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An intricate meshwork of trabeculations lines the luminal side of cardiac ventricles. Compaction, a developmental process, is thought to reduce trabeculations by adding them to the neighboring compact wall which is then enlarged. When pig, a plausible cardiac donor for xenotransplantation, is compared to human, the ventricular walls appear to have fewer trabeculations. We hypothesized the trabecular volume is proportionally smaller in pig than in human. Macroscopically, we observed in 16 pig hearts that the ventricular walls harbor few but large trabeculations. Close inspection revealed a high number of tiny trabeculations, a few hundred, within the recesses of the large trabeculations. While tiny, these were still larger than embryonic trabeculations and even when considering their number, the total tally of trabeculations in pig was much fewer than in human. Volumetrics based on high-resolution MRI of additional six pig hearts compared to six human hearts, revealed the left ventricles were not significantly differently trabeculated (21.5 versus 22.8%, respectively), and the porcine right ventricles were only slightly less trabeculated (42.1 vs 49.3%, respectively). We then analyzed volumetrically 10 pig embryonic hearts from gestational day 14-35. The trabecular and compact layer always grew, as did the intertrabecular recesses, in contrast to what compaction predicts. The proportions of the trabecular and compact layers changed substantially, nonetheless, due to differences in their growth rate rather than compaction. In conclusion, processes that affect the trabecular morphology do not necessarily affect the proportion of trabecular-to-compact myocardium and they are then distinct from compaction.
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Ventrículos Cardíacos , Corazón , Humanos , Animales , Porcinos , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/anatomía & histología , Corazón/anatomía & histología , MiocardioRESUMEN
Ventricular arrhythmias, consisting of single ectopic beats (sEB), multiple EB (mEB), and torsades de pointes (TdP, defined as ≥5 beats with QRS vector twisting around isoelectric line) can be induced in the anesthetized chronic atrioventricular block (CAVB) dog by dofetilide (IKr blocker). The interplay between temporal dispersion of repolarization, quantified as short-term variability (STV), and spatial dispersion of repolarization (SDR) in the initiation and perpetuation of these arrhythmias remains unclear. Five inducible (≥3 TdPs/10 min) CAVB dogs underwent one mapping experiment and were observed for 10 min from the start of dofetilide infusion (0.025 mg/kg, 5 min). An intracardiac decapolar electrogram (EGM) catheter and 30 intramural cardiac needles in the left ventricle (LV) were introduced. STVARI was derived from 31 consecutive activation recovery intervals (ARIs) on the intracardiac EGM, using the formula: [Formula: see text]. The mean SDR3D in the LV was determined as the three-dimensional repolarization time differences between the intramural cardiac needles. Moments of measurement included baseline (BL) and after dofetilide infusion before first 1) sEB (occurrence at 100 ± 35 s), 2) mEB (224 ± 96 s), and 3) non-self-terminating TdP (454 ± 298 s). STVARI increased from 2.15 ± 0.32 ms at BL to 3.73 ± 0.99 ms* before the first sEB and remained increased without further significant progression to mEB (4.41 ± 0.45 ms*) and TdP (5.07 ± 0.84 ms*) (*P < 0.05 compared with BL). SDR3D did not change from 31 ± 11 ms at BL to 43 ± 13 ms before sEB but increased significantly before mEB (68 ± 7 ms*) and to TdP (86 ± 9 ms*+) (+P < 0.05 compared with sEB). An increase in STV contributes to the initiation of sEB, whereas an increase in SDR is important for the perpetuation of non-self-terminating TdPs.NEW & NOTEWORTHY This study compared two well-established electrophysiological parameters, being temporal and spatial dispersion of repolarization, and provided new insights into their interplay in the arrhythmogenesis of torsades de pointes arrhythmias. Although it confirmed that an increase in temporal dispersion of repolarization contributes to the initiation of single ectopic beats, it showed that an increase in spatial dispersion of repolarization is important for the perpetuation of non-self-terminating torsades de pointes arrhythmias.
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Bloqueo Atrioventricular/fisiopatología , Modelos Cardiovasculares , Torsades de Pointes/fisiopatología , Potenciales de Acción , Animales , Bloqueo Atrioventricular/complicaciones , Perros , Femenino , Masculino , Tiempo de Reacción , Torsades de Pointes/etiologíaRESUMEN
INTRODUCTION: Chronic total coronary occlusions (CTOs) have been associated with a higher prevalence of ventricular arrhythmias compared to patients without a CTO. We evaluated the effect of CTO revascularization on electrocardiographic (ECG) variables. METHODS: We studied a selection of ST-elevation myocardial infarction patients with a concomitant CTO enrolled in the EXPLORE trial. ECG variables and cardiac function were analysed at baseline and at 4â¯months follow-up. RESULTS: Patients were randomized to percutaneous coronary intervention (PCI) of their CTO (nâ¯=â¯77) or to no-CTO PCI (nâ¯=â¯81). At follow-up, median QT dispersion was significantly lower in the CTO PCI group compared to the no-CTO PCI group (46â¯ms [33-58] vs. 54â¯ms [37-68], Pâ¯=â¯0.043). No independent association was observed between ECG variables and cardiac function. CONCLUSION: Revascularization of a CTO after STEMI significantly shortened QT dispersion at 4â¯months follow-up. These findings support the hypothesis that CTO revascularization reduces the pro-arrhythmic substrate in CTO patients.
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Oclusión Coronaria/terapia , Electrocardiografía , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST/fisiopatología , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/etiología , Oclusión Coronaria/complicaciones , Oclusión Coronaria/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Infarto del Miocardio con Elevación del ST/complicaciones , Infarto del Miocardio con Elevación del ST/terapiaRESUMEN
AIMS: The chronic complete atrioventricular block (CAVB) dog is highly sensitive for drug-induced torsade de pointes (TdP) arrhythmias. Focal mechanisms have been suggested as trigger for TdP onset; however, its exact mechanism remains unclear. In this study, detailed mapping of the ventricles was performed to assess intraventricular heterogeneity of repolarization in relation to the initiation of TdP. METHODS AND RESULTS: In 8 CAVB animals, 56 needles, each containing 4 electrodes, were inserted in the ventricles. During right ventricular apex pacing (cycle length: 1000-1500 ms), local unipolar electrograms were recorded before and after administration of dofetilide to determine activation and repolarization times (RTs). Maximal RT differences were calculated in the left ventricle (LV) within adjacent electrodes in different orientations (transmural, vertical, and horizontal) and within a square of four needles (cubic dispersion). Dofetilide induced TdP in five out of eight animals. Right ventricle-LV was similar between inducible and non-inducible dogs at baseline (327 ± 30 vs. 345 ± 17 ms) and after dofetilide administration (525 ± 95 vs. 508 ± 15 ms). All measurements of intraventricular dispersion were not different at baseline, but this changed for horizontal (206 ± 20 vs. 142 ± 34 ms) and cubic dispersion (272 ± 29 vs. 176 ± 48 ms) after dofetilide: significantly higher values in inducible animals. Single ectopic beats and the first TdP beat arose consistently from a subendocardially located electrode terminal with the shortest RT in the region with largest RT differences. CONCLUSION: Chronic complete atrioventricular block dogs susceptible for TdP demonstrate higher RT differences. Torsade de pointes arises from a region with maximal heterogeneity of repolarization suggesting that a minimal gradient is required in order to initiate TdP.
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Bloqueo Atrioventricular/complicaciones , Bloqueo Atrioventricular/fisiopatología , Mapeo del Potencial de Superficie Corporal/métodos , Modelos Animales de Enfermedad , Sistema de Conducción Cardíaco/fisiopatología , Torsades de Pointes/etiología , Torsades de Pointes/fisiopatología , Animales , Enfermedad Crónica , Perros , Humanos , Especificidad de la EspecieRESUMEN
Background An elegant bedside provocation test has been shown to aid the diagnosis of long-QT syndrome (LQTS) in a retrospective cohort by evaluation of QT intervals and T-wave morphology changes resulting from the brief tachycardia provoked by standing. We aimed to prospectively determine the potential diagnostic value of the standing test for LQTS. Methods and Results In adults suspected for LQTS who had a standing test, the QT interval was assessed manually and automated. In addition, T-wave morphology changes were determined. A total of 167 controls and 131 genetically confirmed patients with LQTS were included. A prolonged heart rate-corrected QT interval (QTc) (men ≥430 ms, women ≥450 ms) at baseline before standing yielded a sensitivity of 61% (95% CI, 47-74) in men and 54% (95% CI, 42-66) in women, with a specificity of 90% (95% CI, 80-96) and 89% (95% CI, 81-95), respectively. In both men and women, QTc≥460 ms after standing increased sensitivity (89% [95% CI, 83-94]) but decreased specificity (49% [95% CI, 41-57]). Sensitivity further increased (P<0.01) when a prolonged baseline QTc was accompanied by a QTc≥460 ms after standing in both men (93% [95% CI, 84-98]) and women (90% [95% CI, 81-96]). However, the area under the curve did not improve. T-wave abnormalities after standing did not further increase the sensitivity or the area under the curve significantly. Conclusions Despite earlier retrospective studies, a baseline ECG and the standing test in a prospective evaluation displayed a different diagnostic profile for congenital LQTS but no unequivocal synergism or advantage. This suggests that there is markedly reduced penetrance and incomplete expression in genetically confirmed LQTS with retention of repolarization reserve in response to the brief tachycardia provoked by standing.
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Electrocardiografía , Síndrome de QT Prolongado , Masculino , Humanos , Adulto , Femenino , Estudios Retrospectivos , Electrocardiografía/métodos , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/congénito , Taquicardia , Posición de PieRESUMEN
Background: An electrical storm of Torsade de Pointes arrhythmias (TdP) can be reproducibly induced in the anesthetized chronic AV-block (CAVB) dog by infusion of the IKr-blocker dofetilide. Earlier studies showed that these arrhythmias 1) arise from locations with high spatial dispersion in repolarization (SDR) and 2) can be suppressed by high-rate pacing. We examined whether suppression of TdP by high-rate pacing is established through a decrease in SDR in the CAVB dog. Methods: Dofetilide (25 µg/kg in 5 min) was administered to 5 anesthetized CAVB dogs to induce TdP arrhythmias. During the experiments, animals were continuously paced from the right ventricular apex at 50 beats/minute (RVA50). Upon TdP occurrence and conversion, RVA pacing was consecutively set to 100, 80 and 60 beats/minute for 2 min, referred to as pacing blocks. To determine the additional anti-arrhythmic effects of HRP over defibrillation alone, the number of arrhythmic events and SDR at RVA100 were compared to data from three previously conducted experiments, in which dogs underwent the same experimental protocol but were paced at RVA60 upon TdP occurrence (RVA60retro). In all experiments, recordings included surface electrocardiogram and mapping by 56 intramural needles, each recording four electrograms, evenly inserted into the ventricular walls and septum. For each pacing block, the number of ectopic beats (EB), and TdP severity were scored. SDR was quantified as the average difference in repolarization time within four squared needles (SDRcubic). Results: In 4 out of 5 animals, pacing at RVA100 suppressed TdP occurrence. One dog could not be converted by defibrillation after the initial TdP. Compared to RVA50, pacing at RVA100, but not RVA80 and RVA60, significantly reduced the TdP score (78 ± 33 vs. 0 ± 0, p < 0.05 and vs. 12.5 ± 25 and 25 ± 50, both p > 0.05). The reduction in TdP score was reflected by a significant decrease in SDRcubic (125 ± 46 ms before TdP vs. 49 ± 18 ms during RVA100, p < 0.05), and SDR was smaller than in the RVA60retro animals (101 ± 52 ms, p < 0.05 vs. RVA100). Conclusion: In CAVB dogs, high-rate pacing effectively suppresses TdP, which, at least in part, results from a spatial homogenization of cardiac repolarization, as reflected by a decrease in SDR.
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Obesity is a significant risk factor for arrhythmic cardiovascular death. Interactions between epicardial adipose tissue (EAT) and myocytes are thought to play a key role in the development of arrhythmias. In this review, the authors investigate the influence of EAT on arrhythmogenesis. First, they summarize electrocardiographic evidence showing the association between increased EAT volume and atrial and ventricular conduction delay. Second, they detail the structural cross talk between EAT and the heart and its arrhythmogenicity. Adipose tissue infiltration within the myocardium constitutes an anatomical obstacle to cardiac excitation. It causes activation delay and increases the risk of arrhythmias. Intercellular electrical coupling between cardiomyocytes and EAT can further slow conduction and increase the risk of block, favoring re-entry and arrhythmias. Finally, EAT secretes multiple substances that influence cardiomyocyte electrophysiology either by modulating ion currents and electrical coupling or by stimulating fibrosis. Thus, structural and paracrine cross talk between EAT and cardiomyocytes facilitates arrhythmias.
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Tejido Adiposo/fisiopatología , Arritmias Cardíacas/etiología , Trastorno del Sistema de Conducción Cardíaco/fisiopatología , Cardiología/métodos , Pericardio/fisiopatología , Adipocitos/citología , Adipoquinas/metabolismo , Tejido Adiposo/metabolismo , Animales , Cardiología/normas , Enfermedades Cardiovasculares/metabolismo , Electrofisiología , Uniones Comunicantes/metabolismo , Atrios Cardíacos/fisiopatología , Frecuencia Cardíaca , Ventrículos Cardíacos/fisiopatología , Humanos , Ratones , Miocardio/metabolismo , Miocardio/patología , Miocitos Cardíacos/metabolismo , Obesidad , Potasio/metabolismo , PrevalenciaRESUMEN
Ablation of sites showing Purkinje activity is antiarrhythmic in some patients with idiopathic ventricular fibrillation (iVF). The mechanism for the therapeutic success of ablation is not fully understood. We propose that deeper penetrance of the Purkinje network allows faster activation of the ventricles and is proarrhythmic in the presence of steep repolarization gradients. Reduction of Purkinje penetrance, or its indirect reducing effect on apparent propagation velocity may be a therapeutic target in patients with iVF.
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Background: The detection and localization of electrophysiological substrates currently involve invasive cardiac mapping. Electrocardiographic imaging (ECGI) using the equivalent dipole layer (EDL) method allows the noninvasive estimation of endocardial and epicardial activation and repolarization times (AT and RT), but the RT validation is limited to in silico studies. We aimed to assess the temporal and spatial accuracy of the EDL method in reconstructing the RTs from the surface ECG under physiological circumstances and situations with artificially induced increased repolarization heterogeneity. Methods: In four Langendorff-perfused pig hearts, we simultaneously recorded unipolar electrograms from plunge needles and pseudo-ECGs from a volume-conducting container equipped with 61 electrodes. The RTs were computed from the ECGs during atrial and ventricular pacing and compared with those measured from the local unipolar electrograms. Regional RT prolongation (cooling) or shortening (pinacidil) was achieved by selective perfusion of the left anterior descending artery (LAD) region. Results: The differences between the computed and measured RTs were 19.0 ± 17.8 and 18.6 ± 13.7 ms for atrial and ventricular paced beats, respectively. The region of artificially delayed or shortened repolarization was correctly identified, with minimum/maximum RT roughly in the center of the region in three hearts. In one heart, the reconstructed region was shifted by ~2.5 cm. The total absolute difference between the measured and calculated RTs for all analyzed patterns in selectively perfused hearts (n = 5) was 39.6 ± 27.1 ms. Conclusion: The noninvasive ECG repolarization imaging using the EDL method of atrial and ventricular paced beats allows adequate quantitative reconstruction of regions of altered repolarization.
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BACKGROUND: Torsades de pointes arrhythmia is a potentially lethal polymorphic ventricular tachyarrhythmia (pVT) in the setting of long QT syndrome. Arrhythmia susceptibility is influenced by risk factors modifying repolarization. OBJECTIVE: The purpose of this article was to characterize repolarization duration and heterogeneity in relation to pVT inducibility and maintenance. METHODS: Sotalol was infused regionally or globally in isolated Langendorff blood-perfused pig hearts (N = 7) to create repolarization time (RT) heterogeneities. Programmed stimulation and epicardial activation and repolarization mapping were performed. The role of RT (heterogeneities) was studied in more detail using a computer model of the human heart. RESULTS: pVTs (n = 11) were inducible at a critical combination of RT and RT heterogeneities. The pVT cycle lengths were similar in the short and long RT regions. Short-lasting pVTs were maintained by focal activity while longer-lasting pVTs by reentry wandering along the interface between the 2 regions. Local restitution curves from the long and short RT regions crossed. This was associated with T-wave inversion at coupling intervals at either side of the crossing point. These experimental observations were confirmed by the computer simulations. CONCLUSION: pVTs are inducible within a critical range of RT and RT heterogeneities and are maintained by reentry wandering along the repolarization gradient. Double potentials localize at the core of the reentrant circuit and reflect phase singularities. RT gradient and T waves invert with short-coupled premature beats in the long RT region as a result of the crossing of the restitution curves allowing reentry initiation.
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Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca/fisiología , Síndrome de QT Prolongado/fisiopatología , Torsades de Pointes/complicaciones , Potenciales de Acción/fisiología , Animales , Modelos Animales de Enfermedad , Electrocardiografía , Síndrome de QT Prolongado/etiología , Porcinos , Torsades de Pointes/fisiopatologíaRESUMEN
AIMS: Enhanced sympathetic activity during acute ischaemia is arrhythmogenic, but the underlying mechanism is unknown. During ischaemia, a diastolic current flows from the ischaemic to the non-ischaemic myocardium. This 'injury' current can cause ventricular premature beats (VPBs) originating in the non-ischaemic myocardium, especially during a deeply negative T wave in the ischaemic zone. We reasoned that shortening of repolarization in myocardium adjacent to ischaemic myocardium increases the 'injury' current and causes earlier deeply negative T waves in the ischaemic zone, and re-excitation of the normal myocardium. We tested this hypothesis by activation and repolarization mapping during stimulation of the left stellate ganglion (LSG) during left anterior descending coronary artery (LAD) occlusion. METHODS AND RESULTS: In nine pigs, five subsequent episodes of acute ischaemia, separated by 20 min of reperfusion, were produced by occlusion of the LAD and 121 epicardial local unipolar electrograms were recorded. During the third occlusion, left stellate ganglion stimulation (LSGS) was initiated after 3 min for a 30-s period, causing a shortening of repolarization in the normal myocardium by about 100 ms. This resulted in more negative T waves in the ischaemic zone and more VPBs than during the second, control, occlusion. Following the decentralization of the LSG (including removal of the right stellate ganglion and bilateral cervical vagotomy), fewer VPBs occurred during ischaemia without LSGS. During LSGS, the number of VPBs was similar to that recorded before decentralization. CONCLUSION: LSGS, by virtue of shortening of repolarization in the non-ischaemic myocardium by about 100 ms, causes deeply negative T waves in the ischaemic tissue and VPBs originating from the normal tissue adjacent to the ischaemic border.
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Potenciales de Acción , Frecuencia Cardíaca , Corazón/inervación , Isquemia Miocárdica/complicaciones , Ganglio Estrellado/fisiopatología , Complejos Prematuros Ventriculares/etiología , Animales , Modelos Animales de Enfermedad , Estimulación Eléctrica , Femenino , Isquemia Miocárdica/fisiopatología , Sus scrofa , Factores de Tiempo , Complejos Prematuros Ventriculares/fisiopatologíaRESUMEN
INTRODUCTION: Torsade de pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog model result from proarrhythmic factors, which trigger TdP and/or reinforce the arrhythmic substrate. This study investigated electrophysiological and arrhythmogenic consequences of severe bradycardia for TdP. METHODS: Dofetilide (25 µg/kg per 5 min) was administered to eight anesthetized, idioventricular rhythm (IVR) remodeled CAVB dogs in two serial experiments: once under 60 beats per minute (bpm), right ventricular apex paced (RVA60) conditions, once under more bradycardic IVR conditions. Recordings included surface electrocardiogram and short-term variability (STV) of repolarization from endocardial unipolar electrograms. TdP inducibility (three or more episodes within 10 min after start of dofetilide) and arrhythmic activity scores (AS) were established. Mapping experiments in 10 additional dogs determined the effect of lowering rate on STV and spatial dispersion of repolarization (SDR) in baseline. RESULTS: IVR-tested animals had longer baseline RR-interval (1,403 ± 271 ms) and repolarization intervals than RVA60 animals. Dofetilide increased STV similarly under both rhythm strategies. Nevertheless, TdP inducibility and AS were higher under IVR conditions (6/8 and 37 ± 27 vs. 1/8 and 8 ± 12 in RVA60, respectively, both p < 0.05). Mapping: Pacing from high (128 ± 10 bpm) to middle (88 ± 10 bpm) to experimental rate (61 ± 3 bpm) increased all electrophysiological parameters, including interventricular dispersion, due to steeper left ventricular restitution curves, and intraventricular SDR: maximal cubic dispersion from 60 ± 14 (high) to 69 ± 17 (middle) to 84 ± 22 ms (p < 0.05 vs. high and middle rate). CONCLUSION: In CAVB dogs, severe bradycardia increases the probability and severity of arrhythmic events by heterogeneously causing electrophysiological instability, which is mainly reflected in an increased spatial, and to a lesser extent temporal, dispersion of repolarization.
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Genome Wide Association Studies (GWAS) have provided an enormous amount of data on genomic loci associated with cardiac electrophysiology and arrhythmias. Clinical relevance, however, remains unclear since GWAS do not provide a mechanistic explanation for this association. Determining the electrophysiological relevance of variants for arrhythmias would aid development of risk stratification models for patients with arrhythmias. In this review, we give an overview of genetic variants related to ECG intervals and arrhythmogenic pathologies and discuss how these variants may influence cardiac electrophysiology and the occurrence of arrhythmias.
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BACKGROUND: Re-entrant ventricular tachycardia may be non-inducible or haemodynamically compromising, requiring assessment of the electrophysiological properties of the myocardium during sinus rhythm (i.e., substrate mapping). Areas of heart tissue with slow conduction can act as a critical isthmus for re-entrant electrical excitation and are a potential target for ablation therapy. AIM: To develop and validate a novel metric of local conduction delay in the heart, the amplitude-normalized electrogram area (norm_EA). METHODS: A computational model of a propagating mouse action potential was used to establish the impact of altering sodium channel conductance, intracellular conductivity, fibrosis density, and electrode size/orientation on bipolar electrogram morphology. Findings were then validated in experimental studies in mouse and guinea pig hearts instrumented for the recording of bipolar electrograms from a multipolar linear mapping catheter. norm_EA was calculated by integrating the absolute area of a bipolar electrogram divided by the electrogram amplitude. Electrogram metrics were correlated with the local conduction delay during sodium channel block, gap junction inhibition, and acute ischemia. RESULTS: In computational simulations, reducing sodium channel conductance and intracellular conductivity resulted in a decrease in signal amplitude and increase in norm_EA (reflecting a broadening of electrogram morphology). For larger electrodes (3 mm diameter/7.1 mm2 area), the change in norm_EA was essentially linear with the change in local conduction delay. Experimental studies supported this finding, showing that the magnitude of change in norm_EA induced by flecainide (1-4 µM), carbenoxolone (10-50 µM), and low-flow ischemia (25% of initial flow rate) was linearly correlated with the local conduction delay in each condition (r 2 = 0.92). Qualitatively similar effects were observed in guinea pig hearts perfused with flecainide. Increasing fibrosis density in the computational model also resulted in a decrease in signal amplitude and increase in norm_EA. However, this remains to be validated using experimental/clinical data of chronic infarct. CONCLUSION: norm_EA is a quantitative measure of local conduction delay between the electrode pair that generates a bipolar electrogram, which may have utility in electrophysiological substrate mapping of non-inducible or haemodynamically compromising tachyarrhythmia.
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BACKGROUND: Dispersion in ventricular repolarization is relevant for arrhythmogenesis. OBJECTIVE: The purpose of this study was to determine the spatiotemporal effects of sympathetic stimulation on ventricular repolarization. METHODS: In 5 anesthetized female open-chest pigs, ventricular repolarization was measured from the anterior, lateral, and posterior walls of the left ventricle (LV) and right ventricle using up to 40 transmural plunge needles (4 electrodes each) before and after left stellate ganglion stimulation (LSGS) and right stellate ganglion stimulation. In addition, LSGS was performed in 3 pigs (2 male, 1 female) before and after verapamil (5-10 mg/h) administration. RESULTS: LSGS yielded a biphasic response in repolarization in the lateral and posterior walls of the LV, with prolongation at â¼5 seconds (10 ± 1.5 ms) and shortening at 20-30 seconds of stimulation (-28.9 ± 4.4 ms) during a monotonic pressure increase. While the initial prolongation was abolished by verapamil, late shortening was augmented. Sequential transections of the vagal nerve and stellate ganglia augmented repolarization dispersion responses to LSGS in 2 of 5 hearts. An equal pressure increase by aortic occlusion resulted in a homogeneous shortening of repolarization in the LV, and the effects were smaller than those during LSGS. Right stellate stimulation shortened repolarization mainly in the anterior LV wall, but the effects were smaller than those of LSGS. CONCLUSION: LSGS first prolongs (through the L-type calcium current) and then shortens repolarization. The effect of LSGS was prominent in the posterior and lateral, not the anterior, LV walls.
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Estimulación Eléctrica/métodos , Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca/fisiología , Ventrículos Cardíacos/fisiopatología , Ganglio Estrellado/fisiopatología , Taquicardia Ventricular/terapia , Función Ventricular Izquierda/fisiología , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Pronóstico , Porcinos , Taquicardia Ventricular/fisiopatologíaRESUMEN
BACKGROUND: Observational studies suggest that in patients with a CTO successful recanalization is associated with better clinical outcome. This could be related to a reduction in the occurrence of arrhythmias, which may result from modifications of the hibernating myocardium in a CTO region. METHODS AND RESULTS: We aimed to evaluate the effect of CTO PCI on electrophysiological parameters, and conducted a systematic review and meta-analysis according to the PRISMA guidelines. MEDLINE and EMBASE were searched. Titles and abstracts identified by the search strategy were independently screened by two investigators. Data were extracted and used for meta-analyses where possible. In total, eight studies incorporating 467 patients were included in this review, evaluating the effect of successful CTO PCI on various ECG parameters. Three studies showed a significant decrease in mean QT dispersion of 17.46ms [95% CI 10.62-24.30] after successful CTO PCI. QTc dispersion also decreased significantly, with a mean decrease of 18.74ms [95% CI 11.53-25.94]. In one trial a significant decrease in Tp-e interval in leads V2 and V5, and a significant decrease in Tp-e/QT ratio in leads V2 and V5 post-CTO PCI were observed. CONCLUSIONS: This first systematic review and meta-analysis suggests that successful CTO PCI is associated with an immediate decrease in ECG parameters that reflect heterogeneity in depolarization and repolarization, which could lead to a reduction in the risk for ventricular arrhythmias and sudden cardiac death. We raise the hypothesis that hibernating myocardium in a CTO region may not be as deeply "in sleep" as one would assume.
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Arritmias Cardíacas/diagnóstico , Oclusión Coronaria/cirugía , Electrocardiografía , Intervención Coronaria Percutánea , Potenciales de Acción , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/prevención & control , Enfermedad Crónica , Oclusión Coronaria/diagnóstico , Oclusión Coronaria/fisiopatología , Frecuencia Cardíaca , Humanos , Intervención Coronaria Percutánea/efectos adversos , Valor Predictivo de las Pruebas , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: Enhanced late sodium current (late INa ) in heart failure and long QT syndrome type 3 is proarrhythmic. This study investigated the antiarrhythmic effect and mode of action of the selective and potent late INa inhibitor GS-458967 (GS967) against Torsades de Pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog. EXPERIMENTAL APPROACH: Electrophysiological and antiarrhythmic effects of GS967 were evaluated in isolated canine ventricular cardiomyocytes and CAVB dogs with dofetilide-induced early afterdepolarizations (EADs) and TdP, respectively. Mapping of intramural cardiac electrical activity in vivo was conducted to study effects of GS967 on spatial dispersion of repolarization. KEY RESULTS: GS967 (IC50 ~200nM) significantly shortened repolarization in canine ventricular cardiomyocytes and sinus rhythm (SR) dogs, in a concentration and dose-dependent manner. In vitro, despite addition of 1µM GS967, dofetilide-induced EADs remained present in 42% and 35% of cardiomyocytes from SR and CAVB dogs, respectively. Nonetheless, GS967 (787±265nM) completely abolished dofetilide-induced TdP in CAVB dogs (10/14 after dofetilide to 0/14 dogs after GS967), while single ectopic beats (sEB) persisted in 9 animals. In vivo mapping experiments showed that GS967 significantly reduced spatial dispersion of repolarization: cubic dispersion was significantly decreased from 237±54ms after dofetilide to 123±34ms after GS967. CONCLUSION AND IMPLICATIONS: GS967 terminated all dofetilide-induced TdP without completely suppressing EADs and sEB in vitro and in vivo, respectively. The antiarrhythmic mode of action of GS967, through the reduction of spatial dispersion of repolarization, seems to predominantly impede the perpetuation of arrhythmic events into TdP rather than their initiating trigger.
Asunto(s)
Antiarrítmicos/farmacología , Arritmias Cardíacas/tratamiento farmacológico , Piridinas/farmacología , Torsades de Pointes/tratamiento farmacológico , Triazoles/farmacología , Animales , Antiarrítmicos/administración & dosificación , Arritmias Cardíacas/inducido químicamente , Perros , Relación Dosis-Respuesta a Droga , Miocitos Cardíacos/efectos de los fármacos , Fenetilaminas , Piridinas/administración & dosificación , Sulfonamidas , Torsades de Pointes/inducido químicamente , Triazoles/administración & dosificaciónRESUMEN
The left ventricular (LV) coronary-perfused canine wedge preparation is a model commonly used for studying cardiac repolarization. In wedge studies, transmembrane potentials typically are recorded; whereas, extracellular electrical recordings are commonly used in intact hearts. We compared electrically measured activation recovery interval (ARI) patterns in the intact heart with those recorded at the same location in the LV wedge preparation. We also compared electrically recorded and optically obtained ARIs in the LV wedge preparation. Five Langendorff-perfused canine hearts were paced from the right atrium. Local activation and repolarization times were measured with eight transmural needle electrodes. Subsequently, left ventricular coronary-perfused wedge preparations were prepared from these hearts while the electrodes remained in place. Three electrodes remained at identical positions as in the intact heart. Both electrograms and optical action potentials were recorded (pacing cycle length 400-4000 msec) and activation and repolarization patterns were analyzed. ARIs found in the subepicardium were shorter than in the subendocardium in the LV wedge preparation but not in the intact heart. The transmural ARI gradient recorded at the cut surface of the wedge was not different from that recorded internally. ARIs recorded internally and at the cut surface in the LV wedge preparation, both correlated with optically recorded action potentials. ARI and RT gradients in the LV wedge preparation differed from those in the intact canine heart, implying that those observations in human LV wedge preparations also should be extrapolated to the intact human heart with caution.
Asunto(s)
Potenciales de Acción , Electrocardiografía/métodos , Corazón/fisiología , Función Ventricular Izquierda , Animales , Perros , Reproducibilidad de los Resultados , Imagen de Colorante Sensible al VoltajeRESUMEN
BACKGROUND: To evaluate QT-interval dynamics in patients and in drug safety analysis, beat-to-beat QT-interval measurements are increasingly used. However, interobserver differences, aberrant T-wave morphologies and changes in heart axis might hamper accurate QT-interval measurements. OBJECTIVE: To develop and validate a QT-interval algorithm robust to heart axis orientation and T-wave morphology that can be applied on a beat-to-beat basis. METHODS: Additionally to standard ECG leads, the root mean square (ECGRMS), standard deviation and vectorcardiogram were used. QRS-onset was defined from the ECGRMS. T-wave end was defined per individual lead and scalar ECG using an automated tangent method. A median of all T-wave ends was used as the general T-wave end per beat. Supine-standing tests of 73 patients with Long-QT syndrome (LQTS) and 54 controls were used because they have wide ranges of RR and QT-intervals as well as changes in T-wave morphology and heart axis orientation. For each subject, automatically estimated QT-intervals in three random complexes chosen from the low, middle and high RR range, were compared with manually measured QT-intervals by three observers. RESULTS: After visual inspection of the randomly selected complexes, 21 complexes were excluded because of evident noise, too flat T-waves or premature ventricular beats. Bland-Altman analyses of automatically and manually determined QT-intervals showed a bias of <4ms and limits of agreement of ±25ms. Intra-class coefficient indicated excellent agreement (>0.9) between the algorithm and all observers individually as well as between the algorithm and the mean QT-interval of the observers. CONCLUSION: Our automated algorithm provides reliable beat-to-beat QT-interval assessment, robust to heart axis and T-wave morphology.