Onset Of Ventricular Tachyarrhythmias Research Articles

Arrhythmic risk stratification in patients with clinically-suspected left ventricular arrhythmogenic cardiomyopathy

Abstract Background Arrhythmic risk of patients with left ventricular arrhythmogenic cardiomyopathy (LVAC) is unpredictable. Purpose To identify risk facors associated with major ventricular tachyarrhythmias (VTA) in clinically-suspected LVAC patients. Methods We enrolled 127 consecutive patients (69% males, age 46±13 y, LVEF 54±7%) with clinically-suspected LVAC. All patients presented with either major (VT, VF) or minor VTA (NSVT, frequent VEB), and underwent extensive diagnostic workup to rule-out alternative diagnoses. Medical treatment and ICD implant were clinically-driven. Prospective follow-up was obtained via sequential 24h-Holter ECG (2–4/y) with or without continuous arrhythmia monitoring (ICD or implantable loop recorders, ILR). The primary endpoint was occurrence of major VTA (VT/VF/ICD therapy) by 24-month follow-up. Results At presentation, 56 (44%) and 71 patients (56%) had, respectively, major and minor VTA. Variants in desmosomal genes were identified in 7 of the 9 patients with clinically-indicated genetic test. Delayed gadolinium enhancement (DGE, average 23±12% of the LV mass) had anteroseptal distribution in 43 cases (34%). Monitoring strategy included ICD (n=64), ILR (n=33), or sequential Holer ECGs (n=30). By 24-month follow-up, major VTA occurred in 32 patients (25%). At univariable anlysis, major VTA onset (HR 16.8, 95% CI 5.4–52.2, p<0.001) and anteroseptal DGE (HR 3.0, 95% CI 1.3–6.9, p=0.010) were significantly associated with major VTA by 24-month follow-up. Among patients presenting with minor VTA, the only factor significantly associated with the primary endpoint was anteroseptal DGE (3/4 vs. 14/67, p=0.004). Conclusion Our preliminary experience suggests that, in patients with clinically-suspected LVAC, major VTA onset and anteroseptal DGE are relevant risk factors for major arrhythmic events by 24-month follow-up. Funding Acknowledgement Type of funding sources: None.

FEATURES OF STRUCTURAL AND ELECTRICAL REMODELING OF THE HEART ASSOCIATED WITH HIGH RISK OF LIFETHREATENING VENTRICULAR TACHYARRHYTHMIAS IN PATIENTS WITH ISCHEMIC AND NON-ISCHEMIC CARDIOMYOPATHIES

Objective: to identify the features of myocardial fibrosis and ventricular repolarization disorders associated with malignant ventricular tachyarrhythmias (VT) in patients with ischemic (ICM) and non-ischemic cardiomyopathy (NICM).Material and Methods. Fifty consecutive patients (41 men and 9 women aged 60±13 years; 30 patients with ICM and 20 patients with NICM) underwent contrast magnetic resonance imaging (MRI) of the heart, QT dispersion analysis of 12-lead Holter ECG followed by implantation of cardioverter-defibrillator (ICD) or resynchronizing device with defibrillator (CRTD) to prevent sudden cardiac death.Results. According to data of 32 (28–43)-month follow up, VT paroxysms were registered in 20 of 30 patients (67%) with ICM and in 5 of 20 patients (25%) with NICM on follow-up. Data of successive univariate and ROC analyses of MRI indices differed between patients with and without recurrence of VTs in ICM and NICM patient groups. In ICM patients, VTs were associated with the values of QT (peak) interval dispersion over 80 mc according to data of Holter ECG monitoring and higher gray zone in the left ventricle (≥27%) according to contrast-enhanced MRI. Similar analyses in NICM patients showed that the most valuable diagnostic signs associated with the right ventricular tachycardias were the values of QT (peak) interval dispersion over 90 mc according to data of Holter ECG monitoring and the presence of non-transmural fibrosis of the left ventricle (≥27%) according to contrast-enhanced MRI.Conclusion. The features of structural remodeling of the left ventricle predisposing to VTs significantly differ in patients with ICM and NICM. Nevertheless, the presence of ventricular repolarization disorders, associated with onset of VTs, is universal in patients with ischemic and non-ischemic cardiomyopathies.

FEATURES OF STRUCTURAL AND ELECTRICAL REMODELING OF THE HEART ASSOCIATED WITH HIGH RISK OF LIFETHREATENING VENTRICULAR TACHYARRHYTHMIAS IN PATIENTS WITH ISCHEMIC AND NON-ISCHEMIC CARDIOMYOPATHIES

Objective: to identify the features of myocardial fibrosis and ventricular repolarization disorders associated with malignant ventricular tachyarrhythmias (VT) in patients with ischemic (ICM) and non-ischemic cardiomyopathy (NICM).Material and Methods. Fifty consecutive patients (41 men and 9 women aged 60±13 years; 30 patients with ICM and 20 patients with NICM) underwent contrast magnetic resonance imaging (MRI) of the heart, QT dispersion analysis of 12-lead Holter ECG followed by implantation of cardioverter-defibrillator (ICD) or resynchronizing device with defibrillator (CRTD) to prevent sudden cardiac death.Results. According to data of 32 (28–43)-month follow up, VT paroxysms were registered in 20 of 30 patients (67%) with ICM and in 5 of 20 patients (25%) with NICM on follow-up. Data of successive univariate and ROC analyses of MRI indices differed between patients with and without recurrence of VTs in ICM and NICM patient groups. In ICM patients, VTs were associated with the values of QT (peak) interval dispersion over 80 mc according to data of Holter ECG monitoring and higher gray zone in the left ventricle (≥27%) according to contrast-enhanced MRI. Similar analyses in NICM patients showed that the most valuable diagnostic signs associated with the right ventricular tachycardias were the values of QT (peak) interval dispersion over 90 mc according to data of Holter ECG monitoring and the presence of non-transmural fibrosis of the left ventricle (≥27%) according to contrast-enhanced MRI.Conclusion. The features of structural remodeling of the left ventricle predisposing to VTs significantly differ in patients with ICM and NICM. Nevertheless, the presence of ventricular repolarization disorders, associated with onset of VTs, is universal in patients with ischemic and non-ischemic cardiomyopathies.

Intra-tracheal gene delivery of aerosolized SERCA2a to the lung suppresses ventricular arrhythmias in a model of pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) results in right ventricular (RV) failure, electro-mechanical dysfunction and heightened risk of sudden cardiac death (SCD), although exact mechanisms and predisposing factors remain unclear. Because impaired chronotropic response to exercise is a strong predictor of early mortality in patients with PAH, we hypothesized that progressive elevation in heart rate can unmask ventricular tachyarrhythmias (VT) in a rodent model of monocrotaline (MCT)-induced PAH. We further hypothesized that intra-tracheal gene delivery of aerosolized AAV1.SERCA2a (AAV1.S2a), an approach which improves pulmonary vascular remodeling in PAH, can suppress VT in this model. ObjectiveTo determine the efficacy of pulmonary AAV1.S2a in reversing electrophysiological (EP) remodeling and suppressing VT in PAH. MethodsMale rats received subcutaneous injection of MCT (60 mg/kg) leading to advanced PAH. Three weeks following MCT, rats underwent intra-tracheal delivery of aerosolized AAV1.S2a (MCT + S2a, N = 8) or saline (MCT, N = 9). Age-matched rats served as controls (CTRL, N = 7). The EP substrate and risk of VT were determined using high-resolution optical action potential (AP) mapping ex vivo. The expression levels of key ion channel subunits, fibrosis markers and hypertrophy indices were measured by RT-PCR and histochemical analyses. ResultsOver 80% of MCT but none of the CTRL hearts were prone to sustained VT by rapid pacing (P < .01). Aerosolized gene delivery of AAV1.S2a to the lung suppressed the incidence of VT to <15% (P < .05). Investigation of the EP substrate revealed marked prolongation of AP duration (APD), increased APD heterogeneity, a reversal in the trans-epicardial APD gradient, and marked conduction slowing in untreated MCT compared to CTRL hearts. These myocardial EP changes coincided with major remodeling in the expression of K and Ca channel subunits, decreased expression of Cx43 and increased expression of pro-fibrotic and pro-hypertrophic markers. Intra-tracheal gene delivery of aerosolized AAV1 carrying S2a but not luciferase resulted in selective upregulation of the human isoform of SERCA2a in the lung but not the heart. This pulmonary intervention, in turn, ameliorated MCT-induced APD prolongation, reversed spatial APD heterogeneity, normalized myocardial conduction, and suppressed the incidence of pacing-induced VT. Comparison of the minimal conduction velocity (CV) generated at the fastest pacing rate before onset of VT or at the end of the protocol revealed significantly lower values in untreated compared to AAV1.S2a treated PAH and CTRL hearts. Reversal of EP remodeling by pulmonary AAV1.S2a gene delivery was accompanied by restored expression of key ion channel transcripts. Restored expression of Cx43 and collagen but not the pore-forming Na channel subunit Nav1.5 likely ameliorated VT by improving CV at rapid rates in PAH. ConclusionAerosolized AAV1.S2a gene delivery selectively to the lungs ameliorates myocardial EP remodeling and VT susceptibility at rapid heart rates. Our findings highlight for the first time the utility of a non-cardiac gene therapy approach for arrhythmia suppression.

Abstract 21353: Ccn5 Gene Therapy Suppresses Arrhythmias by Reversing Fibrosis in Mice With Chronic Angiotensin II Infusion

Background: Increased angiotensin II (ANG) levels elicit profibrotic effects which promote ventricular tachyarrhythmias (VT). Hypothesis: Gene delivery of the matricellular protein CCN5 ameliorates ANG related VT by reversing fibrosis. Methods: 8-10 wk old mice underwent ANG infusion (3mg/Kg/d) for 2wk after which they received 5E11 drp AAV9.CCN5 (ANGII+CCN5, n=8) or empty vector (ANGII, n=8) and were maintained for another 2wk. Optical mapping was performed in hearts that were challenged with right atrial (RA) burst trains (20Hz, 5-20 sec) to determine VT propensity. Fibrosis was assessed using trichrome staining. Results: VT was induced in 6/8 ANG, 2/8 ANG+CCN5, and 1/3 control hearts. A total of 34 trains elicited 13 VT episodes (38.4% rate) in ANG whereas 150 trains yielded only 6 episodes in ANG+CCN5 (4.0%). ANG increased the transepicardial APD gradient by causing selective APD prolongation on the RV side which was partially reversed by CCN5. No differences in the APD gradient were found between VT (+) and VT (-) hearts. Activation mapping revealed fixed lines of conduction block leading to onset of VT in ANG hearts. In contrast, RA trains caused shifting ventricular activation patterns that were normalized following the train in ANG+CCN5 (Fig). Extensive fibrotic lesions in ANG were reversed by CCN5 (Fig). Conclusions: Reversal of fibrosis by chronic CCN5 gene therapy suppresses the incidence of ANG related VT.

Abstract 223: Remodeling of K-ATP Channel Expression and Function in Type-2 Diabetes Mellitus

Diabetes mellitus (DM) is associated with enhanced propensity for ventricular tachyarrhythmias (VT). We found that DM hearts exhibit attenuated APD shortening in response to ischemia (Fig). We hypothesized that altered KATP channel expression &amp; function underlie this impaired electrophysiological (EP) adaptation. Methods: We investigated differential effects of the SUR2a activator Pinacidil (PIN, 100 uM) and the SUR1 activator Diazoxide (DZX, 30 uM) on EP properties in Zucker Diabetic Fatty (ZDF) and control (ctrl) rats at baseline and in response to no flow ischemia. We measured the mRNA expression of KATP channel subunits (Kir6.1, Kir6.2, SUR1a, SUR1b, SUR2a, and SUR2b) in normal and ZDF animals. Results: PIN caused comparable APD shortening in ctrl &amp; ZDF hearts during baseline perfusion and promoted early onset of sustained VT within 6 min of ischemia in ctrl &amp; ZDF hearts. In contrast, DZX did not alter APD (p=NS) or cause arrhythmias in either group during baseline perfusion. However, DZX accelerated APD shortening and promoted VT in all (8/8) ZDF hearts during ischemia (Fig 1). The putative molecular mechanism underlying the differential proarrhythmic sensitivity of ZDF vs ctrl hearts to DZX was investigated. We found marked upregulation of Kir6.1 (by 3.7X p&lt;0.001) and SUR1b (by 2.8X p&lt;0.001) mRNA levels with no changes in Kir6.2, SUR1a, SUR2a, or SUR2b expression in ZDF. Conclusion: Remodeling of KATP channel subunits likely underlies the differential sensitivity of ZDF hearts to DZX. Our findings indicate that this classically cardioprotective agent should be avoided in DM patients at risk of ischemic events. Upregulation of Kir6.1 &amp; SUR1b may be markers of proarrhythmia.

Comparison of the new risk prediction model (HCM Risk-SCD) and classic risk factors for sudden death in patients with hypertrophic cardiomyopathy and defibrillator.

Hypertrophic cardiomyopathy is one of the main causes of sudden death in young people. Recent clinical practice guidelines include a risk prediction model for sudden death (HCM Risk-SCD), which facilitates the decision of whether to implant a defibrillator. The aim of our study was to ascertain the percentage of events in our series of primary prevention implantable cardioverter-defibrillator recipients with hypertrophic cardiomyopathy and whether HCM Risk-SCD predicts the onset of arrhythmic events. This was an observational, retrospective cohort study, which included 48 primary prevention defibrillator recipient patients with HCM. We compiled their demographic and clinical characteristics, estimated 5-year risk using HCM Risk-SCD, and collected the documentation on arrhythmias during follow-up. The majority was male (66.7%) and mean age at implantation was 44.44 ± 14.46 years. Non-sustained ventricular tachycardia was the most prevalent risk factor (66.67%), followed by a family history of sudden death (47.92%). Mean HCM Risk-SCD was 6.15 ± 5.01%. HCM Risk-SCD was the only factor independently associated with the onset of ventricular tachyarrhythmia, above any other classic risk factor or association [odds ratio = 1.46 (95% confidence interval 1.051-2.013); P = 0.02]. None of the 11 patients estimated as low risk using HCM Risk-SCD suffered any appropriate events (P < 0.05). During an average follow-up of 4 years, 16.67% presented appropriate events (4.16%/year). HCM Risk-SCD predicted the onset of events more suitably than classic risk factors.

MicroRNA-1 downregulation increases connexin 43 displacement and induces ventricular tachyarrhythmias in rodent hypertrophic hearts.

Downregulation of the muscle-specific microRNA-1 (miR-1) mediates the induction of pathologic cardiac hypertrophy. Dysfunction of the gap junction protein connexin 43 (Cx43), an established miR-1 target, during cardiac hypertrophy leads to ventricular tachyarrhythmias (VT). However, it is still unknown whether miR-1 and Cx43 are interconnected in the pro-arrhythmic context of hypertrophy. Thus, in this study we investigated whether a reduction in the extent of cardiac hypertrophy could limit the pathological electrical remodeling of Cx43 and the onset of VT by modulating miR-1 levels. Wistar male rats underwent mechanical constriction of the ascending aorta to induce pathologic left ventricular hypertrophy (LVH) and afterwards were randomly assigned to receive 10mg/kg valsartan, VAL (LVH+VAL) delivered in the drinking water or placebo (LVH) for 12 weeks. Sham surgery was performed for control groups. Programmed ventricular stimulation reproducibly induced VT in LVH compared to LVH+VAL group. When compared to sham controls, rats from LVH group showed a significant decrease of miR-1 and an increase of Cx43 expression and its ERK1/2-dependent phosphorylation, which displaces Cx43 from the gap junction. Interestingly, VAL administration to rats with aortic banding significantly reduced cardiac hypertrophy and prevented miR-1 down-regulation and Cx43 up-regulation and phosphorylation. Gain- and loss-of-function experiments in neonatal cardiomyocytes (NCMs) in vitro confirmed that Cx43 is a direct target of miR-1. Accordingly, in vitro angiotensin II stimulation reduced miR-1 levels and increased Cx43 expression and phosphorylation compared to un-stimulated NCMs. Finally, in vivo miR-1 cardiac overexpression by an adenoviral vector intra-myocardial injection reduced Cx43 expression and phosphorylation in mice with isoproterenol-induced LVH. In conclusion, miR-1 regulates Cx43 expression and activity in hypertrophic cardiomyocytes in vitro and in vivo. Treatment of pressure overload-induced myocyte hypertrophy reduces the risk of life-threatening VT by normalizing miR-1 expression levels with the consequent stabilization of Cx43 expression and activity within the gap junction.

Surge of T-Wave Alternans in the Absence of Heart-Rate Acceleration: A New Predictor of Sustained Ventricular Tachyarrhythmias in Patients with Low Ejection Fraction?

Background T-wave alternans (TWA), a proarrhythmic form of repolarization instability, is usually observed in the setting of increased heart rate (HR). It is unknown, however, whether TWA can occur in the absence of HR acceleration before the onset of spontaneous, sustained ventricular tachyarrhythmia (VTA). Methods We examined ambulatory ECGs with spontaneous, sustained (>30 seconds, rate >100 bpm) VTA during 1 hour before the event; 34 patients had continuous, beat-to-beat HR and TWA data for ≥60 minutes (21% female, 65 ± 8 years; 87% had ischemic heart disease; ejection fraction [EF] 32 ± 17%). The data were averaged in 10-minute intervals. For consistency, TWA was analyzed using both spectral and time-domain methods as previously described. Results Overall, both HR and TWA increased in the hour before the event in the studied group. Sixteen patients (47%) had concomitant increase in HR and TWA. In 10 patients (29%), TWA increased without HR acceleration (HR-independent TWA). These patients had a twofold lower EF than the rest of the patients (median EF: 15% and 35%; interquartile ranges of EF: 27% and 22%, respectively, P = .018). The time of occurrence, duration, and cycle length of the events associated with HR-independent TWA were similar to those for the rest of the events. Conclusions An isolated increase in TWA in the absence of HR acceleration precedes the onset of VTA in patients with low EF. Chronically enhanced sympathetic activity and exhausted repolarization reserve may contribute to this phenomenon. Predictive value of HR-independent TWA warrants further study.

Relationship between T-wave alternans magnitude and T-wave amplitude before onset of ventricular tachyarrhythmias during emergent reperfusion in acute coronary syndrome patients: a response

I would like to thank Dr Takasugi and his co-authors for their response to my inquiry regarding a possible relationship between T-wave alternans (TWA) magnitude (TWAM) and the corresponding T-wave amplitude prior to the emergence of ventricular tachyarrhythmias (VTA) in patients undergoing acute coronary interventions, reported in their recent article in the Journal.1 They did not find a ‘significant positive correlation between TWAM and the corresponding T-wave …

Relationship between T-wave alternans magnitude and T-wave amplitude before the onset of ventricular tachyarrhythmias during emergent reperfusion in acute coronary syndrome patients

We greatly appreciate Dr Madias’ remarks on our recent study demonstrating the usefulness of continuous T-wave alternans (TWA) monitoring in ultra-short-term prediction of impending life-threatening ventricular tachyarrhythmias (VTA) during emergent reperfusion therapy in acute coronary syndrome (ACS) patients.1 He raised an interesting question, namely, was there a relationship between the increase in TWA and the possible increase in T-wave amplitude prior to the occurrence of VTA?2 This question is based on his theory that TWA magnitude is affected …

Continuous T-wave alternans monitoring to predict impending life-threatening cardiac arrhythmias during emergent coronary reperfusion therapy in patients with acute coronary syndrome

T-wave alternans (TWA) can precede onset of ventricular tachyarrhythmia (VTA). We evaluated the usefulness of continuous TWA monitoring in ultra-short-term prediction of impending life-threatening VTA upon emergent reperfusion in acute coronary syndrome (ACS) patients. Twenty consecutive ACS patients undergoing emergent reperfusion therapy were studied. Continuous ambulatory electrocardiograms (ECGs) (leads V1 and V5) were recorded during emergency room visit and therapy. Peak TWA was determined before and after reperfusion by the modified moving average method. Coronary balloon angioplasty/stenting was successfully performed in 19 patients and intracoronary vasodilator was administered in 1 patient with coronary spasm. Three (15.0%) patients developed VTA requiring cardioversion soon after reperfusion. Peak TWA before reperfusion was higher in patients with VTA than in those without (33.0 ± 4.4 vs. 15.8 ± 4.0 µV, P < 0.001). Two patients with arrhythmia exhibited an upsurge in TWA to 75 and 105 µV before onset of VTA. In the third patient, macroscopic TWA appeared in leads V1-V4 in a 12-lead ECG prior to VTA upon pharmacological resolution of vasospasm, although the ambulatory ECG field of view could not detect the upsurge. Acute coronary syndrome patients at risk of developing VTA soon after reperfusion exhibit premonitory episodes of increased TWA. Thus, TWA monitoring may be useful for ultra-short-term prediction of life-threatening cardiac arrhythmia risk upon emergent reperfusion in ACS patients. Continuous 12-lead ECGs may be required to optimize detection of TWA, which is regionally specific.

Early voltage/calcium uncoupling predestinates the duration of ventricular tachyarrhythmias during ischemia/reperfusion

Abnormal intracellular calcium (Ca(i)) kinetics during ischemia/reperfusion (I/R) can alter membrane voltage (V(m)) and destabilize wavefront propagation. We used optical mapping to investigate the hypothesis that early V(m)/Ca(i) uncoupling during a ventricular tachyarrhythmia (VT) can play a primary role in perpetuation of VT episodes. Seventeen Langendorff-perfused guinea pig hearts were subjected to 15 min I/15 min R. Simultaneous optical recordings of V(m) and Ca(i) signals were obtained using a dual-photodiode array. Spatiotemporal entropy (E) was used to quantify differences in V(m)/Ca(i) kinetics during VT and compare wavefront topology during the first 500 ms of a VT episode. A total of 39 episodes of VT were analyzed; VT was classified as self-terminating (ST, n = 28) and non-self-terminating (NST, n = 11). The ST/VTs were further classified into short ST/VT (1 to 5 s in duration; n = 16) and long ST/VT (>5 s, n = 12). E values for NST/VTs were significantly higher than E values for both short and long ST/VTs separately as well as E values for ST/VTs as a group. Further, E values for long ST/VTs were significantly higher than E values for short ST/VTs. Wave breaks were consistently identified during periods of high E. High E during the first 500 ms of the onset of VT (the first 2 to 3 beats) is significantly correlated with long ST or NST episodes. This may be related to destabilization of wave propagation that helps to perpetuate VT. Early V(m)/Ca(i) uncoupling can predestinate the development of a malignant NST/VT.

Cardiac electrical dynamics: maximizing dynamical heterogeneity

The relationships between key features of the cardiac electrical activity, such as electrical restitution, discordant alternans, wavebreak, and reentry, and the onset of ventricular tachyarrhythmias have been characterized extensively under the condition of constant rapid pacing. However, it is unlikely that this scenario applies directly to the clinical situation, where the induction of ventricular tachycardia (VT) typically is associated with the interruption of normal cardiac rhythm by several premature beats. To address this issue, we have developed a general theory to explain why specific patterns of premature stimuli increase dynamic heterogeneity of repolarization and precipitate conduction block. The theory predicts that conduction block is caused by (1) creation of a spatial gradient in diastolic interval (DI) by waves traveling at slightly different velocities (ie, conduction velocity dispersion) and (2) amplification of the spatial gradient in DI over subsequent action potentials, secondary to a strong dependence of action potential duration on the preceding DI (ie, a steep action potential duration restitution function). Tests of this theory have been conducted in computer models of homogeneous tissue, where increased spatial dispersion of repolarization during premature stimulation can be attributed solely to the development of dynamical heterogeneity, and in a canine model exhibiting spontaneously occurring VT and sudden death. Our results thus far indicate that the probability of inducing ventricular fibrillation (VF) in the animal model is highest for those sequences predicted to cause conduction block in the computer model. An understanding of the mechanisms underlying these observations will help to identify key electrical phenomena in the onset of VT and fibrillation. Drug and electrical therapies can then be improved by targeting these specific phenomena.

Bradycardia Pacing-Induced Short-Long-Short Sequences at the Onset of Ventricular Tachyarrhythmias: A Possible Mechanism of Proarrhythmia?

The purpose of this study was to characterize interactions between normal pacing system operation and the initiating sequence of ventricular tachycardia (VT)/ventricular fibrillation (VF). Abrupt changes in ventricular cycle lengths (short-long-short, S-L-S) might initiate VT/VF. The S-L-S sequences might be passively permitted or actively facilitated by bradycardia pacing. Initiating sequences of 1,356 VT/VF episodes in the PainFree Rx II (n = 634) and EnTrust Trial (n = 421) were analyzed with stored electrograms and by pacing mode (DDD/R, VVI/R, and Managed Ventricular Pacing [MVP]). Interactions between pacing and VT/VF initiation were classified as: non-pacing associated, pacing associated, pacing permitted, and pacing facilitated. Non-pacing associated (no pacing, no S-L-S) and pacing associated (ventricular pacing without S-L-S) onset accounted for 44.0% and 29.8% of all VT/VF, respectively. Pacing permitted (S-L-S sequences without ventricular pacing) episodes accounted for 6.4% (DDD/R), 20.0% (MVP), and 25.6% (VVI/R) of 1,356 VT/VF episodes. Pacing facilitated onset (S-L-S sequences actively facilitated by ventricular pacing including the terminal beat after a pause) accounted for 8.2% (MVP), 9.4% (VVI/R), and 14.8% (DDD/R) of 1,356 VT/VF episodes. Pacing facilitated S-L-S VT/VF occurred in 2.6% (MVP), 3.3% (VVI/R), and 5.2% (DDD/R) of patients with episodes and was the sole initiating sequence in approximately 1% of patients. Pause durations during pacing facilitated S-L-S differed between modes (DDD/R 793 +/- 172 ms vs. MVP 865 +/- 278 ms vs. VVI/R 1180 +/- 414 ms, p = 0.002). The majority of these episodes were monomorphic VT. Ventricular tachycardia/VF in some implantable cardioverter-defibrillator patients might be initiated by S-L-S sequences that are actively facilitated by bradycardia pacing operation and might constitute an important mechanism of ventricular proarrhythmia.

Pattern recognition and time-frequency representation of cardiac rhythm dynamics

86 14 14 22/73 Roelke et al, JACC 1994 92 7 – 59/1102 Anderson et al, JACC, 1995 – – 25 38/286 Meyerfeldt et al, EHJ, 1997 85 13 2 90/260 Taylor et al, JCE, 2000 56 – – 52/68 Saeed et al, AJC, 2000 – – 8 309/4973 Gronefeld et al, PACE 2002 complex and includes a multitude of time-varying components. Analysis of changes in these components has proven useful for analysis of the autonomic nervous system activity, as well as stress responses that might be related to clinically significant ischemic and arrhythmic events. However, because of the multicomponent structure of cardiac rhythm, tracking changes in this signal, in particular abrupt and irregular perturbations, is technically challenging. One important goal of the time-series analysis of cardiac rhythm is an identification of patterns and mechanisms predisposing to the initiation of ventricular tachyarrhythmias (VTA). Changes in cardiac rhythm have been consistently found before the onset of VTA in different patient populations. The predominant pattern of changes

Upsurge in T-Wave Alternans and Nonalternating Repolarization Instability Precedes Spontaneous Initiation of Ventricular Tachyarrhythmias in Humans

Analysis of repolarization instability, manifested by T-wave alternans (TWA), has proved useful for arrhythmia risk assessment. However, temporal relations between TWA and the spontaneous initiation of ventricular tachyarrhythmias (VTA) in humans are unknown. We examined continuous dynamics of repolarization in Holter electrocardiograms with spontaneous sustained (>30 seconds) VTA. Ambulatory electrocardiograms from 42 patients (79% with ischemic heart disease; left ventricular ejection fraction, 37+/-15%) were digitized, and the lead with the highest magnitude of the T wave was selected for analysis. TWA was examined by the modified moving average and intrabeat average analyses. To examine non-TWA (longer-period) oscillations in the repolarization segment, spectral energy of oscillations of consecutive T-wave amplitudes was calculated with the use of the short-time Fourier transform. Heart rate variability was assessed with the Fourier transform as well. TWA increased before the onset of VTA and reached a peak value of 23.6+/-11.7 microV 10 minutes before the event (P=0.0007). Spectral power of the oscillations of consecutive T-wave amplitudes increased nonuniformly, with the greatest increase in the respiratory range (2.6 microV2; P=0.005). In the TWA range, the change was smaller but highly pronounced relative to the 60- to 120-minute level (65%; P=0.003). The low-frequency and high-frequency heart rate variability power declined before the arrhythmia (P=0.04 and P=0.06, respectively). The magnitude of repolarization instability, manifested by TWA and beat-to-beat oscillations of T-wave amplitudes at other frequencies, increased before the onset of VTA. Tracking of these dynamics can facilitate timely detection of high-risk periods and may be useful for initiation of preventive treatments.

Coronary sinus lead placement: imaging and tools for implantation

Cardiac resynchronization therapy (CRT) is an established treatment in patients (pts) with progressive heart failure (HF). So far, no data, considering circadian rhythm as well as onset mechanisms (mechs) of ventricular tachyarrhythmia (VT) in patients under implantable Cardioverter/Defibrillator- (ICD) therapy and CRT, has been discussed. Therefore, the aim of this prospective study was to analyze the time of occurrence and the mech of induction of VT in patients under CRT and ICD therapy. Methods: A total of 14 pts (12 male, 66.54-9.8 years, 67% coronary artery disease) with a CRT-ICD device were observed over a mean period of 24.1 4- 18 months. Every three months an analysis of the stored electrograms was performed under special consideration of the mechs of VT onset as well as distribution of VT within a day. The classification of mechs includes sudden onset (SO), short-long-short interval (SLS), and none determinable mechs. The analysis included treated episodes solely. Results: 93% of the pts were classified as NYHA III with a mean ejection fraction of 24 4- 6%. A total of 147 VT were documented: 55 (37.4%) VT, 60 (39%) fast VT and 32 (21%) ventricular fibrillation. SO was identified in 76% (n=112) as the mech of onset, while SLS occurred in 29 (19.7%). The onset of 6 (4.1%) episodes could not be determined. Concerning the circadian rhythmic, the episodes occurred, compared to other times of the day (n=34, between 10 a.m. and 4 p.m.; n=30, between 4 and 10 p.m. and n= 29 between 10 p.m. and 4 a.m.), preferably in the early morning hours (n=54, between 4 and 10 a.m.). Conclusion: Sudden onset and short-long-short interval are the two dominant modes of inductions of VT in our CRT-ICD cohort. The majority of VT episodes was initiated by a sudden onset mode. In terms of the circadian rhythm, episodes occurred predominantly in the early morning hours. Our data show, for the first time, mechs of onset of VT and daily distribution of VT in CRT-ICD pts that are comparable to results of ICD-pts without CRT. 34 Risk stratification in patients with Brugada syndrome. Analysis of

The R-on-T phenomenon in patients with implantable cardioverter-defibrillators

The R-on-T phenomenon, first characterized by Smirk,1 describes superimposition of a ventricular depolarization (R wave) on the T wave of the preceding beat. Critically coupled ventricular premature complexes (VPCs) are able to induce sustained ventricular tachyarrhythmias (VTs); referring to this property, R-on-T VPCs are generally considered to be particularly hazardous. Conflicting data exist concerning the significance of R-on-T VPCs in acute myocardial infarction.2 Recent studies found an increased incidence of R-on-T VPCs in patients with acute myocardial infarction complicated by spontaneous ventricular fibrillation.3,4 Chiladakis and coworkers,5 however, observed R-on-T VPCs only rarely in 93 patients with thrombolyzed myocardial infarction. In contrast, Turitto et al6 assessed increased R-on-T induction of VTs during transient myocardial ischemia in patients with variant angina. Post-myocardial infarction R-on-T VPCs and other ventricular arrhythmias are of prognostic significance,7 although their classification as the most hazardous arrhythmias in the historical Lown grading system does not appear to be justified.8 In a multivariate analysis, the occurrence of R-on-T VPCs after myocardial infarction was found not to be prognostically significant, whereas QT dispersion >100 ms was strongly related to postinfarction mortality.9 Implantable cardioverter-defibrillators (ICDs) are capable of storing arrhythmia-related intracardiac electrograms and allow unique insight into the mode of onset of VTs, which has been analyzed in a number of studies.10–13 This option, however, until now has not been utilized with respect to R-on-T VPCs.

Temporary disturbances of the QT interval precede the onset of ventricular tachyarrhythmias in patients with structural heart diseases.

An increase in sinus rate prior to ventricular tachyarrhythmias has been demonstrated in previous studies. There is no clear data available concerning changes in ventricular de- and repolarization prior to ventricular tachyarrhythmias, especially in patients with structural heart disease. Therefore, the aim of this study was to analyze the QT and QTc interval (Bazett's formula immediately before the onset of ventricular tachyarrhythmias in stored electrograms of patients with ICDs. The study analyzed 228 spontaneous ventricular tachyarrhythmia episodes in 52 patients (mean age 64 +/- 10 years, 49 men, 3 women) and compared them with 146 electrograms of baseline rhythm recorded during regular ICD follow-up. Mean ventricular cycle length (CL), QT interval, and QTc were measured before the onset of ventricular tachyarrhythmia and during baseline rhythm. Prior to ventricular tachyarrhythmias onset, CL was significantly shorter than during baseline rhythm (714 +/- 139 vs 828 +/- 149 ms, P < 0.0001). By contrast, the QT interval (430 +/- 67 ms) and QTc interval (518 +/- 67 ms) were significantly prolonged before the onset of ventricular tachyarrhythmias as compared to baseline rhythm (QT 406 +/- 67 ms, QTc 450 +/- 61 ms; P < 0.0001). CL, QT, and QTc changes were independent of concomitant treatment with antiarrhythmic drugs. Ventricular tachyarrhythmias are preceded by a significant prolongation of the QT and QTc intervals. This phenomenon may represent a greater than normal disparity of repolarization recovery times possibly facilitating the development of ventricular tachyarrhythmias.