Transmural Dispersion Research Articles

Novel conduction-repolarization indices for the stratification of arrhythmic risk.

Sudden cardiac death (SCD) affects approximately 800,000 individuals per annum globally.[1] It is most frequently due to cardiac tachy-arrhythmias, which include mono-morphic or polymorphic ventricular tachycardia (VT), torsade de pointes and ventricular fibrillation (VF). Risk stratification for SCD remains a challenging problem in clinical practice. Patients with structural heart disease or cardiac ion channelopathies have an increased risk of SCD, their risks are not the same. Consequently, several indices have been devised for this purpose, mainly focusing on ventricular repolarization, which is reflected by the QT interval on the electrocardiogram.[2] These include QT interval corrected for heart rate (QTc), QT dispersion (QTd), interval from the peak to the end of the T wave (Tpeak – Tend, reflecting increased transmural dispersion of repolarization, TDR), and (Tpeak – Tend)/QT ratio.[3]

Pro-arrhythmogenic effects of CACNA1C G1911R mutation in human ventricular tachycardia: insights from cardiac multi-scale models.

Mutations in the CACNA1C gene are associated with ventricular tachycardia (VT). Although the CACNA1C mutations were well identified in patients with cardiac arrhythmias, mechanisms by which cardiac arrhythmias are generated in such genetic mutation conditions remain unclear. In this study, we identified a novel mechanism of VT resulted from enhanced repolarization dispersion which is a key factor for arrhythmias in the CACNA1C G1911R mutation using multi-scale computational models of the human ventricle. The increased calcium influx in the mutation prolonged action potential duration (APD), produced steepened action potential duration restitution (APDR) curves as well as augmented membrane potential differences among different cell types during repolarization, increasing transmural dispersion of repolarization (DOR) and the spatial and temporal heterogeneity of cardiac electrical activities. Consequentially, the vulnerability to unidirectional conduction block in response to a premature stimulus increased at tissue level in the G1911R mutation. The increased functional repolarization dispersion anchored reentrant excitation waves in tissue and organ models, facilitating the initiation and maintenance of VT due to less meandering rotor tip. Thus, the increased repolarization dispersion caused by the G1911R mutation is a primary factor that may primarily contribute to the genesis of cardiac arrhythmias in Timothy Syndrome.

Prognostic relevance of electrocardiographic Tpeak-Tend interval in the general and in the hypertensive population: data from the Pressioni Arteriose Monitorate E Loro Associazioni study.

EKG Tpeak-Tend (Tp-Te) interval, an index of transmural dispersion of myocardial repolarization, is gaining interest as possible cardiovascular prognostic variable. Evidence that this is the case in the general population is scanty, however. This was tested in the Pressioni Arteriose Monitorate E Loro Associazioni population. EKG, echocardiographic, office, home and ambulatory (24-h) blood pressure (BP), metabolic and laboratory data were assessed. Cardiovascular and all-cause mortality were evaluated over a mean follow-up of 16 years. Repetition of all measurements after 10 years allowed to evaluate also the risk of developing office and out-of-office hypertension and echocardiographic left ventricular hypertrophy. At baseline, Tp-Te adjusted for confounders (c) showed a significant correlation with office, home and 24-h blood pressure but not with left ventricular mass. The cTp-Te value predicted the risk of cardiovascular and all-cause mortality before and after adjustment for demographic and clinical variables, the increase being 31 and 13% for 1-SD cTp-Te increase, respectively (P < 0.0001 and P < 0.002). This was the case also in hypertensive patients in which the corresponding increase in risk with 1-SD increase of Tp-Te was 47 and 25% (P < 0.05). cTp-Te did not predict the 10-year risk of developing office, home, ambulatory hypertension and left ventricular hypertrophy. Tp-Te interval retains an independent prognostic value both in the general population and in its hypertensive fraction. This easily and cheaply obtainable variable may be employed for improving cardiovascular-risk stratification, representing a useful measure to add to the recommended screening in hypertension.

Characterization of the epicardial substrate for catheter ablation of Brugada syndrome

Catheter ablation in the right ventricular outflow tract (RVOT) may modify the electrophysiologic substrate for recurrent ventricular tachycardia/ventricular fibrillation (VT/VF) in patients with Brugada syndrome (BrS). The purpose of this study was to investigate the mechanism and arrhythmogenic substrate of VT/VF and to evaluate the long-term outcomes of catheter ablation in patients with BrS. Eleven consecutive patients with BrS referred to 2 academic medical centers underwent combined epicardial-endocardial electroanatomic mapping. Catheter ablation was performed in regions of localized conduction slowing. Transmural dispersion of late activation was calculated as the difference between the latest activation between epicardium and endocardium, and low-voltage areas were analyzed. Eleven patients met diagnostic criteria for BrS (spontaneous type 1, n = 9; Na channel provocation = 2). All patients were found to have a localized region in the anterior epicardial RVOT with conduction slowing evidenced by prolonged electrogram duration (78.79 ± 19.87 ms vs 58.93 ± 10.11 ms in epicardial right ventricle, and 59.87 ± 12.61 ms in endocardial RVOT, P <.005, respectively) with variable low voltage (0.97 ± 0.48 mV; median scar area 19.8 ± 25.9 cm2). Epicardial ablation resulted in normalization of spontaneous type 1 Brugada ECG pattern in all patients, and 73% were free from VT/VF at 25 ± 11 months. Prolonged electrograms localized to epicardial RVOT with variable low voltage were identified in all patients with BrS. J-point and ST-segment elevation correlated with greater transmural dispersion of late activation and was independent of total low-voltage area. Despite normalization of spontaneous type 1 pattern in all patients after ablation, recurrence was still observed, suggesting the implantable cardioverter-defibrillator as the cornerstone therapy for BrS.

Short QT Syndrome in Current Clinical Practice.

Short QT syndrome is a rare inherited autosomal dominant cardiac channelopathy associated with malignant ventricular and atrial arrhythmias. A shortened corrected QT interval is a marker for risk of malignant arrhythmias, which are secondary to increased transmural dispersion of repolarization. The underlying gain of function mutations in the potassium channels are most common but genetic testing remains low yield. This review discusses the cellular mechanisms, genetic involvement, clinical presentation, and current recommended management of patients with short QT syndrome relevant to current clinical practice.

Effect of intravenous zoledronic acid infusion on electrocardiographic parameters in patients with osteoporosis.

The aim of the present study was to evaluate the early and late effects of ZA therapy on ECG parameters which might be associated with the tendency for atrial and ventricular arrhythmias. Consecutive patients with osteoporosis who were admitted to our clinic between December 2013 and December 2014 and who were scheduled to receive ZA infusion constituted our study population. Twelve-lead surface ECGs were obtained from all patients before and after ZA infusion on the same day as well as 1month after the infusion. All ECG parameters were measured and compared with each other for each patient. Data of 100 patients were used in the analysis (9 male; 70.5±11.6years of age). There were no significant differences between repeated measurements regarding pmax, pmin, and p dispersion values. QT max and QT min values were significantly increased after infusion; however, there were no significant changes in QT dispersion, Tp-e interval, and Tp-e dispersion values. ZA infusion did not affect P wave dispersion both at the immediate post-infusion period and 1month after infusion. QT values were significantly increased early after ZA infusion; however, there were no significant differences in parameters reflecting disparity of ventricular recovery times and transmural dispersion of ventricular repolarization. Based on these observations, it may be suggested that ZA infusion did not have any short- or long-term effect on any parameter that might be associated with the tendency for atrial fibrillation or ventricular arrhythmias.

169-07: Long term changes in transmural dispersion of repolarisation in patients with heart failure after cardiac resynchronisation therapy- A prospective study

Purpose of the Study: Effects of CRT on sudden cardiac death have not been fully ascertained. Biventricular pacing alters LV depolarisation sequence which may exacerbate transmural dispersion of repolarisation ( TDR). CRT has been proposed to reduce Tpeak-end interval (Tp-e) on long term follow up. However such a hypothesis hasn't been prospectively evaluated. Methods: This is a prospective study of patients with LV dysfunction who underwent CRT implantation between August 2013 & September 2014. Twelve-lead ECGs were recorded at 50mm/s during RV endocardial (EndoP), LV epicardial (EpiP) & biventricular pacing (BiVP) at constant pacing cycle length of 750ms at baseline (within 5 days of CRT implant) and again at 1 year follow up. QRS duration, QT and Tp-e intervals were measured using digital callipers and the highest values in any of the precordial leads were reported. Based on reduction in LV end systolic volumes (LVESV) at 1 year, patients were classified as high CRT responders (>25% reduction) and low responders (<25% reduction). Results: During the study period, 35 consecutive patients (mean age 56.8 ± 11.09 yr; 71.43% males) who underwent CRT implantation were included in the study. Compared to EndoP (130.41 ± 16.75ms), Tp-e was significantly prolonged during BiVP (142.06 ± 21.98ms; p < 0.001) and EpiP (183.45 ± 27.87ms; p < 0.001) at baseline. Follow up data were available for 31 patients of which 22 were high responders while the rest 9 were low responders. There was significant decrease in Tp-e during BiVP on follow up ( 117.93 ± 15.03ms; p < 0.001). High responders had significantly lower Tp-e at 1 year compared to low responders (113.16 ± 14.3ms vs. 129.59 ± 9.75ms, p = 0.004). Tp-e at 1 year had significant negative correlation with reduction in LVESV ( r = -0.51; p = 0.003). Seven patients had sustained ventricular arrhythmias on follow-up and these patients had significantly longer baseline Tp-e (158.19 ± 17.59ms vs. 139.72 ± 20.94ms, p = 0.043). Conclusions: Baseline TDR is greater during BiVP and EpiP compared with EndoP in patients with heart failure. However, BiVP causes significant reduction in TDR on long term follow up. CRT induced reverse LV mechanical remodeling is associated with reverse electrical remodeling.

Prolonged Tp-e Interval and Tp-e/QT Ratio in Children with Mitral Valve Prolapse.

Although it is considered to be a benign condition, previous studies have shown that a subset of patients with mitral valve prolapse (MVP) may be at risk of ventricular arrhythmia and sudden cardiac death (SCD). Previous studies have suggested that the interval between the peak and the end of the T wave (Tp-e) can be used as a marker for the transmural dispersion of repolarization. Increased Tp-e interval and Tp-e/QT ratio are associated with ventricular arrhythmias and SCD. The aim of this study was to assess alterations in ventricular repolarization by using the Tp-e interval and Tp-e/QT ratio in children with MVP and to investigate their relationships with the degree of valvular regurgitation. This study prospectively investigated 110 children with MVP and 107 age- and sex-matched healthy control subjects. Tp-e interval, Tp-e/QT ratio, and QT and QTc dispersions were measured from a 12-lead electrocardiogram and compared between groups. QT and QTc dispersions, Tp-e interval, and Tp-e/QTc ratio were found to be significantly higher in patients with MVP. A positive correlation was found between Tp-e/QTc ratio and increase in the degree of mitral regurgitation (MR) (p<0.05; r=0.2). However, the degree of MR was not associated with QT, QTc, or Tp-e intervals; QT, QTc, or Tp-e dispersions; or Tp-e/QT ratio (all p values >0.05). Individuals with MVP may be more prone to ventricular arrhythmias due to prolonged QTd, QTcd, and Tp-e interval and increased Tp-e/QT and Tp-e/QTc ratios. Therefore, due to their longer life expectancy, children with MVP should be followed up on regarding life-threatening arrhythmias.

Fluconazole-induced long QT syndrome via impaired human ether-a-go-go-related gene (hERG) protein trafficking in rabbits.

hERG protein trafficking deficiency has long been known in drug-induced long QT syndrome (LQTS). However, validated evidence from in vivo data kept scanty. Our goal was to investigate the proarrhythmic action of fluconazole and its underlying mechanism in an animal model. Twenty female Japanese long-eared white rabbits were randomly distributed into a control group and a fluconazole group for a chronic 2-week treatment. The control group was treated with 0.5% sodium carboxymethylcellulose (CMCNa), and the fluconazole group was treated with fluconazole. Electrocardiograms (ECGs) were recorded during the experimental period. Isolated arterially perfused left ventricular wedge preparations from the rabbits were made 2 weeks after treatment, and the arrhythmia events, the transmural ECG, and action potential from both the endocardium and epicardium were recorded. The changes in hERG protein expression were measured by western blot. The fluconazole group showed a longer QT interval 1 week after treatment (P < 0.05) and a higher arrhythmia occurrence 2 weeks after treatment (P < 0.05) than the control group. The fluconazole group also showed a longer transmural dispersion of repolarization and a higher occurrence of life-threatening torsades de pointes in arterially perfused left ventricular preparations. Furthermore, western blot analysis showed that the density of mature hERG protein was lower in the fluconazole group than that in the control group. Fluconazole can prolong the QT interval and possess proarrhythmic activity due to its inhibition of hERG protein trafficking in our experimental model. These findings may impact the clinical potential of fluconazole in humans.

Effects of allocryptopine on outward potassium current and slow delayed rectifier potassium current in rabbit myocardium.

ObjectiveAllocryptopine (ALL) is an effective alkaloid of Corydalis decumbens (Thunb.) Pers. Papaveraceae and has proved to be anti-arrhythmic. The purpose of our study is to investigate the effects of ALL on transmural repolarizing ionic ingredients of outward potassium current (Ito) and slow delayed rectifier potassium current (IKs).MethodsThe monophasic action potential (MAP) technique was used to record the MAP duration of the epicardium (Epi), myocardium (M) and endocardium (Endo) of the rabbit heart and the whole cell patch clamp was used to record Ito and IKs in cardiomyocytes of Epi, M and Endo layers that were isolated from rabbit ventricles.ResultsThe effects of ALL on MAP of Epi, M and Endo layers were disequilibrium. ALL could effectively reduce the transmural dispersion of repolarization (TDR) in rabbit transmural ventricular wall. ALL decreased the current densities of Ito and IKs in a voltage and concentration dependent way and narrowed the repolarizing differences among three layers. The analysis of gating kinetics showed ALL accelerated the channel activation of Ito in M layers and partly inhibit the channel openings of Ito in Epi, M and Endo cells. On the other hand, ALL mainly slowed channel deactivation of IKs channel in Epi and Endo layers without affecting its activation.ConclusionsOur study gives partially explanation about the mechanisms of transmural inhibition of Ito and IKs channels by ALL in rabbit myocardium. These findings provide novel perspective regarding the anti-arrhythmogenesis application of ALL in clinical settings.

0173 : Mechanisms behind the pro-arrhythmogenic state induced by exposure to chronic intermittent hypoxia

Obstructive sleep apnea (OSA) is now recognized as a major risk factor for cardiovascular disorders including ventricular arrhythmias and sudden cardiac death. We have demonstrated that intermittent hypoxia (IH), a major component of OSA, increases the incidence of myocardial ischemiarelated ventricular fibrillation. The aim of the present study was to investigate the mechanisms behind the arrhythmogenic effects of IH. Wistar rats were exposed to IH (60-sec cycles alternating 21 and 5% FiO2, 8h/day) or normoxia (similar air-air cycles) during 14 days. Arterial blood pressure and ECG were recorded for power spectral analysis and ECG interval measurement. Hearts were removed, perfused in Langendorff mode and paced at 300 bpm. Epicardial and endocardial monophasic action potentials were recorded and action potential duration at 50% repolarization (APD50) was measured. Mean arterial blood pressure was significantly increased by IH exposure. Rats exposed to IH exhibited higher low-frequency (LF) power, lower high-frequency (HF) power and higher LF/HF ratio of heart rate and blood pressure variability, indicative of a systemic sympathetic activation. This was corroborated by a significant increase in circulating norepinephine levels. IH exposure also resulted in a significant increase in QTc and Tpeak- Tend intervals, indicative of increased spatial and transmural dispersion of repolarization and associated with an increased vulnerability to ischemic ventricular arrhythmias. The increase in the transmural repolarization gradient was associated with a significantly longer endocardial APD50 in IH-exposed rats (49.07 ± 2.19 ms) compared to normoxia-exposed rats (41.29 ± 0.62 ms, p<0.01) while epicardial APD50 did not differ. Thus, chronic exposure to intermittent hypoxia, such as that occurring during OSA, promotes a pro-arrhythmogenic state characterized by sympathoactivation and alterations in ventricular repolarization. The author hereby declares no conflict of interest

Evaluation of Tp-e Interval, Tp-e/QT Ratio, and Tp-e/QTc Ratio in Patients with Asymptomatic Arrhythmogenic Right Ventricular Cardiomyopathy.

Arrhythmogenic right ventricular dysplasia (ARVD) is characterized by progressive replacement of ventricular myocytes with variable amounts of fibrous and adipose tissue. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate repolarization dispersion measured from the 12-lead surface electrocardiogram (including Tp-e interval, Tp-e/QT, and Tp-e/QTc ratio) in asymptomatic ARVD patients METHODS: We selected 27 patients with asymptomatic ARVD and 27 age- and gender-match young, healthy volunteers. Tp-e interval, Tp-e/QT and Tp-e/QTc ratio were also significantly higher in ARVD group compared to the control group (all P < 0.001). There were negative correlation between S global and Tp-e, Tp-e/QT, Tp-e/QTc ration (r = -0.57, P = 0.02; r = -0.85, P = 0.02; r = -0.63, P < 0.01; respectively). There were also negative correlation between Sm global and Tp-e, Tp-e/QT, Tp-e/QTc ration (r = -0.61, P < 0.01; r = -0.67, P < 0.01; r = -0.68, P < 0.01; respectively). Moreover, Em global were negative correlation between Tp-e, Tp-e/QT, and Tp-e/QTc (r = - 0.64, P < 0.001, r = - 0.75, P < 0.01; r = -0,69, P < 0.01; respectively) CONCLUSION: In conclusion, we have presented strong evidence suggesting that Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio were increased in asymptomatic ARVD patients.

Effect of verapamil in the treatment of type 2 long QT syndrome is not a dose-dependent pattern: a study from bedside to bench, and back

Type 2 long QT syndrome (LQT2) is caused by loss-of-function mutations in KCNH2 gene. This study aimed to investigate the efficacy and mechanism of a calcium channel blocker, verapamil, to improve clinical manifestations in LQT2. A 42-year-old woman with a LQT2 phenotype underwent candidate gene screening. Therapeutic effects of verapamil were evaluated by QT-interval measurement and shock count of implantable cardioverter-defibrillator. The electrophysiological effect of verapamil was assessed in a LQT2 model using rabbit ventricular wedge preparations. Direct sequencing of her DNA revealed a heterozygous D609N mutation in KCNH2 . Acute administration of intravenous verapamil (10 mg/h) successfully abolished electrical storm and shortened the corrected QT (QTc) from 671 to 532 ms in the patient. However, long-term use of oral verapamil (240 mg daily) failed to completely prevent the torsades de pointes (TdP) recurrence over a 3-year follow-up period, whereas a low dose of oral verapamil (120 mg daily) totally suppressed the cardiac events in the following 12 months. In in vitro studies, verapamil preferentially abbreviated endocardial action potential duration leading to a reduction in the QT interval and transmural dispersion of repolarization, and suppressed early afterdepolarization. However, high concentration of verapamil caused a significant decrease in both myocardial effective refractory period (ERP) and post-repolarization refractoriness (PRR), which facilitated TdP in the LQT2 model. Our findings indicate a therapeutic role of verapamil in the management of LQT2 patients. However, an inappropriate dose of verapamil may offset beneficial effects by excessively shortening the ERP and PRR to increase the myocardial excitability.

The Relationship between Ventricular Repolarization Indexes and Neutrophil to Lymphocyte Ratio in Patients with Slow Coronary Flow

Objective: Slow coronary flow (SCF) is characterized by angiographically normal coronary arteries with delayed opacification of the distal vasculature. The peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with ventricular arrhythmias. Neutrophil to lymphocyte ratio (NLR) is a new inflammatory marker using for cardiovascular risk prediction. The aim of this study was to evaluate the relationship between ventricular repolarization and inflammation in patients with SCF. Methods: Forty-six SCF patients and 44 controls were enrolled to the study. Coronary flow rates were measured by Thrombolysis in Myocardial Infarction frame count (TFC). Tp-e interval and Tp-e/QT ratio were measured from a 12-lead electrocardiogram, and Tp-e interval was corrected for heart rate (cTp-e). NLR was calculated as the ratio of neutrophil to lymphocyte count. These parameters were compared between groups. Results: Corrected Tp-e interval and Tp-e/QT ratio were significantly higher in SCF patients (94.5 ± 14.9 vs 88.1 ± 6.3 ms, 0.23 ± 0.03 vs 0.21 ± 0.02; P=0.009, and P=0.002, respectively). Also, NLR was increased in SCF patients (2.40 ± 0.9 vs 1.67 ± 0.5, P<0.001). The cTp-e was significantly correlated with mean TFC and NLR (r=0.50, p<0.001 and, r=0.37, p<0.001, respectively). Tp-e/QT ratio was significantly correlated with mean TFC and NLR (r=0.48, P<0.001 and r=0.28, P=0.006, respectively). Conclusion: Our study revealed that cTp-e interval and Tp-e/QT ratio were increased in SCF patients. These new electrocardiographic ventricular repolarization indexes were significantly correlated with the mean TFC and NLR.

Transmural dispersion of repolarization: a complementary index for cardiac inhomogeneity.

We thank Dr Dogan and his team for his thoughtful comments and suggestions. The first comment to our study relates to the percentage of defective cQTD patients that was higher in our study as compared to previous studies.[1]–[3] We would like to point out that defective cQTD occurred in 40% while recovery of cQTD occurred in the majority of patients (60%). Also, the mean cQTD in the overall population significantly decreased after transcatheter aortic valve implantation (TAVI) (47 to 40 ms, P = 0.049). We do agree, however, that cQTD determination to assess ventricular inhomogeneity and arrhythmia risk suffers from (technical) measurement difficulties resulting in increased inter- and intra-observer variabilities and imperfect estimates of the true ventricular repolarization inhomogeneity. Therefore, a different methodological perspective such as measurement of T-peak to T-end wave dispersion should also be investigated in patients undergoing TAVI albeit that this method is also likely to suffer from measurement difficulties when assessing the end of the T wave (especially in lead V1, V2 or aVF). We agree that further research is indeed needed to investigate whether repolarization dispersion measurements correlate with sudden death and arrhythmia risk as suggested by Dogan et al. with methods that include or correct for the different electrical properties of the different myocardial cells.

Prolonged Tp-e Interval, Tp-e/QT Ratio and Tp-e/QTc Ratio in Patients with Type 2 Diabetes Mellitus.

BackgroundType 2 diabetes mellitus (T2DM) is associated with increased risk of malignant ventricular arrhythmias. Cardiac electrical inhomogeneity may be the leading cause of the increased arrhythmic risk in patients with T2DM. The peak and the end of the T wave (Tp-e) interval and associated Tp-e/QT ratio are promising measures of ventricular repolarization indicating transmural dispersion of repolarization. The aim of this study was to assess ventricular repolarization in patients with T2DM by using Tp-e interval, Tp-e/QT ratio and Tp-e/corrected QT interval (QTc) ratio.MethodsForty-three patients with T2DM and 43 healthy control subjects, matched by gender and age, were studied. All participants underwent electrocardiography (ECG) recording. PR, RR and QT intervals represents the ECG intervals. These are not abbreviations. In all literature these ECG intervals are written like in this text. Tp-e intervals were measured from 12-lead ECG. Rate QTc was calculated by using the Bazett's formula. Tp-e/QT ratio and Tp-e/QTc ratio were also calculated.ResultsMean Tp-e interval was significantly prolonged in patients with T2DM compared to controls (79.4±10.3, 66.4±8.1 ms, respectively; P<0.001). We also found significantly higher values of Tp-e/QT ratio and Tp-e/QTc ratio in patients with diabetes than controls (0.21±0.03, 0.17±0.02 and 0.19±0.02, 0.16±0.02, respectively; P<0.001). There was no difference in terms of the other ECG parameters between the groups.ConclusionTp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio were prolonged in patients with T2DM. We concluded that T2DM leads to augmentation of transmural dispersion of repolarization suggesting increased risk for ventricular arrhythmogenesis.

Congenital long QT syndrome in children

Long QT syndrome (LQTS) is a cardiac repolarization disorder characterized by prolonged QT interval on the electrocardiogram (ECG) and increased propensity to ventricular tachyarrhythmias and cardiac events. LQTS might be acquired or congenital, which presents a group of channelopathies that occur due to mutation in one of 15 so far identified genes. The most frequent types of congenital LTQS are LQT1, LQT2 and LQT3. Prolonged or delayed repolarization leads to the increase of action potential duration which predisposes early afterdepolarization, as well as the amplification of transmural dispersion of repolarization, both contributing to the development of Torsades de Pointes ventricular tachycardia. Clinical manifestations of LQTS are palpitations, syncope, aborted cardiac arrest or sudden cardiac death, but it can also be asymptomatic. Trigger factors for symptoms are specific for certain genotype. LQTS examination includes thorough clinical and family history focused on distinctive data (repeated syncopes, cases of sudden cardiac death in the family, hereditary arrhythmias), resting ECG, exercise stress testing and genetic analysis, with additional methods (serial ECG records, 24h ECG Holter, epinephrine test). Clinical LQTS diagnosis is based on Schwartz's scoring system, while the criteria for final diagnosis of LQTS depend on Schwartz's score, QT interval duration, presence of pathogenic mutation and clinical symptoms. Treatment approach begins with lifestyle modifications and β-blockers therapy, while other options include implantable cardioverter- defibrillator, permanent pacemaker or surgical sympathectomy. Sudden cardiac death is the reason of 90% of sudden deaths in young athletes, while LQTS is one of its causes. Recommendations for physical activities in children with congenital LQTS arise from the ones for adults and they presume very strict limitations. Further researches are expected to advance the understanding of genotype-phenotype correlation of congenital LQTS and enable eventual genetically-guided personalized treatment, novel insight into rare LQTS types, as well as more precise recommendations for physical activity of LQTS children.

Effects of Ang Ⅱ perfusion on transmural heterogeneous of Cx43 in acute myocardial ischemia reperfusion.

To observe the effects of angiotensin Ⅱ(Ang Ⅱ) perfusion on transmural heterogeneity of Cx43 expression in the rabbit model with acute myocardial ischemia reperfusion (MIR), and investigate the role of rennin-angiotensin system in malignant ventricular arrhythmia induced by MIR. Twenty rabbits were randomly divided into MIR group (n=10) and Ang Ⅱ group (n=10). MIR model was produced with traditional ligation and opening of the anterior descending coronary artery in all animal. The hearts invitro in the MIR group and the Ang Ⅱ group were perfused with simply improved Tyrode's solution and containing Ang Ⅱ Tyrode's solution respectively. 90% monophasic action potential repolarization duration, transmural dispersion of repolarization, Cx43 protein (Cx43-pro) and mRNA (Cx43-Cq) expression in subepicardial, midmyocardial and subendocardial myocardium were measured in both groups. The greatest differences of Cx43-pro and Cx43-Cq among three myocardial layers were calculated and shown with ΔCx43-pro and ΔCx43-Cq respectively. After Ang Ⅱ perfusion, 90% monophasic action potential repolarization duration among three myocardial layer were significantly prolonged (P<0.05 and P<0.01), and transmural dispersion of repolarization also significantly increased compared with the MIR group (P<0.05). Compare with the MIR group, three myocardial Cx43-pro and Cx43-Cq expression in the Ang Ⅱ group were significantly decreased (P<0.05 and P<0.01), but ΔCx43-pro and ΔCx43-Cq were significant increased. Renin-angiotensin system increases transmural heterogeneity of Cx43 expression in the rabbit model with MIR by Ang Ⅱ, and enlarge transmural dispersion of repolarization among three myocardial layers of left ventricular which induces malignant ventricular arrhythmia.

Effects of epinephrine over P wave duration and ventricular repolarization in subjects without structural heart disease

BackgroundLittle is known about the effects of epinephrine over atrial electrical function, AV conduction and ventricular repolarization in normal subjects. We intended to study the effects of intravenous epinephrine on the duration of P wave, inter-atrial conduction time, PR, QRS, QT, corrected QT (QTc), QTc dispersion (QTc max–min), the peak-to-end interval of T wave (Tp-e), the Tp-e/QT index, and the middle portion of ventricular repolarization length (QT−(QRS+Tp-e)) in healthy subjects. MethodsForty-three, 37.20±17.05year-old, 25 (58%) female patients without structural heart disease took part in the study. They underwent an electrophysiological study. An epinephrine infusion (50 to 100ng/kg/min) was administered for 5min until an increase of at least 10% of the initial heart rate (HR) was achieved. ResultsNo complication arose from epinephrine infusion, and the drug facilitated arrhythmia induction. A significant increase in heart rate, systolic blood pressure, QRS, QTc, Tp-e, Tp-e/QT index, and QTc max–min interval duration was documented. No significant effect on diastolic blood pressure, P wave duration, inter-atrial conduction time, and PR, QT and QT−(Tp-e+QRS interval) was observed. ConclusionsIn this group of patients without structural heart disease, epinephrine infusion did not produce any complication and it facilitated arrhythmia induction. It did not modify P wave duration, PR interval or inter-atrial conduction time. Moreover, it significantly increased the duration of depolarization, the final portion of repolarization, transmural dispersion of repolarization, and regional dispersion of repolarization without inducing significant changes in the middle portion of repolarization.

Abstract 13875: Torsade de Pointes Arrhythmias Arise at the Site of Maximal Heterogeneity of Repolarization in the Chronic Complete AV-block Dog

Introduction: The chronic complete atrioventricular block (CAVB) dog model is highly sensitive for drug-induced Torsade de Pointes (TdP) arrhythmias. Focal mechanisms have been considered as trigger for the onset of TdP, however, its exact mechanism remains unclear. In this study, detailed mapping of the heart was performed to assess intraventricular heterogeneity of repolarization in relation to the initation of TdP. Methods: In 6 animals, 48 needles, each containing 4 electrodes, were inserted in the ventricles. During right ventricular apex pacing (cycle length: 1000-1500ms) local unipolar electrograms were recorded before and after administration of dofetilide. Activation- and repolarization times (RT) were measured at baseline and before occurrence of the first TdP or at 5 minutes after start of dofetilide infusion in inducible and non-inducible dogs. Maximal RT differences were calculated in the left ventricle 1) within adjacent electrodes in different planes (transmural, apex-base, anterior-posterior) and 2) within a square of 4 needles (3D dispersion). Results: TdP could be induced in 3 out of 6 animals. No difference in mean RT was observed between inducible and non-inducible dogs both at baseline (343±30 vs. 345±17ms) and after dofetilide administration (582±73 vs. 508±15ms). Maximal dispersion of RT was not different between both groups at baseline: 36±32 vs. 32±7ms (transmural), 50±20 vs. 42±9ms (apex-base), 71±28 vs. 47±13ms (anterior-posterior), 83±19 vs. 70±6ms (3D dispersion). After dofetilide infusion anterior-posterior (203±28 vs. 142±34ms, p=0.04) and 3D dispersion (268±41 vs. 176±48ms, p=0.03) showed a higher RT difference in the inducible animals. No differences were observed for transmural (124±14 vs. 116±18ms, p=0.557) and apex-base dispersion (142±12 vs. 121±23ms, p=0.229). The initiating beat of the TdP arose consistently from the region with the largest local spatial dispersion of repolarization moments. Conclusion: TdP arises from a region with maximal heterogeneity of repolarization and animals susceptible for TdP demonstrate higher RT differences. These results suggest that a certain gradient of repolarization moments is required in order to initiate TdP in CAVB dogs.