2+ handling, which showed impaired contractility and intracellular Ca2+ transient amplitude during ß-adrenergic stimulation in SiO2 treatment. The time to 50% Ca2+ decay increased 39%, and the Ca2+ spark frequency and amplitude decreased by 35 and 21%, respectively, which suggest a reduction in sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity. Moreover, SiO2 treatment depolarized the mitochondrial membrane potential and decreased ATP production by 55%. Notable glutathione depletion and H2O2 generation were also observed. These data indicate that SiO2 increases oxidative stress, which leads to mitochondrial dysfunction and low energy status; these underlie reduced SERCA activity, shortened Ca2+ release, and reduced cell shortening. This mechanism of SiO2 cardiotoxicity potentially plays an important role in the pathophysiology mechanism of heart failure, arrhythmias, and sudden death.NEW & NOTEWORTHY Silica particles are used as novel nanotechnology-based vehicles for diagnostics and therapeutics for the heart. However, their potential hazardous effects remain unknown. Here, the cardiotoxicity of silica nanoparticles in rat myocytes has been described for the first time, showing an impairment of mitochondrial function that interfered directly with Ca2+ handling.


Assuntos
Cálcio/metabolismo , Cardiotoxicidade/metabolismo , Metabolismo Energético/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Nanopartículas/toxicidade , Dióxido de Silício/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Membrana Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
16.
Eur J Heart Fail ; 18(2): 169-78, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26749465

RESUMO

AIMS: Ongoing inflammation and endothelial dysfunction occurs within the local microenvironment of heart failure, creating an appropriate scenario for successful use and delivery of nanovectors. This study sought to investigate whether cardiovascular cells associate, internalize, and traffic a nanoplatform called mesoporous silicon vector (MSV), and determine its intravenous accumulation in cardiac tissue in a murine model of heart failure. METHODS AND RESULTS: In vitro cellular uptake and intracellular trafficking of MSVs was examined by scanning electron microscopy, confocal microscopy, time-lapse microscopy, and flow cytometry in cardiac myocytes, fibroblasts, smooth muscle cells, and endothelial cells. The MSVs were internalized within the first hours, and trafficked to perinuclear regions in all the cell lines. Cytotoxicity was investigated by annexin V and cell cycle assays. No significant evidence of toxicity was found. In vivo intravenous cardiac accumulation of MSVs was examined by high content fluorescence and confocal microscopy, with results showing increased accumulation of particles in failing hearts compared with normal hearts. Similar to observations in vitro, MSVs were able to associate, internalize, and traffic to the perinuclear region of cardiomyocytes in vivo. CONCLUSIONS: Results show that MSVs associate, internalize, and traffic in cardiovascular cells without any significant toxicity. Furthermore, MSVs accumulate in failing myocardium after intravenous administration, reaching intracellular regions of the cardiomyocytes. These findings represent a novel avenue to develop nanotechnology-based therapeutics and diagnostics in heart failure.


Assuntos
Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Coração/fisiologia , Coração/fisiopatologia , Miócitos Cardíacos/fisiologia , Nanoestruturas/uso terapêutico , Animais , Materiais Biocompatíveis , Modelos Animais de Doenças , Insuficiência Cardíaca/fisiopatologia , Humanos , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio , Polímeros , Silício
17.
J Am Heart Assoc ; 5(1)2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26769625

RESUMO

BACKGROUND: Limited information exists on the role of B-cell-dependent mechanisms in the progression of heart failure (HF). However, in failing human myocardium, there is evidence of deposition of activated complement components as well as anticardiac antibodies. We aimed to determine the contribution of B-cells in HF progression using a nonsurgical mouse model of nonischemic cardiomyopathy (CMP). METHODS AND RESULTS: CMP protocol involved the use of l-NAME and NaCl in the drinking water and angiotensin-II infusion for 35 days. At day 35, mice were analyzed by cardiac magnetic resonance imaging, gene expression, and histology. Mice (12 weeks old) were divided into 4 groups, all in C57BL/6 background: wild-type (WT) CMP; severe combined immunodeficiency (SCID) CMP (T- and B-cell deficient); CD22(-) CMP (B-cell depleted); and Nude CMP (T-cell deficient), with their respective controls. We performed B-cell depletion and reconstitution protocols. The protective effect of B-cell depletion was demonstrated by a significant reduction of cell hypertrophy and collagen deposition and a preserved ejection fraction in the CD22(-) CMP group compared to WT CMP. Once SCID mice underwent B-cell reconstitution with isolated CMP B-cells, the CMP phenotype was restored. Furthermore, deposition of IgG3 and apoptosis in the myocardium follows the development of CMP; in addition, in vitro studies demonstrated that activated B-cells stimulate collagen production by cardiac fibroblasts. CONCLUSIONS: The absence of B-cells in this model of HF resulted in less hypertrophy and collagen deposition, preservation of left ventricular function, and, in association with these changes, a reduction in expression of proinflammatory cytokines, immunoglobulin G deposition, and apoptosis in the myocardium. Taken together, these data suggest that B-cells play a contributory role in an angiotensin-II-induced HF model.


Assuntos
Apoptose , Linfócitos B/metabolismo , Cardiomiopatias/metabolismo , Citocinas/metabolismo , Insuficiência Cardíaca/metabolismo , Imunoglobulina G/metabolismo , Miocárdio/metabolismo , Angiotensina II , Animais , Linfócitos B/imunologia , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/genética , Cardiomiopatias/imunologia , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Colágeno/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Predisposição Genética para Doença , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/imunologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Imunoglobulina G/imunologia , Imagem por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Camundongos SCID , Miocárdio/imunologia , Miocárdio/patologia , NG-Nitroarginina Metil Éster , Fenótipo , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/deficiência , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Transdução de Sinais , Cloreto de Sódio , Volume Sistólico , Fatores de Tempo , Disfunção Ventricular Esquerda/imunologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda , Remodelação Ventricular
18.
Am J Physiol Heart Circ Physiol ; 310(6): H667-80, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26747502

RESUMO

Mitochondrial dysfunction has been implicated as a cause of energy deprivation in heart failure (HF). Herein, we tested individual and combined effects of two pathogenic factors of nonischemic HF, inhibition of nitric oxide synthesis [with l-N(G)-nitroarginine methyl ester (l-NAME)] and hypertension [with angiotensin II (AngII)], on myocardial mitochondrial function, oxidative stress, and metabolic gene expression. l-NAME and AngII were administered individually and in combination to mice for 5 wk. Although all treatments increased blood pressure and reduced cardiac contractile function, the l-NAME + AngII group was associated with the most severe HF, as characterized by edema, hypertrophy, oxidative stress, increased expression of Nppa and Nppb, and decreased expression of Atp2a2 and Camk2b. l-NAME + AngII-treated mice exhibited robust deterioration of cardiac mitochondrial function, as observed by reduced respiratory control ratios in subsarcolemmal mitochondria and reduced state 3 levels in interfibrillar mitochondria for complex I but not for complex II substrates. Cardiac myofibrils showed reduced ADP-supported and oligomycin-inhibited oxygen consumption. Mitochondrial functional impairment was accompanied by reduced mitochondrial DNA content and activities of pyruvate dehydrogenase and complex I but increased H2O2 production and tissue protein carbonyls in hearts from AngII and l-NAME + AngII groups. Microarray analyses revealed the majority of the gene changes attributed to the l-NAME + AngII group. Pathway analyses indicated significant changes in metabolic pathways, such as oxidative phosphorylation, mitochondrial function, cardiac hypertrophy, and fatty acid metabolism in l-NAME + AngII hearts. We conclude that l-NAME + AngII is associated with impaired mitochondrial respiratory function and increased oxidative stress compared with either l-NAME or AngII alone, resulting in nonischemic HF.


Assuntos
Angiotensina II/farmacologia , Inibidores Enzimáticos/farmacologia , Insuficiência Cardíaca/etiologia , Mitocôndrias Cardíacas/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Cardiomegalia , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/metabolismo , Complexo I de Transporte de Elétrons/efeitos dos fármacos , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/efeitos dos fármacos , Complexo II de Transporte de Elétrons/metabolismo , Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Camundongos , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Peptídeo Natriurético Encefálico/efeitos dos fármacos , Peptídeo Natriurético Encefálico/genética , Peptídeo Natriurético Tipo C/efeitos dos fármacos , Peptídeo Natriurético Tipo C/genética , Precursores de Proteínas/efeitos dos fármacos , Precursores de Proteínas/genética , Complexo Piruvato Desidrogenase/efeitos dos fármacos , Complexo Piruvato Desidrogenase/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/efeitos dos fármacos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética
19.
J Card Fail ; 22(7): 501-11, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26762651

RESUMO

BACKGROUND: Thrombotic events in patients with continuous flow left ventricular assist devices (CF-LVADs) are associated with significant morbidity and mortality. The objective of this study was to delineate the frequency, clinical characteristics, and outcomes of patients with hypercoagulable states who undergo CF-LVAD implantation. METHODS: We performed a retrospective review of 168 consecutive patients who underwent CF-LVAD implantation between 2010 and 2013. Chart and laboratory data were reviewed for the presence of a hereditary and/or acquired hypercoagulable state. Adverse outcomes were defined as death, confirmed pump thrombosis, aortic root clot, stroke, deep vein thrombosis, and pulmonary embolism. Fisher's exact test and Kaplan-Meier estimate were used to analyze frequency of adverse outcomes and event free survival, respectively. RESULTS: A hypercoagulable state was identified in 20 patients (11.9%). There were 18 patients with acquired, 1 with a congenital, and 1 with both congenital and acquired hypercoagulable states. The median follow-up was 429 days and 475 days in patients with and without hypercoagulable states, respectively. During the study period, 15% (3/20) of the patients with a hypercoagulable state had a diagnosis of deep vein thrombosis vs 3% (4/148) of the patients without a hypercoagulable state (P = .030). Only patients with a hypercoagulable state had a subarachnoid hemorrhage (3/20 vs 0/148; P < .01). The event-free survival was lower in the patients with hypercoagulable states (P = .005). CONCLUSION: Hypercoagulable states are not uncommon in patients with CF-LVADs and may be associated with increased morbidity. Prospective studies are needed to more accurately identify the incidence, prevalence, and significance of hypercoagulable states in patients being considered for CF-LVAD.


Assuntos
Insuficiência Cardíaca/cirurgia , Coração Auxiliar/efeitos adversos , Trombofilia/etiologia , Trombose/etiologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Trombofilia/congênito , Trombofilia/diagnóstico
20.
Hypertension ; 67(3): 597-605, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26781283

RESUMO

The insufficiency of compensatory angiogenesis in the heart of patients with hypertension contributes to heart failure transition. The hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling cascade controls responsive angiogenesis. One of the challenges in reprograming the insufficient angiogenesis is to achieve a sustainable tissue exposure to the proangiogenic factors, such as HIF1α stabilization. In this study, we identified Rnd3, a small Rho GTPase, as a proangiogenic factor participating in the regulation of the HIF1α-VEGF signaling cascade. Rnd3 physically interacted with and stabilized HIF1α, and consequently promoted VEGFA expression and endothelial cell tube formation. To demonstrate this proangiogenic role of Rnd3 in vivo, we generated Rnd3 knockout mice. Rnd3 haploinsufficient (Rnd3(+/-)) mice were viable, yet developed dilated cardiomyopathy with heart failure after transverse aortic constriction stress. The poststress Rnd3(+/-) hearts showed significantly impaired angiogenesis and decreased HIF1α and VEGFA expression. The angiogenesis defect and heart failure phenotype were partially rescued by cobalt chloride treatment, a HIF1α stabilizer, confirming a critical role of Rnd3 in stress-responsive angiogenesis. Furthermore, we generated Rnd3 transgenic mice and demonstrated that Rnd3 overexpression in heart had a cardioprotective effect through reserved cardiac function and preserved responsive angiogenesis after pressure overload. Finally, we assessed the expression levels of Rnd3 in the human heart and detected significant downregulation of Rnd3 in patients with end-stage heart failure. We concluded that Rnd3 acted as a novel proangiogenic factor involved in cardiac responsive angiogenesis through HIF1α-VEGFA signaling promotion. Rnd3 downregulation observed in patients with heart failure may explain the insufficient compensatory angiogenesis involved in the transition to heart failure.


Assuntos
Vasos Coronários/patologia , Regulação da Expressão Gênica , Hipertensão/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neovascularização Patológica/genética , Fator A de Crescimento do Endotélio Vascular/genética , Proteínas rho de Ligação ao GTP/genética , Animais , Western Blotting , Vasos Coronários/metabolismo , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Humanos , Hipertensão/metabolismo , Hipertensão/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neovascularização Patológica/metabolismo , RNA/genética , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/biossíntese , Proteínas rho de Ligação ao GTP/biossíntese
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