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Background: Sole pulmonary vein (PV) isolation by ablation therapy prevents atrial fibrillation (AF) in patients with short episodes of AF and without comorbidities. Since incomplete PV isolation can be curative, we tested the hypothesis that the PV in the absence of remodeling and comorbidities contains structural and functional properties that are proarrhythmic for AF initiation by reentry. Methods: We performed percutaneous transvenous in vivo endocardial electrophysiological studies and quantitative histological analysis of PV from healthy sheep. Results: The proximal PV contained more myocytes than the distal PV and a higher percentage of collagen and fat tissue relative to myocytes than the left atrium. Local fractionated electrograms occurred in both the distal and proximal PVs, but a large local activation (>0.75 mV) was more often present in the proximal PV than in the distal PV (86 vs. 50% of electrograms, respectively, p = 0.017). Atrial arrhythmias (run of premature atrial complexes) occurred more often following the premature stimulation in the proximal PV than in the distal PV (p = 0.004). The diastolic stimulation threshold was higher in the proximal PV than in the distal PV (0.7 [0.3] vs. 0.4 [0.2] mA, (median [interquartile range]), p = 0.004). The refractory period was shorter in the proximal PV than in the distal PV (170 [50] vs. 248 [52] ms, p < 0.001). A linear relation existed between the gradient in refractoriness (distal-proximal) and atrial arrhythmia inducibility in the proximal PV. Conclusion: The structural and functional properties of the native atrial-PV junction differ from those of the distal PV. Atrial arrhythmias in the absence of arrhythmia-induced remodeling are caused by reentry in the atrial-PV junction. Ablative treatment of early paroxysmal AF, rather than complete isolation of focal arrhythmia, may be limited to inhibition of reentry.
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A comprehensive understanding of the interaction between triggers and electrical substrates leading to ventricular fibrillation (VF) and sudden cardiac arrest is lacking, and electrical substrates are difficult to detect and localize with current clinical tools. Here, we created repolarization time (RT) dispersion by regional drug infusion in perfused explanted human (n = 1) and porcine (n = 6) hearts and in a computational model of the human ventricle. Arrhythmia induction was tested with a single ventricular extrastimulus applied at the early or late RT region. Arrhythmias could only be induced from early RT regions. Vulnerability to VF increased with RT gradient steepness and with larger areas of early RT, but not with markers on the body-surface electrocardiogram. Noninvasive electrocardiographic imaging was performed in survivors of idiopathic VF (n = 11), patients with frequent premature ventricular complexes (PVCs) but no history of sudden cardiac arrest (n = 7), and controls (n = 10). In survivors of idiopathic VF, RT gradients were steeper than in controls, without differences in the clinical electrocardiogram, consistent with the ex vivo results. Patients with idiopathic VF also showed local myocardial regions with distinctly early-versus-late RT that were more balanced in size than in controls. Premature beats originated more often from the early RT regions in idiopathic VF survivors than in patients with frequent PVCs only. Thus, idiopathic VF emerges from the spatiotemporal interaction of a premature beat from an early-repolarization region with critical repolarization dispersion in that region. Electrocardiographic imaging can uncover the co-occurrence of these abnormalities.
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Parada Cardíaca , Fibrilação Ventricular , Animais , Eletrocardiografia/métodos , Ventrículos do Coração , Humanos , Suínos , Fibrilação Ventricular/diagnósticoRESUMO
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: Pulmonary vein (PV) ablation is unsuccessful in atrial fibrillation (AF) patients with high left atrial (LA) pressure. Increased atrial stretch by increased pressure is proarrhythmic for AF, and myocardial scar alters wall deformation. We hypothesized that localized PV scar is proarrhythmic for AF in high LA pressure. METHODS: Radiofrequency energy was delivered locally in the right PV of healthy sheep. The sheep recovered for 4 months. Explanted hearts (n = 9 PV scar, n = 9 controls) were perfused with 1:4 blood:Tyrode's solution in a four-chamber working heart setup. Programmed PV stimulation was performed during low (â¼12 mmHg) and high (â¼25 mmHg) LA pressure. An AF inducibility index was calculated based on the number of induction attempts and the number of attempts causing AF (run of ≥ 20 premature atrial complexes). RESULTS: In high LA pressure, the presence of PV scar increased the AF inducibility index compared with control hearts (0.83 ± 0.20 vs. 0.38 ± 0.40 arb. unit, respectively, p = 0.014). The diastolic stimulation threshold in high LA pressure was higher (108 ± 23 vs. 77 ± 16 mA, respectively, p = 0.006), and its heterogeneity was increased in hearts with PV scar compared with controls. In high LA pressure, the refractory period was shorter in PV scar than in control hearts (178 ± 39 vs. 235 ± 48 ms, p = 0.011). CONCLUSION: Localized PV scar only in combination with increased LA pressure facilitated the inducibility of AF. This was associated with changes in tissue excitability remote from the PV scar. Localized PV ablation is potentially proarrhythmic in patients with increased LA pressure.
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Mammalian heart cells and cells of leaves of Dionaea muscipula share the ability to generate propagated action potentials, because the excitable cells are electrically coupled. In the heart the propagated action potential causes synchronized contraction of the heart muscle after automatic generation of the impulse in the sinus node. In Dionaea propagation results in closure of the trap after activation of trigger hairs by an insect. The electrical activity can be recorded in the extracellular space as an extracellular electrogram, resulting from transmembrane currents. Although the underlying physiological mechanism that causes the electrogram is similar for heart and Dionaea cells, the contribution of the various ions to the transmembrane current is different. We recorded extracellular electrograms from Dionaea leaves and compared the recorded signals with those known from the heart. The morphology of the electrograms differed considerably. In comparison to activation in mammalian myocardium, electrograms of Dionaea are more temporally and spatially variable. Whereas electrograms in healthy myocardium recorded at some distance from the site of activation reveal a simple biphasic pattern, Dionaea activation showed positive, negative or biphasic deflections. Comparison of patch clamp data from plant cells and cardiomyocytes suggests a role of temperature and ion concentrations in extracellular space for the diversity of morphologies of the Dionaea electrograms.
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Droseraceae/fisiologia , Fenômenos Eletrofisiológicos , Coração/fisiologia , Droseraceae/citologia , Espaço Extracelular/metabolismoRESUMO
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 Condução Cardíaco/fisiopatologia , Frequência Cardíaca/fisiologia , Síndrome do QT Longo/fisiopatologia , Torsades de Pointes/complicações , Potenciais de Ação/fisiologia , Animais , Modelos Animais de Doenças , Eletrocardiografia , Síndrome do QT Longo/etiologia , Suínos , Torsades de Pointes/fisiopatologiaRESUMO
BACKGROUND: With increasing clinical use of Electrocardiographic Imaging (ECGI), it is imperative to understand the limits of this technique. The objective of this study is to evaluate a potential-based ECGI approach for activation and repolarization mapping in sinus rhythm. METHOD: Langendorff-perfused pig hearts were suspended in a human-shaped torso tank. Electrograms were recorded with a 108-electrode sock and ECGs with 256 electrodes embedded in the tank surface. Left bundle branch block (LBBB) was developed in 4 hearts through ablation, and repolarization abnormalities in another 4 hearts through regional perfusion of dofetilide and pinacidil. Electrograms were noninvasively reconstructed and reconstructed activation and repolarization features were compared to those recorded. RESULTS: Visual consistency between ECGI and recorded activation and repolarization maps was high. While reconstructed repolarization times showed significantly more error than activation times quantitatively, patterns were reconstructed with a similar level of accuracy. The number of epicardial breakthrough sites was underestimated by ECGI and these were misplaced (>20â¯mm) in location. Likewise, ECGI reconstructed activation maps demonstrated artificial lines of block resulting from a W-shaped QRS waveform that were not present in recorded maps. Nevertheless, ECGI allowed identification of regions of abnormal repolarization reasonably accurately in terms of size, location and timing. CONCLUSIONS: This study validates a potential-based ECGI approach to noninvasively image activation and recovery in sinus rhythm. Despite inaccuracies in epicardial breakthroughs and lines of conduction block, other important clinical features such as regions of abnormal repolarization can be accurately derived making ECGI a valuable clinical tool.
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Arritmias Cardíacas , Mapeamento Potencial de Superfície Corporal , Eletrocardiografia , Animais , Arritmias Cardíacas/diagnóstico , Diagnóstico por Imagem , Testes Diagnósticos de Rotina , SuínosRESUMO
The cardiac autonomic nervous system (ANS) controls normal atrial electrical function. The cardiac ANS produces various neuropeptides, among which the neurokinins, whose actions on atrial electrophysiology are largely unknown. We here demonstrate that the neurokinin substance-P (Sub-P) activates a neurokinin-3 receptor (NK-3R) in rabbit, prolonging action potential (AP) duration through inhibition of a background potassium current. In contrast, ventricular AP duration was unaffected by NK-3R activation. NK-3R stimulation lengthened atrial repolarization in intact rabbit hearts and consequently suppressed arrhythmia duration and occurrence in a rabbit isolated heart model of atrial fibrillation (AF). In human atrial appendages, the phenomenon of NK-3R mediated lengthening of atrial repolarization was also observed. Our findings thus uncover a pathway to selectively modulate atrial AP duration by activation of a hitherto unidentified neurokinin-3 receptor in the membrane of atrial myocytes. NK-3R stimulation may therefore represent an anti-arrhythmic concept to suppress re-entry-based atrial tachyarrhythmias, including AF.
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Átrios do Coração/metabolismo , Canais de Potássio/metabolismo , Receptores da Neurocinina-3/fisiologia , Potenciais de Ação , Animais , Arritmias Cardíacas , Fibrilação Atrial , Função Atrial , Humanos , Bloqueadores dos Canais de Potássio , Coelhos , Receptores da Neurocinina-3/metabolismoRESUMO
Background Electrocardiographic ( ECG ) parameters are regarded as intermediate phenotypes of cardiac arrhythmias. Insight into the genetic underpinnings of these parameters is expected to contribute to the understanding of cardiac arrhythmia mechanisms. Here we used HXB / BXH recombinant inbred rat strains to uncover genetic loci and candidate genes modulating ECG parameters. Methods and Results RR interval, PR interval, QRS duration, and QT c interval were measured from ECG s obtained in 6 male rats from each of the 29 available HXB / BXH recombinant inbred strains. Genes at loci displaying significant quantitative trait loci (QTL) effects were prioritized by assessing the presence of protein-altering variants, and by assessment of cis expression QTL ( eQTL ) effects and correlation of transcript abundance to the respective trait in the heart. Cardiac RNA -seq data were additionally used to generate gene co-expression networks. QTL analysis of ECG parameters identified 2 QTL for PR interval, respectively, on chromosomes 10 and 17. At the chromosome 10 QTL , cis- eQTL effects were identified for Acbd4, Cd300lg, Fam171a2, and Arhgap27; the transcript abundance in the heart of these 4 genes was correlated with PR interval. At the chromosome 17 QTL , a cis- eQTL was uncovered for Nhlrc1 candidate gene; the transcript abundance of this gene was also correlated with PR interval. Co-expression analysis furthermore identified 50 gene networks, 6 of which were correlated with PR interval or QRS duration, both parameters of cardiac conduction. Conclusions These newly identified genetic loci and gene networks associated with the ECG parameters of cardiac conduction provide a starting point for future studies with the potential of identifying novel mechanisms underlying cardiac electrical function.
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Doença do Sistema de Condução Cardíaco/genética , Doença do Sistema de Condução Cardíaco/fisiopatologia , Eletrocardiografia , Redes Reguladoras de Genes , Locos de Características Quantitativas , Animais , Masculino , RatosRESUMO
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.
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Potenciais de Ação , Eletrocardiografia/métodos , Coração/fisiologia , Função Ventricular Esquerda , Animais , Cães , Reprodutibilidade dos Testes , Imagens com Corantes Sensíveis à VoltagemRESUMO
BACKGROUND: J-waves in inferolateral leads are associated with a higher risk for idiopathic ventricular fibrillation. We aimed to test potential mechanisms (depolarization or repolarization dependent) responsible for inferolateral J-waves. We hypothesized that inferolateral J-waves can be caused by regional delayed activation of myocardium that is activated late during normal conditions. METHODS: Computer simulations were performed to evaluate how J-point elevation is influenced by reducing sodium current conductivity (GNa), increasing transient outward current conductivity (Gto), or cellular uncoupling in three predefined ventricular regions (lateral, anterior, or septal). Two pig hearts were Langendorff-perfused with selective perfusion with a sodium channel blocker of lateral or anterior/septal regions. Volume-conducted pseudo-electrocardiograms (ECG) were recorded to detect the presence of J-waves. Epicardial unipolar electrograms were simultaneously recorded to obtain activation times (AT). RESULTS: Simulation data showed that conduction slowing, caused by reduced sodium current, in lateral, but not in other regions induced inferolateral J-waves. An increase in transient outward potassium current or cellular uncoupling in the lateral zone elicited slight J-point elevations which did not meet J-wave criteria. Additional conduction slowing in the entire heart attenuated J-waves and J-point elevations on the ECG, because of masking by the QRS. Experimental data confirmed that conduction slowing attributed to sodium channel blockade in the left lateral but not in the anterior/septal ventricular region induced inferolateral J-waves. J-waves coincided with the delayed activation. CONCLUSION: Reduced sodium current in the left lateral ventricular myocardium can cause inferolateral J-waves on the ECG.
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BACKGROUND: Noninvasive imaging of cardiac activation before ablation of the arrhythmogenic substrate can reduce electrophysiological procedure duration and help choosing between an endocardial or epicardial approach. A noninvasive imaging technique was evaluated that estimates both endocardial and epicardial activation from body surface potential maps. We performed a study in isolated and in situ pig hearts, estimating activation from body surface potential maps during sinus rhythm and localizing endocardial and epicardial stimulation sites. METHODS AND RESULTS: From 3 Langendorff-perfused pig hearts, 180 intramural unipolar electrograms were recorded during sinus rhythm and ectopic activation, together with pseudo-body surface potential map ECGs in 2 of them. From 4 other anesthetized pigs, 64-lead body surface potential maps were recorded during sinus rhythm and ventricular stimulation from 27 endocardial and epicardial sites. The ventricular activation pattern was computed from the recorded QRS complexes. For both Langendorff-perfused hearts, the calculated epicardial and endocardial activation patterns showed good qualitative correspondence to the patterns obtained with needle electrodes. Absolute timing difference for sinus rhythm was 10±5 and 11±8 ms respectively, and for ectopic activation 6±5 and 7±6 ms, respectively. Calculated activation for the in situ hearts in sinus rhythm was similar to patterns recorded in Langendorff-perfused hearts. During stimulation, the distance between the stimulation site and calculated site of earliest activation was 18 (15-27) mm, and 23 of 27 stimulation sites were correctly mapped to either endocardium or epicardium. CONCLUSIONS: Noninvasive activation imaging is able to determine earliest ventricular activation and discriminate endocardial from epicardial origin of activation with clinically relevant accuracy.
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Mapeamento Potencial de Superfície Corporal , Endocárdio/fisiologia , Pericárdio/fisiologia , Tomografia Computadorizada por Raios X , Animais , Cateterismo Cardíaco , Eletrocardiografia , Fluoroscopia , Sistema de Condução Cardíaco/fisiologia , Imageamento Tridimensional , SuínosRESUMO
Following myocardial infarction and atherosclerotic lesion development, monocytes contribute to myocardial protection and repair, while also partaking in myocardial ischemic injury. The balance of proinflammatory and reparative monocyte subsets is crucial in governing these therapeutic and pathological outcomes. Myocardial ischemic damage displays heterogeneity across the myocardium, whereby the subendocardium shows greatest vulnerability to ischemic damage. In this study we examined the transmural distribution of monocyte subsets in response to gradual coronary artery occlusion. CD14(+) monocytes were isolated from peripheral blood of New Zealand White rabbits and divided into two subgroups based on the expression of CD62L. We employed a rabbit model of progressive coronary artery obstruction to induce chronic myocardial ischemia and reinfused fluorescently labeled autologous monocytes. The distribution of fluorescently labeled autologous monocytes was examined with a high-resolution three-dimensional imaging cryomicrotome. The subepicardial layer contained the largest infiltration of both monocyte subgroups, with a significantly greater proportion of CD14(+)CD62L(+) monocytes at the time when the ischemic area was at a maximum. By targeting CD13(+) angiogenic vessels, we confirmed the presence of angiogenesis in epicardial and midmyocardial regions. These myocardial regions demonstrated the highest level of infiltration of both monocyte subsets. Furthermore, CD14(+)CD62L(+) monocytes showed significantly greater migration towards monocyte chemoattractant protein-1, greater adhesive capacity, and higher expression of C-C chemokine receptor type-2 relative to CD14(+)CD62L(-) monocytes. In conclusion, we note selective subepicardial distribution of monocyte subpopulations, with changes in proportion depending on the time after onset of coronary narrowing. Selective homing is supported by divergent migratory properties of each respective monocyte subgroup.
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Quimiotaxia de Leucócito , Estenose Coronária/patologia , Vasos Coronários/patologia , Monócitos/patologia , Infarto do Miocárdio/patologia , Miocárdio/patologia , Animais , Biomarcadores/sangue , Antígenos CD13/metabolismo , Células Cultivadas , Constrição , Estenose Coronária/sangue , Estenose Coronária/fisiopatologia , Vasos Coronários/metabolismo , Vasos Coronários/fisiopatologia , Vasos Coronários/cirurgia , Modelos Animais de Doenças , Selectina L/sangue , Receptores de Lipopolissacarídeos/sangue , Monócitos/metabolismo , Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Neovascularização Fisiológica , Fenótipo , Coelhos , Regeneração , Fatores de TempoRESUMO
Hyperoxia and hyperbaric oxygen therapy can restore oxygen tensions in tissues distressed by ischemic injury and poor vascularization and is believed to also yield angiogenesis and regulate tissue perfusion. The aim of this study was to develop a model in which hyperoxia-driven microvascular changes could be quantified and to test the hypothesis that microcirculatory responses to both normobaric (NB) and hyperbaric (HB) hyperoxic maneuvers are reversible. Sublingual mucosa microcirculation vessel density, proportion of perfused vessels, vessel diameters, microvascular flow index, macrohemodynamic, and blood gas parameters were examined in male rabbits breathing sequential O2/air mixtures of 21%, 55%, 100%, and return to 21% during NB (1.0 bar) and HB (2.5 bar) conditions. The results indicate that NB hyperoxia (55% and 100%) produced significant decreases in microvascular density and vascular diameters (p<0.01 and p<0.05, respectively) accompanied by significant increases in systolic and mean arterial blood pressure (p<0.05, respectively) with no changes in blood flow indices when compared to NB normoxia. HB normoxia/hyperoxia resulted in significant decreases in microvascular density (p<0.05), a transient rise in systolic blood pressure at 55% (p<0.01), and no changes in blood vessel diameter and blood flow indices when compared to NB hyperoxia. All microcirculation parameters reverted back to normal values upon return to NB normoxia. We conclude that NB/HB hyperoxia-driven changes elicit reversible physiological control of sublingual mucosa blood perfusion in the presence of steady cardiovascular function and that the absence of microvascular vasoconstriction during HB conditions suggests a beneficial mechanism associated with maintaining peak tissue perfusion states.
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Oxigenoterapia Hiperbárica , Hiperóxia/fisiopatologia , Microcirculação , Microvasos/fisiopatologia , Soalho Bucal/irrigação sanguínea , Mucosa Bucal/irrigação sanguínea , Animais , Velocidade do Fluxo Sanguíneo , Modelos Animais de Doenças , Hiperóxia/etiologia , Masculino , Microscopia de Vídeo , Coelhos , Fluxo Sanguíneo Regional , Fatores de Tempo , VasoconstriçãoRESUMO
AIMS: The aim of this study was to evaluate the effect of increase in left ventricular (LV) pressure on repolarization and activation-recovery intervals. METHODS AND RESULTS: Six pig hearts were Langendorff-perfused. A compliant liquid-filled balloon, connected with a pressure transducer, inserted through the mitral orifice, could be filled until the required LV systolic pressure was obtained. A grid of 121 electrodes (11 × 11; 5 mm interelectrode distance) was sutured on the LV free wall. Ventricular pacing at 600 ms and at 400 or 450 ms was either performed from the LV wall or from the ventricular septum. Under all these four conditions, the pressure wave occurred at the same moment relative to the onset of the QRS complex. Consequently, the time relation between local repolarization and the pressure wave differed between the various pacing sites. Repolarization times (RTs) at a cycle length (CL) of 600 ms were prolonged by increased pressure. With stimulation from the LV, when the pressure wave coincides with the action potentials (APs) late in their phase (sites with relatively early repolarization), an increase in pressure from 0 to 100 mmHg delayed repolarization more than with stimulation from the septum, when the pressure wave occurs at a relatively earlier phase of the AP (sites with relatively late repolarization). At pacing at CL 400/450 ms, an increase in pressure caused RT prolongation at the LV free wall during LV stimulation, but less RT prolongation or even shortening during septal stimulation. CONCLUSION: The effect of increased LV pressure is synchronization of repolarization.
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Coração/fisiologia , Potenciais de Ação , Animais , Pressão Sanguínea , Estimulação Cardíaca Artificial , Eletrocardiografia , Masculino , Suínos , Função Ventricular EsquerdaRESUMO
Cellular imaging modalities are important for revealing the behavior and role of monocytes in response to neovascularization progression in coronary artery disease. In this study we aimed to develop methods for high-resolution three-dimensional (3D) imaging and quantification of monocytes relative to the entire coronary artery network using a novel episcopic imaging modality. In a series of ex vivo experiments, human umbilical vein endothelial cells and CD14+ monocytes were labeled with fluorescent live cell tracker probes and infused into the coronary artery network of excised rat hearts by a Langendorff perfusion method. Coronary arteries were subsequently infused with fluorescent vascular cast material and processed with an imaging cryomicrotome, whereby each heart was consecutively cut (5 µm slice thickness) and block face imaged at appropriate excitation and emission wavelengths. The resulting image stacks yielded 3D reconstructions of the vascular network and the location of cells administered. Successful detection and quantification of single cells and cell clusters were achieved relative to the coronary network using customized particle detection software. These methods were then applied to an in vivo rabbit model of chronic myocardial ischemia in which autologous monocytes were isolated from peripheral blood, labeled with a fluorescent live cell tracker probe and re-infused into the host animal. The processed 3D image stacks revealed homing of monocytes to the ischemic myocardial tissue. Monocytes detected in the ischemic tissue were predominantly concentrated in the mid-myocardium. Vessel segmentation identified coronary collateral connections relative to monocyte localization. This study established a novel imaging platform to efficiently determine the localization of monocytes in relation to the coronary microvascular network. These techniques are invaluable for investigating the role of monocyte populations in the progression of coronary neovascularization in animal models of chronic and sub-acute myocardial ischemia.
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Vasos Coronários/imunologia , Monócitos/fisiologia , Isquemia Miocárdica/imunologia , Animais , Movimento Celular , Células Cultivadas , Vasos Coronários/patologia , Secções Congeladas , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Masculino , Microscopia de Fluorescência , Isquemia Miocárdica/patologia , Coelhos , Ratos WistarRESUMO
BACKGROUND: The genesis of the electrocardiographic T wave is incompletely understood and subject to controversy. We have correlated the ventricular repolarization sequence with simultaneously recorded T waves. METHODS AND RESULTS: Nine pig hearts were Langendorff-perfused (atrial pacing, cycle length 650 ms). Local activation and repolarization times were derived from unipolar electrograms sampling the ventricular myocardium. Dispersion of repolarization time was determined along 4 anatomic axes: left ventricle (LV)-right ventricle (RV), LV:apico-basal, LV:anterior-posterior, and LV:transmural. The heart was immersed in a fluid-filled bucket containing 61 electrodes to determine Tp (Tpeak in lead of maximum integral), TpTe (Tp to Tend), and TpTe_total (first Tpeak in any lead to last Tend in any lead). Repolarization was nonlinearly distributed in time. RT25 (time at which 25% of sites were repolarized, 288±26 ms) concurred with Tp. TpTe was 38±8 ms, and TpTe_total was 75±9 ms. TpTe_total correlated with dispersion of repolarization time in the entire heart (73±18 ms), but not with dispersion of repolarization times along individual axes (LV-RV, 66±17 ms; LV:apico-basal, 51±18 ms; LV:anterior-posterior, 51±27 ms; mean LV:transmural, 14±7 ms; all n=9). CONCLUSIONS: We provide a correlation between local repolarization and T wave in a pseudo-ECG. Repolarization differences along all anatomic axes contribute to the T wave. TpTe_total represents total dispersion of repolarization. At Tp, ≈25% of ventricular sites have been repolarized.
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Potenciais de Ação/fisiologia , Eletrocardiografia , Sistema de Condução Cardíaco/fisiologia , Função Ventricular/fisiologia , Animais , Eletrodos Implantados , Técnicas Eletrofisiológicas Cardíacas , Coração/fisiologia , Humanos , Masculino , Modelos Animais , Tempo de Reação , Sensibilidade e Especificidade , SuínosRESUMO
AIMS: Recurrences of ventricular fibrillation (VF) during cardiopulmonary resuscitation (CPR) are associated with a reduced chance of survival. The effect of VF during CPR on the myocardium is unknown. We tested the hypothesis that VF during simulated CPR reduces the restoration of the myocardial energy state and contractile function. METHODS AND RESULTS: Twelve porcine hearts were isolated and perfused with the pig's own blood. First, cardiac oxygen consumption was measured by blood gas analysis. Secondly, we simulated sudden cardiac arrest by VF (7 min VF, zero flow) followed by simulated CPR (7 min, 0.3 mL/g/min perfusion rate) in the absence and presence of VF [six hearts were maintained in VF (VF-group), six were defibrillated (defib-group)]. The VF increased the cardiac oxygen consumption by 71% (0.87 ± 0.12 vs. 1.49 ± 0.14 µmol O2/g/min; mean ± SEM, P< 0.001) compared with a ventricular rhythm of 62 beats/min. The presence of VF during simulated CPR after 7 min of cardiac arrest hampered restoration of myocardial creatine-phosphate levels compared with defibrillated hearts (61 ± 9 vs. 87 ± 7% of baseline values, respectively; P< 0.05). The cardiac contractile function was significantly higher in the defib- than in the VF-group (area under the pressure curve 2.29 ± 0.22 vs. 1.72 ± 0.14 s×mm Hg respectively; P< 0.05). CONCLUSIONS: These data demonstrate that the cardiac oxygen consumption is increased by VF and that the presence of VF during CPR hampers the restoration of the myocardial energy state and contractility. Strategies that reduce VF duration without disrupting chest compressions will benefit the restoration of the cardiac energy state during resuscitations.
Assuntos
Reanimação Cardiopulmonar , Fosfocreatina/metabolismo , Fibrilação Ventricular/fisiopatologia , Animais , Gasometria , Morte Súbita Cardíaca/etiologia , Cardioversão Elétrica , Frequência Cardíaca/fisiologia , Técnicas In Vitro , Masculino , Contração Miocárdica/fisiologia , Consumo de Oxigênio/fisiologia , Fosfocreatina/análise , Suínos , Fibrilação Ventricular/complicaçõesRESUMO
BACKGROUND: During heart failure (HF), cardiac metabolic substrate preference changes from fatty acid (FA) toward glucose oxidation. This change may cause progression toward heart failure. We hypothesize that a diet rich in FAs may prevent this process, and that dietary ω3-FAs have an added antiarrhythmic effect based on action potential (AP) shortening in animals with HF. METHODS AND RESULTS: Rabbits were fed a diet containing 1.25% (w/w) high oleic sunflower oil (HF-ω9, N=11), 1.25% fish oil (HF-ω3, N=11), or no supplement (HF-control, N=8). Subsequently, HF was induced by volume and pressure overload. After 4 months, HF-parameters were assessed, electrocardiograms were recorded, and blood and ventricular tissue were collected. Myocytes were isolated for patch clamp or intracellular Ca(2+)- recordings to study electrophysiologic remodeling and arrhythmogenesis. Both the HF-ω9 and the HF-ω3 groups had larger myocardial FA oxidation capacity than HF control. The HF-ω3 group had significantly lower mean (± SEM) relative heart and lung weight (3.3±0.13 and 3.2±0.12 g kg(-1), respectively) than HF control (4.8±0.30 and 4.5±0.23), and shorter QTc intervals (167±2.6 versus 182±6.4). The HF-ω9 also displayed a significantly reduced relative heart weight (3.6±0.26), but had similar QTc (179±4.3) compared with HF control. AP duration in the HF-ω3 group was ≈20% shorter due to increased I(to1) and I(K1) and triggered activity, and Ca(2+)-aftertransients were less than in the HF-ω9 group. CONCLUSIONS: Dietary unsaturated FAs started prior to induction of HF prevent hypertrophy and HF. In addition, fish oil FAs prevent HF-induced electrophysiologic remodeling and arrhythmias.
Assuntos
Arritmias Cardíacas/prevenção & controle , Cardiomegalia/prevenção & controle , Gorduras Insaturadas na Dieta/uso terapêutico , Ácidos Graxos Insaturados/uso terapêutico , Insuficiência Cardíaca/prevenção & controle , Insuficiência Cardíaca/fisiopatologia , Potenciais de Ação/fisiologia , Administração Oral , Animais , Arritmias Cardíacas/patologia , Arritmias Cardíacas/fisiopatologia , Cálcio/metabolismo , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Gorduras Insaturadas na Dieta/administração & dosagem , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Ácidos Graxos Insaturados/administração & dosagem , Insuficiência Cardíaca/patologia , Masculino , Modelos Animais , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Técnicas de Patch-Clamp , CoelhosRESUMO
BACKGROUND: Heterogeneity of repolarization and conduction is a potential source of arrhythmogenesis. In heart failure (HF), intercellular coupling is reduced and heterogeneities may become evident because of reduced intercellular coupling. OBJECTIVE: This study sought to investigate connexin43 (Cx43) expression, conduction velocity (CV), refractoriness and inducibility of arrhythmias at multiple sites of the left ventricle during HF. METHODS: HF was induced by pressure-volume overload in rabbits. Epicardial and intramural mapping was performed in isolated perfused hearts following programmed stimulation. Myocytes were enzymatically dissociated and studied using D-4-ANEPPS fluorescence. Western blotting and immunohistochemistry was performed to quantify heterogeneity of Cx43 expression. RESULTS: Cx43 was heterogeneously reduced in the midmyocardial, but not in the sub epicardium layer of the left ventricular free wall in HF compared to control rabbits. In HF, subepicardial and midmyocardial refractory periods (RPs) were increased compared to control rabbits (148 +/- 3 ms and 143 +/- 3 versus 131 +/- 2 and 129 +/- 2 ms, respectively, both P < 0.001). Also, transmural dispersion of RPs was larger in HF (30 +/- 4 ms) than in control rabbits (24 +/- 3 ms, P < 0.05). Intrinsic dispersion of action potential duration in isolated myocytes was similar in HF and control rabbits. Transmural CV was heterogeneous, although the mean CV was not different between groups. Arrhythmias were more easily inducible in HF, especially from midmyocardium. CONCLUSION: In HF, midmyocardial Cx43 expression is heterogeneously reduced. This is associated with increased transmural dispersion in refractoriness and conduction, and with increased arrhythmia inducibility.