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NEW FINDINGS: What is the central question of this study? What is the effect of chronic intermittent low-level transcutaneous vagus nerve stimulation on cardiac inflammation, fibrosis and diastolic dysfunction in a rat model of heart failure with preserved ejection fraction? What is the main finding and its importance? In salt-sensitive rats fed with high salt diet, low-level transcutaneous vagus nerve stimulation significantly attenuated blood pressure elevation, ameliorated diastolic function, and attenuated left ventricular inflammation and fibrosis compared to the sham group. Further studies to examine the efficacy of this novel treatment in humans are warranted. ABSTRACT: Inflammation and fibrosis play a central role in the development of heart failure with preserved ejection fraction (HFpEF). We previously showed that low-level, transcutaneous stimulation of the vagus nerve at the tragus (LLTS) is anti-inflammatory. We investigated the effect of chronic intermittent LLTS on cardiac inflammation, fibrosis and diastolic dysfunction in a rat model of HFpEF. Dahl salt-sensitive (DS) rats were randomized in three groups: low salt (LS, 0.3% NaCl; n = 12; control group without stimulation) and high salt (HS, 4% NaCl) with either active (n = 18) or sham (n = 18) LLTS at 7 weeks of age. After 6 weeks of diet (baseline), sham or active LLTS (20 Hz, 2 mA, 0.2 ms) was implemented for 30 min daily for 4 weeks. Echocardiography was performed at baseline and 4 weeks after treatment (endpoint). At endpoint, left ventricle (LV) histology and gene expression were examined. After 6 weeks of diets, HS rats developed hypertension and LV hypertrophy compared to LS rats. At endpoint, LLTS significantly attenuated blood pressure elevation, prevented the deterioration of diastolic function and improved LV circumferential strain, compared to the HS sham group. LV inflammatory cell infiltration and fibrosis were attenuated in the HS active compared to the HS sham group. Pro-inflammatory and pro-fibrotic genes (tumour necrosis factor, osteopontin, interleukin (IL)-11, IL-18 and IL-23A) were differentially altered in the two groups. Chronic intermittent LLTS ameliorates diastolic dysfunction, and attenuates cardiac inflammation and fibrosis in a rat model of HFpEF, suggesting that LLTS may be used clinically as a novel non-invasive neuromodulation therapy in HFpEF.
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Insuficiencia Cardíaca/fisiopatología , Hipertensión/fisiopatología , Estimulación del Nervio Vago , Nervio Vago/fisiopatología , Animales , Ventrículos Cardíacos/fisiopatología , Masculino , Ratas Endogámicas Dahl , Ratas Sprague-Dawley , Cloruro de Sodio Dietético/metabolismo , Volumen Sistólico/fisiología , Nervio Vago/metabolismo , Función Ventricular Izquierda/fisiologíaRESUMEN
Diabetes has been identified as major risk factor for atrial fibrillation (AF). Although glucose and insulin disturbances during diabetes may affect atrial function, little is known about the potential pathogenic role of glucose metabolism during AF. Glucose transport into the cell via glucose transporters (GLUTs) is the rate-limiting step of glucose utilization. Although GLUT4 is the major isoform, GLUT8 has emerged as a novel insulin-sensitive cardiac isoform. We hypothesized that atrial glucose homeostasis will be impaired during insulin resistance-induced AF. AF was induced by transesophageal atrial pacing in healthy mice and following a long-term high-fat-diet-induced insulin resistance. Active cell surface GLUT content was measured using the biotinylated photolabeling assay in the intact perfused heart. Atrial fibrosis, advanced glycation end products (AGEs) and glycogen were measured in the atria using histological analyses. Animals fed a high-fat-diet were obese and mildly hyperglycemic, and developed insulin resistance compared to controls. Insulin-resistant (IR) animals demonstrated an increased vulnerability to induced AF, as well as spontaneous AF. Insulin-stimulated translocation of GLUT4 and GLUT8 was down-regulated in the atria of IR animals, as well as their total protein expression. We also reported the absence of fibrosis, glycogen and AGE accumulation in the atria of IR animals. In the absence of structural remodeling and atrial fibrosis, these data suggest that insulin signaling dysregulation, resulting in impaired glucose transport in the atria, could provide a metabolic arrhythmogenic substrate and be a novel early pathogenic factor of AF.
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Fibrilación Atrial/metabolismo , Regulación de la Expresión Génica , Transportador de Glucosa de Tipo 4/biosíntesis , Resistencia a la Insulina , Animales , Fibrilación Atrial/genética , Fibrilación Atrial/patología , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Transportador de Glucosa de Tipo 4/genética , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Masculino , RatonesRESUMEN
INTRODUCTION: The electrophysiologic mechanism for rate-dependent PVBs associated with double potentials (DPs) was investigated in infarcted canine hearts using bipolar and intracellular microelectrode recordings. METHODS AND RESULTS: Dogs exhibiting rate-related ventricular ectopic beats (coupling interval, 390 ± 54 milliseconds) during sinus rhythm or atrial pacing were studied 4-5 days (N = 63) or 25 days (N = 16) following anterior descending coronary artery ligation. Sites of DP and rate-dependent arrhythmia formation were identified in vivo using bipolar recordings for subsequent ex vivo studies. Rate-dependent conduction delays with increasing duration isoelectric intervals representing very slow conduction were observed at sites of DP formation, frequently provoking both manifest and concealed reentry (non-stimulated beats) over a narrow range of paced cycle lengths. Both slow antegrade and retrograde activation across an inexcitable gap (reflection) were integral components of extrasystole formation. Retrograde reflection to a region of very slow conduction (mid-potential) during antegrade activation was routinely observed at 4-5 days (42 of 63 preparations, 67%) and 25 days (22 of 26 preparations, 85%) postcoronary artery ligation. Reflection and premature re-activation of the proximal site was then observed in 6 of 63 (9%), and 3 of 26 preparations (12%). CONCLUSION: The present experiments demonstrate DP formation and rate-dependent constant-coupled late epicardial premature beats in infarcted dog hearts. Microelectrode recordings at DP sites demonstrating prolonged isoelectric intervals display very slow conduction preceding distal activation and "reentrant" re-activation of more proximal sites, representing reflection as an arrhythmia mechanism in ischemically injured epicardium during subacute myocardial infarction.
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Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Infarto del Miocardio/complicaciones , Infarto del Miocardio/fisiopatología , Animales , Anisotropía , Antiarrítmicos/farmacología , Complejos Cardíacos Prematuros/complicaciones , Complejos Cardíacos Prematuros/fisiopatología , Perros , Electrocardiografía , Fenómenos Electrofisiológicos/efectos de los fármacos , Epinefrina/farmacología , Sistema de Conducción Cardíaco/fisiopatología , Lidocaína/farmacología , Masculino , Microelectrodos , Taquicardia por Reentrada en el Nodo Atrioventricular/fisiopatología , Vasoconstrictores/farmacología , Complejos Prematuros Ventriculares/fisiopatologíaRESUMEN
INTRODUCTION: The electrophysiologic basis for characteristic rate-dependent, constant-late-coupled (390 + 54 milliseconds) premature ventricular beats (PVBs) present 4-5 days following coronary artery occlusion were examined in 108 anesthetized dogs. METHODS AND RESULTS: Fractionated/double potentials were observed in injured zone bipolar and composite electrograms at prolonged sinus cycle lengths (1,296 ± 396 milliseconds). At shorter cycle lengths, conduction of the delayed potential decremented, separating from the initial electrogram by a progressively prolonged isoelectric interval. With sufficient delay of the second potential following an isoelectric interval, a PVB was initiated. Both metastable and stable constant-coupled PVBs were associated with Wenckebach-like patterns of delayed activation following an isoelectric interval. Signal-averaging from the infarct border confirmed the presence of an isoelectric interval preceding the PVBs (N = 15). Pacing from the site of double potential formation accurately reproduced the surface ECG morphology (N = 15) of spontaneous PVBs. Closely-spaced epicardial mapping demonstrated delayed activation across an isoelectric interval representing "an arc of conduction block." Rate-dependent very slow antegrade conduction through a zone of apparent conduction block (N = 8) produced decremental activation delays until the delay was sufficient to excite epicardium distal to the original "arc of conduction block," resulting in PVB formation. CONCLUSION: The present experiments demonstrate double potential formation and rate-dependent constant-coupled late PVB formation in infarcted dog hearts. Electrode recordings demonstrate a prolonged isoelectric period preceding PVB formation consistent with very slow conduction (<70 mm/s) across a line of apparent conduction block and may represent a new mechanism of PVB formation following myocardial infarction.
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Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Bloqueo Cardíaco/complicaciones , Bloqueo Cardíaco/fisiopatología , Infarto del Miocardio/complicaciones , Infarto del Miocardio/fisiopatología , Animales , Enfermedad de la Arteria Coronaria/fisiopatología , Perros , Electrocardiografía , Fenómenos Electrofisiológicos , Mapeo Epicárdico , Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca , Masculino , Taquicardia Ventricular/complicaciones , Taquicardia Ventricular/fisiopatología , Complejos Prematuros Ventriculares/etiología , Complejos Prematuros Ventriculares/fisiopatologíaRESUMEN
Atropine (ATr) is well known as a cholinergic antagonist, however, at low concentrations ATr could paradoxically accentuate the parasympathetic actions of acetylcholine (ACh). In 22 pentobarbital anesthetized dogs, via a left and right thoracotomy, a leak-proof barrier was attached to isolate the atrial appendages (AAs) from the rest of the atria. In group 1 (Ach+ATr+Ach), ACh, 100 mM, was placed on the AA followed by the application of ATr, 2 mg/mL. The average atrial fibrillation (AF) duration was 17 ± 7 minutes. After ATr was applied to the AA and ACh again tested, the AF duration was markedly attenuated (2 ± 2 minutes, P < 0.05). In group 2 (ATr+Ach), ATr was initially applied to the AA followed by the application of ACh, 100 mM. There was no significant difference in AF duration (16 ± 4 minutes vs. 18 ± 2 minutes, P = NS). The inhibitory effect of ATr on induced HR reduction (electrical stimulation of the anterior right ganglionated plexi and vagal nerves) was similar between groups 1 and 2. These observations suggest that when ATr is initially administered it attaches to the allosteric site of the muscarinic ACh receptor (M2) leaving the orthosteric site free to be occupied by ACh. The M3 receptor that controls HR slowing does not show the same allosteric properties.
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Acetilcolina/farmacología , Antiarrítmicos/farmacología , Apéndice Atrial/efectos de los fármacos , Fibrilación Atrial/tratamiento farmacológico , Atropina/farmacología , Agonistas Colinérgicos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Antagonistas Muscarínicos/farmacología , Acetilcolina/metabolismo , Animales , Antiarrítmicos/metabolismo , Apéndice Atrial/metabolismo , Apéndice Atrial/fisiopatología , Fibrilación Atrial/etiología , Fibrilación Atrial/metabolismo , Fibrilación Atrial/fisiopatología , Atropina/metabolismo , Sitios de Unión , Estimulación Cardíaca Artificial , Agonistas Colinérgicos/metabolismo , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Antagonistas Muscarínicos/metabolismo , Unión Proteica , Receptor Muscarínico M2/efectos de los fármacos , Receptor Muscarínico M2/metabolismo , Factores de TiempoRESUMEN
BACKGROUND: We aimed to develop a novel predictive marker for atrial fibrillation (AF) recurrence in patients with inducible AF after catheter ablation, based on power spectral analysis of baseline and postablation electrocardiograms. METHODS: Twenty-five patients who had undergone their first AF ablation procedure (pulmonary vein isolation and ganglionated plexi ablation) and had inducible AF after ablation were included. A 30-second interval of AF was chosen for each patient before and after ablation, and a periodogram of the atrial activity was computed. A ratio of the power in the dominant frequency to the power in the remainder of the periodogram (DFR) was calculated. RESULTS: Eight (32%) patients had recurrent AF at 1 year. The clinical and echocardiographic characteristics of patients with and without recurrence were similar (P > 0.05). After ablation, there was organization of atrial activity, evidenced by an increase in the DFR (0.28 ± 0.22 vs 0.53 ± 0.29; P = 0.001). The percent change in DFR before and after ablation (median [interquartile range]) was significantly higher in patients without AF recurrence (120% [30% to 344%] vs 3% [-27% to 66%]; P = 0.01). Receiver operating curve (ROC) analysis demonstrated that a less than 16% increase in DFR postablation was able to predict recurrence of AF (area under ROC curve = 0.82; P = 0.03) with 75% sensitivity and 94% specificity. CONCLUSION: AF ablation leads to variable organization of atrial activity. Organization of atrial activity after AF ablation is associated with lower 1-year recurrence rates and may be used intraprocedurally after as a novel end point for AF ablation. Larger prospective studies are warranted.
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Fibrilación Atrial/fisiopatología , Fibrilación Atrial/cirugía , Ablación por Catéter/métodos , Electrocardiografía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Recurrencia , Factores de Riesgo , Resultado del TratamientoRESUMEN
In this review we present evidence from many experimental studies which challenge the concept of predestination of His bundle fibers. Using both intra- and extracellular His bundle pacing in the context of atrio-ventricular block and the development of bundle branch blocks these experimental studies provide the underlying mechanisms for the recent clinical findings showing the benefits of permanent His bundle pacing.
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Bloqueo Atrioventricular/prevención & control , Bloqueo Atrioventricular/fisiopatología , Fascículo Atrioventricular/fisiopatología , Bloqueo de Rama/prevención & control , Bloqueo de Rama/fisiopatología , Estimulación Cardíaca Artificial/métodos , Medicina Basada en la Evidencia , Humanos , Resultado del TratamientoRESUMEN
BACKGROUND: We evaluated the ability of spectral analysis of the baseline ECG during atrial fibrillation (AF) to predict the response of persistent AF to antiarrhythmic drug therapy. METHODS: Patients with persistent AF who were admitted for dofetilide loading were prospectively enrolled in the study. Atrial activity was extracted from the ECG using an Independent Component Analysis method and then subjected to a Modified Periodogram. The regularity index was computed as the ratio of the power in the dominant frequency and all its harmonics to the total power in the spectrum. Patients were followed at 1 month, 3 months and every 3 months thereafter. RESULTS: Of 28 patients enrolled in the study, 14 (50%) converted acutely to sinus rhythm during the 3-day hospital loading period. The clinical and echocardiographic characteristics of patients with and without acute pharmacologic conversion were similar. The regularity index was significantly higher in those who converted to sinus rhythm compared to those who did not (0.71 ± 0.20 vs. 0.38 ± 0.13, respectively; P < 0.0001). A regularity index ≥0.44 had a 79% sensitivity and 93% specificity to predict acute conversion and was associated with a nearly 5-fold increase in the acute conversion rate (odds ratio = 4.89; 95% confidence interval 1.74-13.75; P = 0.003). The regularity index was the only independent predictor of acute conversion. Neither acute conversion, nor the regularity index predicted sinus rhythm maintenance, after a median follow-up of 10 months. CONCLUSION: Increased regularity index predicts acute conversion of persistent AF during dofetilide loading, but does not predict long-term sinus rhythm maintenance.
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BACKGROUND: The mechanism(s) of how atrial fibrillation (AF) sustains itself in the first 24 hours is not well understood. OBJECTIVE: We sought to investigate the role of autonomic remodeling in the first 24 hours of AF simulated by rapid atrial pacing (RAP). METHODS: Forty-eight rabbits were divided into 6 groups. One group (n = 8) was euthanized after baseline recordings. Another group (n = 8) did not receive RAP during the 24-hour period to serve as controls. In the other 4 groups, rabbits were euthanized after RAP for 4, 8, 12, or 24 hours (n = 8 for each). Before and after designated hours of RAP, atrial effective refractory period, heart rate variability, and left vagal and sympathetic nerve activity (VNA and SNA, respectively) were determined. The right and left atrial tissues were obtained for immunocytochemical analysis for growth-associated protein 43 (GAP43), tyrosine hydroxylase (TH), and choline acetyltransferase (ChAT). RESULTS: RAP resulted in progressively shortened atrial effective refractory period and slower heart rate. In the first 12 hours of RAP, both SNA and VNA progressively increased. Then, VNA remained stably elevated but SNA began to attenuate. The high-frequency component and low-frequency/high-frequency ratio of heart rate variability followed the trend of VNA and SNA, respectively. The density of GAP43-positive, ChAT-positive, and TH-positive neural elements in the right and left atria was progressively higher with RAP. CONCLUSIONS: AF resulted in progressive autonomic remodeling, manifesting as nerve sprouting, sympathetic and vagal hyperinnervation. Autonomic remodeling may play an important role in sustaining AF in the first 24 hours.
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Fibrilación Atrial/fisiopatología , Atrios Cardíacos/inervación , Sistema de Conducción Cardíaco/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Nervio Vago/fisiopatología , Animales , Estimulación Cardíaca Artificial , Modelos Animales de Enfermedad , Técnicas Electrofisiológicas Cardíacas , Frecuencia Cardíaca/fisiología , Masculino , Conejos , Periodo Refractario Electrofisiológico/fisiología , Factores de Tiempo , Estimulación del Nervio VagoRESUMEN
BACKGROUND: Recent clinical studies have shown conflicting results of the efficacy of renal sympathetic denervation (RSD) to mitigate hypertension. In this study, we compared electrical stimulation (ES) of autonomic nerves on the surface of the left pulmonary artery (LPA) and renal arteries (RAs) on heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), and cardiac arrhythmias. METHODS: In 16 pentobarbital anesthetized dogs, standard electrocardiography leads and blood pressure (BP) were continuously recorded. After a left thoracotomy, a circumferential multielectrode catheter was secured around the LPA. Atrial pacing was coupled to the ES applied around the LPA during the QRS complex to avoid ventricular excitation. Flank incisions allowed retroperitoneal expose of the RAs and the aortico-renal ganglia (ARG). HR and SBP/DBP were determined at baseline (BL) and during ES of LPA, RA, or ARG. RESULTS: During ES applied to the LPA, HR was unchanged compared to BL values. In four of six animals, ventricular tachyarrhythmias were induced by ES. SBP increased significantly (BL vs ES, 129 ± 17 mm Hg vs 163 ± 21 mm Hg, P ≤ 0.05). ES applied to the RAs and ARG did not affect the HR, but significantly increased SBP/DBP (baseline: 134 ± 24/96 ± 18 mm Hg; RAs stimulation: 157 ± 26/114 ± 18 mm Hg; ARG stimulation: 207 ± 44/147 ± 26 mm Hg, P < 0.05). CONCLUSION: ES of vascular autonomic nerves on LPA, RAs, and ARG significantly increased BP but without effects on HR. ES of ARG induced substantially greater hypertensive responses than ES of RAs, implying that ES of ARG may serve as a biomarker or ablation targets for RSD.
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Vías Autónomas/fisiopatología , Presión Sanguínea , Estimulación Eléctrica/métodos , Frecuencia Cardíaca , Arteria Renal/fisiopatología , Taquicardia Ventricular/fisiopatología , Animales , Perros , Arteria Pulmonar/inervación , Arteria Pulmonar/fisiopatología , Arteria Renal/inervaciónRESUMEN
Previous studies demonstrated burst pacing and intravenous infusion of ACh induced sustained atrial tachycardia when rabbits were immunized to produce ß2-adrenergic receptor (ß2AR)-activating autoantibodies. The objective of this study was to examine the arrhythmogenic effect of ß1-adrenergic receptor (ß1AR)-activating autoantibodies in the rabbit. Eight New Zealand white rabbits were immunized with a ß1AR second extracellular loop peptide to raise ß1AR antibody titers. A catheter-based electrophysiological study was performed on anesthetized rabbits before and after immunization. Arrhythmia occurrence was determined in response to burst pacing before and after ACh infusion in incremental concentrations of 10 µM, 100 µM, and 1 mM. The baseline sinus heart rate before and after immunization averaged 149 ± 17 per min and 169 ± 16 per min, respectively (P < 0.05). In the preimmune studies, there were five sustained (≥10 s) arrhythmias in 32 induction attempts, which occurred in only four of eight rabbits. In the postimmune studies, there were 22 sustained arrhythmias in 32 induction attempts, which occurred in all eight rabbits (P < 0.0001 for the independent effect of immunization). Of the 22 sustained arrhythmias postimmunization, 15 were sinus tachycardia compared with only two before immunization (P < 0.01 for the independent effect of immunization). Postimmune (but not preimmune) rabbit sera demonstrated specific binding to ß1AR and induced significant ß1AR activation in transfected cells in vitro. No cross-reactivity with ß2AR was observed. In conclusion, in contrast with rabbits with ß2AR-activating autoantibodies that demonstrate predominantly atrial tachycardias, enhanced autoantibody activation of ß1AR in the rabbit leads to tachyarrhythmias mainly in the form of sustained sinus tachycardia.
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Arritmias Cardíacas/inmunología , Autoanticuerpos/metabolismo , Receptores Adrenérgicos beta 1/inmunología , Acetilcolina/farmacología , Animales , Arritmias Cardíacas/metabolismo , Autoanticuerpos/inmunología , Frecuencia Cardíaca , Conejos , Receptores Adrenérgicos beta 1/metabolismoRESUMEN
INTRODUCTION: Renal sympathetic nerve (RSN) activity plays a key role in systemic sympathetic hyperactivity. Previous studies have shown that cardiac sympathetic hyperactivity, especially the left stellate ganglion (LSG), contributes to the pathogenesis of ventricular arrhythmias (VAs) after acute myocardial infarction (AMI). METHODS AND RESULTS: Twenty-eight dogs received 3 hours of continuous left-sided electrical stimulation of RSN (LRS; Group-1, n = 9), sham RSN stimulation (Group-2, n = 9), or LSG ablation plus 3 hours of LRS (Group-3, n = 10) were included. AMI was induced by ligating the proximal left anterior descending coronary artery. LRS was performed using electrical stimulation on the adventitia of left renal artery at the voltage increasing the systolic blood pressure (BP) by 10%. BP, heart rate variability (HRV), serum norepinephrine (NE) level, and LSG function were measured at baseline and the end of each hour of LRS. C-fos and nerve growth factor (NGF) protein expressed in the LSG were examined in Group-1 and Group-2. Compared with baseline, 3 hours of LRS induced a significant increase in BP, sympathetic indices of HRV, serum NE level, and LSG function. The incidence of VAs in Group-1 was significantly higher than other groups. The expression of c-fos and NGF protein in the LSG was significantly higher in Group-1 than Group-2. CONCLUSION: Three hours of LRS induces both systemic and cardiac sympathetic hyperactivity and increases the incidence of ischemia-induced VAs.
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Riñón/inervación , Isquemia Miocárdica/fisiopatología , Ganglio Estrellado/fisiología , Taquicardia Ventricular/fisiopatología , Animales , Perros , Estimulación Eléctrica/efectos adversos , Estimulación Eléctrica/métodos , Riñón/fisiología , Masculino , Isquemia Miocárdica/complicaciones , Taquicardia Ventricular/etiologíaRESUMEN
Atrial-fibrillation (AF) is the most common clinically encountered arrhythmia affecting over 1 per cent of population in the United States and its prevalence seems to be moving only in forward direction. A recent systemic review estimates global prevalence of AF to be 596.2 and 373.1 per 100,000 population in males and females respectively. Multiple mechanisms have been put forward in the pathogenesis of AF, however; multiple wavelet hypothesis is the most accepted theory so far. Similar to the conduction system of the heart, a neural network exists which surrounds the heart and plays an important role in formation of the substrate of AF and when a trigger is originated, usually from pulmonary vein sleeves, AF occurs. This neural network includes ganglionated plexi (GP) located adjacent to pulmonary vein ostia which are under control of higher centers in normal people. When these GP become hyperactive owing to loss of inhibition from higher centers e.g. in elderly, AF can occur. We can control these hyperactive GP either by stimulating higher centers and their connections, e.g. vagus nerve stimulation or simply by ablating these GP. This review provides detailed information about the different proposed mechanisms underlying AF, the exact role of autonomic neural tone in the pathogenesis of AF and the possible role of neural modulation in the treatment of AF.
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Fibrilación Atrial/epidemiología , Fibrilación Atrial/etiología , Fibrilación Atrial/fisiopatología , Ganglios Autónomos/fisiopatología , Modelos Biológicos , Red Nerviosa/fisiopatología , Fibrilación Atrial/terapia , Femenino , Humanos , Masculino , Prevalencia , Venas Pulmonares/fisiopatología , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Recent clinical reports that used cholinergic and adrenergic blockade (CAB) as an alternative to ganglionated plexi (GP) ablation to terminate atrial fibrillation (AF) showed mixed results. We investigated the role of other neurotransmitters in AF inducibility. METHODS: In 23 pentobarbital anesthetized dogs, a left and right thoracotomy allowed the attachment of electrode catheters to the left and right pulmonary veins and atrial appendages (AA). Programmed stimulation was used to determine the effective refractory periods (ERP) and AF inducibility, measured by the window of vulnerability (WOV). AF duration in response to acetylcholine (Ach; 100 mM) applied to the AA was measured before and after GP ablation + CAB and with vagus nerve stimulation (VNS). After GP ablation + CAB, Ach induced AF duration was determined in response to vasoactive intestinal peptide (VIP) and its specific antagonist ([Ac-Tyr1,D-phe2]-VIP). RESULTS: GP ablation + CAB significantly prolonged ERP, eliminated WOV, and suppressed the duration of Ach induced AF (P ≤ 0.01 for all). Also slowing of the heart rate by VNS was essentially blocked; however, with Ach 100 mM applied to the AA, VNS, and VIP applied to the AA markedly prolonged AF duration. This effect was blocked by the VIP antagonist. CONCLUSIONS: Neither GP ablation nor CAB can fully suppress AF inducibility arising from the atrial neural network. Our findings suggest that other neurotransmitters, such as VIP released during VNS, can promote sustained AF despite GP ablation and "autonomic blockade," which may further define the substrate for AF outside the pulmonary vein-atrial junctions.
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Fibrilación Atrial/metabolismo , Sistema Nervioso Autónomo/metabolismo , Ganglión/metabolismo , Sistema de Conducción Cardíaco/metabolismo , Red Nerviosa/metabolismo , Neurotransmisores/metabolismo , Neuronas Adrenérgicas/metabolismo , Animales , Neuronas Colinérgicas/metabolismo , PerrosRESUMEN
BACKGROUND: The mechanisms underlying focal atrial tachycardia (AT) are unclear. METHODS: In 14 pentobarbital anesthetized dogs, a right thoracotomy allowed electrical stimulation (ES) of the anterior right ganglionated plexi (ARGP). After ES was applied to the ARGP at baseline, atropine, 1 mg/cc, was injected into the ARGP and repeat stimulation applied. After a left thoracotomy (n = 8), a similar procedure was followed by atropine injected into the superior left (SL) GP. RESULTS: ES (0.6-3.2 V) applied to the ARGP and SLGP caused an average reduction in sinus rate from 151 ± 14/min to 60 ± 11/min. At ≥4.5 V atrial fibrillation (AF) was induced (duration 48 ± 14 seconds). After injection of atropine into the ARGP or SLGP, ES applied to these GP induced no slowing of the sinus rate. Runs of AT were induced at an average voltage of 10 ± 2 V in 14 experiments (duration ≥4 minutes). AT was localized by ice mapping or by 3D noncontact mapping to the crista terminalis (n = 6), AV junction (n = 2) or a focal site at the left superior pulmonary vein (6). In AT lasting <4 minutes (n = 2), epinephrine injected into the GP significantly increased the AT duration. In 4/4 experiments, sustained AT could be terminated by intravenous esmolol. CONCLUSIONS: Atropine injected into the ARGP or SLGP promotes ES-induced AT whose duration is increased by adrenergic agonists and terminated by beta blockade. Presumably cholinergic blockade and accentuated release of adrenergic neurotransmitters provide the AT mechanism. The induced AT was found to be localized at sites similar to those reported clinically.
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Sistema de Conducción Cardíaco/fisiopatología , Taquicardia Supraventricular/fisiopatología , Animales , Atropina/farmacología , Modelos Animales de Enfermedad , Perros , Estimulación Eléctrica , Técnicas Electrofisiológicas Cardíacas , Epinefrina/farmacología , Sistema de Conducción Cardíaco/efectos de los fármacos , Propanolaminas/farmacologíaRESUMEN
Abnormal cardiac metabolism or cardiac metabolic remodeling is reported before the onset of heart failure with reduced ejection fraction (HFrEF) and is known to trigger and maintain the mechanical dysfunction and electrical, and structural abnormalities of the ventricle. A dysregulated cardiac autonomic tone characterized by sympathetic overdrive with blunted parasympathetic activation is another pathophysiological hallmark of HF. Emerging evidence suggests a link between autonomic nervous system activity and cardiac metabolism. Chronic ß-adrenergic activation promotes maladaptive metabolic remodeling whereas cholinergic activation attenuates the metabolic aberrations through favorable modulation of key metabolic regulatory molecules. Restoration of sympathovagal balance by neuromodulation strategies is emerging as a novel nonpharmacological treatment strategy in HF. The current review attempts to evaluate the 'neuro-metabolic axis' in HFrEF and whether neuromodulation can mitigate the adverse metabolic remodeling in HFrEF.
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Insuficiencia Cardíaca , Humanos , Volumen Sistólico/fisiología , Corazón , Sistema Nervioso Autónomo , ColinérgicosRESUMEN
BACKGROUND: We examined the antiarrhythmic effects of vasostatin-1, a recently identified cardioregulatory peptide, in canine models of atrial fibrillation (AF). METHODS AND RESULTS: In 13 pentobarbital-anesthetized dogs bilateral thoracotomies allowed the attachment of multielectrode catheters to superior and inferior pulmonary veins and atrial appendages (AA). Rapid atrial pacing (RAP) was maintained for 6 hours. Each hour, programmed stimulation was performed to determine the window of vulnerability (WOV), a measure of AF inducibility, at all sites. During the last 3 hours, vasostatin-1, 33 nM, was injected into the anterior right (AR) ganglionated plexus (GP) and inferior right (IR) GP every 30 minutes (n = 6). Seven dogs underwent 6 hours of RAP only (controls). At baseline, acetylcholine, 100 mM, was applied on the right AA and AF duration was recorded before and after injection of vasostatin-1, 33 nM, into the ARGP and IRGP. In separate experiments (n = 8), voltage-sinus rate response curves (surrogate for GP function) were constructed by applying high-frequency stimulation to the ARGP with incremental voltages with or without vasostatin-1. Vasostatin-1 significantly decreased the duration of acetylcholine-induced AF (11.0 ± 4.1 vs 5.5 ± 2.6 min, P = 0.02). The cumulative WOV (the sum of individual WOVs) significantly increased (P < 0.0001) during the first 3 hours and decreased toward baseline in the presence of vasostatin-1 (P < 0.0001). Cumulative WOV in controls steadily increased. Vasostatin-1 blunted the slowing of sinus rate with increasing stimulation voltage of ARGP. CONCLUSIONS: Vasostatin-1 suppresses AF inducibility, likely by inhibiting GP function. These data may provide new insights into the role of peptide neuromodulators for AF therapy.
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Antiarrítmicos/farmacología , Fibrilación Atrial/prevención & control , Cromogranina A/farmacología , Fragmentos de Péptidos/farmacología , Acetilcolina , Potenciales de Acción , Animales , Fibrilación Atrial/etiología , Fibrilación Atrial/fisiopatología , Estimulación Cardíaca Artificial , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Electrocardiografía , Técnicas Electrofisiológicas Cardíacas , Ganglios Autónomos/efectos de los fármacos , Ganglios Autónomos/fisiopatología , Humanos , Masculino , Periodo Refractario Electrofisiológico , Factores de TiempoRESUMEN
BACKGROUND: In malignant melanoma, it has been published that up to 40% of cancer patients will suffer from brain metastasis. The prognosis for these patients is poor, with a life expectancy of 4 to 6 months. Calcium exchange is involved in numerous cell functions. Recently, three types of cellular calcium sequestration have been reported in the medical literature. The first describes a transgenic mouse model in which an increase of aberrant calcium channels triggers hypertrophy and apoptosis. The second provides a protective mechanism whereby astrocytes in the brain inhibit apoptosis of tumor cells by moving ionic calcium out of the tumor cells thru gap junctions. The third is via calcium chelation, which causes cell apoptosis by converting ionic calcium into a calcium salt. This process has been shown to operate in atrial myocardial cells, thus not allowing the intracellular calcium stores to flow through the myocytes intercalated discs. Ideally chemotherapeutic agents would be those that initiate apoptosis in tumor cells. PRESENTATION OF THE HYPOTHESIS: We hypothesize that the recent reported intracellular calcium sequestration by oxalate chelation, due to its chemical process of converting ionic calcium into a calcium salt, may inhibit the protective effect of astrocytes on brain tumor metastasized melanoma cells by not allowing free calcium to leave the metastatic cells, simultaneously apoptosis of tumor and some healthy adjacent cells could occur. This hypothesis could be extended to include other cancerous tumors such as skin cancers amongst others. TESTING THE HYPOTHESIS: Using the experimental model showing the protective mechanism of co-cultured reactive astrocytes and tumor cells treated with oxalates could be used to test this hypothesis in vitro. The calcium specific von Kossa technique could be used to confirm the presence of chelated intracellular calcium architecture of the metastatic cells (which is a sign of apoptosis), and extracellular calcium chelation stores of the Astrocytes (which has been shown to slow neural conduction). IMPLICATIONS OF THE HYPOTHESIS: The life expectancy in patients with metastasized malignant melanoma brain tumors could be significantly prolonged if the chemotherapeutic issue of brain metastasis is overcome. Other cancerous tumors can also be treated by this Targeted Chelation Approach. Ionic calcium sequestration using naturally occurring calcium chelators, viz., oxalates, could accomplish this desired outcome.
RESUMEN
AIMS: Patients undergo ablation for focal atrial fibrillation (AF) as a result of failure of anti-arrhythmic drugs. Our basic studies have implicated cholinergic and adrenergic neurotransmitter release as the underlying mechanism for focal AF. Therefore, we tested the efficacy of a combination of sodium channel-blocking agents with additional vagolytic properties and a ß-blocker to terminate and prevent focal AF. METHODS AND RESULTS: In 18 Na-pentobarbital-anaesthetized dogs, after a right or left thoracotomy, acetylcholine (Ach, 0.5 cc, 100 mM) was injected into a fat pad containing ganglionated plexi (GP) or applied on an atrial appendage (AA) to induce focal firing at the pulmonary veins (PVs) or AA, respectively. Disopyramide (2-4 mg/kg, n= 6) or quinidine (3-6 mg/kg, n= 12) combined with esmolol or propranolol (1 mg/kg, n= 13 and 5, respectively) were slowly injected to terminate (Group I, n= 12) or prevent (Group II, n= 6) Ach-induced sustained focal AF. In another four dogs, only the sodium channel-blocking agents with additional vagolytic properties or only the ß-blocker was injected prior to or after the initiation of focal AF. At baseline, the mean duration of AF induced by Ach was 26 ± 4 min. Group I: After drugs, Ach-induced AF duration was 3 ± 1 min (P< 0.001). Group II: Prior to drugs, Ach-induced AF lasted for 19 ± 3 min. With the drug combination the duration of Ach-induced AF, decreased to 6 ± 1/min, P< 0.001. Either quinidine or propranolol alone did not change the duration of Ach-induced AF, mean 25 ± 10 min compared with Ach alone, 28 ± 16 min, P= 0.2. CONCLUSIONS: Type IA (cholinergic antagonist) plus Type II (ß-adrenergic antagonist) provides significant prevention and suppression of focal AF arising at PV and non-PV sites.