Variability Of Repolarization Research Articles

Assessment of the human response to acute mental stress-An overview and a multimodal study.

Numerous vital signs are reported in association with stress response assessment, but their application varies widely. This work provides an overview over methods for stress induction and strain assessment, and presents a multimodal experimental study to identify the most important vital signs for effective assessment of the response to acute mental stress. We induced acute mental stress in 65 healthy participants with the Mannheim Multicomponent Stress Test and acquired self-assessment measures (Likert scale, Self-Assessment Manikin), salivary α-amylase and cortisol concentrations as well as 60 vital signs from biosignals, such as heart rate variability parameters, QT variability parameters, skin conductance level, and breath rate. By means of statistical testing and a self-optimizing logistic regression, we identified the most important biosignal vital signs. Fifteen biosignal vital signs related to ventricular repolarization variability, blood pressure, skin conductance, and respiration showed significant results. The logistic regression converged with QT variability index, left ventricular work index, earlobe pulse arrival time, skin conductance level, rise time and number of skin conductance responses, breath rate, and breath rate variability (F1 = 0.82). Self-assessment measures indicated successful stress induction. α-amylase and cortisol showed effect sizes of -0.78 and 0.55, respectively. In summary, the hypothalamic-pituitary-adrenocortical axis and sympathetic nervous system were successfully activated. Our findings facilitate a coherent and integrative understanding of the assessment of the stress response and help to align applications and future research concerning acute mental stress.

Abstract 16616: Automatic Measurement of Short-Term Variability of Repolarization Captures Modulation by Pacing on Human Intracardiac Electrograms

Introduction: Short-term variability of repolarization (STV) increases prior to ventricular arrhythmias (VA) both in humans and in animal models of VA, and is therefore a promising tool for real-time monitoring of arrhythmic risk. To integrate this concept in cardiac devices, a method to automatically determine STV on intracardiac electrograms (EGM) was developed. This STV algorithm demonstrated high efficacy in predicting life-threatening VA in animal studies, but still needs to be evaluated on human signals. Objective: To assess the performance of the novel automatic method of STV measurement on human EGMs during sinus rhythm (SR) and pacing. Methods: ECG and EGM signals with a 1 kHz sampling frequency were recorded in 14 dual chamber implantable cardioverter-defibrillator (ICD) patients during implantation (n=4) or replacement (n=10) procedures. Recordings were obtained in SR, atrial pacing at 80 beats per minute (AAI80) and atrioventricular pacing at the same frequency (DDD80). STV was calculated over 31 consecutive beats as Σ

Automatic measurement of short-term variability of repolarization to indicate ventricular arrhythmias in a porcine model of cardiac ischaemia.

An automated method for determination of short-term variability (STV) of repolarization on intracardiac electrograms (STV-ARIauto) has previously been developed for arrhythmic risk monitoring by cardiac implantable devices, and has proved effective in predicting ventricular arrhythmias (VA) and guiding preventive high-rate pacing (HRP) in a canine model. Current study aimed to assess (i) STV-ARIauto in relation to VA occurrence and secondarily (ii-a) to confirm the predictive capacity of STV from the QT interval and (ii-b) explore the effect of HRP on arrhythmic outcomes in a porcine model of acute myocardial infarction (MI). Myocardial infarction was induced in 15 pigs. In 7/15 pigs, STV-QT was assessed at baseline, occlusion, 1 min before VA, and just before VA. Eight of the 15 pigs were additionally monitored with an electrogram catheter in the right ventricle, underwent echocardiography at baseline and reperfusion, and were randomized to paced or control group. Paced group received atrial pacing at 20 beats per min faster than sinus rhythm 1 min after occlusion. Short-term variability increased prior to VA in both STV modalities. The percentage change in STV from baseline to successive timepoints correlated well between STV-QT and STV-ARIauto. High-rate pacing did not improve arrhythmic outcomes and was accompanied by a stronger decrease in ejection fraction. STV-ARIauto values increase before VA onset, alike STV-QT in a porcine model of MI, indicating imminent arrhythmias. This highlights the potential of automatic monitoring of arrhythmic risk by cardiac devices through STV-ARIauto and subsequently initiates preventive strategies. Continuous HRP during onset of acute MI did not improve arrhythmic outcomes.

Time-Warping Analysis of the T-Wave Peak-to-End Interval to Quantify Ventricular Repolarization Dispersion During Ischemia.

The presence of myocardial ischemia can increase ventricular arrhythmic risk due to a raised dispersion of ventricular repolarization. This is reflected on the morphology of the T-wave on the electrocardiogram (ECG), and can be quantified by time-warping based indexes, like dw. However, T-wave morphology can also be affected by ischemia-induced ST segment changes, impacting the accuracy of dw. We hypothesize that ischemia-induced repolarization dispersion can be better quantified by restricting dw to the T-wave peak-to-end (T pe) interval. 101 ECG recordings from patients undergoing a percutaneous coronary intervention (PCI) were analyzed together with their control ECG recordings, acquired before the intervention. A series of dw values was calculated by quantifying the T pe morphological variations between the T-waves from the PCI and a reference derived from the control ECG recordings. We proposed a normalized version of dw, Rd, reflecting relative variations of dw during PCI to control recordings, and compare it with traditional indices behaviour. Values of dw followed a gradually increasing trend as PCI inflation time progressed, reaching a median[range] Rd value of 9.44 [1.01, 80.74] at the occlusion end. During control recordings, dw remained stable, with a low intra-patient standard deviation, range [0.02, 2.09] ms and a median[range] Rd of 1.00 [0.03, 2.93]. Rd at oclussion end was significantly higher than threshold values of 1, 2, 5, and 10 in 94.1%, 85.11%, 64.4% and 48.5% of patients, respectively. The spatial lead-wise analysis of dw showed distinct distributions depending on the occluded artery, suggesting a relation with the ischemia location. The relative variation R with ischemia of index dw (9.4) is greater than for traditional T wave amplitude (7.7), T peak-to-end interval (2.7) and T width (3.0). The index dw, quantifying T pe morphology variations, allows to follow the ischemia induced variations in repolarization in a more robust manner than classical indexes, avoiding ST segment and early T wave distortions not related to repolarization dispersion, and warranting further clinical studies to evaluate its ventricular arrhythmia risk predictive value during ischemia.

Effect of Head-Up/-Down Tilt on ECG Segments and Myocardial Temporal Dispersion in Healthy Subjects.

The head-up/-down tilt test acutely modifies the autonomic nervous system balance throughout a deactivation of the cardiopulmonary reflexes. The present study examines the influence of head-up/-down tilt on a number of ECG segments. A total of 20 healthy subjects underwent a 5 min ECG and noninvasive hemodynamic bio-impedance recording, during free and controlled breathing, lying at (a) 0°; (b) -45°, tilting up at 45°, and tilting up at 90°. Heart rate variability power spectral analysis was obtained throughout some ECG intervals: P-P (P), P-Q (PQ), PeQ (from the end of P to Q wave), Q-R peak (QR intervals), Q-R-S (QRS), Q-T peak (QTp), Q-T end (QTe), STp, STe, T peak-T end (Te), and, eventually, the TeP segments (from the end of T to the next P waves). Results: In all study conditions, the Low Frequency/High FrequencyPP and LFPP normalized units (nu) were significantly lower than the LF/HFRR and LFRRnu, respectively. Conversely, the HFPP and HFPPnu were significantly higher in all study conditions. STe, QTp, and QTe were significantly related to the PP and RR intervals, whereas the T wave amplitude was inversely related to the standard deviations of all the myocardial repolarization variables and to the left ventricular end-systolic volume (LVEDV). The T wave amplitude diminished during head-up tilt and significantly correlated with the LVEDV.

Regional beat-to-beat variability of repolarization increases during ischemia and predicts imminent arrhythmias in a pig model of myocardial infarction.

Ventricular arrhythmia (VT/VF) can complicate acute myocardial ischemia (AMI). Regional instability of repolarization during AMI contributes to the substrate for VT/VF. Beat-to-beat variability of repolarization (BVR), a measure of repolarization lability increases during AMI. We hypothesized that its surge precedes VT/VF. We studied the spatial and temporal changes in BVR in relation to VT/VF during AMI. In 24 pigs, BVR was quantified on 12-lead electrocardiogram recorded at a sampling rate of 1 kHz. AMI was induced in 16 pigs by percutaneous coronary artery occlusion (MI), whereas 8 underwent sham operation (sham). Changes in BVR were assessed at 5 min after occlusion, 5 and 1 min pre-VF in animals that developed VF, and matched time points in pigs without VF. Serum troponin and ST deviation were measured. After 1 mo, magnetic resonance imaging and VT induction by programmed electrical stimulation were performed. During AMI, BVR increased significantly in inferior-lateral leads correlating with ST deviation and troponin increase. BVR was maximal 1 min pre-VF (3.78 ± 1.36 vs. 5 min pre-VF, 1.67 ± 1.56, P < 0.0001). After 1 mo, BVR was higher in MI than in sham and correlated with the infarct size (1.43 ± 0.50 vs. 0.57 ± 0.30, P = 0.009). VT was inducible in all MI animals and the ease of induction correlated with BVR. BVR increased during AMI and temporal BVR changes predicted imminent VT/VF, supporting a possible role in monitoring and early warning systems. BVR correlated to arrhythmia vulnerability suggesting utility in risk stratification post-AMI.NEW & NOTEWORTHY The key finding of this study is that BVR increases during AMI and surges before ventricular arrhythmia onset. This suggests that monitoring BVR may be useful for monitoring the risk of VF during and after AMI in the coronary care unit settings. Beyond this, monitoring BVR may have value in cardiac implantable devices or wearables.

PO-02-216 SEGMENTAL INCREASE IN HETEROGENEITY OF REPOLARIZATION CORRESPONDS TO REGIONS OF DECREASED INNERVATION AFTER MYOCARDIAL INFARCTION

Myocardial infarction (MI) results in a dense scar region surrounded by a heterogeneous remodeled border zone. In this region denervation and nerve regeneration during healing could be region dependent and contribute to segmental differences in the functional substrate for arrhythmias. To examine regional electrophysiological remodeling in relation to perfusion and innervation changes after myocardial infarction. Anterio-septal MI was induced in 6 domestic pigs by a 120-minute occlusion of the left anterior descending artery (LAD) followed by reperfusion. After one month, PET-MR imaging was performed to evaluate myocardial perfusion (13N-ammonia) and innervation (11C-epinephrine), together with late gadolinium enhanced MR imaging for scar quantification. The next day electro-anatomical mapping was performed. The BZ was defined using contact mapping as the region with bipolar voltage between 0.5 and 1.5 mV. A non-contact recording of a 64-electrode array was translated to 2048 non-contact electrograms distributed over the LV (EnSite PrecisionTM, St. Jude/Abbott Medical). In each of the 2048 points non-contact electrograms over 25 consecutive beats were processed to determine the beat-to-beat variability of repolarization (BVR). Spatial heterogeneity of repolarization was quantified in each point as the repolarization time variability within a 1cm radius neighborhood. MI size was 14.2±3.2% of the left ventricle on gadolinium enhanced MR imaging. The perfusion and innervation defects were significantly larger (22.3±3.2%, P<0.01 and 28.1±4.3%, P<0.01 respectively). The innervation defect was also significantly larger than the perfusion defect (P=0.03). Regional analysis revealed less innervation in the anterior versus the septal border zone (14.2±2.9 %/min vs 18.6+3.1 %/min, P<0.01). In one animal the electrophysiology study was unsuccessful due to a high baseline heart rate (>120 BPM). In the remaining animals, the average spatial heterogeneity was higher in the anterior than septal border zone (5.8±3.0 ms vs 3.8±2.6 ms, P<0.01). Additionally, the maximum BVR tended to be higher in the anterior than septal border zone (2.6±1.3 ms vs 2.02±0.77 ms, P=0.08). MI resulting from LAD occlusion/reperfusion leads to increased denervation on the anterior side of the infarct, correlating with increased repolarization heterogeneity in this region.

Electric Field-Based Spatial Analysis of Noncontact Unipolar Electrograms to Map Regional Activation-Repolarization Intervals

BackgroundSpatial heterogeneity in repolarization plays an important role in generating and sustaining cardiac arrhythmias. Reliable determination of repolarization times remains challenging. ObjectivesThe goal of this study was to improve processing of densely sampled noncontact unipolar electrograms to yield reliable high-resolution activation and repolarization maps. MethodsEndocardial noncontact unipolar electrograms were both simulated and recorded in pig left ventricle. Electrical activity on the endocardial surface was processed in terms of a pseudo-electric field. Activation and repolarization times were calculated by using an amplitude-weighted average on QRS and T waves (ie, the E-field method). This was compared vs the conventional Wyatt method on unipolar electrograms. Timing maps were validated against timing on endocardial action potentials in a simulation study. In vivo, activation and repolarization times determined by using this alternative E-field method were validated against simultaneously recorded endocardial monophasic action potentials (MAPs). ResultsSimulation showed that the E-field method provides viable measurements of local endocardial action potential activation and repolarization times. In vivo, correlation of E-field activation times with MAP activation times (rE = 0.76; P < 0.001) was similar to those of Wyatt (rWyatt = 0.80, P < 0.001; P[h1:rE > rWyatt] = 0.82); for repolarization times, correlation improved significantly (rE = 0.96, P < 0.001; rWyatt = 0.82, P < 0.001; P[h1:rE > rWyatt] < 0.00001). This resulted in improved correlations of activation-repolarization intervals to endocardial action potential duration on MAP (rE = 0.96, P < 0.001; rWyatt = 0.86, P < 0.001; P[h1:rE > rWyatt] < 0.00001). Spatial beat-to-beat variation of repolarization could only be calculated by using the E-field methodology and correlated well with the MAP beat-to-beat variation of repolarization (rE = 0.76; P = 0.001). ConclusionsThe E-field method substantially enhances information from endocardial noncontact electrogram data, allowing for dense maps of activation and repolarization times and derived parameters.

Cardiac electrophysiological remodeling associated with enhanced arrhythmia susceptibility in a canine model of elite exercise.

The health benefits of regular physical exercise are well known. Even so, there is increasing evidence that the exercise regimes of elite athletes can evoke cardiac arrhythmias including ventricular fibrillation and even sudden cardiac death (SCD). The mechanism of exercise-induced arrhythmia and SCD is poorly understood. Here, we show that chronic training in a canine model (12 sedentary and 12 trained dogs) that mimics the regime of elite athletes induces electrophysiological remodeling (measured by ECG, patch-clamp, and immunocytochemical techniques) resulting in increases of both the trigger and the substrate for ventricular arrhythmias. Thus, 4 months sustained training lengthened ventricular repolarization (QTc: 237.1±3.4 ms vs. 213.6±2.8 ms, n=12; APD90: 472.8±29.6 ms vs. 370.1±32.7 ms, n=29 vs. 25), decreased transient outward potassium current (6.4±0.5 pA/pF vs. 8.8±0.9 pA/pF at 50 mV, n=54 vs. 42), and increased the short-term variability of repolarization (29.5±3.8 ms vs. 17.5±4.0 ms, n=27 vs. 18). Left ventricular fibrosis and HCN4 protein expression were also enhanced. These changes were associated with enhanced ectopic activity (number of escape beats from 0/hr to 29.7±20.3/hr) in vivo and arrhythmia susceptibility (elicited ventricular fibrillation: 3 of 10 sedentary dogs vs. 6 of 10 trained dogs). Our findings provide in vivo, cellular electrophysiological and molecular biological evidence for the enhanced susceptibility to ventricular arrhythmia in an experimental large animal model of endurance training.

Nonlinear analysis of beat-to-beat variability of action potential time series data identifies dynamic re-entrant substrates in a hypokalaemic mouse model of acquired long QT syndrome

BackgroundPrevious studies have quantified repolarization variability using time-domain, frequency-domain and nonlinear analysis in mouse hearts. Here, we investigated the relationship between these parameters and ventricular arrhythmogenicity in a hypokalaemia model of acquired long QT syndrome.MethodsLeft ventricular monophasic action potentials (MAPs) were recorded during right ventricular regular 8 Hz pacing during normokalaemia (5.2 mM [K+]), hypokalaemia modeling LQTS (3 mM [K+]) or hypokalaemia with 0.1 mM heptanol in Langendorff-perfused mouse hearts.ResultsDuring normokalaemia, mean APD was 33.5 ± 3.7 ms. Standard deviation (SD) of APDs was 0.63 ± 0.33 ms, coefficient of variation was 1.9 ± 1.0% and the root mean square (RMS) of successive differences in APDs was 0.3 ± 0.1 ms. Low- and high-frequency peaks were 0.6 ± 0.5 and 2.3 ± 0.7 Hz, respectively, with percentage powers of 38 ± 22 and 61 ± 23%. Poincaré plots of APDn+1 against APDn revealed ellipsoid morphologies with SD along the line-of-identity (SD2) to SD perpendicular to the line-of-identity (SD1) ratio of 4.6 ± 1.1. Approximate and sample entropy were 0.49 ± 0.12 and 0.64 ± 0.29, respectively. Detrended fluctuation analysis revealed short- and long-term fluctuation slopes of 1.62 ± 0.27 and 0.60 ± 0.18, respectively. Hypokalaemia provoked ventricular tachycardia in six of seven hearts, prolonged APDs (51.2 ± 7.9 ms), decreased SD2/SD1 ratio (3.1 ± 1.0), increased approximate and sample entropy (0.68 ± 0.08 and 1.02 ± 0.33) and decreased short-term fluctuation slope (1.23 ± 0.20) (ANOVA, P < 0.05). Heptanol prevented VT in all hearts studied without further altering the above repolarization parameters observed during hypokalaemia.ConclusionReduced SD2/SD1, increased entropy and decreased short-term fluctuation slope may reflect arrhythmic risk in hypokalaemia. Heptanol exerts anti-arrhythmic effects without affecting repolarization variability.

Abstract 13503: Assessment of Automatic Measurement of Short-Term Variability of Repolarization for Arrhythmic Risk Monitoring in a Porcine Model of Ischemic Ventricular Fibrillation

Background: Short-term variability of repolarization derived from the QT-interval (STV-QT) has previously been demonstrated to increase prior to arrhythmias in both humans and animals. To continuously monitor the arrhythmic risk by a cardiovascular implantable electronic device (CIED), a fully automatic method to determine STV on intracardiac electrograms (STV-EGM auto ) has been developed. This method demonstrated high effectiveness in monitoring and predicting Torsade de Pointes arrhythmias in the CAVB dog model. However, this technique has not been evaluated in arrhythmias related to ischemia yet. Purpose: To assess the novel automatic method of arrhythmic risk monitoring by CIEDs through STV-EGM auto measurements in a porcine model of ischemia-induced ventricular fibrillation (VF). Methods: Myocardial infarction was induced in 8 anesthetized pigs by balloon occlusion of the left anterior descending coronary artery for 75 minutes, followed by reperfusion. Monitoring included a 12-lead ECG and a duodecapolar EGM catheter in the right ventricle. STV-EGM auto and STV-QT, our gold standard calculated by the method of fiducial segment averaging, were assessed at baseline, occlusion, one minute before VF and just before VF. The STV values and the percentual changes from baseline to the successive three timepoints were compared between STV-EGM auto and STV-QT. Results: VF occurred 21±8.8 minutes after occlusion. Both STV-EGM auto and STV-QT increased significantly from baseline to VF (1.1±0.8 ms vs 2.4±1.5 ms, p&lt;0.05; 1.0±0.5 ms vs 2.2±0.9 ms, p&lt;0.05, respectively). The percentual change in STV-EGM auto from baseline to occlusion, one minute before VF and VF showed an excellent correlation with the changes in STV-QT from baseline to the successive timepoints (r 2 = 0.94; p&lt;0.001). Bland-Altman analysis of the values showed a small bias of 0.26 ms and 95% limits of agreement between -1.1 and 1.6 ms. Conclusion: The STV values derived from the fully-automatic method for continuous STV measurements on intracardiac EGM signals (STV-EGM auto ) show values and trends similar to the clinically validated STV-QT in a porcine model of ischemia-related VF. Future integration of this technique in CIEDs can furnish continuous monitoring of arrhythmic risk.

QT interval variability and athlete's heart remodeling

At present, the prevention of sudden cardiac death in athletes is of great interest. A large amount of literature data concerning the correlation between the length of the QT interval and the proarrhythmic potential of the myocardium has been accumulated. However, new potential predictors of the fatal arrhythmias occurrence in athletes have emerged in recent years — an increase in the dispersion of the QT interval, as well as short-term variability in repolarization. This review provides detailed data on the diagnosis, prevalence, classifi cation, etiology of long QT as one of the manifestations of QT variance. The variety of causes leading to long QT syndrome (LQTS) causes diffi culties in the diff erential diagnosis of this condition and, and as a result, LQTS often remains outside the attention of practitioners. The data of recent studies of the athlete’s heart remodelling are presented as well.

Endo- and epicardial mapping of spontaneous ventricular fibrillation during acute myocardial infarction in a porcine model

Abstract Introduction Ventricular fibrillation (VF) during the first minutes of acute myocardial infarction (AMI) is among the most frequent causes of sudden cardiac death. Albeit mechanisms for arrhythmogenesis during ischemia are well understood on a cellular level, little is known in an in-vivo setting. Aim Aim of this study was the development and characterization of a porcine model of AMI and spontaneous VF with continuous electrical mapping using a non-contact mapping system (EnSite Array) in the left ventricle (LV) and an electrode sock covering the whole heart. Activation-recovery intervals (ARI), beat-to-beat variation in repolarization (BVR), and ectopic activation were measured. Methods Nineteen Danish Landrace pigs (56±4 kg, heart weight 251±20 g) were anaesthetized, equipped with electrophysiological (EP) catheters in the coronary sinus, right and LV as well as a multi electrode array (St. Jude, EnSite Array) catheter in the LV. Thoracotomy was performed and the sock electrode was placed on the pericardium covering the anterior and the posterior surface of the heart. Finally, the mid-left anterior descendent artery was occluded with a percutaneous transluminal coronary angioplasty balloon to induce AMI and kept in place for 45 minutes followed by 20 minutes of reperfusion. Data from both systems were analyzed offline using a custom-made software. Results All pigs had stable hemodynamic parameters during the procedure. Spontaneous VF occurred in 8/19 pigs during the occlusion period. Epi- and endocardial mapping showed similar shortening of ARI in the infarcted area (Figure 1A). AMI shortened ARI in the ischemic area to a greater extend in pigs that developed VF (Figure 1B) and caused beat-to-beat variation in repolarization (BVR) in later phases (Figure 1C). Ectopic beats proceeding spontaneous VF varied in activation site and subsequent repolarization (Figure 1D, left). Multiple short-coupled ectopic beats destabilized the electrical substrate further and led to progressive ARI shortening (Figure 1D, last 4 beats). Conclusion We present the first whole heart mapping experiments of spontaneous VF during AMI with endo- and epicardial mapping. Pigs with VF had shorter ARI, greater dispersion but similar BVR during AMI compared to those without VF. These findings provide a deeper understanding of arrhythmogenesis during AMI and can help to develop new antiarrhythmic drugs or to assess risk factors of VF. Funding Acknowledgement Type of funding sources: None.

QT and Tpeak-Tend interval variability: Predictive electrical markers of hospital stay length and mortality in acute decompensated heart failure. Preliminary data.

As previously reported, an increased repolarization temporal imbalance induces a higher risk of total/cardiovascular mortality. The aim of this study was to assess if the electrocardiographic short period markers of repolarization temporal dispersion could be predictive of the hospital stay length and mortality in patients with acutely decompensated chronic heart failure (CHF). Mean, standard deviation (SD), and normalized variance (VN) of QT (QT) and Tpeak-Tend (Te) were obtained on 5-minECG recording in 139 patients hospitalized for acutely decompensated CHF, subgrouping the patients for hospital length of stay (LoS): less or equal 1 week (≤1 W) and those with more than 1week (>1 W). We observed an increase of short-period repolarization variables (TeSD and TeVN, p < .05), a decrease of blood pressure (p < .05), lower ejection fraction (p < .05), and higher plasma level of biomarkers (NT-proBNP, p < .001; Troponin, p < .05) in >1 W LoS subjects. 30-day deceased subjects reported significantly higher levels of QTSD (p < .05), Te mean (p < .001), TeSD (p < .05), QTVN (p < .05) in comparison to the survivors. Multivariable Cox regression analysis reported that TeVN was a risk factor for longer hospital stay (hazard ratio: 1.04, 95% confidence limit: 1.01-1.08, p < .05); whereas, a longer Te mean was associated with higher mortality risk (hazard ratio: 1.02, 95% confidence limit: 1.01-1.03, p < .05). A longer hospital stay is considered a clinical surrogate of CHF severity, we confirmed this finding. Therefore, these electrical and simple parameters could be used as noninvasive, transmissible, inexpensive markers of CHF severity and mortality.

Role of cardiac α1-adrenoreceptors for the torsadogenic action of IKr blocker nifekalant in the anesthetized atrioventricular block rabbit

We analyzed role of cardiac α1-adrenoreceptors for the torsadogenic action of IKr blocker nifekalant in isoflurane-anesthetized atrioventricular block rabbits. Bradycardia was induced by atrioventricular node ablation, and the ventricle was electrically driven at a constant rate of 60 beats/min throughout the experiments to prevent rate-dependent modification by the IKr blocker in ventricular repolarization phase. Nifekalant (3 mg/kg per 10 min, n = 5) prolonged the duration of monophasic action potential (MAP90) by +178 ± 43 ms, increased the short-term variability of repolarization (STV) to 4.2 ± 1.2 ms, and induced torsade de pointes (TdP) in 1 animal. In the presence of methoxamine (n = 5), nifekalant prolonged the MAP90 by +328 ± 32 ms, increased the STV to 8.0 ± 1.0 ms, and induced TdP in 2 animals. In the presence of prazosin and methoxamine (n = 5), nifekalant prolonged the MAP90 by +267 ± 22 ms, increased the STV to 9.2 ± 3.6 ms, and induced no TdP. These results suggest that cardiac α1-adrenoreceptor activation by methoxamine essentially sensitizes the rabbit heart to nifekalant-induced QT interval prolongation, leading to the onset of TdP.

Endurance training-induced cardiac remodeling in a guinea pig athlete's heart model.

Besides the health benefits of regular exercise, high-level training-above an optimal level-may have adverse effects. In this study, we investigated the effects of long-term vigorous training and its potentially detrimental structural-functional changes in a small animal athlete's heart model. Thirty-eight 4-month-old male guinea pigs were randomized into sedentary and exercised groups. The latter underwent a 15-week-long endurance-training program. To investigate the effects of the intense long-term exercise, in vivo (echocardiography, electrocardiography), ex vivo, and in vitro (histopathology, patch-clamp) measurements were performed. Following the training protocol, the exercised animals exhibited structural left ventricular enlargement and a significantly higher degree of myocardial fibrosis. Furthermore, resting bradycardia accompanied by elevated heart rate variability occurred, representing increased parasympathetic activity in the exercised hearts. The observed prolonged QTc intervals and increased repolarization variability parameters may raise the risk of electrical instability in exercised animals. Complex arrhythmias did not occur in either group, and there were no differences between the groups in ex vivo or cellular electrophysiological experiments. Accordingly, the high parasympathetic activity may promote impaired repolarization in conscious exercised animals. The detected structural-functional changes share similarities with the human athlete's heart; therefore, this model might be useful for investigations on cardiac remodeling.

Temporal Changes in Beat‐to‐Beat Variability of Repolarization Predict Imminent Nonsustained Ventricular Tachycardia in Patients With Ischemic and Nonischemic Dilated Cardiomyopathy

BackgroundAn increase in beat‐to‐beat variability of repolarization (BVR) predicts arrhythmia onset in experimental models, but its clinical translation is not well established. We investigated the temporal changes in BVR before nonsustained ventricular tachycardia (nsVT) in patients with implantable cardioverter defibrillator (ICD).Methods and ResultsPatients with nsVT on 24‐hour Holter before ICD implantation for ischemic cardiomyopathy (ischemic cardiomyopathy+nsVT, n=43) or dilated cardiomyopathy (dilated cardiomyopathy+nsVT, n=37), matched ICD candidates without nsVT (ischemic cardiomyopathy‐nsVT, n=29 and dilated cardiomyopathy‐nsVT, n=26), and patients without ICD without structural heart disease (n=50) were studied. Digital Holter recordings from these patients were analyzed using a modified fiducial segment averaging technique to detect the QT interval. The nsVT episodes were semi‐automatically identified and QT‐BVR was assessed 1‐, 5‐, and 30‐minutes before nsVT, and at rest (at 3:00 am). Resting BVR was higher in ICD patients compared with controls without structural heart disease. In ICD patients with nsVT, BVR increased significantly 1‐minute pre‐nsVT in ischemic cardiomyopathy (2.21±0.59 ms, versus 5 minutes pre‐nsVT: 1.78±0.50 ms, P<0.001) and dilated cardiomyopathy (2.09±0.57 ms, versus 5‐minutes pre‐nsVT: 1.58±0.51 ms, P<0.001), but not in patients without nsVT. In multivariable Cox regression analysis, pre‐nsVT BVR was a significant predictor for appropriate therapy during follow‐up.ConclusionsBaseline BVR is elevated and temporal changes in BVR predict imminent nsVT events in patients with ICD independent of underlying cause. Real‐time BVR monitoring could be used to predict impending ventricular arrhythmia and allow preventive therapy to be incorporated into ICDs.

Glucose dysregulation and repolarization variability markers are short-term mortality predictors in decompensated heart failure

ObjectiveAs recently reported, elevated fasting glucose plasma level constitutes a risk factor for 30-day total mortality in acutely decompensated chronic heart failure (CHF). Aim of this study was to evaluate the 30-day mortality risk in decompensated CHF patients by fasting glucose plasma level and some repolarization ECG markers.MethodA total of 164 decompensated CHF patients (M/F: 94/71; mean age, 83 ± 10 years) were studied; Tend (Te), QT interval (QT) and 5 min of ECG recordings were obtained, studying mean, SD and normalized index of the abovementioned ECG intervals. These repolarization variables and fasting glucose were analyzed to assess the 30-day mortality risk among these patients.ResultsThirty-day mortality rate was 21%, deceased subjects showed a significant increase in N terminal-pro-brain natriuretic peptide (P < 0.001), higher sensitivity cardiac troponin, fasting glucose, creatinine clearance, QTSD, QTVN, Te mean, TeSD and TeVN than the survivals. Multivariable regression analysis reported that fasting glucose (hazard ratio, 1.59; 95% confidence interval, 1.09–2.10; P < 0.01), Te mean (hazard ratio, 1.03; 95% confidence interval, 1.01–1.05; P < 0.01) and QTSD (hazard ratio, 1.17; 95% confidence interval, 1.01–1.36; P < 0.05) were significantly related to higher mortality risk, whereas only fasting glucose (hazard ratio, 1.84; 95% confidence interval, 1.12–3.02; P < 0.05) and Te mean (hazard ratio, 1.07; 95% confidence interval, 1.02–1.11; P < 0.01) were associated to cardiovascular mortality.ConclusionData suggest that two simple, inexpensive, noninvasive markers, as fasting glucose and Te, were capable to stratify the short-term total and cardiovascular mortality risk in acutely decompensated CHF.

Adrenergic stimulation amplifies the difference in beat-to-beat variability between the scar border zone and remote region

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): KU Leuven BOF-C1 “Blood pressure induced premature ventricular beats as triggers for ventricular arrhythmia in ischemic cardiomyopathy” Background Myocardial infarction (MI) results in a dense scar region surrounded by a heterogeneous region of fibrosis and remodeled myocytes called the border zone (BZ). Beta-adrenergic stimulation results in increased beat-to-beat variability of repolarization (BVR) which could increase spatial heterogeneity and arrhythmia vulnerability. Objective To examine the effect of adrenergic stimulation on the beat-to-beat variability in the BZ, compared to the remote region, using novel methodology for determining spatially dense activation-repolarization intervals. Methods Anterior-septal myocardial infarction (MI) was induced in 10 domestic pigs by 120-minute occlusion of the left anterior descending artery followed by reperfusion. Electro-anatomical mapping was performed after one month. The BZ was defined using contact mapping as the region with bipolar voltage between 0.5 and1.5mV. A non-contact recording of a 64-electrode array was translated to 2048 non-contact electrograms distributed over the LV (EnSite PrecisionTM, St. Jude/Abbott Medical). Electrophysiological recordings were made during baseline and during an isoproterenol (ISO) infusion (incremental doses of 0.01µg/kg until 0.04µg/kg). In each of the 2048 points non-contact electrograms over 25 consecutive beats were processed to determine the BVR using a custom-made algorithm, validated against monophasic action potential recordings. Results During baseline conditions the maximal BVR was increased in the BZ compared to the remote region (BZ: 3.28±0.90 ms vs remote: 2.61±0.67 ms, P=0.002). During ISO infusion the maximal BVR was also increased in the BZ (BZ: 3.55±0.74 ms vs remote: 2.21±0.60 ms, P&amp;lt;0.001). During baseline the BZ exhibited a larger spatial variance of BVR than the remote region (BZ: 0.20±0.11 ms2 vs remote: 0.087±0.055 ms2, P=0.002). During ISO infusion the spatial variance of BVR was larger in the BZ (BZ: 0.23±0.12 ms2 vs remote: 0.083±0.056 ms2, P=0.001). The maximal BVR was not significantly different during baseline and ISO in the BZ, nor the remote region (P&amp;gt;0.05). However, the difference of the maximal BVR between BZ and remote regions was significantly increased during ISO (baseline: 0.67±0.48 ms vs ISO: 1.34±0.49ms, P=0.001). Conclusion The MI BZ showed increased temporal heterogeneity in repolarization that could serve as functional substrate for re-entry. Adrenergic stimulation amplified this vulnerability by increasing the difference in maximal BVR between BZ and remote regions.

Long-Term Endurance Exercise Training Alters Repolarization in a New Rabbit Athlete's Heart Model.

In the present study, the effect of long-term exercise training was investigated on myocardial morphological and functional remodeling and on proarrhythmic sensitivity in a rabbit athlete’s heart model. New-Zealand white rabbits were trained during a 12-week long treadmill running protocol and compared with their sedentary controls. At the end of the training protocol, echocardiography, in vivo and in vitro ECG recordings, proarrhythmic sensitivity with dofetilide (nM) were performed in isolated hearts, and action potential duration (APD) measurements at different potassium concentrations (4.5 and 2 mM) were made in the isolated papillary muscles. Expression levels of the slow component of delayed rectifier potassium current and fibrosis synthesis and degradation biomarkers were quantified. Echocardiography showed a significantly dilated left ventricle in the running rabbits. ECG PQ and RR intervals were significantly longer in the exercised group (79 ± 2 vs. 69 ± 2 ms and 325 ± 11 vs. 265 ± 6 ms, p < 0.05, respectively). The in vivo heart rate variability (HRV) (SD of root mean square: 5.2 ± 1.4 ms vs. 1.4 ± 0.2 ms, p < 0.05) and Tpeak-Tend variability were higher in the running rabbits. Bradycardia disappeared in the exercised group in vitro. Dofetilide tended to increase the QTc interval in a greater extent, and significantly increased the number of arrhythmic beats in the trained animals in vitro. APD was longer in the exercised group at a low potassium level. Real-time quantitative PCR (RT-qPCR) showed significantly greater messenger RNA expression of fibrotic biomarkers in the exercised group. Increased repolarization variability and higher arrhythmia incidences, lengthened APD at a low potassium level, increased fibrotic biomarker gene expressions may indicate higher sensitivity of the rabbit “athlete’s heart” to life-threatening arrhythmias.