RESUMO
Low levels of the molecular inotrope S100A1 are sufficient to rescue post-ischemic heart failure (HF). As a prerequisite to clinical application and to determine the safety of myocardial S100A1 DNA-based therapy, we investigated the effects of high myocardial S100A1 expression levels on the cardiac contractile function and occurrence of arrhythmia in a preclinical large animal HF model. At 2 weeks after myocardial infarction domestic pigs presented significant left ventricular (LV) contractile dysfunction. Retrograde application of AAV6-S100A1 (1.5 × 10(13) tvp) via the anterior cardiac vein (ACV) resulted in high-level myocardial S100A1 protein peak expression of up to 95-fold above control. At 14 weeks, pigs with high-level myocardial S100A1 protein overexpression did not show abnormalities in the electrocardiogram. Electrophysiological right ventricular stimulation ruled out an increased susceptibility to monomorphic ventricular arrhythmia. High-level S100A1 protein overexpression in the LV myocardium resulted in a significant increase in LV ejection fraction (LVEF), albeit to a lesser extent than previously reported with low S100A1 protein overexpression. Cardiac remodeling was, however, equally reversed. High myocardial S100A1 protein overexpression neither increases the occurrence of cardiac arrhythmia nor causes detrimental effects on myocardial contractile function in vivo. In contrast, this study demonstrates a broad therapeutic range of S100A1 gene therapy in post-ischemic HF using a preclinical large animal model.
Assuntos
Arritmias Cardíacas/terapia , Terapia Genética/efeitos adversos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/efeitos adversos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/terapia , Infarto do Miocárdio/complicações , Isquemia Miocárdica/complicações , Miocárdio/metabolismo , Proteínas S100/uso terapêutico , Animais , Dependovirus/genética , Modelos Animais de Doenças , Insuficiência Cardíaca/fisiopatologia , Humanos , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Isquemia Miocárdica/fisiopatologia , Isquemia Miocárdica/terapia , Miocárdio/patologia , Proteínas S100/genética , Proteínas S100/metabolismo , Volume Sistólico/fisiologia , SuínosRESUMO
Two types of electrocardiographic data series were investigated using appropriate tests based on a selection of semi-quantitative analysis algorithms. Distribution histograms, power spectra, auto-correlation functions, state-space portraits, Lyapunov exponents and wavelet transformations were applied to electrocardiograms of normal and stressed subjects. Statistical analysis using the Student's t-test revealed significant and non-significant alterations in stress-loaded cases compared to normal ones. Higher levels of adrenaline may account for a more complex dynamics (deterministic chaos) revealed in the stressed subjects.
Assuntos
Eletrocardiografia/métodos , Processamento de Sinais Assistido por Computador , Algoritmos , Epinefrina/metabolismo , Fractais , Coração/fisiologia , Humanos , Modelos Estatísticos , Miocárdio/patologia , Dinâmica não LinearRESUMO
In the rats, mechanical lesion or isolation of the PVH either alone or together with the medial hypothalamic sympathetic area, which includes hypophyseotropic area, too, induces a long lasting decrease of the total number of leukocytes and of the most components of the leukocytary formula, which are attributed mainly to the decreased sympathetic tonus, induced by medial hypothalamus disconnection.
Assuntos
Hipotálamo Médio/fisiologia , Imunidade/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Animais , Denervação , Contagem de Leucócitos , Leucopenia/etiologia , Leucopenia/patologia , Masculino , Ratos , Ratos Wistar , Sistema Nervoso Simpático/fisiologiaRESUMO
Substances ASFA-2 and ASFA-4, new derivatives of phenoxyacetic acid, induce, in normal conditions, the hyperpolarization of the striated muscle fibre membrane, inhibition the depolarization due to the absence of external Ca2+, the restoration of membrane potential of the liver cells poisoned with ally alcohol and the change of redox potential of the environment. It results that these substances have important pharmacological properties--influence upon the membrane potential and cellular excitability, membrane stabilization, redox modulation and hepatic protection--that can be useful in therapy.