Arrhythmia Vulnerability Research Articles

Modulation of spatial variance of ventricular repolarization after myocardial infarction

Fil: Bonomini, Maria Paula. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Saavedra 15. Instituto Argentino de Matematica Alberto Calderon; Argentina. Universidad de Buenos Aires. Facultad de Ingenieria. Instituto de Ingenieria Biomedica; Argentina

Conditional knockout of Fgf13 in murine hearts increases arrhythmia susceptibility and reveals novel ion channel modulatory roles

The intracellular fibroblast growth factors (iFGF/FHFs) bind directly to cardiac voltage gated Na+ channels, and modulate their function. Mutations that affect iFGF/FHF-Na+ channel interaction are associated with arrhythmia syndromes. Although suspected to modulate other ionic currents, such as Ca2+ channels based on acute knockdown experiments in isolated cardiomyocytes, the in vivo consequences of iFGF/FHF gene ablation on cardiac electrical activity are still unknown. We generated inducible, cardiomyocyte-restricted Fgf13 knockout mice to determine the resultant effects of Fgf13 gene ablation. Patch clamp recordings from ventricular myocytes isolated from Fgf13 knockout mice showed a ~25% reduction in peak Na+ channel current density and a hyperpolarizing shift in steady-state inactivation. Electrocardiograms on Fgf13 knockout mice showed a prolonged QRS duration. The Na+ channel blocker flecainide further prolonged QRS duration and triggered ventricular tachyarrhythmias only in Fgf13 knockout mice, suggesting that arrhythmia vulnerability resulted, at least in part, from a loss of functioning Na+ channels. Consistent with these effects on Na+ channels, action potentials in Fgf13 knockout mice, compared to Cre control mice, exhibited slower upstrokes and reduced amplitude, but unexpectedly had longer durations. We investigated candidate sources of the prolonged action potential durations in myocytes from Fgf13 knockout mice and found a reduction of the transient outward K+ current (Ito). Fgf13 knockout did not alter whole-cell protein levels of Kv4.2 and Kv4.3, the Ito pore-forming subunits, but did decrease Kv4.2 and Kv4.3 at the sarcolemma. No changes were seen in the sustained outward K+ current or voltage-gated Ca2+ current, other candidate contributors to the increased action potential duration. These results implicate that FGF13 is a critical cardiac Na+ channel modulator and Fgf13 knockout mice have increased arrhythmia susceptibility in the setting of Na+ channel blockade. The unanticipated effect on Ito revealed new FGF13 properties and the unexpected lack of an effect on voltage-gated Ca2+ channels highlight potential compensatory changes in vivo not readily revealed with acute Fgf13 knockdown in cultured cardiomyocytes.

Acute Oestradiol Increases the Propensity for Atrial Arrhythmias in the Isolated Mouse Heart

Atrial fibrillation (AF) is the most common sustained arrhythmia, significantly contributing to cardiovascular morbidity/mortality. Epidemiological studies have reported sex differences in AF incidence and outcomes. The influence of sex steroids on AF vulnerability is poorly understood, though clinical trial findings (ie WHI) have indicated that hormone supplementation using oestrogen-only therapy significantly increased AF risk. Experimental data addressing oestrogenic influence on atrial arrhythmias are lacking. We have previously shown that oestrogen influences ventricular electromechanical properties and arrhythmia vulnerability. The aim of this study was to assess the influence of acute oestradiol treatment on atrial arrhythmias in isolated mouse hearts. Bipolar electrograms were recorded from hearts subjected to programmed pulse stimulations in the presence/absence of 10 nM estradiol (vs vehicle control). Oestradiol significantly increased the incidence of atrial arrhythmias (# episodes; 2.8 ± 0.5 vs 0.9 ± 0.3), with the mean duration of each arrhythmic episode exhibiting similar trend. The total duration of atrial arrhythmias throughout the pulse stimulation protocol was significantly increased in the presence of oestradiol (s; 6.9 ± 3.2 vs 1.0 ± 0.4). Augmented atrial arrhythmia vulnerability was likely not due to oestrogenic action on sinus node automaticity, as no effect was observed on sinus node recovery time (ms; 424 ± 46 vs 397 ± 47). These data show for the first time in an experimental setting that acute oestrogen exposure increases cardiac vulnerability to atrial arrhythmia. This finding demonstrates potential cardiac vulnerability to local increase in oestrogen of endogenous and exogenous origin. Further studies are required to identify and target the cellular mechanisms by which oestrogen exerts this arrhythmogenic influence.

Augmented Capacity of Pericardial Adipose to Synthesise Oestrogen Linked with Greater Vulnerability to Atrial Arrhythmias

A link exists between atrial fibrillation (AF) risk and the extent of pericardial adipose (epicardial/paracardial). The underlying mechanisms remain poorly understood. We recently reported that aromatase is expressed in human epicardial adipose–thus providing capacity for local cardiac oestrogen synthesis. Earlier clinical trial findings (WHI) indicated that oestrogen-only therapy was associated with significantly increased AF risk. The extent to which endogenous oestrogen, produced locally, might contribute to AF substrate is unknown. The aim of this study was to determine the relationship between pericardial adipose accumulation, local oestrogen synthesis capability and atrial arrhythmia vulnerability in mouse models of adiposity: aged (50wks) and aged high-fat diet (HFD) fed. Pericardial adipose expression was measured by Western immunoblot. Atrial arrhythmias were assessed using bipolar electrograms recorded from isolated hearts subjected to programmed pulse stimulation. Compared with young controls (age 12wks), pericardial adipose weight was significantly increased in HFD and aged mice (mg; 260 ± 36 vs 114 ± 15 vs 22 ± 9, HFD vs aged vs young). Total aromatase content was similarly elevated (arb. units; 10.2 ± 1.7 vs 4.6 ± 0.9 vs 0.1 ± 0.0). The hearts from these mice exhibited a greater incidence of atrial arrhythmias (# episodes; 3.6 ± 1.3 vs 2.8 ± 1.0 vs 0.4 ± 0.1). A significant positive correlation was determined between the total aromatase content of pericardial adipose and the incidence (p = 0.0015) and duration (p = 0.0136) of triggered arrhythmias. This study provides the first evidence linking atrial arrhythmia with augmented local oestrogen biosynthetic capacity in pericardial adipose. These findings provide new leads for the targeting of anti-arrhythmic therapies in aged/obese populations exposed to AF risk.

Effect of anisotropy on ventricular vulnerability to unidirectional block and reentry by single premature stimulation during normal sinus rhythm in rat heart.

Single high-intensity premature stimuli when applied to the ventricles during ventricular drive of an ectopic site, as in Winfree's "pinwheel experiment," usually induce reentry arrhythmias in the normal heart, while single low-intensity stimuli barely do. Yet ventricular arrhythmia vulnerability during normal sinus rhythm remains largely unexplored. With a view to define the role of anisotropy on ventricular vulnerability to unidirectional conduction block and reentry, we revisited the pinwheel experiment with reduced constraints in the in situ rat heart. New features included single premature stimulation during normal sinus rhythm, stimulation and unipolar potential mapping from the same high-resolution epicardial electrode array, and progressive increase in stimulation strength and prematurity from diastolic threshold until arrhythmia induction. Measurements were performed with 1-ms cathodal stimuli at multiple test sites (n = 26) in seven rats. Stimulus-induced virtual electrode polarization during sinus beat recovery phase influenced premature ventricular responses. Specifically, gradual increase in stimulus strength and prematurity progressively induced make, break, and graded-response stimulation mechanisms. Hence unidirectional conduction block occurred as follows: 1) along fiber direction, on right and left ventricular free walls (n = 23), initiating figure-eight reentry (n = 17) and tachycardia (n = 12), and 2) across fiber direction, on lower interventricular septum (n = 3), initiating spiral wave reentry (n = 2) and tachycardia (n = 1). Critical time window (55.1 ± 4.7 ms, 68.2 ± 6.0 ms) and stimulus strength lower limit (4.9 ± 0.6 mA) defined vulnerability to reentry. A novel finding of this study was that ventricular tachycardia evolves and is maintained by episodes of scroll-like wave and focal activation couplets. We also found that single low-intensity premature stimuli can induce repetitive ventricular response (n = 13) characterized by focal activations.NEW & NOTEWORTHY We performed ventricular cathodal point stimulation during sinus rhythm by progressively increasing stimulus strength and prematurity. Virtual electrode polarization and recovery gradient progressively induced make, break, and graded-response stimulation mechanisms. Unidirectional conduction block occurred along or across fiber direction, initiating figure-eight or spiral wave reentry, respectively, and tachycardia sustained by scroll wave and focal activations.

Stress-Activated Kinase Mitogen-Activated Kinase Kinase-7 Governs Epigenetics of Cardiac Repolarization for Arrhythmia Prevention.

Ventricular arrhythmia is a leading cause of cardiac mortality. Most antiarrhythmics present paradoxical proarrhythmic side effects, culminating in a greater risk of sudden death. We describe a new regulatory mechanism linking mitogen-activated kinase kinase-7 deficiency with increased arrhythmia vulnerability in hypertrophied and failing hearts using mouse models harboring mitogen-activated kinase kinase-7 knockout or overexpression. The human relevance of this arrhythmogenic mechanism is evaluated in human-induced pluripotent stem cell-derived cardiomyocytes. Therapeutic potentials by targeting this mechanism are explored in the mouse models and human-induced pluripotent stem cell-derived cardiomyocytes. Mechanistically, hypertrophic stress dampens expression and phosphorylation of mitogen-activated kinase kinase-7. Such mitogen-activated kinase kinase-7 deficiency leaves histone deacetylase-2 unphosphorylated and filamin-A accumulated in the nucleus to form a complex with Krüppel-like factor-4. This complex leads to Krüppel-like factor-4 disassociation from the promoter regions of multiple key potassium channel genes (Kv4.2, KChIP2, Kv1.5, ERG1, and Kir6.2) and reduction of their transcript levels. Consequent repolarization delays result in ventricular arrhythmias. Therapeutically, targeting the repressive function of the Krüppel-like factor-4/histone deacetylase-2/filamin-A complex with the histone deacetylase-2 inhibitor valproic acid restores K+ channel expression and alleviates ventricular arrhythmias in pathologically remodeled hearts. Our findings unveil this new gene regulatory avenue as a new antiarrhythmic target where repurposing of the antiepileptic drug valproic acid as an antiarrhythmic is supported.

Mechanisms of arrhythmogenesis related to calcium-driven alternans in a model of human atrial fibrillation.

The occurrence of atrial fibrillation (AF) is associated with progressive changes in the calcium handling system of atrial myocytes. Calcium cycling instability has been implicated as an underlying mechanism of electrical alternans observed in patients who experience AF. However, the extent to which calcium-induced alternation of electrical activity in the atria contributes to arrhythmogenesis is unknown. In this study, we investigated the effects of calcium-driven alternans (CDA) on arrhythmia susceptibility in a biophysically detailed, 3D computer model of the human atria representing electrical and structural remodeling secondary to chronic AF. We found that elevated propensity to CDA rendered the atria vulnerable to ectopy-induced arrhythmia. It also increased the complexity and persistence of arrhythmias induced by fast pacing, with unstable scroll waves meandering and frequently breaking up to produce multiple wavelets. Our results suggest that calcium-induced electrical instability may increase arrhythmia vulnerability and promote increasing disorganization of arrhythmias in the chronic AF-remodeled atria, thus playing an important role in the progression of the disease.

LONG-TERM CARDIAC RESYNCHRONIZATION THERAPY REDUCES T-WAVE ALTERNANS IN PATIENTS WITH CARDIOMYOPATHY

Cardiac resynchronization therapy (CRT) promotes molecular and mechanical remodeling in patients with cardiomyopathy. In particular, SERCA levels and intracellular calcium cycling are augmented. T wave alternans (TWA), a marker of ventricular arrhythmia vulnerability, arises from abnormal intracellular calcium cycling. We tested the hypothesis that native TWA will be reduced with long-term CRT and is associated with functional improvement after CRT.

Ventricular repolarization time, location of pacing stimulus and current pulse amplitude conspire to determine arrhythmogenicity in mice.

In this study, we investigate the impact of altered action potential durations (APD) on ventricular repolarization time and proarrhythmia in mice with and without genetic deletion of the K+ -channel-interacting protein 2 (KChIP2-/- and WT respectively). Moreover, we examine the interrelationship between the dispersion of repolarization time and current pulse amplitude in provoking ventricular arrhythmia. Intracardiac pacing in anesthetized mice determined refractory periods and proarrhythmia susceptibility. Regional activation time (AT), APD and repolarization time (=AT+APD) were measured in isolated hearts using floating microelectrodes. Proarrhythmia in WT and KChIP2-/- was not sensitive to changes in refractory periods. Action potentials were longer in KChIP2-/- hearts compared to WT hearts. Isolated WT hearts had large apico-basal dispersion of repolarization time, whereas hearts from KChIP2-/- mice had large left-to-right ventricular dispersion of repolarization time. Pacing from the right ventricle in KChIP2-/- mice invivo revealed significant lower current pulse amplitudes needed to induce arrhythmias in these mice. Large heterogeneity of repolarization time is proarrhythmic when pacing is delivered from the location of earlier repolarization time. Ventricular repolarization time, location of the pacing stimulus and theamplitude of the stimulating current pulse are critical parameters underlying arrhythmia vulnerability.

Usefulness of microvolt T-wave alternans for predicting outcome in patients with Chagas disease with implantable cardioverter defibrillators

BackgroundChagas disease (ChD) may lead to life-threatening heart disease, including malignant ventricular arrhythmias. The use of implantable cardioverter defibrillators (ICDs) has become the main therapeutic strategy for secondary prevention of SCD in Chagas disease (ChD). Microvolt T-wave alternans (MTWA) is a direct measure of ventricular repolarization instability and has emerged as a potentially useful way of determining arrhythmia vulnerability. However, this methodology has not been evaluated in patients with ChD. ObjectiveTo evaluate the predictive value of MTWA testing for appropriate therapy or death in ChD patients with ICDs. MethodsThis prospective study included consecutive patients who received ICD implantations in a Brazilian tertiary referral center. ResultsSeventy-two patients were followed for a median time of 422 (range 294–642) days. Thirty-three patients had ChD. The MTWA was non-negative (positive or indeterminate) in 27 (81.8%) of ChD patients. The combined primary outcome (appropriate ICD therapy or death) occurred in 29 patients (40.3%); 17 out 33 ChD patients presented the primary outcome. There was a statistically significant difference in event-free survival between ChD patients with negative and non-negative MTWA results (p=0.02). Non-negative MTWA tests nearly triple the risk of appropriate ICD therapy or death (HR=2.7, 95% CI: 1.7–4.4, p=0.01) in patients with ChD and was the only variable associated with outcomes. The sensitivity and the negative predictive value was 100% in ChD patients. ConclusionsMTWA may be useful in recognizing high-risk ICD patients who may require adjunctive therapies with antiarrhythmic drugs or catheter ablation.

56-03: Increased arrhythmia vulnerability in KChIP2 knock-out mice is explained by different spatial dispersion of ventricular repolarization and location of cardiac stimulation

Purpose of the study: Downregulation of ventricular K+ channel-interacting protein 2 (KChIP2) and loss of the transient outward K+ current (Ito), is observed in failing hearts. In this study, we investigate the impact of KChIP2 and heart failure (HF) on action potential duration (APD) and repolarization time (RT) in mouse hearts. We hypothese that a dispersion of RT will provoke arrhythmias if cardiac pacing is performed from the region with the shortest RT. Method used: HF in WT and KChIP2-/- mice was induced by transverse aortic constriction and verified by echocardiography. Regional activation time (AT), APD and RT (=AT + APD) were subsequently measured in isolated, perfused and apically paced hearts using floating microelectrodes. Finally, in-vivo intracardiac pacing of the right ventricle tested arrhythmia vulnerability. Summary of results: Within the left ventricle, APD is longer at the base in KChIP2-/- hearts (n = 6) when compared to WT (n = 6) (APD90: 52.4 ± 5.3 vs. 37.6 ± 3.8 ms, p < 0.05). However, including the AT, the apico-basal dispersion of RT in KChIP2-/- hearts is not different from WT. KChIP2-/- hearts have a larger interventricular dispersion of APD (Δ-APD90: 18.7 ± 4.8 vs. 6.1 ± 1.5 ms, p < 0.05), which translates into a larger left-to-right ventricular dispersion of RT compared to WT hearts (Δ-RT: 22.7 ± 6.7 vs. 5.0 ± 1.5 ms, p < 0.05). HF prolongs AT and APD in WT and KChIP2-/- hearts, and makes spatial dispersion of RT comparable. Pacing the right ventricle of KChIP2-/- control mice to test if pacing from a region with a shorter RT will provoke arrhythmias revealed significant increased arrhythmia vulnerability in these mice. Conclusion: Absence of KChIP2 leads to a prolongation of the left ventricular action potential and an increased interventricular dispersion of RT. HF alters the APD gradients, but reduces the differences in spatial dispersion of RT between WT and KChIP2-/- hearts. Finally, the location of cardiac pacing is crucial when evaluating arrhythmia vulnerability.

0307 : Acute activation of the hexosamine biosynthetic pathway promotes electrical instability

The hexosamine biosynthetic pathway (HBP) is heightened in cardiomyopathies. We aimed at understanding how over-activation of HBP impacts on cardiac electrophysiology, and acts as a trigger or a substrate of cardiac arrhythmias. Overactivation of the HBP by injection of glucosamine (GlcN 270mg/kg) was assessed under basal conditions and during beta-adrenergic stress on the myocardial energetic status (phosphocreatine to ATP ratio) of rats by 31 P nuclear magnetic resonance spectroscopy. Rat hearts were perfused ex vivo to evaluate the effects of the HBP activation (physiologically: glutamine 0.5mM – gln; overactivated: GlcN 1mM) on: cardiac function, MVO 2 , and arrhythmia score (AS) under basal (spontaneous arrhythmias: sAS) and pacing (pAS) conditions. At the cellular level (HL1 cells), HBP overactivation (GlcN) was assessed on conduction velocity characterized by micro-electrode arrays recordings, and properties of voltage gated ionic channels involved in cellular excitability and conduction by patch clamp experiments. In vivo GlcN did not modify PCr/ATP of the left ventricle under basal conditions. This ratio was significantly decreased during beta-adrenergic stress, while a similar increased heart rate was reported. When hearts were isolated and perfused ex vivo , GlcN induced a decrease of the heart rate and MVO 2 temporarily, and an increase of the sAS and pAS. Physiological activation of HBP with gln did not impact the ex vivo cardiac function and the sAS, but further increased the probability of atrial arrhythmias during pacing. In HL1 cells, GlcN reduced the rate of spontaneous depolarization, modified the direction and the velocity of the impulse propagation, and altered activation and inactivation properties of the sodium channel. Acute HBP activation is associated with an increased vulnerability for arrhythmias and alteration of impulse conduction, suggesting its potential role in the atrial and ventricular arrhythmias. The author hereby declares no conflict of interest

Effects of urate-lowering agents on arrhythmia vulnerability in post-infarcted rat hearts

Hyperuricemia has been shown to be associated with ventricular arrhythmias. However, the mechanisms remained unknown. We assessed whether different urate-lowering agents can attenuate arrhythmias through lowering urate itself or inhibiting xanthenes oxidize (XO) activity in infarcted rats. Male Wistar rats after ligating coronary artery were randomized to either allopurinol, or febuxostat, chemically unrelated inhibitors of XO, benzbromarone or vehicle for 4 weeks. Post-infarction was associated with increased oxidant stress, as measured by myocardial superoxide, isoprostane, XO activity and dihydroethidine fluorescence staining. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham-operated rats. Sympathetic hyperinnervation was blunted after administering both XO inhibitors, assessed by immunofluorescent analysis, Western blotting and real-time quantitative RT-PCR. Besides, the XO inhibitors-attenuated nerve growth factor levels were reversed in the presence of peroxynitrite generator. Arrhythmic scores in the XO inhibitors-treated infarcted rats were significantly lower than that in vehicle. For similar levels of urate lowering, the uricosuric agent benzbromarone had no beneficial effects on oxidative stress, sympathetic hyperinnervation or arrhythmia vulnerability. Chronic use of XO inhibitors, but not uricosuric agent, down-regulated sympathetic innervation probably through a superoxide-dependent pathway and plays a role in the beneficial effect on arrhythmogenic response.

Techniques for Ventricular Repolarization Instability Assessment From the ECG

Instabilities in ventricular repolarization have been documented to be tightly linked to arrhythmia vulnerability. Translation of the information contained in the repolarization phase of the electrocardiogram (ECG) into valuable clinical decision-making tools remains challenging. This work aims at providing an overview of the last advances in the proposal and quantification of ECG-derived indices that describe repolarization properties and whose alterations are related with threatening arrhythmogenic conditions. A review of the state of the art is provided, spanning from the electrophysiological basis of ventricular repolarization to its characterization on the surface ECG through a set of temporal and spatial risk markers.

Relaxin suppresses atrial fibrillation in aged rats by reversing fibrosis and upregulating Na+ channels

Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly patients and has been correlated with enhanced age-dependent atrial fibrosis. Reversal of atrial fibrosis has been proposed as therapeutic strategy to suppress AF. To test the ability of relaxin to reverse age-dependent atrial fibrosis and suppress AF. Aged F-344 rats (24 months old) were treated with subcutaneous infusion of vehicle or relaxin (0.4 mg/kg/day) for 2 weeks. Rat hearts were excised, perfused on a Langendorff apparatus, and stained with voltage and Ca(2+) indicator dyes. Optical mapping and programmed electrical stimulation was used to test arrhythmia vulnerability and changes in electrophysiological characteristics. Changes in protein expression and Na(+) current density (INa) were measured by tissue immunofluorescence and whole-cell patch clamp technique. In aged rats, sustained AF was readily induced with a premature pulse (n = 7/8) and relaxin treatment suppressed sustained AF by a premature impulse or burst pacing (n = 1/6) (P < .01). Relaxin significantly increased atrial action potential conduction velocity and decreased atrial fibrosis. Relaxin treatment increased Nav1.5 expression (n = 6; 36% ± 10%) and decreased total collagen and collagen I (n = 5-6; 55%-66% ± 15%) in aged atria (P < .05) and decreased collagen I and III and TGF-β1 mRNA (P < .05). Voltage-clamp experiments demonstrated that relaxin treatment (100 nM for 2 days) increased atrial INa by 46% ± 4% (n = 12-13/group, P < .02). Relaxin suppresses AF through an increase in atrial conduction velocity by decreasing atrial fibrosis and increasing INa. These data provide compelling evidence that relaxin may serve as an effective therapy to manage AF in geriatric patients by reversing fibrosis and modulating cardiac ionic currents.

Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects

Brugada syndrome (BrS) is an inherited cardiac arrhythmia syndrome first described as a new clinical entity in 1992. Electrocardiographically characterized by distinct coved type ST segment elevation in the right-precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young adults, and less frequently in infants and children. The electrocardiographic manifestations of BrS are often concealed and may be unmasked or aggravated by sodium channel blockers, a febrile state, vagotonic agents, as well as by tricyclic and tetracyclic antidepressants. An implantable cardioverter defibrillator is the most widely accepted approach to therapy. Pharmacologic therapy is designed to produce an inward shift in the balance of currents active during the early phases of the right ventricular action potential (AP) and can be used to abort electrical storms or as an adjunct or alternative to device therapy when use of an implantable cardioverter defibrillator is not possible. Isoproterenol, cilostazol, and milrinone boost calcium channel current and drugs like quinidine, bepridil, and the Chinese herb extract Wenxin Keli inhibit the transient outward current, acting to diminish the AP notch and thus to suppress the substrate and trigger for ventricular tachycardia or fibrillation. Radiofrequency ablation of the right ventricular outflow tract epicardium of patients with BrS has recently been shown to reduce arrhythmia vulnerability and the electrocardiographic manifestation of the disease, presumably by destroying the cells with more prominent AP notch. This review provides an overview of the clinical, genetic, molecular, and cellular aspects of BrS as well as the approach to therapy.

TCTAP A-129 Time of Onset of Acute Myocardial Infarction to First Balloon Dilatation and T Wave Alternans

T-wave alternans (TWA) is a heart rate dependent repolarization measurement and correlates with arrhythmia vulnerability in animal and human studies. TWA is one of established marker and can predict individuals at high risk of developing a potentially lethal cardiac arrhythmia. We evaluate the

Arrhythmic vulnerability in primary cardiac hypertrophy is associated with augmented CaMKII/PKA signaling

Arrhythmic vulnerability in primary cardiac hypertrophy is associated with augmented CaMKII/PKA signaling

Effect of a successful percutaneous coronary intervention for chronic total occlusion on parameters of ventricular repolarization.

Coronary collaterals may be insufficient for restoring blood flow to normal levels in patients with chronic total occlusions (CTO), leading to myocardial ischemia and electrical inhomogeneity in the ventricles. We evaluated the effect of percutaneous CTO revascularization on parameters of ventricular repolarization, including the T wave peak-to-end interval (TpTe) interval, the TpTe/QT ratio, and QT dispersion. A total of 114 patients who underwent CTO percutaneous coronary intervention (PCI) of any major coronary artery were divided into two groups: the successful CTO PCI group (n=90) and the failed CTO PCI group (n=24). Patients' 12-lead ECGs were analyzed within 24 h before revascularization and 24-48 h after the procedure for the following parameters: corrected QT interval (QTc) dispersion, TpTe interval (V2 and V5), and TpTe/QT ratio (V2 and V5). Subsequently, the successful CTO PCI group was divided into subgroups according to the Rentrop class, number of diseased vessels, and target vessels for further evaluation. There was no significant difference between the successful and the failed CTO PCI groups in terms of any baseline demographic or angiographic characteristic, or ventricular repolarization parameter. The post-PCI values of TpTe (85.3±12.8 vs. 74.8±10.4; P<0.001), the TpTe/QT ratio (0.21±0.02 vs. 0.19±0.02; P<0.001), and QTc dispersion (65.6±9.8 vs. 53.4±11.6; P<0.001) were significantly decreased compared with the pre-PCI values after successful CTO PCI. The patients in Rentrop class 1 and patients with multivessel disease had higher pre-PCI values for TpTe and the TpTe/QT ratio than those in the other groups (P<0.05). No significant differences were detected when the preprocedure values of TpTe, the TpTe/QT ratio, and QTc dispersion were compared according to the target vessel. In patients with CTO, a poor coronary collateral status and multivessel disease may further impair electrical homogeneity. Our results indicate that successful CTO PCI reduces the arrhythmic vulnerability of the myocardium on the basis of an analysis of the TpTe, the TpTe/QT ratio, and QTc dispersion.

15 * Early pharmacological enhancement of gap junction coupling with rotigaptide reduces arrhythmia vulnerability and modulates structural remodelling in reperfused myocardial infarction

Introduction: Survivors of myocardial infarction (MI) are at increased risk of late ventricular arrhythmias and sudden cardiac death with infarct size and scar heterogeneity as key determinants of arrhythmic risk. Current preventative strategies are limited to few, select antiarrhythmic drugs or an implantable cardioverter-defibrillator. Cardiac gap junctions (GJ) have a key role in allowing the passage of small molecules between cells and may mediate the spread of acute myocardial infarction. We hypothesised that enhancing GJ coupling in the acute phase of MI may beneficially modify the extent and pattern of necrosis and infarction acutely, thus affording a protective effect against late arrhythmogenesis. Methods: A small-animal model of infarction-reperfusion, mimicking clinical reperfusion, was used to study the effects of Rotigaptide on arrhythmogenicity and structural remodelling in a four-week healed model of MI. Male Sprague-Dawley rats (250–300g) underwent infarction-reperfusion surgery with either Rotigaptide (n=15) or Saline (n=15) via minipump. The arrhythmia phenotype was characterised at four-weeks with in-vivo telemetry, 6-lead ECG, ex-vivo arrhythmia provocation studies and dual optical mapping. Structural changes post-MI were studied with diffusion-weighted MRI (DWI) and Masson's Trichrome histology. Results: Rotigaptide resulted in a significant reduction in arrhythmias induced by programmed stimulation (arrhythmia score ROT 3.2 vs. CON 1.4, p<0.05), driven by a reduction in sustained VT (20% vs. 53%, p<0.06). Rotigaptide had no effect on mortality or the incidence of spontaneous arrhythmias or ECG parameters. Remodelling of the optical action potential (AP) was similar between groups a reduction in conduction velocity at the border zone and slowing of the AP upstroke. DWI provided quantifiable measures of structural remodelling in the remote, IBZ and infarct. In control hearts, the infarct demonstrated a significant reduction in fractional anisotropy, and a significant increase in mean diffusivity, compared to remote, partially reversed by Rotigaptide (FA: CON -15% vs. ROT -5%, p<0.05, MD: 6% vs. 2%, p<0.05). The 3D laminar structure of the IBZ was remodelled by Rotigaptide, with a reduction in mean (ROT 16 degrees vs. CON 19 degrees, p<0.05) and dispersion (9 degrees vs. 12 degrees, p<0.05) of the transverse angle. There was no remodelling of helix or transverse angle in remote of either treatment group. Conclusions: Pharmacological GJ enhancement in the early healing phase in reperfused infarction modifies the infarct scar morphology to render myocardium less vulnerable to arrhythmias during programmed stimulation, without affecting the properties of the cardiac action potential or calcium transient. The effects of Rotigaptide were limited to at-risk regions with attenuation of remodelling in the infarct and reduced fibre dispersion in the IBZ offering potential mechanistic explanations for the reduced arrhythmic risk.