Anti-Arrhythmic Mechanisms of Epidural Blockade After Myocardial Infarction.

BACKGROUND: Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular tachycardia and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear, and its use after myocardial infarction is limited by concerns for potential right ventricular dysfunction. METHODS: Myocardial infarction was created in Yorkshire pigs (N=22) by left anterior descending coronary artery occlusion. Six weeks after myocardial infarction, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. Right and left ventricular hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity and intrinsic cardiac neural activity, and ventricular effective refractory periods and slope of restitution (Smax) were assessed before and after TEA. Ventricular tachyarrhythmia inducibility was assessed by programmed electrical stimulation. RESULTS: TEA reduced inducibility of ventricular tachyarrhythmias by 70%. TEA did not affect right ventricular-systolic pressure or contractility although left ventricular-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular effective refractory periods prolonged significantly at critical sites of arrhythmogenesis, and Smax was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both baroreflex sensitivity and intrinsic cardiac neural activity. CONCLUSIONS: TEA does not compromise right ventricular function in infarcted hearts. Its antiarrhythmic mechanisms are mediated by increases in ventricular effective refractory period and ARIs, decreases in Smax, and reductions in border zone electrophysiological heterogeneities. TEA improves parasympathetic function, which may independently underlie some of its observed antiarrhythmic mechanisms. This study provides novel insights into the antiarrhythmic mechanisms of TEA while highlighting its applicability to the clinical setting.

Thoracic epidural blockade after myocardial infarction benefits from anti-arrhythmic pathways mediated in part by parasympathetic modulation.

Background: Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachyarrhythmias (VT) in small case-series of patients with refractory VT and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear and its use after myocardial infarction (MI) is limited by concerns for potential RV dysfunction. Methods: MI was created in Yorkshire pigs ( N =22) by LAD occlusion. Six weeks post-MI, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. RV and LV hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation-recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity (BRS) and intrinsic cardiac neural activity, and ventricular effective refractory periods (ERP) and slope of restitution (S max ) were assessed before and after TEA. VT/VF inducibility was assessed by programmed electrical stimulation. Results: TEA reduced inducibility of VT/VF by 70%. TEA did not affect RV-systolic pressure or contractility, although LV-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular ERPs prolonged significantly at critical sites of arrhythmogenesis, and S max was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both BRS and intrinsic cardiac neural activity. Conclusion: TEA does not compromise RV function in infarcted hearts. Its anti-arrhythmic mechanisms are mediated by increases in ventricular ERP and ARIs, decreases in S max , and reductions in border zone heterogeneity. TEA improves parasympathetic function, which may independently underlie some of its observed anti-arrhythmic mechanisms. This study provides novel insights into the anti-arrhythmic mechanisms of TEA, while highlighting its applicability to the clinical setting. Abstract Illustration: Myocardial infarction is known to cause cardiac autonomic dysfunction characterized by sympathoexcitation coupled with reduced vagal tone. This pathological remodeling collectively predisposes to ventricular arrhythmia. Thoracic epidural anesthesia not only blocks central efferent sympathetic outflow, but by also blocking ascending projections of sympathetic afferents, relieving central inhibition of vagal function. These complementary autonomic effects of thoracic epidural anesthesia may thus restore autonomic balance, thereby improving ventricular electrical stability and suppressing arrhythmogenesis. DRG=dorsal root ganglion, SG=stellate ganglion.

The derivative of tissue activation as a marker of arrhythmogenic myocardium.

BACKGROUND: Mapping techniques to identify diseased myocardial substrate during ventricular tachycardia ablation procedures remain limited. OBJECTIVE: We hypothesized that tissue derivative of the voltage with respect to time (dV/dt), the slope of the unipolar ventricular electrogram registered by local ventricular activation, represents a unique parameter for identifying potential arrhythmogenic tissue in the ischemic scar border zone. METHODS: Using high-resolution electrical mapping, we examined dV/dt characteristics in the border zone of animals after chronic myocardial infarction (MI). RESULTS: Minimum dV/dt (dV/dtmin) in MI animals was less than that in control animals (-344.7 ± 68.7 in controls vs -174.2 ± 104.5 in MI; P < .001) and related to ventricular fibrosis. In MI animals, dV/dtmin values were divided into high (≤-200 µV/ms) and low (>-200 µV/ms) dV/dtmin. Low dV/dtmin regions harbored arrhythmogenic substrates that were characterized by (1) high responsiveness to sympathetic stimulation, (2) presence of late potentials, and (3) lower unipolar and bipolar voltage amplitudes. CONCLUSION: Our data indicate that dV/dtmin is a unique parameter for identifying arrhythmogenic myocardium and may add a useful metric to conventional mapping strategies.

Proarrhythmic Effects of Sympathetic Activation Are Mitigated by Vagal Nerve Stimulation in Infarcted Hearts.

OBJECTIVES: The goal of this study was to evaluate whether intermittent VNS reduces electrical heterogeneities and arrhythmia inducibility during sympathoexcitation. BACKGROUND: Sympathoexcitation increases the risk of ventricular tachyarrhythmias (VT). Vagal nerve stimulation (VNS) has been antiarrhythmic in the setting of ischemia-driven arrhythmias, but it is unclear if it can overcome the electrophysiological effects of sympathoexcitation in the setting of chronic myocardial infarction (MI). METHODS: In Yorkshire pigs after chronic MI, a sternotomy was performed, a 56-electrode sock was placed over the ventricles (n = 17), and a basket catheter was positioned in the left ventricle (n = 6). Continuous unipolar electrograms from sock and basket arrays were obtained to analyze activation recovery interval (ARI), a surrogate of action potential duration. Bipolar voltage mapping was performed to define scar, border zone, or viable myocardium. Hemodynamic and electrical parameters and VT inducibility were evaluated during sympathoexcitation with bilateral stellate ganglia stimulation (BSS) and during combined BSS with intermittent VNS. RESULTS: During BSS, global epicardial ARIs shortened from 384 ± 59 milliseconds to 297 ± 63 milliseconds and endocardial ARIs from 359 ± 36 milliseconds to 318 ± 40 milliseconds. Dispersion in ARIs increased in all regions, with the greatest increase observed in scar and border zone regions. VNS mitigated the effects of BSS on border zone ARIs (from -18.3% ± 6.3% to -2.1% ± 14.7%) and ARI dispersion (from 104 ms2 [1 to 1,108 ms2] to -108 ms2 [IQR: -588 to 30 ms2]). VNS reduced VT inducibility during sympathoexcitation (from 75%-40%; P < 0.05). CONCLUSIONS: After chronic MI, VNS overcomes the detrimental effects of sympathoexcitation by reducing electrophysiological heterogeneities exacerbated by sympathetic stimulation, decreasing VT inducibility.

Innervation and Neuronal Control of the Mammalian Sinoatrial Node a Comprehensive Atlas.

[Figure: see text].

Genome Editing of Induced Pluripotent Stem Cells to Decipher Cardiac Channelopathy Variant.

BACKGROUND: The long QT syndrome (LQTS) is an arrhythmogenic disorder of QT interval prolongation that predisposes patients to life-threatening ventricular arrhythmias such as Torsades de pointes and sudden cardiac death. Clinical genetic testing has emerged as the standard of care to identify genetic variants in patients suspected of having LQTS. However, these results are often confounded by the discovery of variants of uncertain significance (VUS), for which there is insufficient evidence of pathogenicity. OBJECTIVES: The purpose of this study was to demonstrate that genome editing of patient-specific induced pluripotent stem cells (iPSCs) can be a valuable approach to delineate the pathogenicity of VUS in cardiac channelopathy. METHODS: Peripheral blood mononuclear cells were isolated from a carrier with a novel missense variant (T983I) in the KCNH2 (LQT2) gene and an unrelated healthy control subject. iPSCs were generated using an integration-free Sendai virus and differentiated to iPSC-derived cardiomyocytes (CMs). RESULTS: Whole-cell patch clamp recordings revealed significant prolongation of the action potential duration (APD) and reduced rapidly activating delayed rectifier K+ current (IKr) density in VUS iPSC-CMs compared with healthy control iPSC-CMs. ICA-105574, a potent IKr activator, enhanced IKr magnitude and restored normal action potential duration in VUS iPSC-CMs. Notably, VUS iPSC-CMs exhibited greater propensity to proarrhythmia than healthy control cells in response to high-risk torsadogenic drugs (dofetilide, ibutilide, and azimilide), suggesting a compromised repolarization reserve. Finally, the selective correction of the causal variant in iPSC-CMs using CRISPR/Cas9 gene editing (isogenic control) normalized the aberrant cellular phenotype, whereas the introduction of the homozygous variant in healthy control cells recapitulated hallmark features of the LQTS disorder. CONCLUSIONS: The results suggest that the KCNH2T983I VUS may be classified as potentially pathogenic.

Basis and ECG measurement of global ventricular repolarization.

Ventricular repolarization and its manifestation in the T wave of the electrocardiogram have long been a focus of clinical and experimental electrocardiology. In this short article, we shall review the basics of cellular and organ repolarization electrophysiology, the classical and emerging methods of measuring global repolarization, and methodology that relates directly measured cardiac indices of repolarization to the body surface electrocardiogram.

Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis.

The influence of cardiac sympathetic innervation on electrical activation in normal and chronically infarcted ventricular myocardium is not understood. Yorkshire pigs with normal hearts (NL, n = 12) or anterior myocardial infarction (MI, n = 9) underwent high-resolution mapping of the anteroapical left ventricle at baseline and during left and right stellate ganglion stimulation (LSGS and RSGS, respectively). Conduction velocity (CV), activation times (ATs), and directionality of propagation were measured. Myocardial fiber orientation was determined using diffusion tensor imaging and histology. Longitudinal CV (CVL) was increased by RSGS (0.98 ± 0.11 vs. 1.2 ± 0.14m/s, P < 0.001) but not transverse CV (CVT). This increase was abrogated by ß-adrenergic receptor and gap junction (GJ) blockade. Neither CVL nor CVT was increased by LSGS. In the peri-infarct region, both RSGS and LSGS shortened ARIs in sinus rhythm (423 ± 37 vs. 322 ± 30 ms, P < 0.001, and 423 ± 36 vs. 398 ± 36 ms, P = 0.035, respectively) and altered activation patterns in all animals. CV, as estimated by mean ATs, increased in a directionally dependent manner by RSGS (14.6 ± 1.2 vs. 17.3 ± 1.6 ms, P = 0.015), associated with GJ lateralization. RSGS and LSGS inhomogeneously modulated AT and induced relative or absolute functional activation delay in parts of the mapped regions in 75 and 67%, respectively, in MI animals, and in 0 and 15%, respectively, in control animals (P < 0.001 for both). In conclusion, sympathoexcitation increases CV in normal myocardium and modulates activation propagation in peri-infarcted ventricular myocardium. These data demonstrate functional control of arrhythmogenic peri-infarct substrates by sympathetic nerves and in part explain the temporal nature of arrhythmogenesis.NEW & NOTEWORTHY This study demonstrates regional control of conduction velocity in normal hearts by sympathetic nerves. In infarcted hearts, however, not only is modulation of propagation heterogeneous, some regions showed paradoxical conduction slowing. Sympathoexcitation altered propagation in all infarcted hearts studied, and we describe the temporal arrhythmogenic potential of these findings.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/sympathetic-nerves-and-cardiac-propagation/.

A fundamental relationship between intraventricular conduction and heart rate.

BACKGROUND: Existence of a relationship between the electrocardiographic QRS interval duration and the diurnally varying heart rate, of consistent sign and magnitude, is controversial and the relationship has not been fully characterized in normal populations. METHODS AND RESULTS: We analyzed the QRS-RR interval relationship in 884 Holter recordings in 410 normal subjects participating in 5 clinical trials. The slope of the linear regression of QRS on RR was positive in 93% of subjects with an average slope of 0.0125, which indicates an increase in QRS duration of 1.25msec for an increase in RR interval of 100msec. The increase was 15% larger in women than in men. Age had no significant effect on the slope. CONCLUSIONS: In two populations of normal subjects we observed a robust, direct relationship between the spontaneously changing RR interval and intraventricular conduction time represented by the duration of the QRS interval. As heart rate increases, QRS duration decreases. The change is larger in women. These observations have important physiological and clinical implications.

In memoriam: A tribute to the work and lives of Ron Selvester and Rory Childers.

At the April, 2015 International Society for Computerized Electrocardiology (ISCE) Annual Conference in San Jose, CA, a special session entitled Remembering Ron & Rory was held to pay tribute to the extraordinary work and lives of two experts in electrocardiology. The session was well attended by conference attendees, Childers' family members and friends, and additional colleagues who traveled to San Jose solely to participate in this session. The purpose of the present paper is to document the spirit of this special session as faithfully as possible using the words of the session speakers.

A near-infrared fluorescent voltage-sensitive dye allows for moderate-throughput electrophysiological analyses of human induced pluripotent stem cell-derived cardiomyocytes.

Human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM)-based assays are emerging as a promising tool for the in vitro preclinical screening of QT interval-prolonging side effects of drugs in development. A major impediment to the widespread use of human iPSC-CM assays is the low throughput of the currently available electrophysiological tools. To test the precision and applicability of the near-infrared fluorescent voltage-sensitive dye 1-(4-sulfanatobutyl)-4-{ß[2-(di-n-butylamino)-6-naphthyl]butadienyl}quinolinium betaine (di-4-ANBDQBS) for moderate-throughput electrophysiological analyses, we compared simultaneous transmembrane voltage and optical action potential (AP) recordings in human iPSC-CM loaded with di-4-ANBDQBS. Optical AP recordings tracked transmembrane voltage with high precision, generating nearly identical values for AP duration (AP durations at 10%, 50%, and 90% repolarization). Human iPSC-CMs tolerated repeated laser exposure, with stable optical AP parameters recorded over a 30-min study period. Optical AP recordings appropriately tracked changes in repolarization induced by pharmacological manipulation. Finally, di-4-ANBDQBS allowed for moderate-throughput analyses, increasing throughput >10-fold over the traditional patch-clamp technique. We conclude that the voltage-sensitive dye di-4-ANBDQBS allows for high-precision optical AP measurements that markedly increase the throughput for electrophysiological characterization of human iPSC-CMs.

Functional and pharmacological analysis of cardiomyocytes differentiated from human peripheral blood mononuclear-derived pluripotent stem cells.

Advances in induced pluripotent stem cell (iPSC) technology have set the stage for routine derivation of patient- and disease-specific human iPSC-cardiomyocyte (CM) models for preclinical drug screening and personalized medicine approaches. Peripheral blood mononuclear cells (PBMCs) are an advantageous source of somatic cells because they are easily obtained and readily amenable to transduction. Here, we report that the electrophysiological properties and pharmacological responses of PBMC-derived iPSC CM are generally similar to those of iPSC CM derived from other somatic cells, using patch-clamp, calcium transient, and multielectrode array (MEA) analyses. Distinct iPSC lines derived from a single patient display similar electrophysiological features and pharmacological responses. Finally, we demonstrate that human iPSC CMs undergo acute changes in calcium-handling properties and gene expression in response to rapid electrical stimulation, laying the foundation for an in-vitro-tachypacing model system for the study of human tachyarrhythmias.

Beat-to-beat cycle length variability of spontaneously beating guinea pig sinoatrial cells: relative contributions of the membrane and calcium clocks.

The heartbeat arises rhythmically in the sino-atrial node (SAN) and then spreads regularly throughout the heart. The molecular mechanism underlying SAN rhythm has been attributed by recent studies to the interplay between two clocks, one involving the hyperpolarization activated cation current If (the membrane clock), and the second attributable to activation of the electrogenic NaCa exchanger by spontaneous sarcoplasmic releases of calcium (the calcium clock). Both mechanisms contain, in principle, sources of beat-to-beat cycle length variability, which can determine the intrinsic variability of SAN firing and, in turn, contribute to the heart rate variability. In this work we have recorded long sequences of action potentials from patch clamped guinea pig SAN cells (SANCs) perfused, in turn, with normal Tyrode solution, with the If inhibitor ivabradine (3 µM), then back to normal Tyrode, and again with the ryanodine channels inhibitor ryanodine (3 µM). We have found that, together with the expected increase in beating cycle length (+25%), the application of ivabradine brought about a significant and dramatic increase in beat-to-beat cycle length variability (+50%). Despite the similar effect on firing rate, ryanodine did not modify significantly beat-to-beat cycle length variability. Acetylcholine was also applied and led to a 131% increase of beating cycle length, with only a 70% increase in beat-to-beat cycle length variability. We conclude that the main source of inter-beat variability of SANCs firing rate is related to the mechanism of the calcium clock, whereas the membrane clock seems to act in stabilizing rate. Accordingly, when the membrane clock is silenced by application of ivabradine, stochastic variations of the calcium clock are free to make SANCs beating rhythm more variable.

The application of root mean square electrocardiography (RMS ECG) for the detection of acquired and congenital long QT syndrome.

BACKGROUND: Precise measurement of the QT interval is often hampered by difficulty determining the end of the low amplitude T wave. Root mean square electrocardiography (RMS ECG) provides a novel alternative measure of ventricular repolarization. Experimental data have shown that the interval between the RMS ECG QRS and T wave peaks (RTPK) closely reflects the mean ventricular action potential duration while the RMS T wave width (TW) tracks the dispersion of repolarization timing. Here, we tested the precision of RMS ECG to assess ventricular repolarization in humans in the setting of drug-induced and congenital Long QT Syndrome (LQTS). METHODS: RMS ECG signals were derived from high-resolution 24 hour Holter monitor recordings from 68 subjects after receiving placebo and moxifloxacin and from standard 12 lead ECGs obtained in 97 subjects with LQTS and 97 age- and sex-matched controls. RTPK, QTRMS and RMS TW intervals were automatically measured using custom software and compared to traditional QT measures using lead II. RESULTS: All measures of repolarization were prolonged during moxifloxacin administration and in LQTS subjects, but the variance of RMS intervals was significantly smaller than traditional lead II measurements. TW was prolonged during moxifloxacin and in subjects with LQT-2, but not LQT-1 or LQT-3. CONCLUSION: These data validate the application of RMS ECG for the detection of drug-induced and congenital LQTS. RMS ECG measurements are more precise than the current standard of care lead II measurements.

Focal myocardial infarction induces global remodeling of cardiac sympathetic innervation: neural remodeling in a spatial context.

Myocardial infarction (MI) induces neural and electrical remodeling at scar border zones. The impact of focal MI on global functional neural remodeling is not well understood. Sympathetic stimulation was performed in swine with anteroapical infarcts (MI; n = 9) and control swine (n = 9). A 56-electrode sock was placed over both ventricles to record electrograms at baseline and during left, right, and bilateral stellate ganglion stimulation. Activation recovery intervals (ARIs) were measured from electrograms. Global and regional ARI shortening, dispersion of repolarization, and activation propagation were assessed before and during sympathetic stimulation. At baseline, mean ARI was shorter in MI hearts than control hearts (365 ± 8 vs. 436 ± 9 ms, P < 0.0001), dispersion of repolarization was greater in MI versus control hearts (734 ± 123 vs. 362 ± 32 ms(2), P = 0.02), and the infarcted region in MI hearts showed longer ARIs than noninfarcted regions (406 ± 14 vs. 365 ± 8 ms, P = 0.027). In control animals, percent ARI shortening was greater on anterior than posterior walls during right stellate ganglion stimulation (P = 0.0001), whereas left stellate ganglion stimulation showed the reverse (P = 0.0003). In infarcted animals, this pattern was completely lost. In 50% of the animals studied, sympathetic stimulation, compared with baseline, significantly altered the direction of activation propagation emanating from the intramyocardial scar during pacing. In conclusion, focal distal anterior MI alters regional and global pattern of sympathetic innervation, resulting in shorter ARIs in infarcted hearts, greater repolarization dispersion, and altered activation propagation. These conditions may underlie the mechanisms by which arrhythmias are initiated when sympathetic tone is enhanced.

Modulation of regional dispersion of repolarization and T-peak to T-end interval by the right and left stellate ganglia.

Left stellate or right stellate ganglion stimulation (LGSG or RSGS, respectively) is associated with ventricular tachyarrhythmias; however, the electrophysiological mechanisms remain unclear. We assessed 1) regional dispersion of myocardial repolarization during RSGS and LSGS and 2) regional electrophysiological mechanisms underlying T-wave changes, including T-peak to T-end (Tp-e) interval, which are associated with ventricular tachyarrhythmia/ventricular fibrillation. In 10 pigs, a 56-electrode sock was placed around the heart, and both stellate ganglia were exposed. Unipolar electrograms, to asses activation recovery interval (ARI) and repolarization time (RT), and 12-lead ECG were recorded before and during RSGS and LSGS. Both LSGS and RSGS increased dispersion of repolarization; with LSGS, the greatest regional dispersion occurred on the left ventricular (LV) anterior wall and LV apex, whereas with RSGS, the greatest regional dispersion occurred on the right ventricular posterior wall. Baseline, LSGS, and RSGS dispersion correlated with Tp-e. The increase in RT dispersion, which was due to an increase in ARI dispersion, correlated with the increase in Tp-e intervals (R(2) = 0.92 LSGS; and R(2) = 0.96 RSGS). During LSGS, the ARIs and RTs on the lateral and posterior walls were shorter than the anterior LV wall (P < 0.01) and on the apex versus base (P < 0.05), explaining the T-wave vector shift posteriorly/inferiorly. RSGS caused greater ARI and RT shortening on anterior versus lateral or posterior walls (P < 0.01) and on base versus apex (P < 0.05), explaining the T-wave vector shift anteriorly/superiorly. LSGS and RSGS cause differential effects on regional myocardial repolarization, explaining the ECG T-wave morphology. Sympathetic stimulation, in line with its proarrhythmic effects, increases Tp-e interval, which correlates with increases in myocardial dispersion of repolarization.

Functional differences between junctional and extrajunctional adrenergic receptor activation in mammalian ventricle.

Increased cardiac sympathetic activation worsens dispersion of repolarization and is proarrhythmic. The functional differences between intrinsic nerve stimulation and adrenergic receptor activation remain incompletely understood. This study was undertaken to determine the functional differences between efferent cardiac sympathetic nerve stimulation and direct adrenergic receptor activation in porcine ventricles. Female Yorkshire pigs (n = 13) underwent surgical exposure of the heart and stellate ganglia. A 56-electrode sock was placed over the ventricles to record epicardial electrograms. Animals underwent bilateral sympathetic stimulation (BSS) (n = 8) or norepinephrine (NE) administration (n = 5). Activation recovery intervals (ARIs) were measured at each electrode before and during BSS or NE. The degree of ARI shortening during BSS or NE administration was used as a measure of functional nerve or adrenergic receptor density. During BSS, ARI shortening was nonuniform across the epicardium (F value 9.62, P = 0.003), with ARI shortening greatest in the mid-basal lateral right ventricle and least in the midposterior left ventricle (LV) (mean normalized values: 0.9 ± 0.08 vs. 0.56 ± 0.08; P = 0.03). NE administration resulted in greater ARI shortening in the LV apex than basal segments [0.91 ± 0.04 vs. 0.63 ± 0.05 (averaged basal segments); P = 0.003]. Dispersion of ARIs increased in 50% and 60% of the subjects undergoing BSS and NE, respectively, but decreased in the others. There is nonuniform response to cardiac sympathetic activation of both porcine ventricles, which is not fully explained by adrenergic receptor density. Different pools of adrenergic receptors may mediate the cardiac electrophysiological effects of efferent sympathetic nerve activity and circulating catecholamines.

Sympathetic stimulation increases dispersion of repolarization in humans with myocardial infarction.

The sympathetic nervous system is thought to play a key role in genesis and maintenance of ventricular arrhythmias. The myocardial effect of sympathetic stimulation on myocardial repolarization in humans is poorly understood. The purpose of this study was to evaluate the effects of direct and reflex sympathetic stimulation on ventricular repolarization in patients with postinfarct cardiomyopathy (ICM). The effects of direct sympathetic stimulation were assessed using isoproterenol, while those of reflex sympathetic stimulation were assessed with nitroprusside infusion in ICM patients (n = 5). Five patients without cardiomyopathy were also studied. Local repolarization was measured from intracardiac electrograms that were used to calculate the activation recovery interval (ARI), a surrogate of action potential duration. Isoproterenol significantly increased heterogeneity in repolarization in patients with ICM; the decrease in ARI from baseline was 72.9 ± 9.1 ms in more viable regions, 64.5 ± 8.9 ms in the scar, and 54.9 ± 9.1 ms in border zones (P = 0.0002 and 0.014 comparing normal and scar to border zones, respectively). In response to nitroprusside, the ARI at the border zones decreased significantly more than either scar or surrounding viable myocardium, which showed an increase in ARI (P = 0.014 and 0.08 comparing normal tissue and scar to border zones, respectively). Furthermore, isoproterenol increased ARI dispersion by 70%, while nitroprusside increased ARI dispersion by 230% when ICM patients were compared to those with structurally normal hearts (P = 0.0015 and P < 0.001, respectively). In humans, both direct and reflex sympathetic stimulations increase regional differences in repolarization. The normal tissue surrounding the scar appears denervated. Dispersion of ARI in response to sympathetic stimulation is significantly increased in patients with ICM.

Repolarization heterogeneity and rate dependency in a canine rapid pacing model of heart failure.

BACKGROUND: Repolarization heterogeneity and rate dependency have long been established as factors contributing to arrhythmogenic risk. However, there are conflicting observations regarding the nature and extent of ventricular repolarization heterogeneity that complicate understanding of arrhythmogenic mechanisms. To explore these disparate findings, we studied ventricular repolarization heterogeneity and rate dependency in a canine, rapid pacing model of heart failure. METHODS AND RESULTS: We studied ventricular repolarization heterogeneity and rate dependency in 10 canine hearts (5 normal and 5 after 1 month of rapid pacing at 240 beats per minute) by analyzing 64 body surface electrocardiograms, 64 epicardial, and 190 intramural plunge electrograms. We estimated mean ventricular depolarization and repolarization times from R- and T-wave peaks of the root-mean-square electrocardiogram (body surface) and local depolarization and repolarization times using activation-recovery interval (ARI) methods from recordings obtained during a range of fixed rate pacing. In addition, we estimated local epicardial and transmural gradients of ARIs to assess cardiac locations of greatest spatial repolarization heterogeneity. We compared changes in repolarization at different rates between normal and heart failure hearts. Findings documented prolongation of repolarization, repolarization rate dependency, and increased repolarization gradients in the heart failure hearts compared with control as observed from body surface, epicardial, and transmural measurements. Maximum local epicardial and intramural ARI gradients were comparable both in heart failure and control hearts. Intramural ARI distributions tended to be more irregular in the heart failure hearts compared with the systematic epicardium to endocardium ARI increase observed in control animals. CONCLUSIONS: This study documented prolongation of repolarization, increase in both epicardial and transmural repolarization gradients, and irregularity of transmural distribution in a rapid pacing canine model of heart failure compared with control animals. The findings support previously published results of increased repolarization heterogeneity and repolarization prolongation observed in rapid pacing models of heart failure. New findings are the irregularity of transmural heterogeneity and the ability of noninvasive root-mean-square electrocardiogram R-T intervals to estimate mean ventricular repolarization duration in the setting of rapid pacing models of heart failure. These findings suggest increased arrhythmogenic risk in this model and potentially in patients with heart failure.