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1.
Circ J ; 84(2): 226-234, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31875585

RESUMO

BACKGROUND: Left ventricular non-compaction (LVNC) is a cardiomyopathy characterized by prominent trabeculae and intertrabecular recesses. We present the cases of 3 girls with the sameryanodine receptor type 2(RYR2) mutation who had phenotypes of both catecholaminergic polymorphic ventricular tachycardia (CPVT) and LVNC .Methods and Results:Clinical characteristics and genetic background of the 3 patients were analyzed retrospectively. Age at onset was 5, 6, and 7 years, respectively. Clinical presentation included syncope during exercise in all 3 patients and cardiac arrest in 2 patients. LVNC diagnosis was confirmed on echocardiography according to previously defined criteria. Exercise stress testing provoked ventricular arrhythmia in two of the patients. Beta-blockers (n=3) and flecainide (n=2) were given, and an implantable cardioverter defibrillator was used in 1 patient. Genotyping identified the sameRYR2-R169Q missense mutation and no other CPVT- or LVNC-related gene mutations. Functional analysis of the mutation using HEK293 cells with single-cell Ca2+imaging and [3H]ryanodine binding analysis, indicated a gain of function: a reduced threshold for overload-induced Ca2+release from the sarcoplasmic reticulum and increased fractional Ca2+release. CONCLUSIONS: The rare association of LVNC and CPVT phenotypes withRYR2mutations is less likely to be coincidental. Screening for life-threatening arrhythmias using exercise or pharmacologic stress tests is recommended in LVNC patients to prevent sudden cardiac death in those with preserved LV function.


Assuntos
Miocárdio Ventricular não Compactado Isolado/genética , Mutação de Sentido Incorreto , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Taquicardia Ventricular/genética , Antagonistas Adrenérgicos beta/uso terapêutico , Antiarrítmicos/uso terapêutico , Sinalização do Cálcio , Criança , Pré-Escolar , Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis , Cardioversão Elétrica/instrumentação , Feminino , Flecainida/uso terapêutico , Predisposição Genética para Doença , Células HEK293 , Hereditariedade , Humanos , Miocárdio Ventricular não Compactado Isolado/diagnóstico por imagem , Miocárdio Ventricular não Compactado Isolado/metabolismo , Miocárdio Ventricular não Compactado Isolado/terapia , Linhagem , Fenótipo , Estudos Retrospectivos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/terapia
2.
Toxicol Lett ; 318: 57-64, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31585160

RESUMO

3-Bromopyruvate (3-BrPA) is a promising agent that has been widely studied in the treatment of cancer and pulmonary hypertension. Rotenone is a pesticide commonly used on farms and was shown to have anti-cancer activity and delay fibrosis progression in chronic kidney disease in a recent study. However, there are few studies showing the toxicity of rotenone and 3-BrPA in the myocardium. To support further medical exploration, it is necessary to clarify the side effects of these compounds on the heart. This study was designed to examine the cardiotoxicity of 3-BrPA and rotenone by investigating electrical and structural cardiac remodeling in rats. Forty male rats were divided into 4 groups (n = 10 in each group) and injected intraperitoneally with 3-BrPA, rotenone or a combination of 3-BrPA and rotenone. The ventricular effective refractory period (VERP), corrected QT interval (QTc), and ventricular tachycardia/ventricular fibrillation (VT/VF) inducibility were measured. The expression of Cx43, Kir2.1, Kir6.2, DHPRα1, KCNH2, caspase3, caspase9, Bax, Bcl2, and P53 was detected. Masson's trichrome, TUNEL, HE, and PAS staining and transmission electron microscopy were used to detect pathological and ultrastructural changes. Our results showed that rotenone alone and rotenone combined with 3-BrPA significantly increased the risk of ventricular arrhythmias. Rotenone combined with 3-BrPA caused myocardial apoptosis, and rotenone alone and rotenone combined with 3-BrPA caused electrical and structural cardiac remodeling in rats.


Assuntos
Antineoplásicos/toxicidade , Ventrículos do Coração/efeitos dos fármacos , Inseticidas/toxicidade , Piruvatos/toxicidade , Rotenona/toxicidade , Taquicardia Ventricular/induzido quimicamente , Fibrilação Ventricular/induzido quimicamente , Remodelação Ventricular/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Cardiotoxicidade , Conexina 43/genética , Conexina 43/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/ultraestrutura , Masculino , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Ratos Wistar , Período Refratário Eletrofisiológico/efeitos dos fármacos , Medição de Risco , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/patologia , Taquicardia Ventricular/fisiopatologia , Fibrilação Ventricular/metabolismo , Fibrilação Ventricular/patologia , Fibrilação Ventricular/fisiopatologia
3.
Life Sci ; 239: 117075, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31751587

RESUMO

AIMS: Arrhythmogenesis of chronic myocardial infarction (MI) is associated with the prolongation of action potential, reduction of inward rectifier potassium (IK1, Kir) channels and hyper-activity of Calcium/calmodulin-dependent kinase II (CaMKII) in cardiomyocytes. Zacopride, a selective IK1 agonist, was applied to clarify the cardioprotection of IK1 agonism via a CaMKII signaling on arrhythmias post-MI. METHODS: Male SD rats were implanted wireless transmitter in the abdominal cavity and subjected to left main coronary artery ligation or sham operation. The telemetric ECGs were monitored per day throughout 4 weeks. At the endpoint, isoproterenol (1.28 mg/kg, i.v.) was administered for provocation test. The expressions of Kir2.1 (dominant subunit of IK1 in ventricle) and CaMKII were detected by Western-blotting. KEY FINDINGS: In the telemetric rats post-MI, zacopride significantly reduced the episodes of atrioventricular conduction block (AVB), premature ventricular contraction (PVC), ventricular tachycardia (VT) and ventricular fibrillation (VF), without significant effect on superventricular premature contraction (SPVC). In provocation test, zacopride suppressed the onset of ventricular arrhythmias in conscious PMI or sham rats. The expression of Kir2.1 was significantly downregulated and p-CaMKII was upregulated post-MI, whereas both were restored by zacopride treatment. SIGNIFICANCE: IK1/Kir2.1 might be an attractive target for pharmacological controlling of lethal arrhythmias post MI.


Assuntos
Benzamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Infarto do Miocárdio/fisiopatologia , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Potenciais de Ação , Animais , Arritmias Cardíacas/tratamento farmacológico , Benzamidas/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Eletrocardiografia/métodos , Ventrículos do Coração/metabolismo , Isoproterenol/farmacologia , Masculino , Miócitos Cardíacos/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Ratos , Ratos Sprague-Dawley , Taquicardia Ventricular/metabolismo
4.
Life Sci ; 239: 117062, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31734261

RESUMO

AIMS: Endothelin has been implicated in various processes in the brain, including the modulation of sympathetic responses. The present study examined the pathophysiologic role of brain endothelin-receptors in the setting of acute myocardial infarction, characterized by high incidence of ventricular tachyarrhythmias. MAIN METHODS: We investigated the effects of intracerebroventricular administration of antagonists of endothelin-receptors ETA, ETB, or both, during a 24 h-observation period post-coronary ligation in (n = 70) rats. Continuous recording was performed via implanted telemetry transmitters, followed by arrhythmia-analysis and calculation of autonomic indices derived from heart rate variability. The regional myocardial electrophysiologic properties were assessed by monophasic action potentials and multi-electrode recordings. KEY FINDINGS: Sympathetic-activity was decreased and vagal-activity was enhanced after intracerebroventricular ETA-receptor blockade, thus attenuating regional myocardial repolarization inhomogeneity. As a result, the incidence of ventricular tachyarrhythmias was markedly lower in this group. Such effects were also observed after intracerebroventricular blockade of ETB-, or both, ETA- and ETB-receptors, although to a lesser extent. SIGNIFICANCE: ETA-receptors in the brain modulate sympathetic and vagal responses and alter arrhythmogenesis during evolving myocardial necrosis in rats. These findings provide insights into arrhythmogenic mechanisms during acute myocardial infarction and call for further investigation on the role of endothelin in the central autonomic network.


Assuntos
Endotelinas/farmacologia , Infarto do Miocárdio/fisiopatologia , Receptores de Endotelina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Arritmias Cardíacas/complicações , Arritmias Cardíacas/metabolismo , Sistema Nervoso Autônomo/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiologia , Antagonistas dos Receptores de Endotelina/metabolismo , Antagonistas dos Receptores de Endotelina/farmacologia , Endotelina-1/farmacologia , Endotelinas/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Wistar , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Receptores de Endotelina/fisiologia , Sistema Nervoso Simpático/efeitos dos fármacos , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia
5.
Physiol Res ; 68(5): 867-871, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31424250

RESUMO

Endothelin alters central sympathetic responses, but the resultant effects on arrhythmogenesis are unknown. We examined ventricular tachyarrhythmias after endothelin receptor-A blockade in the brain of Wistar rats with acute myocardial infarction. For this aim, BQ-123 (n=6) or phosphate-buffered saline (n=6) were injected intracerebroventricularly. After 10 min, the left coronary artery was ligated, followed by implantation of telemetry transmitters. Electrocardiography and voluntary activity (as a surrogate of acute left ventricular failure) were continuously monitored for 24 h. Infarct-size was similar in the two groups. There were fewer episodes of ventricular tachyarrhythmias of shorter average duration in treated rats, leading to markedly shorter total duration (12.3+/-8.9 s), when compared to controls (546.2+/-130.3 s). Voluntary activity increased in treated rats during the last hours of recording, but bradyarrhythmic episodes were comparable between the two groups. Endothelin receptor-A blockade in the brain of rats decreases the incidence of ventricular tachyarrhythmias post-ligation, without affecting bradyarrhythmic episodes. These findings call for further research on the pathophysiologic role of endothelin during acute myocardial infarction.


Assuntos
Ventrículos Cerebrais/efeitos dos fármacos , Antagonistas do Receptor de Endotelina A/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Peptídeos Cíclicos/administração & dosagem , Receptor de Endotelina A/efeitos dos fármacos , Taquicardia Ventricular/prevenção & controle , Complexos Ventriculares Prematuros/prevenção & controle , Animais , Ventrículos Cerebrais/metabolismo , Ventrículos Cerebrais/fisiopatologia , Modelos Animais de Doenças , Injeções Intraventriculares , Infarto do Miocárdio/complicações , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Ratos Wistar , Receptor de Endotelina A/metabolismo , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia , Complexos Ventriculares Prematuros/etiologia , Complexos Ventriculares Prematuros/metabolismo , Complexos Ventriculares Prematuros/fisiopatologia
6.
PLoS One ; 14(5): e0216928, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31083689

RESUMO

BACKGROUND: Heart failure (HF) is a leading cause of mortality and is associated with cardiac remodeling. Vulnerability to atrial fibrillation (AF) has been shown to be greater in the early stages of HF, whereas ventricular tachycardia/fibrillation develop during late stages. Here, we explore changes in gene expression that underlie the differential development of fibrosis and structural alterations that predispose to atrial and ventricular arrhythmias. OBJECTIVE: To study transcriptomic changes associated with the development of cardiac arrhythmias in early and late stages of heart failure. METHODS: Dogs were tachy-paced from right ventricle (RV) for 2-3 or 5-6 weeks (early and late HF). We performed transcriptomic analysis of right atria (RA) and RV isolated from control dogs and those in early and late HF. Transcripts with mean relative log2-fold change ≥2 were included in the differential analysis with significance threshold adjusted to p<0.05. RESULTS: Early HF remodeling was more prominent in RA with enrichment of extracellular matrix, circulatory system, wound healing and immune response pathways; many of these processes were not present in RA in late HF. RV showed no signs of remodeling in early HF but enrichment of extracellular matrix and wound healing in late HF. CONCLUSION: Our transcriptomic data indicate significant fibrosis-associated transcriptional changes in RA in early HF and in RV in late HF, with strong atrial predominance. These alterations in gene expression are consistent with the development of arrhythmogenesis in atria in early but not late HF and in the ventricle in late but not early HF.


Assuntos
Fibrilação Atrial/genética , Proteínas da Matriz Extracelular/genética , Insuficiência Cardíaca/genética , Marca-Passo Artificial/veterinária , Taquicardia Ventricular/genética , Transcriptoma , Animais , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Cães , Ecocardiografia , Proteínas da Matriz Extracelular/metabolismo , Fibrose , Perfilação da Expressão Gênica , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Hemodinâmica/genética , Imunidade Inata/genética , Análise em Microsséries , Taquicardia Ventricular/diagnóstico por imagem , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo , Cicatrização/genética
7.
Circ Arrhythm Electrophysiol ; 12(4): e007045, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30943765

RESUMO

BACKGROUND: Circulating SN (secretoneurin) concentrations are increased in patients with myocardial dysfunction and predict poor outcome. Because SN inhibits CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) activity, we hypothesized that upregulation of SN in patients protects against cardiomyocyte mechanisms of arrhythmia. METHODS: Circulating levels of SN and other biomarkers were assessed in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT; n=8) and in resuscitated patients after ventricular arrhythmia-induced cardiac arrest (n=155). In vivo effects of SN were investigated in CPVT mice (RyR2 [ryanodine receptor 2]-R2474S) using adeno-associated virus-9-induced overexpression. Interactions between SN and CaMKIIδ were mapped using pull-down experiments, mutagenesis, ELISA, and structural homology modeling. Ex vivo actions were tested in Langendorff hearts and effects on Ca2+ homeostasis examined by fluorescence (fluo-4) and patch-clamp recordings in isolated cardiomyocytes. RESULTS: SN levels were elevated in patients with CPVT and following ventricular arrhythmia-induced cardiac arrest. In contrast to NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity troponin T), circulating SN levels declined after resuscitation, as the risk of a new arrhythmia waned. Myocardial pro-SN expression was also increased in CPVT mice, and further adeno-associated virus-9-induced overexpression of SN attenuated arrhythmic induction during stress testing with isoproterenol. Mechanistic studies mapped SN binding to the substrate binding site in the catalytic region of CaMKIIδ. Accordingly, SN attenuated isoproterenol induced autophosphorylation of Thr287-CaMKIIδ in Langendorff hearts and inhibited CaMKIIδ-dependent RyR phosphorylation. In line with CaMKIIδ and RyR inhibition, SN treatment decreased Ca2+ spark frequency and dimensions in cardiomyocytes during isoproterenol challenge, and reduced the incidence of Ca2+ waves, delayed afterdepolarizations, and spontaneous action potentials. SN treatment also lowered the incidence of early afterdepolarizations during isoproterenol; an effect paralleled by reduced magnitude of L-type Ca2+ current. CONCLUSIONS: SN production is upregulated in conditions with cardiomyocyte Ca2+ dysregulation and offers compensatory protection against cardiomyocyte mechanisms of arrhythmia, which may underlie its putative use as a biomarker in at-risk patients.


Assuntos
Parada Cardíaca/metabolismo , Neuropeptídeos/metabolismo , Secretogranina II/metabolismo , Taquicardia Ventricular/metabolismo , Animais , Biomarcadores/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Parada Cardíaca/fisiopatologia , Humanos , Camundongos , Miócitos Cardíacos/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Técnicas de Patch-Clamp , Fragmentos de Peptídeos/metabolismo , Fosforilação , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Taquicardia Ventricular/fisiopatologia , Troponina T/metabolismo , Regulação para Cima
8.
Mol Genet Genomics ; 294(4): 1059-1071, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31020414

RESUMO

Ventricular tachycardia (VT) causes sudden cardiac death, however, the majority of risk genes for VT remain unknown. SCN4B encodes a ß-subunit, Navß4, for the voltage-gated cardiac sodium channel complex involved in generation and conduction of the cardiac action potential. We hypothesized that genomic variants in SCN4B increase the risk of VT. We used high-resolution melt analysis followed by Sanger sequencing to screen 199 VT patients to identify nonsynonymous variants in SCN4B. Two nonsynonymous heterozygous variants in SCN4B were identified in VT patients, including p.Gly8Ser in four VT patients and p.Ala145Ser in one VT patient. Case-control association studies were used to assess the association between variant p.Gly8Ser and VT in two independent populations for VT (299 VT cases vs. 981 controls in population 1 and 270 VT patients vs. 639 controls in population 2). Significant association was identified between p.Gly8Ser and VT in population 1 (P = 1.21 × 10-4, odds ratio or OR = 11.04), and the finding was confirmed in population 2 (P = 0.03, OR = 3.62). The association remained highly significant in the combined population (P = 3.09 × 10-5, OR = 6.17). Significant association was also identified between p.Gly8Ser and idiopathic VT (P = 1.89 × 10-5, OR = 7.27). Functional analysis with Western blotting showed that both p.Gly8Ser and p.Ala145Ser variants significantly reduced the expression level of Navß4. Based on 2015 ACMG Standards and Guidelines, p.Gly8Ser and p.Ala145Ser can be classified as the pathogenic and likely pathogenic variant, respectively. Our data suggest that SCN4B is a susceptibility gene for common VT and idiopathic VT and link rare SCN4B variants with large effects (OR = 6.17-7.27) to common VT.


Assuntos
Substituição de Aminoácidos , Análise de Sequência de DNA/métodos , Taquicardia Ventricular/genética , Subunidade beta-4 do Canal de Sódio Disparado por Voltagem/genética , Adulto , Idoso , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Taquicardia Ventricular/metabolismo , Subunidade beta-4 do Canal de Sódio Disparado por Voltagem/metabolismo
9.
PLoS One ; 14(2): e0208301, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30763348

RESUMO

BACKGROUND: Clinical and experimental data give evidence that transplantation of stem and progenitor cells in myocardial infarction could be beneficial, although the underlying mechanism has remained elusive. Ventricular tachyarrhythmia is the most frequent and potentially lethal complication of myocardial infarction, but the impact of mono nuclear cells on the incidence of ventricular arrhythmia is still not clear. OBJECTIVE: We aimed to characterize the influence of splenic mononuclear cell populations on ventricular arrhythmia after myocardial infarction. METHODS: We assessed electrical vulnerability in vivo in mice with left ventricular cryoinfarction 14 days after injury and intramyocardial injection of specific subpopulations of mononuclear cells (MNCs) (CD11b-positive cells, Sca-1-positive cells, early endothelial progenitor cells (eEPCs)). As positive control group we used embryonic cardiomyocytes (eCMs). Epicardial mapping was performed for analysing conduction velocities in the border zone. Left ventricular function was quantified by echocardiography and left heart catheterization. RESULTS: In vivo pacing protocols induced ventricular tachycardia (VT) in 30% of non-infarcted mice. In contrast, monomorphic or polymorphic VT could be evoked in 94% of infarcted and vehicle-injected mice (p<0.01). Only transplantation of eCMs prevented post-infarction VT and improved conduction velocities in the border zone in accordance to increased expression of connexin 43. Cryoinfarction resulted in a broad aggravation of left ventricular function. All transplanted cell types augmented left ventricular function to a similar extent. CONCLUSIONS: Transplantation of different MNC populations after myocardial infarction improves left ventricular function similar to effects of eCMs. Prevention of inducible ventricular arrhythmia is only seen after transplantation of eCMs.


Assuntos
Arritmias Cardíacas/terapia , Infarto/terapia , Leucócitos Mononucleares/fisiologia , Infarto do Miocárdio/terapia , Animais , Arritmias Cardíacas/metabolismo , Antígeno CD11b/metabolismo , Conexina 43/metabolismo , Células Progenitoras Endoteliais/metabolismo , Mapeamento Epicárdico/métodos , Infarto/metabolismo , Leucócitos Mononucleares/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/terapia , Função Ventricular Esquerda/fisiologia
10.
Int J Cardiol ; 279: 64-71, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30642646

RESUMO

BACKGROUND: It is reported interleukin (IL)-17A, a classical proinflammatory cytokine, is implicated in neuroimmune-associated remodeling in neural plasticity and pathological conditions. However, the effect of IL-17A on left stellate ganglion (LSG) remodeling remains unclear. OBJECTIVE: This study was performed to determine whether exogenous IL-17A promotes LSG remodeling and destabilize ventricular electrophysiological properties (EPs) in normal canines. METHODS: 24 beagles were randomly allocated into three groups. In the first group, animals were subjected to 0.1 ml phosphate buffer saline (PBS) microinjection of into LSG (n = 8), an equivalent IL-17A was administrated in the second group (n = 8), and an equivalent anti-IL-17A mAb plus IL-17A was administrated in the third group (n = 8). The ventricular EPs, neural function and activity of the LSG were determined at baseline and 30 min after administration. In the end, LSG tissues were collected. RESULTS: Compared with the control group, the experimental group had a significantly shorter effective refractory period (ERP) and action potential duration (APD)90, an increased ERP, APD90, Smax dispersion, and APD alternans cycle length; and steepened APD restitution curves. In addition, IL-17A enhanced the neural function and activity of the LSG, upregulated the expressions of neuropeptides and proinflammatory cytokines and cells. And all these effects were attenuated by anti-IL-17A mAb. Importantly, IL-17 receptor A (IL-17R-A) was detected in sympathetic neurons in the LSG. CONCLUSION: IL-17A promoted LSG remodeling by regulating the neural inflammation response. It did so by binding to IL-17R-A, resulting in unstable ventricular electrophysiology in normal structural hearts.


Assuntos
Interleucina-17/administração & dosagem , Neuroimunomodulação/efeitos dos fármacos , Gânglio Estrelado/efeitos dos fármacos , Remodelação Vascular/efeitos dos fármacos , Animais , Cães , Interleucina-17/metabolismo , Microinjeções/métodos , Neuroimunomodulação/fisiologia , Gânglio Estrelado/imunologia , Gânglio Estrelado/metabolismo , Taquicardia Ventricular/tratamento farmacológico , Taquicardia Ventricular/imunologia , Taquicardia Ventricular/metabolismo , Remodelação Vascular/fisiologia
13.
Cardiovasc Toxicol ; 19(2): 129-135, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30238354

RESUMO

Ivabradine has recently been demonstrated to have antiarrhythmic properties in atrial fibrillation. The aim of the present study was to assess the electrophysiologic profile of ivabradine in an experimental whole-heart model of long-QT-syndrome. In 12 isolated rabbit hearts long-QT-2-syndrome (LQT2) was simulated by infusion of D,L-sotalol (100 µM). 12 rabbit hearts were treated with veratridine (0.5 µM) to mimic long-QT-3-syndrome (LQT3). Sotalol induced a significant prolongation of QT-interval (+ 40 ms, p < 0.01) and action potential duration (APD, + 20 ms, p < 0.01). Similar results were obtained in veratridine-treated hearts (QT-interval: +52 ms, p < 0.01; APD: + 41 ms, p < 0.01). Of note, both sotalol (+ 26 ms, p < 0.01) and veratridine (+ 42 ms, p < 0.01) significantly increased spatial dispersion of repolarisation. Additional infusion of ivabradine (5 µM) did not change these parameters in sotalol-pretreated hearts but resulted in a further significant increase of QT-interval (+ 26 ms, p < 0.05) and APD (+ 49 ms, p < 0.05) in veratridine-treated hearts. Lowering of potassium concentration in bradycardic AV-blocked hearts resulted in the occurrence of early afterdepolarizations (EAD) or polymorphic ventricular tachycardias (VT) resembling torsade de pointes in 6 of 12 sotalol-treated hearts (56 episodes) and 6 of 12 veratridine-treated hearts (73 episodes). Additional infusion of ivabradine increased occurrence of polymorphic VT. Ivabradine treatment resulted in occurrence of EAD and polymorphic VT in 9 of 12 sotalol-treated hearts (212 episodes), and 8 of 12 veratridine-treated hearts (155 episodes). Treatment with ivabradine in experimental models of LQT2 and LQT3 increases proarrhythmia. A distinct interaction with potassium currents most likely represents a major underlying mechanism. These results imply that ivabradine should be employed with caution in the presence of QT-prolongation.


Assuntos
Antiarrítmicos/toxicidade , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Ivabradina/toxicidade , Síndrome do QT Longo/induzido quimicamente , Sotalol/toxicidade , Taquicardia Ventricular/induzido quimicamente , Veratridina/toxicidade , Potenciais de Ação/efeitos dos fármacos , Animais , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Preparação de Coração Isolado , Síndrome do QT Longo/metabolismo , Síndrome do QT Longo/fisiopatologia , Potássio/metabolismo , Coelhos , Medição de Risco , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo
14.
Angiology ; 70(1): 69-77, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29962233

RESUMO

We evaluated the effect of serum potassium (K) deviation on in-hospital and long-term clinical outcomes in patients with ST-segment elevation myocardial infarction who were normokalemic at admission. A total of 2773 patients with an admission serum K level of 3.5 to 4.5 mEq/L were retrospectively analyzed. The patients were categorized into 3 groups according to their K deviation: normokalemia-to-hypokalemia, normokalemia-to-normokalemia, and normokalemia-to-hyperkalemia. In-hospital mortality, long-term mortality, and ventricular arrhythmias rates were compared among the groups. In a hierarchical multivariable regression analysis, the in-hospital mortality risk was higher in normokalemia-to-hypokalemia (odds ratio [OR] 3.03; 95% confidence interval [CI], 1.72-6.82) and normokalemia-to-hyperkalemia groups (OR 2.81; 95% CI, 1.93-4.48) compared with the normokalemia-to-normokalemia group. In a Cox regression analysis, long-term mortality risk was also higher in normokalemia-to-hypokalemia (hazard ratio [HR] 3.78; 95% CI, 2.07-7.17) and normokalemia-to-hyperkalemia groups (HR, 2.97; 95% CI, 2.10-4.19) compared with the normokalemia-to-normokalemia group. Ventricular arrhythmia risk was also higher in normokalemia-to-hypokalemia group (OR 2.98; 95% CI, 1.41-5.75) compared with normokalemia-to-normokalemia group. The current study showed an increased in-hospital ventricular arrhythmia and mortality and long-term mortality rates with the deviation of serum K levels from normal ranges.


Assuntos
Mortalidade Hospitalar , Potássio/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/mortalidade , Biomarcadores/sangue , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
16.
FASEB J ; 33(2): 2537-2552, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30289750

RESUMO

KCNE5 is an X-linked gene encoding KCNE5, an ancillary subunit to voltage-gated potassium (KV) channels. Human KCNE5 mutations are associated with atrial fibrillation (AF)- and Brugada syndrome (BrS)-induced cardiac arrhythmias that can arise from increased potassium current in cardiomyocytes. Seeking to establish underlying molecular mechanisms, we created and studied Kcne5 knockout ( Kcne5-/0) mice. Intracardiac ECG revealed that Kcne5 deletion caused ventricular premature beats, increased susceptibility to induction of polymorphic ventricular tachycardia (60 vs. 24% in Kcne5+/0 mice), and 10% shorter ventricular refractory period. Kcne5 deletion increased mean ventricular myocyte KV current density in the apex and also in the subpopulation of septal myocytes that lack fast transient outward current ( Ito,f). The current increases arose from an apex-specific increase in slow transient outward current-1 ( IKslow,1) (conducted by KV1.5) and Ito,f (conducted by KV4) and an increase in IKslow,2 (conducted by KV2.1) in both apex and septum. Kcne5 protein localized to the intercalated discs in ventricular myocytes, where KV2.1 was also detected in both Kcne5-/0 and Kcne5+/0 mice. In HL-1 cardiac cells and human embryonic kidney cells, KCNE5 and KV2.1 colocalized at the cell surface, but predominantly in intracellular vesicles, suggesting that Kcne5 deletion increases IK,slow2 by reducing KV2.1 intracellular sequestration. The human AF-associated mutation KCNE5-L65F negative shifted the voltage dependence of KV2.1-KCNE5 channels, increasing their maximum current density >2-fold, whereas BrS-associated KCNE5 mutations produced more subtle negative shifts in KV2.1 voltage dependence. The findings represent the first reported native role for Kcne5 and the first demonstrated Kcne regulation of KV2.1 in mouse heart. Increased KV current is a manifestation of KCNE5 disruption that is most likely common to both mouse and human hearts, providing a plausible mechanistic basis for human KCNE5-linked AF and BrS.-David, J.-P., Lisewski, U., Crump, S. M., Jepps, T. A., Bocksteins, E., Wilck, N., Lossie, J., Roepke, T. K., Schmitt, N., Abbott, G. W. Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia.


Assuntos
Fibrilação Atrial/complicações , Síndrome de Brugada/complicações , Genes Ligados ao Cromossomo X , Ativação do Canal Iônico , Miócitos Cardíacos/patologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Taquicardia Ventricular/etiologia , Animais , Fibrilação Atrial/genética , Síndrome de Brugada/genética , Células Cultivadas , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Potássio/metabolismo , Deleção de Sequência , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/patologia
17.
Int J Cardiol ; 275: 120-128, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30309679

RESUMO

BACKGROUND: Low-density lipoprotein receptor-related protein 5 (LRP5) has been intensively studied as a co-receptor for ß-catenin-dependent Wnt signaling. Emerging evidences have demonstrated ß-catenin-independent functions of LRP5. However, the biological role of LRP5 in the mammalian heart is largely unknown. METHODS AND RESULTS: Conditional cardiac-specific Lrp5 knockout (Lrp5-CKO) mice were generated by crossing Lrp5flox/flox mice with αMHC/MerCreMer mice. Lrp5-CKO mice consistently displayed normal cardiac structure and function. Telemetric electrocardiogram recordings revealed a short QT interval in Lrp5-CKO mice, which was tightly linked to the striking abbreviation of action potential duration (APD) in ventricular myocytes. The analysis of whole-cell currents indicated that a reduction in activity and protein expression of L-type calcium channel (LTCC), rather than other ion channels, contributed to the abnormality in APD. Furthermore, we showed that Lrp5 ablation induced a significant convergence of CaV1.2α1c proteins to the endoplasmic reticulum. Consequently, increased proteasomal degradation of these proteins was observed, which was independent of the Wnt/ß-catenin signaling pathway. CONCLUSIONS: LRP5 directly modulates the degradation of LTCC to control cardiac QT interval. These findings provide compelling evidence for the potential role of LRPs in cardiac electrophysiology.


Assuntos
Canais de Cálcio Tipo L/genética , Eletrocardiografia , Regulação da Expressão Gênica , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Miócitos Cardíacos/metabolismo , RNA/genética , Taquicardia Ventricular/metabolismo , Animais , Western Blotting , Canais de Cálcio Tipo L/biossíntese , Modelos Animais de Doenças , Homeostase , Camundongos Knockout , Miócitos Cardíacos/patologia , Reação em Cadeia da Polimerase , Taquicardia Ventricular/patologia , Taquicardia Ventricular/fisiopatologia
18.
J Cardiovasc Pharmacol Ther ; 24(3): 262-268, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30474396

RESUMO

Myocardial ischemia-reperfusion (IR) injury is associated with high disability and mortality worldwide. This study was to explore the roles of dioscin in the myocardial IR rats and discover the related molecular mechanisms. Rats were divided into 5 groups: sham, IR, IR + 15 mg/kg dioscin, IR + 30 mg/kg dioscin, and IR + 60 mg/kg dioscin. Heart rate (HR), mean arterial blood pressure (MAP), and rate pressure product (RPP) were evaluated at 10 minutes before ischemia, immediately after ischemia, and at the beginning, middle, and end of reperfusion. Arrhythmia score and myocardial infarct size were examined in rats of all groups. The serum creatine kinase-muscle/brain (CKMB) and cardiac troponin I (cTnI) levels were analyzed via enzyme-linked immunosorbent assay. Protein amount of total connexin 43 (T-Cx43) and phosphorylated connexin 43 (P-Cx43) was evaluated by Western blot. Ischemia reperfusion significantly decreased HR, MAP, and RPP of rats compared to the sham group. However, dioscin significantly attenuated the above phenomena in a dose-dependent manner. Dioscin markedly inhibited IR-induced increase in arrhythmias score, infarct size, and serum CKMB and cTnI levels. In addition, dioscin strikingly induced IR-repressed expression of T-Cx43 and P-Cx43. Our results suggested that dioscin pretreatment exhibited protective effects against myocardial IR injury. Moreover, we found that dioscin attenuated myocardial IR-induced ventricular arrhythmias via upregulating Cx43 expression and activation.


Assuntos
Arritmias Cardíacas/prevenção & controle , Conexina 43/metabolismo , Diosgenina/análogos & derivados , Frequência Cardíaca/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Substâncias Protetoras/farmacologia , Animais , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Biomarcadores/sangue , Creatina Quinase Forma MB/sangue , Diosgenina/farmacologia , Modelos Animais de Doenças , Masculino , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Fosforilação , Ratos Sprague-Dawley , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/prevenção & controle , Troponina I/sangue , Regulação para Cima , Fibrilação Ventricular/metabolismo , Fibrilação Ventricular/fisiopatologia , Fibrilação Ventricular/prevenção & controle , Complexos Ventriculares Prematuros/metabolismo , Complexos Ventriculares Prematuros/fisiopatologia , Complexos Ventriculares Prematuros/prevenção & controle
19.
Biochim Biophys Acta Mol Cell Res ; 1866(7): 1197-1206, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30392897

RESUMO

S100 proteins are members of the superfamily of Ca2+-binding proteins characterized by the specific Ca2+-binding motif, the EF-hand. Proteins of this superfamily are of clinical use as important diagnostic and prognostic biomarkers in adult and pediatric Laboratory Medicine. For example, measurements of troponin are nowadays the 'gold standard' in the diagnosis of patients with acute coronary syndrome. Parvalbumins were identified as major fish allergens and blocking antibodies, induced by immunization with a hypoallergenic parvalbumin mutant, were shown to reduce allergic symptoms. Mutations in calmodulin are linked to inherited ventricular tachycardia, and cardiac arrhythmias. S100 proteins, the largest sub-group within the EF-hand protein family, are closely associated with cardiovascular diseases, various types of cancer, inflammation and autoimmune pathologies and brain diseases. The intention of this review is to focus on the clinical use of S100 proteins as biomarkers and potential drug targets helping to improve the diagnosis of these human diseases in children and adults leading to more selective therapeutic interventions.


Assuntos
Biomarcadores Tumorais , Encefalopatias , Proteínas de Neoplasias , Neoplasias , Proteínas S100 , Taquicardia Ventricular , Adolescente , Adulto , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Encefalopatias/diagnóstico , Encefalopatias/genética , Encefalopatias/metabolismo , Calmodulina/genética , Calmodulina/metabolismo , Criança , Pré-Escolar , Humanos , Inflamação , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/metabolismo , Parvalbuminas/genética , Parvalbuminas/metabolismo , Proteínas S100/genética , Proteínas S100/metabolismo , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/genética , Taquicardia Ventricular/metabolismo
20.
Circ Res ; 123(8): 953-963, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30355031

RESUMO

RATIONALE: Autosomal-dominant mutations in ryanodine receptor type 2 ( RYR2) are responsible for ≈60% of all catecholaminergic polymorphic ventricular tachycardia. Dysfunctional RyR2 subunits trigger inappropriate calcium leak from the tetrameric channel resulting in potentially lethal ventricular tachycardia. In vivo CRISPR/Cas9-mediated gene editing is a promising strategy that could be used to eliminate the disease-causing Ryr2 allele and hence rescue catecholaminergic polymorphic ventricular tachycardia. OBJECTIVE: To determine if somatic in vivo genome editing using the CRISPR/Cas9 system delivered by adeno-associated viral (AAV) vectors could correct catecholaminergic polymorphic ventricular tachycardia arrhythmias in mice heterozygous for RyR2 mutation R176Q (R176Q/+). METHODS AND RESULTS: Guide RNAs were designed to specifically disrupt the R176Q allele in the R176Q/+ mice using the SaCas9 ( Staphylococcus aureus Cas9) genome editing system. AAV serotype 9 was used to deliver Cas9 and guide RNA to neonatal mice by single subcutaneous injection at postnatal day 10. Strikingly, none of the R176Q/+ mice treated with AAV-CRISPR developed arrhythmias, compared with 71% of R176Q/+ mice receiving control AAV serotype 9. Total Ryr2 mRNA and protein levels were significantly reduced in R176Q/+ mice, but not in wild-type littermates. Targeted deep sequencing confirmed successful and highly specific editing of the disease-causing R176Q allele. No detectable off-target mutagenesis was observed in the wild-type Ryr2 allele or the predicted putative off-target site, confirming high specificity for SaCas9 in vivo. In addition, confocal imaging revealed that gene editing normalized the enhanced Ca2+ spark frequency observed in untreated R176Q/+ mice without affecting systolic Ca2+ transients. CONCLUSIONS: AAV serotype 9-based delivery of the SaCas9 system can efficiently disrupt a disease-causing allele in cardiomyocytes in vivo. This work highlights the potential of somatic genome editing approaches for the treatment of lethal autosomal-dominant inherited cardiac disorders, such as catecholaminergic polymorphic ventricular tachycardia.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Terapia Genética/métodos , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Taquicardia Ventricular/terapia , Potenciais de Ação/genética , Animais , Proteína 9 Associada à CRISPR/genética , Sinalização do Cálcio/genética , Dependovirus/genética , Modelos Animais de Doenças , Predisposição Genética para Doença , Vetores Genéticos , Frequência Cardíaca/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , RNA Guia/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Taquicardia Ventricular/genética , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia
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