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3.
Proc Natl Acad Sci U S A ; 117(14): 7990-8000, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32198206

RESUMO

Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na+ current (INa) and repolarizing K+ current (IK) carried by voltage gated K+ (Kv1.5) channels were reduced. The reduction in INa occurred in association with reduced expression of SCN5a and voltage gated Na+ (NaV1.5) channels as well as a shift in INa activation kinetics. Insulin potently and selectively increased INa in Akita mice without affecting IK Chronic insulin treatment increased INa in association with increased expression of NaV1.5. Acute insulin also increased INa, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP3). Our study reveals a critical, selective role for insulin in regulating atrial INa, which impacts susceptibility to AF in type 1 DM.


Assuntos
Fibrilação Atrial/metabolismo , Remodelamento Atrial/fisiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Insulina/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/etiologia , Fibrilação Atrial/fisiopatologia , Remodelamento Atrial/imunologia , Células Cultivadas , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Eletrocardiografia , Átrios do Coração/citologia , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Humanos , Insulina/administração & dosagem , Insulina/genética , Canal de Potássio Kv1.5/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Miócitos Cardíacos/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Técnicas de Patch-Clamp , Potássio/metabolismo , Cultura Primária de Células , Sódio/metabolismo , Estreptozocina/toxicidade
5.
JACC Clin Electrophysiol ; 5(9): 1036-1044, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31537332

RESUMO

OBJECTIVES: This study sought to evaluate the effect of cardiac resynchronization therapy with defibrillator (CRT-D) as compared with implantable cardioverter-defibrillator (ICD) on mortality, heart failure (HF) hospitalization, and ventricular arrhythmia in women versus men. BACKGROUND: CRT-D has demonstrated reduced mortality and HF hospitalizations with greater benefit observed in women compared with men. However, whether CRT-D prevented ventricular arrhythmias in women compared with men was unclear. METHODS: The RAFT (Resynchronization-Defibrillation for Ambulatory Heart Failure Trial) study randomized 1,798 patients to an ICD or CRT-D. In this post hoc analysis, women and men were compared by randomized group. By using a multivariable model, the outcomes of death and HF hospitalization and incidence of ventricular arrhythmia were compared between men and women. RESULTS: There were 1,490 (83%) men (732, ICD; 758, CRT-D) and 308 (17%) women (172, ICD; 136, CRT-D) included in the analysis. Women with CRT-D had a significantly reduced incidence of death and HF hospitalization compared with men with CRT-D (hazard ratio: 0.52; 95% confidence interval: 0.33 to 0.81; p < 0.001) on multivariable analysis. Women with a primary prevention indication and CRT-D had the lowest rate of ventricular arrhythmia compared with men (hazard ratio: 0.59; 95% confidence interval: 0.39 to 0.91; p = 0.016). CONCLUSIONS: Women have improved rates of death and HF hospitalization with CRT-D and were less likely to experience ventricular arrhythmia when compared with men, after adjusting for differences in baseline characteristics over a prolonged follow-up. Whether these improved outcomes reflect inherent sex differences in the underlying myocardial substrate resulting in an enhanced response to CRT-D requires further research.

6.
J Physiol ; 597(13): 3297-3313, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31087820

RESUMO

KEY POINTS: Vagal reflexes slow heart rate and can change where the heartbeat originates within the sinoatrial node (SAN). The mechanisms responsible for this process - termed leading pacemaker (LP) shift - have not been investigated fully. We used optical mapping to measure the effects of baroreflex, chemoreflex and carbachol on pacemaker entrainment and electrical conduction across the SAN. All methods of stimulation triggered shifts in LP site from the central SAN to one or two caudal pacemaker regions. These shifts were associated with reduced current generation capacity centrally and increased electrical load caudally. Previous studies suggest LP shift is a rate-dependent phenomenon whereby acetylcholine slows central pacemaker rate disproportionately, enabling caudal cells that are less acetylcholine sensitive to assume control. However, our findings indicate the LP region is defined by both pacemaker rate and capacity to drive activation. Shifts in LP site provide an important homeostatic mechanism for rapid switches in heart rate. ABSTRACT: Reflex vagal activity causes abrupt heart rate slowing with concomitant caudal shifts of the leading pacemaker (LP) site within the sinoatrial node (SAN). However, neither the mechanisms responsible nor their dynamics have been investigated fully. Therefore, the objective of this study was to elucidate the mechanisms driving cholinergic LP shift. Optical maps of right atrial activation were acquired in a rat working heart-brainstem preparation during baroreflex and chemoreflex stimulation or with carbachol. All methods of stimulation triggered shifts in LP site from the central SAN to caudal pacemaker regions, which were positive for HCN4 and received uniform cholinergic innervation. During baroreflex onset, the capacity of the central region to drive activation declined with a decrease in amplitude and gradient of optical action potentials (OAPs) in the surrounding myocardium. Accompanying this decline, there was altered entrainment in the caudal SAN as shown by decreased conduction velocity, OAP amplitude, gradient and activation time. Atropine abolished these responses. Chemoreflex stimulation produced similar effects but central capacity to drive activation was preserved before the LP shift. In contrast, carbachol produced a prolonged period of reduced capacity to drive and altered entrainment. Previous studies suggest LP shift is a rate-dependent phenomenon whereby acetylcholine slows central pacemaker rate disproportionately, enabling caudal cells that are less acetylcholine sensitive to assume control. Our findings indicate that cholinergic LP shifts are also determined by altered electrical source-to-sink balance in the SAN. We conclude that the LP region is defined by both rate and capacity to drive atrial activation.

7.
Front Physiol ; 10: 135, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863315

RESUMO

A number of clinical studies have reported that diabetes mellitus (DM) is an independent risk factor for Atrial fibrillation (AF). After adjustment for other known risk factors including age, sex, and cardiovascular risk factors, DM remains a significant if modest risk factor for development of AF. The mechanisms underlying the increased susceptibility to AF in DM are incompletely understood, but are thought to involve electrical, structural, and autonomic remodeling in the atria. Electrical remodeling in DM may involve alterations in gap junction function that affect atrial conduction velocity due to changes in expression or localization of connexins. Electrical remodeling can also occur due to changes in atrial action potential morphology in association with changes in ionic currents, such as sodium or potassium currents, that can affect conduction velocity or susceptibility to triggered activity. Structural remodeling in DM results in atrial fibrosis, which can alter conduction patterns and susceptibility to re-entry in the atria. In addition, increases in atrial adipose tissue, especially in Type II DM, can lead to disruptions in atrial conduction velocity or conduction patterns that may affect arrhythmogenesis. Whether the insulin resistance in type II DM activates unique intracellular signaling pathways independent of obesity requires further investigation. In addition, the relationship between incident AF and glycemic control requires further study.

8.
Europace ; 20(10): 1621-1629, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30137296

RESUMO

Aims: Implantable cardioverter-defibrillators (ICDs) are key in the prevention of sudden cardiac death, but outcomes may vary by type of device or programming [single chamber (SC) vs. dual chamber (DC)] in patients without a bradycardia pacing indication. We sought to meta-analyse patient outcomes of randomized trials of SC vs. DC devices or programming. Methods and results: We searched PubMed, Embase, Scopus, Web of Science, and Cochrane trials databases for relevant studies excluding those published before 2000, involving children, or not available in English. Endpoints included mortality, inappropriate ICD therapies, and implant complications. Endpoints with at least three reporting studies were meta-analysed. We identified eight studies meeting inclusion criteria representing 2087 patients with 16.1 months mean follow-up. Mean age was 62.7 years (SD 1.92); in six studies reporting sex, most patients were male (85%). Comparing patients with a SC or DC ICD or programming, we found similar rates of mortality [odds ratio (OR) 0.95, 95% confidence interval (CI) 0.54-1.68; P = 0.86] and inappropriate therapies (OR 1.46, 95% CI 0.97-2.19; P = 0.07) in five and six studies, respectively. In three studies of SC vs. DC ICDs (but not programming) rates of pneumothorax and lead dislodgement were not different (OR 2.12, 95% CI 0.18-24.72; P = 0.55 and OR 0.87, 95% CI 0.32-2.47; P = 0.83, respectively). Conclusion: In this meta-analysis of randomized controlled trials comparing SC vs. DC ICD device or programming, there was no significant difference in inappropriate therapies, mortality, pneumothorax, or lead dislodgement. Future studies should compare these devices over longer follow-up and in specific patient populations.


Assuntos
Morte Súbita Cardíaca/prevenção & controle , Desfibriladores Implantáveis , Desenho de Equipamento , Bradicardia/terapia , Estimulação Cardíaca Artificial , Humanos , Implantação de Prótese
9.
Front Physiol ; 9: 835, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30018571

RESUMO

Background: Meta-analysis is a widely used tool in which weighted information from multiple similar studies is aggregated to increase statistical power. However, the exponential growth of publications in key areas of medical science has rendered manual identification of relevant studies increasingly time-consuming. The aim of this work was to develop a machine learning technique capable of robust automatic study selection for meta-analysis. We have validated this approach with an up-to-date meta-analysis to investigate the association between diabetes mellitus (DM) and new-onset atrial fibrillation (AF). Methods: The PubMed online database was searched from 1960 to September 2017 where 4,177 publications that mentioned both DM and AF were identified. Relevant studies were selected as follows. First, publications were clustered based on common text features using an unsupervised K-means algorithm. Clusters that best matched the selected set of potentially relevant studies (a "training" set of 139 articles) were then identified by using maximum entropy classification. The 139 articles selected automatically on this basis were screened manually to identify potentially relevant studies. To determine the validity of the automated process, a parallel set of studies was also assembled by manually screening all initially searched publications. Finally, detailed manual selection was performed on the full texts of the studies in both sets using standard criteria. Quality assessment, meta-regression random-effects models, sensitivity analysis and publication bias assessment were then conducted. Results: Machine learning-assisted screening identified the same 29 studies for meta-analysis as those identified by using manual screening alone. Machine learning enabled more robust and efficient study selection, reducing the number of studies needed for manual screening from 4,177 to 556 articles. A pooled analysis using the most conservative estimates indicated that patients with DM had ~49% greater risk of developing AF compared with individuals without DM. After adjusting for three additional risk factors i.e., hypertension, obesity and heart disease, the relative risk was 23%. Using multivariate adjusted models, the risk for developing AF in patients with DM was similar for all DM subtypes. Women with DM were 24% more likely to develop AF than men with DM. The risk for new-onset AF in patients with DM has also increased over the years. Conclusions: We have developed a novel machine learning method to identify publications suitable for inclusion in meta-analysis.This approach has the capacity to provide for a more efficient and more objective study selection process for future such studies. We have used it to demonstrate that DM is a strong, independent risk factor for AF, particularly for women.

11.
Biochem J ; 475(1): 169-183, 2018 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-29170159

RESUMO

Reduced protein expression of the cardiac ryanodine receptor type 2 (RyR2) is thought to affect the susceptibility to stress-induced ventricular tachyarrhythmia (VT) and cardiac alternans, but direct evidence for the role of RyR2 protein expression in VT and cardiac alternans is lacking. Here, we used a mouse model (crrm1) that expresses a reduced level of the RyR2 protein to determine the impact of reduced RyR2 protein expression on the susceptibility to VT, cardiac alternans, cardiac hypertrophy, and sudden death. Electrocardiographic analysis revealed that after the injection of relatively high doses of caffeine and epinephrine (agents commonly used for stress test), wild-type (WT) mice displayed long-lasting VTs, whereas the crrm1 mutant mice exhibited no VTs at all, indicating that the crrm1 mutant mice are resistant to stress-induced VTs. Intact heart Ca2+ imaging and action potential (AP) recordings showed that the crrm1 mutant mice are more susceptible to fast-pacing induced Ca2+ alternans and AP duration alternans compared with WT mice. The crrm1 mutant mice also showed an increased heart-to-body-weight ratio and incidence of sudden death at young ages. Furthermore, the crrm1 mutant hearts displayed altered Ca2+ transients with increased time-to-peak and decay time (T50), increased ventricular wall thickness and ventricular cell area compared with WT hearts. These results indicate that reduced RyR2 protein expression suppresses stress-induced VTs, but enhances the susceptibility to cardiac alternans, hypertrophy, and sudden death.


Assuntos
Cálcio/metabolismo , Cardiomegalia/genética , Ventrículos do Coração/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Taquicardia Ventricular/genética , Potenciais de Ação/efeitos dos fármacos , Animais , Cafeína/farmacologia , Sinalização do Cálcio , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Morte Súbita Cardíaca/patologia , Modelos Animais de Doenças , Epinefrina/farmacologia , Expressão Gênica , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Camundongos , Camundongos Transgênicos , Contração Muscular , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Técnicas de Cultura de Órgãos , Periodicidade , Canal de Liberação de Cálcio do Receptor de Rianodina/deficiência , Estresse Fisiológico/efeitos dos fármacos , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/fisiopatologia
19.
Circulation ; 135(6): 593-608, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28153995

RESUMO

Sex-specific differences in the epidemiology, pathophysiology, clinical presentation, clinical treatment, and clinical outcomes of atrial fibrillation (AF), sustained ventricular arrhythmias, and sudden cardiac death are recognized. Sex hormones cause differences in cardiac electrophysiological parameters between men and women that may affect the risk for arrhythmias. The incidence and prevalence of AF is lower in women than in men. However, because women live longer and AF prevalence increases with age, the absolute number of women with AF exceeds that of men. Women with AF are more symptomatic, present with more atypical symptoms, and report worse quality of life in comparison with men. Female sex is an independent risk factor for death or stroke attributable to AF. Oral anticoagulation therapy for stroke prevention has similar efficacy for men and women, but older women treated with warfarin have a higher residual risk of stroke in comparison with men. Women with AF are less likely to receive rhythm control antiarrhythmic drug therapy, electric cardioversion, or catheter ablation in comparison with men. The incidence and prevalence of sustained ventricular arrhythmias and sudden cardiac death are lower in women than in men. Women receiving implantable cardioverter defibrillators for primary prevention of sudden cardiac death are less likely to experience sustained ventricular arrhythmias in comparison with men. In contrast, women receiving a cardiac resynchronization therapy implantable cardioverter defibrillator for the treatment of heart failure are more likely to benefit than men. Women are less likely to be referred for implantable cardioverter defibrillator therapy despite current guideline recommendations. Women are more likely to experience a significant complication related to implantable cardioverter defibrillator implantation in comparison with men. Whether sex differences in treatment decisions reflect patient preferences or treatment biases requires further study.


Assuntos
Arritmias Cardíacas/epidemiologia , Fibrilação Atrial/epidemiologia , Fatores Sexuais , Morte Súbita , Feminino , Humanos , Masculino , Resultado do Tratamento
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