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Introduction: Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by the increased number of CTG repeats in 3' UTR of Dystrophia Myotonia Protein Kinase (DMPK) gene. DM1 patients experience conduction abnormalities as well as atrial and ventricular arrhythmias with increased susceptibility to sudden cardiac death. The ionic basis of these electrical abnormalities is poorly understood. Methods: We evaluated the surface electrocardiogram (ECG) and key ion currents underlying the action potential (AP) in a mouse model of DM1, DMSXL, which express over 1000 CTG repeats. Sodium current (INa), L-type calcium current (ICaL), transient outward potassium current (Ito), and APs were recorded using the patchclamp technique. Results: Arrhythmic events on the ECG including sinus bradycardia, conduction defects, and premature ventricular and atrial arrhythmias were observed in DMSXL homozygous mice but not in WT mice. PR interval shortening was observed in homozygous mice while ECG parameters such as QRS duration, and QTc did not change. Further, flecainide prolonged PR, QRS, and QTc visually in DMSXL homozygous mice. At the single ventricular myocyte level, we observed a reduced current density for Ito and ICaL with a positive shift in steady state activation of L-type calcium channels carrying ICaL in DMSXL homozygous mice compared with WT mice. INa densities and action potential duration did not change between DMSXL and WT mice. Conclusion: The reduced current densities of Ito, and ICaL and alterations in gating properties in L-type calcium channels may contribute to the ECG abnormalities in the DMSXL mouse model of DM1. These findings open new avenues for novel targeted therapeutics. [ABSTRACT FROM AUTHOR]

Purpose: to evaluate the Retinopathy of prematurity prevalence and screening outcome in a tertiary hospital in Cairo, Egypt. Also, to assess the risk factors for its development and to suggest modifications to the international guidelines for screening for Retinopathy of prematurity to fit the Egyptian population. Methods: A prospective observational study was carried out in Neonatal Intensive Care Unit (NICU) in Ain Shams University Hospital. In this study 159 premature infants born in the period between 1 September 2018 to 1 September 2021 were screened for Retinopathy of Prematurity (ROP). Screening was based on the most inclusive criteria reported to date. All premature infants with gestational age (GA) of ≤34 weeks or birth weight (BW) of ≤2000 grams were included. Infants were also included if GA>34 weeks or BW>2000 grams, but multiple co-morbidities existed. The prevalence of retinopathy of prematurity and plus disease and their correlation with risk factors of interest were studied. Results: The gestational age of the included infants ranged from 27 to 36 weeks, with a mean (SD) of 31.87 (‡ 1.81) weeks. Infants had birth weight ranging from 640 to 3900 grams, with a mean (SD) of 1784.71 (± 560.30) grams. The prevalence of ROP changes more than stage 0 in the screened infants was 25.8% (41 infants) with 7.3% of cases (11 infants) showing plus disease and 6.3% of cases (10 infants) showing severe changes that needed treatment. Of those, 2 cases (20%) fell outside the British Guideline's criteria for Screening. there was a highly significant (p<0.0001) correlation between appearance of Retinopathy of prematurity changes more than stage 0 and low gestational age, low birth weight of the screened infants, receiving mechanical ventilation, respiratory distress syndrome stage, presence of Necrotizing enterocolitis, Intraventricular haemorrhage and blood transfusion. On the other hand, no significant correlation was found between appearance of Retinopathy of prematurity changes more than stage 0 and gender (p=0.911), presence of PDA (p=0.187), or sepsis (p=0.998). Conclusion: Retinopathy of prematurity is a significant problem in the premature infants in Cairo, Egypt. Extremely premature infants with lower birth weight are more prone to develop this disease. However, cases with higher gestational age and birth weight than mentioned in the British guidelines screening criteria especially with multiple comorbidities showed severe Retinopathy of prematurity changes that needed intervention, which implies the need to develop a screening guideline for the Egyptian population. [ABSTRACT FROM AUTHOR]

Assessment of myocardial ischemia and viability is now mandatory for treatment decisions in patients with coronary artery disease (CAD). The high subjectivity of the noninvasive imaging tools such as dobutamine stress cardiovascular magnetic resonance (DS-CMR) in viability and ischemia assessment and late gadolinium enhancement (LGE) in scar transmurality detection, as well as the risks imposed by the contrast administration in patients with renal affection, paved the way for the evolution of more objective and safer techniques. Strain analysis provides quantifiable measurable values of the degree of myocardial deformation. Feature tracking-cardiac magnetic resonance (FTCMR) is a novel strain analysis technique that uses only routinely acquired cine images in strain analysis. Our study aimed to assess the quantitative ability of the CMR-FT in assessment of myocardial ischemia and viability in patients with CAD. We investigated 20 patients (n=320 myocardial segments), known or suspected CAD. DS-CMR and LGE were used to identify the viable non-ischemic, ischemic and non-viable myocardial segments. Then calculations of the rest segmental radial (Err), circumferential (Ecc) and longitudinal (Ell) strain were done by manual contouring of endocardial and epicardial borders using Segment Software. Results: Based on the results of both DS-CMR and LGE of the 320 myocardial segments, 210 segments were defined as viable non-ischemic (remote), 71 segments were viable ischemic and 39 segments were non-viable. Rest segmental Ecc, Err and Ell values were statistically significantly reduced in the non-viable (mean6 SD = -3.98 6 5.08%, 12.26 6 12.62% and - 7.39 6 7.05%, respectively) compared to both viable groups, p<0.001. Furthermore, segmental Ecc and Err significantly differentiated between non-ischemic and ischemic group (mean6 SD = -18.60 6 7.09% vs -13.49 6 8.53% and 44.09 6 20.38% vs 32.21 6 16.92% respectively), p1<0.001. However, Ell was weak to find a statistical significance between them, despite showing lower values in the ischemic group (mean6 SD = -16.17 6 8.86% vs -15.27 6 9.82%, p=0.741). Conclusions: FT-CMR strain analysis can provide a more objective metric in myocardial strain analysis to differentiate between viable and non-viable as well as ischemic and nonischemic myocardial segments. Therefore, such technique has a promising objective role in ischemia and viability assessment in conjunction with CMR or even may replace it in the future. [ABSTRACT FROM AUTHOR]

Background: Liver transplantation is the treatment of choice for end-stage hepatic diseases. The most important factor responsible for the success of the transplant is the size of the graft and the remnant liver volume in the donor. A small graft may not meet the metabolic demands of the recipient resulting in impaired liver functions such as hyperbilirubinemia, prolonged prothrombin time (PT), ascites and portal hypertension. Patient and Methods: This comparative study was conducted on manual contrast enhanced hepatic CT scans of 40 potential living liver donors (29) male and (11) female Age range from (18 to 50) in Ain shams specialized hospital and some private centers during the period from May 2021 till July 2022. The potential donors were investigated using 16 channel multi-detector row CT scanner (Alexion; Toshiba medical systems). All potential donors underwent 1st step laboratory investigations to enter the 2nd step investigations for living donor liver transplantation operations. All potential donors were of average weight and physically fit for operation with no history of any medical diseases. Results: We correlated the results of CT volumetry of right lobe graft weight with the intra-operative weight of liver graft in patients undergoing Living Donor Liver Transplantation(LDLT). CT Volumetry is an efficient and a reliable tool for assessing potential donors undergoing liver transplant, and this information is essential for donor selection and pre operative surgical planning as well as it ensure that the liver remnant volume is at least 30 % which guarantee the safety of the donor. Conclusion: The size of the right lobe graft for LDLT can be precisely calculated from pre-operative CT Volumetry with confidence and accuracy up to 95%. [ABSTRACT FROM AUTHOR]

Background: Clinical experience showed that the majority of Torsade de Pointes (TdP) ventricular tachyarrhythmia (VT) in patients with long QT syndrome (LQTS) are self-terminating (ST), but the few that are non-self-terminating (NST) are potentially fatal. A paramount issue in clinical arrhythmology is to understand the electrophysiological mechanism of ST vs. NST TdP VT. Methods: We investigated the electrophysiological mechanism of ST vs. NST TdP VT in the guinea pig Anthopleurin-A experimental model of LQTS, a close surrogate model of congenital LQT3. We utilized simultaneous optical recordings of membrane voltage (V m ) and intracellular calcium (Ca i ) and a robust analytical method based on spatiotemporal entropy difference (E d ) to investigate the hypothesis that early V m /Ca i uncoupling during TdP VT can play a primary role in perpetuation of VT episodes. Results: We analyzed a total of 35 episodes of TdP VT from 14 guinea pig surrogate models of LQTS, including 23 ST and 12 NST VTs. E d values for NST VT were significantly higher than E d values for ST VT. Analysis of wave front topology during the early phase of ST VT showed the Ca i wave front following closely V m wave front consistent with a lower degree of E d . In contrast, NST VT was associated with uncoupling of V m /Ca i wave fronts during the first 2 or 3 cycles of VT associated with early wave break propagation pattern. Conclusions: Utilizing a robust analytical method we showed that, in comparison to ST TdP VT, NST VT was consistently predated by early uncoupling of V m /Ca i that destabilized wave front propagation and can explain a sustained complex reentrant excitation pattern. [ABSTRACT FROM AUTHOR]

Background: Men normally have shorter heart rate-corrected QT interval (QTc) than women, at least in part due to accelerating effects of testosterone on ventricular repolarization. Accumulating data suggest that androgen-deprivation therapy (ADT) used for the treatment of prostatic cancer, may increase Torsades de Pointes (TdP) risk by prolonging QTc. However, the evidence for such an association is currently limited to few case reports, in most cases deriving from the analysis of uncontrolled sources such as pharmacovigilance databases. Objective: To better determine the clinical impact of ADT on TdP development, we examined the prevalence of this therapy in a consecutive cohort of 66 TdP patients, prospectively collected over a ~10 years period. Methods and Results: We found and described four patients who were under ADT for prostatic cancer when TdP occurred, and in two cases degenerated to cardiac arrest. Notably, in this unselected population, ADTs unexpectedly represented the second most frequently administered QT-prolonging medication in males (4/24, 17%), after amiodarone. Moreover, in the ADT patients, a blood withdrawal was performed within 24 h from TdP/marked QTc prolongation occurrence and circulating concentration of androgens and gonadothropins were measured. As expected, all cases showed markedly reduced testosterone levels (total, free, and available). Conclusion: We provide evidence that a significant proportion of patients developing TdP were under treatment with ADT for prostatic cancer, thus confirming the clinical relevance of previous pharmacovigilance signals. An accurate assessment of the arrhythmic risk profile should be included in the standard of care of prostatic cancer patients before starting ADT. [ABSTRACT FROM AUTHOR]

Since its initial description by Jervell and Lange-Nielsen in 1957, the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. A prolonged QT interval in the surface electrocardiogram is the sine qua non of the LQTS and is a surrogate measure of the ventricular action potential duration (APD). Congenital as well as acquired alterations in certain cardiac ion channels can affect their currents in such a way as to increase the APD and hence the QT interval. The inhomogeneous lengthening of the APD across the ventricular wall results in dispersion of APD. This together with the tendency of prolonged APD to be associated with oscillations at the plateau level, termed early afterdepolarizations (EADs), provides the substrate of ventricular tachyarrhythmia associated with LQTS, usually referred to as torsade de pointes (TdP) VT. This review will discuss the genetic, molecular, and phenotype characteristics of congenital LQTS as well as current management strategies and future directions in the field. [ABSTRACT FROM AUTHOR]

Increased proinflammatory interleukin-6 (IL-6) levels are associated with acquired long QT-syndrome (LQTS) in patients with systemic inflammation, leading to higher risks for life-threatening polymorphic ventricular tachycardia such as Torsades de Pointes. However, the functional and molecular mechanisms of this association are not known. In most cases of acquired LQTS, the target ion channel is the human ether-á-go-go-related gene (hERG) encoding the rapid component of the delayed rectifier K current, IKr, which plays a critical role in cardiac repolarization. Here, we tested the hypothesis that IL-6 may cause QT prolongation by suppressing IKr. Electrophysiological and biochemical assays were used to assess the impact of IL-6 on the functional expression of IKr in HEK293 cells and adult guinea-pig ventricular myocytes (AGPVM). In HEK293 cells, IL-6 alone or in combination with the soluble IL-6 receptor (IL-6R), produced a significant depression of IKr peak and tail current densities. Block of IL-6R or Janus kinase (JAK) reversed the inhibitory effects of IL-6 on IKr. In AGPVM, IL-6 prolonged action potential duration (APD) which was further prolonged in the presence of IL-6R. Similar to heterologous cells, IL-6 reduced endogenous guinea pig ERG channel mRNA and protein expression. The data are first to demonstrate that IL-6 inhibition of IKr and the resulting prolongation of APD is mediated via IL-6R and JAK pathway activation and forms the basis for the observed clinical QT interval prolongation. These novel findings may guide the development of targeted anti-arrhythmic therapeutic interventions in patients with LQTS and inflammatory disorders. [ABSTRACT FROM AUTHOR]

Abstract: Since its initial description by Jervell and Lange‐Nielsen in 1957, the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. Although congenital LQTS continues to remain the domain of cardiologists, cardiac electrophysiologists, and specialized centers, the by far more frequent acquired drug‐induced LQTS is the domain of all physicians and other members of the health care team who are required to make therapeutic decisions. This report will review the electrophysiological mechanisms of LQTS and torsade de pointes, electrocardiographic characteristics of acquired LQTS, its clinical presentation, management, and future directions in the field. [ABSTRACT FROM AUTHOR]

Objective: Increasing evidence indicates systemic inflammation as a new potential cause of acquired long QT syndrome (LQTS), via cytokine-mediated changes in cardiomyocyte ion channels. Torsade de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia occurring in patients with LQTS, usually when multiple QT-prolonging factors are simultaneously present. Since classical risk factors cannot fully explain TdP events in a number of patients, we hypothesised that systemic inflammation may represent a currently overlooked risk factor contributing to TdP development in the general population.Methods: Forty consecutive patients who experienced TdP (TdP cohort) were consecutively enrolled and circulating levels of C-reactive protein (CRP) and proinflammatory cytokines (interleukin-6 (IL-6), tumour necrosis factor alpha (TNFα), interleukin-1 (IL-1)) were compared with patients with active rheumatoid arthritis (RA), comorbidity or healthy controls. An additional 46 patients with different inflammatory conditions (acute infections, n=31; immune-mediated diseases, n=12; others, n=3) and elevated CRP (inflammatory cohort) were prospectively enrolled, and corrected QT (QTc) and cytokine levels were measured during active disease and after a CRP decrease of >75% subsequent to therapy.Results: In the TdP cohort, 80% of patients showed elevated CRP levels (median: ~3 mg/dL), with a definite inflammatory disease identifiable in 18/40 cases (acute infections, n=12; immune-mediated diseases, n=5; others, n=1). In these subjects, IL-6, but not TNFα and IL-1, was ~15-20 times higher than in controls, and comparable to RA patients. In the inflammatory cohort, where QTc prolongation was common (mean values: 456.6±30.9 ms), CRP reduction was associated with IL-6 level decrease and significant QTc shortening (-22.3 ms).Conclusion: The data are first to show that systemic inflammation via elevated IL-6 levels may represent a novel QT-prolonging risk factor contributing to TdP occurrence in the presence of other classical risk factors. If confirmed, this could open new avenues in antiarrhythmic therapy. [ABSTRACT FROM AUTHOR]

Ambulatory ECG (AECG) is very commonly employed in a variety of clinical contexts to detect cardiac arrhythmias and/or arrhythmia patterns which are not readily obtained from the standard ECG. Accurate and timely characterization of arrhythmias is crucial to direct therapies that can have an important impact on diagnosis, prognosis or patient symptom status. The rhythm information derived from the large variety of AECG recording systems can often lead to appropriate and patient-specific medical and interventional management. The details in this document provide background and framework from which to apply AECG techniques in clinical practice, as well as clinical research. [ABSTRACT FROM AUTHOR]

Background. Takotsubo cardiomyopathy (TCM) is sudden and reversible myocardial dysfunction often attributable to physical or emotional triggers. Case Report. We describe a 51-year-old man presented to emergency department with sepsis from urinary tract infection (UTI). He was placed on cefepime for UTI and non-ST-elevation myocardial infarction protocol given elevated troponins with chest pain. Subsequently, patient was pulseless with torsades de pointes (TdP) and then converted to sinus rhythm with cardioversion. An echocardiogram revealed low ejection fraction with hypokinesis of the apical wall. Over 48 hours, the patient was extubated and stable on 3 L/min nasal cannula. He underwent a cardiac catheterization to evaluate coronary artery disease (CAD) and was found to have mild nonobstructive CAD with no further findings. Conclusion. TCM is a rare disorder presenting with symptoms similar to acute coronary syndrome. Though traditionally elicited by physical and emotional triggers leading to transient left ventricular dysfunction, our case suggests that it may also be triggered by a urinary tract infection and lead to severe QT prolongation and a malignant ventricular arrhythmia in TdP. [ABSTRACT FROM AUTHOR]

Background The aim of the study is to contrast the role of conventional ambulatory electrocardiographic monitoring (AEM) artifacts with a less emphasized problem with potentially more serious implications, that is, the failure to recognize, and therefore misinterpret, a genuine arrhythmia episode in the AEM recording. Methods The study material included 500 Holter recordings and 500 recordings from the cardiac telemetry unit. Results Electrocardiographic (ECG) artifacts were more common in telemetry recordings (5.6%) compared to Holter recordings (4%) for a total of 4.8%. There were 35 examples of misinterpretation of AEM recordings (3.5%). These were significantly more common in telemetry recordings (2.6%) compared to Holter recordings (0.9%). The most common ECG artifacts were examples of pseudo ventricular tachyarrhythmia (VT). The majority of misinterpretation (26 of 35 examples) were fast supraventricular tachyarrhythmias with aberrant QRS (including six examples of atrial flutter with periods of 1:1 atrioventricular conduction) that were misdiagnosed as ventricular VT. Other examples were misinterpretation of arrhythmic episodes consistent with sick sinus syndrome, pacemaker malfunction, and long QT syndrome. Only 5 of 48 examples of AEM artifacts resulted in management errors of commission or errors of omission compared to all 35 examples of misinterpretation. Conclusions Compared to conventional artifacts in AEM, misinterpretation of nonartifactual arrhythmic episodes consistently resulted in management errors. Misinterpretation was significantly more common with telemetry recordings compared to Holter ECG. This highlights the need for more appropriate training of the entire clinical team in charge of the management of the cardiac telemetry unit. [ABSTRACT FROM AUTHOR]

Key points Early afterdepolarizations (EADs) are a known trigger for arrhythmias, but the effect of surrounding tissue on EADs is poorly understood., Neurotoxin anthopleurin-A (AP-A) increases action potential duration and gives rise to EADs in isolated myocytes. We investigate the effect of AP-A on connected networks of cultured cardiac cells., We show that EADs are markedly suppressed in well-coupled neonatal rat ventricular monolayers treated with AP-A, but reappear when gap junction connectivity is blocked., The ability of cell coupling to electrotonically damp EADs is confirmed in a two-cell simulation where connectivity is systematically varied., Taken together, these results suggest that cell-cell coupling can act to suppress EADs in normal cardiac tissue. Results also suggest that EADs may emerge and propagate in poorly coupled tissue., Abstract Pathologies that result in early afterdepolarizations (EADs) are a known trigger for tachyarrhythmias, but the conditions that cause surrounding tissue to conduct or suppress EADs are poorly understood. Here we introduce a cell culture model of EAD propagation consisting of monolayers of cultured neonatal rat ventricular myocytes treated with anthopleurin-A (AP-A). AP-A-treated monolayers display a cycle length dependent prolongation of action potential duration (245 ms untreated, vs. 610 ms at 1 Hz and 1200 ms at 0.5 Hz for AP-A-treated monolayers). In contrast, isolated single cells treated with AP-A develop prominent irregular oscillations with a frequency of 2.5 Hz, and a variable prolongation of the action potential duration of up to several seconds. To investigate whether electrotonic interactions between coupled cells modulates EAD formation, cell connectivity was reduced by RNA silencing gap junction Cx43. In contrast to well-connected monolayers, gap junction silenced monolayers display bradycardia-dependent plateau oscillations consistent with EADs. Further, simulations of a cell displaying EADs electrically connected to a cell with normal action potentials show a coupling strength-dependent suppression of EADs consistent with the experimental results. These results suggest that electrotonic effects may play a critical role in EAD-mediated arrhythmogenesis. [ABSTRACT FROM AUTHOR]

Aims: The present study attempts to develop an objective, statistically based set of criteria for activation time determination from unipolar electrograms (U-EGMs) using a standard of activation related to biophysical theory. Methods: A high-resolution assembly of U-EGMs obtained from the epicardial surface of the canine postinfarction heart were analyzed in order to achieve the best prediction of local versus distant activation. An activation time standard (ATS) consisted of three properties: (1) propagation of activation, evidenced by a linear temporal shift of waveforms from closely spaced U-EGMs with little or no decay in amplitude; (2) cycle length-dependent changes of those propagating waveforms; and (3) evidence of electrotonic deflections, seen as nonpropagating potentials having decaying amplitude with distance. Results: A number of U-EGM features were calculated and subjected to analysis by comparing their occurrence with the ATS. A discriminant function analysis incorporating multiple features (Voltage, −dV/dt and Ratio) of major U-EGM deflections improved prediction of activation time of complex fractionated EMGs from ischemic canine epicardium to 90%. Conclusion: A unique discriminant function based on sound biophysical principles markedly improved prediction of activation time of complex U-EGMs from ischemic canine epicardium. A computerized version of the algorithm could be developed to provide more accurate activation maps for both basic and clinical use. (PACE 2011; 34:1105-1115) [ABSTRACT FROM AUTHOR]

A 74-year-old man with past history of near syncope presented with frequent periods of second-degree atrioventricular block (2° AVB). An electrophysiological study revealed prolonged atrial-His and His-ventricular (HV) intervals and frequent His bundle (H) extrasystoles. The latter manifested in the surface electrocardiogram as premature atrial, junctional, or ventricular beats, as well as 2° AVB that mimicked Wenckebach or Mobitz II block. Procainamide markedly suppressed H extrasystole. However, because of the presence of prolonged HV interval and history of presyncope, a permanent pacemaker was inserted. The case illustrates the varied manifestation of H extrasystole and presents guidelines for management. (PACE 2010; 1-4) [ABSTRACT FROM AUTHOR]

Management of Sudden Cardiac Death (SCD) is undergoing a radical change in direction. It is becoming increasingly appreciated that besides depressed left ventricular systolic function and the conventional risk stratification tools, new markers for plaque vulnerability, enhanced thrombogenesis, specific genetic alterations of the autonomic nervous system, cardiac sarcolemmal and contractile proteins, and familial clustering may better segregate patients with atherosclerotic coronary artery disease who are at high risk for SCD from those who may suffer from nonfatal ischemic events. Better understanding of pathophysiological processes, such as postmyocardial infarction remodeling, the transition from compensated hypertrophy to heart failure, and the increased cardiovascular risk of coronary artery disease in the presence of diabetes or even a prediabetic state will help to improve both risk stratification and management. The rapidly developing fields of microchips technology and proteomics may allow rapid and cost-effective mass screening of multiple risk factors for SCD. The ultimate goal is to identify novel methods for risk stratification, risk modification, and prevention of SCD that could be applied to the general public at large. [Copyright &y& Elsevier]

Aims: To compare patients with atrial flutter (AFl) and 1:1 atrioventricular conduction (AVC) with patients with AFl and higher AVC. Methods: The characteristics of 19 patients with AFl and 1:1 AVC (group A) were compared with those of 116 consecutive patients with AFl and 2:1 AVC or higher degree AV block (group B). Results: Age, gender, and left ventricular function were similar in the two groups. In group A versus group B, more patients had no structural heart disease (42% vs 17%, P < 0.05) and syncope/presyncope (90% vs 12%, P < 0.05). The AFl cycle length (CL) in group A was longer than in group B (265 ± 24 ms vs 241 ± 26 ms, P < 0.01). The transition from AFl with 1:1 to 2:1 AVC or vice versa was associated with small but definite changes in AFl CL, which showed larger variations in response to sympathetic stimulation. In group A patients who were studied off drugs, the atrial-His interval was not different from group B, but maximal atrial pacing rate with 1:1 AVC was faster. In group A, five patients were misdiagnosed as ventricular tachyarrhythmias, and three with a defibrillator received inappropriate shocks. Four patients had ablation of AVC and six had ablation of AFl circuit. Conclusions: The main difference between groups A and B may be an inherent capacity of the AV node for faster conduction, especially in response to increased sympathetic tone. The latter affects not only AVC but also the AFl CL. One should be aware of the different presentations of AFl with 1:1 AVC to avoid misdiagnosis/mismanagement and to consider the diagnosis in patients with narrow or wide QRS tachycardia and rates above 220/min. [ABSTRACT FROM AUTHOR]

Mancarella S, Yue Y, Karnabi E, Qu Y, El-Sherif N, Boutjdir M. Impaired Ca[sup2+] homeostasis is associated with atrial fibrillation in the α1D L-type Ca[sup2+] channel KU mouse. Am J Physiol Heart Circ Physiol 295: H2017-H2024, 2008. First published September 12, 2008; doi: 10.1152/ajpheart.00537.2008.-The novel α1D Ca[sup2+] channel together with α1D Ca[sup2+] channel contribute to the L-type Ca[sup2+] current (I[subCa-L]) in the mouse supraventricular tissue. However, its functional role in the heart is just emerging. We used the α1D gene knockout (KO) mouse to investigate the electrophysiological features, the relative contribution of the α1D Ca[sup2+] channel to the global I[subCa-L], the intracellular Ca[sup2+] transient, the Ca[sup2+] handling by the sarcoplasmic reticulum (SR), and the inducibility of atrial fibrillation (AF). In vivo and ex vivo ECG recordings from α1D KO mice demonstrated significant sinus bradycardia, atrioventricular block, and vulnerability to AF. The wild-type mice showed no ECG abnormalities and no AF. Patch-clamp recordings from isolated α1D KO atrial myocytes revealed a significant reduction of I[subCa-L] (24.5%; P < 0.05). However, there were no changes in other currents such as I[subNa], I[subCa-T], I[subK], If, and I[subf] and no changes in α[subIC] mRNA levels of α1D KO atria. Fura 2-loaded atrial myocytes showed reduced intracellular Ca[sup2+] transient (-40%; P < 0.05) and rapid caffeine application caused a 17% reduction of the SR Ca[sup2+] content (P < 0.05) and a 28% reduction (P < 0.05) of fractional SR Ca[sup2+] release in α1D KO atria. In conclusion, genetic deletion of α1D Ca[sup2+] channel in mice results in atrial electrocardiographic abnormalities and AF vulnerability. The electrical abnormalities in the α1D KO mice were associated with a decrease in the total I[subCa-L] density, a reduction in intracellular Ca[sup2+] transient, and impaired intracellular Ca[sup2+] handling. These findings provide new insights into the mechanism leading to atrial electrical dysfunction in the α1D KO mice. [ABSTRACT FROM AUTHOR]

Aims: The present study addresses the controversy regarding the ‘primary’ role of the subendocardial Purkinje network in triggering torsade de pointes (TdP) ventricular tachyarrhythmia (VAs) in the long QT syndrome (LQTS). [ABSTRACT FROM PUBLISHER]

Introduction: Atrial standstill is a rare heterogeneous arrhythmia characterized by electrical and mechanical standstill and electrical inexcitability. A long-lasting progressive form is seen with cardiac and neuromuscular diseases, and a familial or idiopathic form may have a genetic basis. A transient form was described secondary to drug intoxication, electrolyte imbalance, cardiac inflammation, and ischemia. Methods: We investigated three patients with long-standing atrial tachyarrhythmia (AT) (atrial flutter in two, and focal atrial tachycardia in one). All patients underwent a complete electrophysiological study with mapping of right and left atrial activity and radiofrequency ablation (RF Abl) of AT. Results: Following RF Abl of AT, all three patients manifested transient atrial electrical silence in the absence of known reversible causes. Atrial electrical silence was observed when, following AT termination, an escape atrioventricular (AV) junctional rhythm (in two patients) and an escape VVI pacemaker rhythm (in one patient) showed transient ventriculo-atrial (VA) conduction block (up to 30 seconds). A dominant sinus rhythm was observed to return 30 minutes, 90 minutes, and 12 hours, respectively, in the three patients. Two patients received a dual chamber pacemaker and a decision was made not to upgrade the patient with VVI pacemaker. Discussion and Conclusions: The present report expands the spectrum of the syndrome of atrial standstill and raises interesting questions regarding possible electrophysiologic mechanism(s) of prolonged post overdrive atrial standstill. The report suggests that chronic overdrive of sinus and subsidiary atrial pacemakers may result in calcium overloading of cardiac cells, which is known to cause suppression of pacemaker activity as well as increased intracellular resistance. These mechanisms can possibly result in either prolonged suppression of sinus and atrial pacemaker activity and/or pacemaker exit block. [ABSTRACT FROM AUTHOR]

Available evidence supports the hypothesis that cardiac resynchronization therapy (CRT) results in favorable structural as well as electrical remodeling. Electrical remodeling seems to be related, to a large extent, to structural remodeling, usually referred to as reverse remodeling of left ventricular (LV) dysfunction. This can lead to amelioration of the arrhythmogenic substrate associated with depressed LV systolic function and heart failure. However, a direct electrophysiological effect due to favorable remodeling of repolarization with reduction of the dispersion of repolarization cannot be ruled out. On the other hand, in a small subgroup of patients, CRT could increase the dispersion of repolarization and induce malignant ventricular tachyarrhythmias. Clinical trials have consistently shown improved outcome with CRT-defibrillators (CRT-D) and more trials have demonstrated the benefits of the defibrillator in the population with depressed LV function. However, some physicians argue that implanting the less expensive and less complicated CRT-pacemaker (CRT-P) may be appropriate in certain groups of patients. Before this position is accepted, it is imperative that criteria for the selection of this group of patients with presumably low risk for sudden arrhythmic death as well as the proarrhythmic effect of CRT be clearly defined. [ABSTRACT FROM AUTHOR]

The cardiovascular drug carvedilol is characterized by multiple pharmacological actions, which translate into a wide-spectrum therapeutic potential. Its major molecular targets are membrane adrenoceptors, ion channels, and reactive oxygen species. Carvedilol's favorable hemodynamic effects are due to the fact that the drug competitively blocks β1-, β2-, and α1- adrenoceptors. Several additional properties have been documented and may be clinically important, including antioxidant, antiproliferative/antiatherogenic, anti-ischemic, and antihypertrophic effects. The antiarrhythmic action of carvedilol may be related to a combination of its β-blocking effects with its modulating effects on a variety of ion channels and currents. Several studies suggest that the drug may be useful in reducing cardiac death in high-risk patients with prior myocardial infarction and/or heart failure, as well as for primary and secondary prevention of atrial fibrillation. This article will review experimental data available on the electrophysiologic properties of carvedilol, with a focus on their clinical relevance. [ABSTRACT FROM AUTHOR]

α1D L-type Ca channel was assumed to be of neuroendocrine origin only; however, α1D L-type Ca channel knockout mice exhibit sinus bradycardia and atrioventricular block, indicating a distinct role of α1D in the heart. The presence and distribution of α1D Ca channel in the heart and its regulation by protein kinase A (PKA) are just emerging. Our objective was to examine the localization of α1D L-type Ca channel in rabbit and rat hearts and its modulation by PKA. Here, we show the exclusive presence of α1D Ca channel transcript in the sinoatrial node, atrioventricular node, and atria but not in the ventricle by RT-PCR and the expression of α1D Ca channel protein in atrial myocytes' sarcolemma by indirect immunostaining and Western blot. There is no significant difference in the expression level of α1D Ca channel in the left versus right atrium. Superfusion of membrane-permeable 8-bromo-cAMP resulted in a significant increase of the peak current density of α1D Ca current expressed in tsA201 cells. This increase was inhibited by the PKA inhibitor (PKI). Application of 8-bromo-cAMP also readily phosphorylated the α1D Ca channel protein. The results are first to demonstrate that PKA phosphorylation of L-type Ca channel α1D subunit resulted in an increase of the α1D Ca channel activity. Together with the observation that α1D Ca channel is exclusively present in the sinoatrial node and atria, the findings suggest that α1D Ca channel plays a unique role in the sinoatrial tissue and is a target for sympathetic control of heart rhythm. [ABSTRACT FROM AUTHOR]

Repolarization alternans has been considered a strong marker of electrical instability. The objective of this study was to investigate the hypothesis that ischemia-induced contrasting effects on the kinetics of membrane voltage and intracellular calcium transient (CaiT) can explain the vulnerability of the ischemic heart to repolarization alternans. Ischemia-induced changes in action potential (AP) and CaiT resulting in alternans were investigated in perfused Langendorff guinea pig hearts subjected to 10–15 min of global no-flow ischemia followed by 10–15 min of reperfusion. The heart was stained with 100 μl of rhod-2 AM and 25 μl of RH-237, and AP and CaiT were simultaneously recorded with an optical mapping system of two 16 × 16 photodiode arrays. Ischemia was associated with shortening of AP duration (D) but delayed upstroke, broadening of peak, and slowed decay of CaiT resulting in a significant increase of CaiT-D. The changes in APD were spatially heterogeneous in contrast to a more spatially homogeneous lengthening of CaiT-D. CaiT alternans could be consistently induced with the introduction of a shorter cycle when the upstroke of the AP occurred before complete relaxation of the previous CaiT and generated a reduced CaiT. However, alternans of CaiT was not necessarily associated with alternans of APD, and this was correlated with the degree of spatially heterogeneous shortening of APD. Sites with less shortening of APD developed alternans of both CaiT and APD, whereas sites with greater shortening of APD could develop a similar degree of CaiT alternans but slight or no APD alternans. This resulted in significant spatial dispersion of APD. The study shows that the contrasting effects of ischemia on the duration of AP and CaiT anad, in particular, on their spatial distribution explain the vulnerability of ischemic heart to alternans and the increased dispersion of repolarization during alternans. [ABSTRACT FROM AUTHOR]

Repolarization Distribution in LQT3. Introduction: The occurrence of significant spatial dispersion of repolarization in vivo as it relates to the mechanism of arrhythmia formation in the long QT syndrome (LQTS) continues to be questioned. Methods and Results: We investigated a guinea pig model of LQT3 using anthopleurin-A (AP-A) to study the contribution of rate-dependent spatial dispersion of repolarization in the intact heart to the arrhythmogenicity of LQTS. Optical action potentials were measured using potentiometric fluorescent dye di-4ANEPPS in Langendorff-perfused hearts with induced AV block. AP-A exacerbated the normal uniform epicardial apex-base action potential duration (APD) gradient, resulting in rate-dependent increased APD dispersion and nonuniform APD gradient. Spontaneous focal premature beats induced functional conduction block along boundaries where large nonuniform APD gradient occurred setting the stage for circulating wavefronts and ventricular tachyarrhythmia (VT). Endocardial ablation abolished spontaneous VT, but nonuniform epicardial APD gradient persisted and could be challenged by a stimulated premature stimulus to induce VT. Conclusion: The study shows that in LQT3, spatial variations in steady-state properties result in zones of nonuniform APD gradients. These provide a substrate for functional conduction block and reentrant excitation when challenged by subendocardial “early afterdepolarization-triggered” premature beats. The study emphasizes the key importance of spatial dispersion of repolarization, whether located in epicardial or intramyocardial layers, in arrhythmia formation in LQTS. (J Cardiovasc Electrophysiol, Vol. 15, pp. 323-331, March 2004) [ABSTRACT FROM AUTHOR]

Risk Stratification and Management of SCD. Management of SCD is undergoing radical change in direction. It is becoming increasingly appreciated that besides depressed left ventricular systolic function and the conventional risk stratification tools, new markers for plaque vulnerability, enhanced thrombogenesis, specific genetic alterations of the autonomic nervous system, cardiac sarcolemmal and contractile proteins, and familial clustering may better segregate patients with atherosclerotic coronary artery disease who are at high risk for SCD from those who may suffer from nonfatal ischemic events. Better understanding of pathophysiologic processes, such as postmyocardial infarction remodeling, the transition from compensated hypertrophy to heart failure, and the increased cardiovascular risk of coronary artery disease in the presence of diabetes or even a prediabetic state will help to improve both risk stratification and management. The rapidly developing fields of microchips technology and proteomics may allow rapid and cost-effective mass screening of multiple risk factors for SCD. The ultimate goal is to identify novel methods for risk stratification, risk modification, and prevention of SCD that could be applied to the general public at large. (J Cardiovasc Electrophysiol, Vol. 14, pp. 1113-1119, October 2003) [ABSTRACT FROM AUTHOR]

Introduction: Compared to concordant T wave alternans (CA), discordant T wave alternans (DA) may be associated with an increased dispersion of repolarization (DR) and a greater propensity to develop reentrant ventricular tachyarrhythmias. The electrophysiologic mechanisms of DA in the in vivo heart are not well understood. Methods and Results: The mechanisms of DA were investigated in the canine anthopleurin-A surrogate model of long QT3 syndrome using tridimensional analysis of activation and repolarization patterns from 256 to 384 unipolar electrograms. Cardiac repolarization was evaluated as the activation-recovery interval (ARI) of local electrograms. Two mechanisms for the development of DA were observed. (1) Stepwise shortening of cycle length (CL) superimposed on preexisting DR resulted in different diastolic intervals (DI) at midmyocardial sites compared to epicardial and endocardial sites. The dispersion of DI coupled with different restitution kinetics at those sites induced DA. (2) The dependence of conduction velocity on DI as the CL is abruptly shortened could result in differential conduction delays at mid sites. This enhanced the dispersion of DI between sites and, coupled with the different restitution kinetics, induced DA. The critical step for the development of DA in both mechanisms was the occurrence of short ARI in two consecutive beats either at epicardial sites in the first mechanism or at mid sites in the second mechanism. Sites with DA had significantly more DR compared to sites with concordant T wave alternans, and ventricular tachyarrhythmias developed mainly in the presence of DA. Conclusion: In the in vivo heart, DA developed due to critical interaction between dispersion of DI and differences in restitution kinetics at different myocardial sites. The dispersion of DI could result from preexisting DR or differential conduction delay at a critical short CL. DA is critically linked to the development of malignant tachyarrhythmias. (J... [ABSTRACT FROM AUTHOR]

Objectives: Recently, the Janus kinase/signal transducer and activator of transcription (JAK–STAT) signaling pathway was found to be prominently associated with activation of the autocrine loop of the heart tissue-localized renin angiotensin system (RAS). We investigated if the JAK–STAT pathway is activated in the post-myocardial infarction (MI) non-ischemic myocardium (NIM), destined to undergo remodeling and whether blockade of the pathway in vivo can modify early post-MI remodeling. Methods: We investigated the time course of tyrosine phosphorylation of JAK–STAT and gp130 proteins in the NIM of post-MI rat heart as well as the binding activity of STAT proteins to the St-domain of the angiotensinogen gene promoter. We further compared the effects of in vivo blockade of RAS by the AT1 receptor (AT1R) blocker losartan with the in vivo blockade of JAK–STAT pathway by the specific JAK2 blocker tyrphostin AG490 on certain aspects of early post-MI remodeling. Results: We showed that JAK2, STATs 1, 3, 5a and 6 and gp130 proteins are tyrosine phosphorylated as early as 5–30 min post-MI and that STATs 1, 3, and 5a remain activated up to 7 days post-MI. Gel mobility shift assay showed a strong binding activity of STAT proteins to the St-domain of angiotensinogen gene promoter in 1-day post-MI NIM. The binding was significantly reduced in rat hearts previously treated with losartan or tyrphostin AG490. Supershift experiments identified STATs 3 and 5a as specifically interacting with the St-domain. Both AT1R and JAK2 blockade resulted in significant amelioration of the increase of protein phosphatase 1 activity and decrease in basal level of p16-phospholamban that may underlie early diastolic dysfunction, as well as partial amelioration of early downregulation of Kv4.2 gene expression that may underlie increased arrhythmogenicity of 3-day post-MI heart. On the other hand, while blockade of AT1R significantly ameliorated apoptotic changes in 1-day post-MI border zone, blockade of JAK2 increased apoptosis. Conclusions: The study provides compelling evidence in favor of the linkage of the JAK–STAT pathway with the angiotensin II autocrine loop and uncovers a mechanism by which selective activation of a set of STAT proteins underlies mobilization of the gene activation program intrinsic to post-MI remodeling. It also suggests that drugs that inhibit JAK–STAT phosphorylation may provide a new approach to modify post-MI remodeling. This needs to be confirmed in long term in vivo studies in the post-MI heart. [Copyright &y& Elsevier]

Introduction: Microvolt T wave alternans (TWA) has been proposed as a strong independent predictor of malignant ventricular tachyarrhythmias and sudden cardiac death. TWA reproducibility during bicycle stress test has not been previously investigated. We sought to assess the short-term reproducibility of TWA, as well as heart rate (HR) threshold for TWA, and its spatial distribution and magnitude. Methods and Results: The study enrolled 42 patients who were able to complete two bicycle stress tests with HR at peak exercise > 110 beats/min within 4 hours of each other and who had technically adequate recordings for TWA analysis during both tests. Concordant results for TWA determination were obtained in 39 (93%) of 42 cases. TWA was present during both tests in 23 patients and was absent during both tests in 16 patients. In the 23 patients with two positive tests, HR at the onset of TWA was not significantly different during the two tests. Further, the number of leads showing TWA and the magnitude of TWA were not significantly different between the two tests. Conclusion: TWA is characterized by satisfactory short-term reproducibility and, when present, by high temporal and spatial stability. [ABSTRACT FROM AUTHOR]

Introduction: Azimilide dihydrochloride blocks both the rapid (IKr) and slow (IKs) components of the delayed rectified K+ current; dofetilide blocks only IKr. Their efficacies were assessed on atrial flutter reentrant circuits in dogs with surgically induced right atrial enlargement. Methods and Results: Multiple biopsies of the tricuspid valve and banding of the pulmonary artery in male mongrel dogs made them susceptible, about 3 weeks postoperatively, to stimulation-induced sustained (5 min or longer) atrial flutter. Azimilide 3 mg/kg administered intravenously (IV) terminated flutter in 8 of 8 dogs, but a slower, nonsustained arrhythmia could be reinduced in 5. In these 5 dogs, azimilide 10 mg/kg terminated flutter and prevented reinduction. This dose increased effective refractory period significantly more in the slow conduction zone (25%) than in the normal zone (17%) and increased flutter cycle length (37%). Termination followed progressive conduction delay in the slow zone of the reentrant circuit. Dofetilide 1 μg/kg IV terminated flutter in 6 of 6 dogs, but the arrhythmia could be reinduced. At 3 μg/kg, flutter terminated in all dogs and could not be reinduced. Dofetilide also increased the effective refractory period significantly more in the slow zone (17%) than in the normal zone (12%) and increased cycle length (33%), leading to interruption of the arrhythmia circuit. Conclusion: In the canine right atrial enlargement model of circus movement atrial flutter, both azimilide 10 mg/kg IV and dofetilide 3 μg/kg IV were 100% effective in terminating flutter and preventing reinduction. Efficacy relied on a similar mechanism of differentially prolonged refractoriness in the slow conduction component of the reentrant circuit where drug-induced termination occurred. [ABSTRACT FROM AUTHOR]

Previous tridimensional activation mapping showed that the development of functional conduction block at the onset of torsades de pointes was regionally heterogeneous; conduction block was frequently observed in the L V and the interventricular septum (IVS) but not in the RV, in the canine anthopleurin-A (AP-A) model of long QT syndrome (LQTS). This may be related to the distribution of mvocytes with M celllike electrophysiological characteristics. To better understand the regional difference of arrhythmogenicity in LQTS, the authors investigated cycle length related modulation of ventricular repolarization among three different layers: the endocardium (End), mid-myocardium (Mid), and epicardium (Epi) of the LV and RV and at two different areas: the Epi and septum (Sep) in the IVS. The LQT3 model was produced by AP-A in dogs. Using constant pacing and single premature stimulation (S1S2), the ventricular repolarization pattern was analyzed from 256 unipolar electrograms. Activation-recovery intervals (ARIs) were used to estimate local repolarization. In seven experiments, AP-A increased regional AW dispersion to 88.1 ± 36.0 ins in the LV, to 72.9 ± 35.7ms in the IVS. and to 23.0 ± 8.7 ms in the RV at the pacing cycle length (CL) of 7,000 ms. Development of the large ARI dispersion was due to greater ARI prolongation at the Mid site in the LV and at Sep site in the IVS. As the S1S2 interval was shortened, regional ARI dispersion decreased gradually, and finally, ARI dispersion showed a reversal gradient of repobarization between the Mid and Epi sites in the LV and between the Sep and Epi sites in the IVS. Two factors contributed to create the reversal gradient of repolarization: (1) a difference in restitution kinetics at the Mid site in the LV and at the Sep site in the IVS, characterized by a larger Δ ARI and slower time constant (τ), and (2) a difference in diastolic intervals at each site resulting in different input to restitution at the same CL. However, the RV showed small alteration in the transmural dispersion of repolarization in the S1S2 protocol. S2 created heterogeneous functional conduction block in the LV and IVS but not in the RV. In the LQT3 model, the arrhvthmogenicity of torsades do pointes is primarily due to dispersion of repolarizatian in the LV and IVS because of prominent distribution of M cells. The RV seems to participate passively in reentrant excitation during torsades de pointes. [ABSTRACT FROM AUTHOR]

Both the congenital and acquired long QT syndrome are due to abnormalities (intrinsic and/or acquired) of the ionic currents underlying repolarization. The prolongation of repolarization acts as a priming step for the generation of early afterdepolarizations. In the long QT syndrome, it also is associated with increased dispersion of repolarization. Focal early afterdepolarization-induced triggered beat(s) can infringe on the underlying substrate of inhomogeneous repolarization to initiate polymorphic reentrant ventricular tachycardia that sometimes has a characteristic twisting of the QRS axis, referred to as torsades de pointes. [ABSTRACT FROM AUTHOR]

Objectives: This study was conducted to determine the optimal target heart rate (HR) for the use of exercise-induced T-wave alternans (TWA) as an index for risk of malignant ventricular tachyarrhythmias. Background: Rate-dependent TWA is an index of vulnerability to ventricular tachyarrhythmias. However, false positive TWA was reported to occur in normal subjects at high HR. Methods: Two groups were evaluated: Group I: 50 patients with malignant ventricular tachyarrhythmias, who received an implantable cardioverter-defibrillator (ICD); and Group II: 55 agematched normal subjects. In both Groups, TWA was evaluated during symptom-limited bicycle exercise test. Results: Peak HR during exercise test was 103 ± 17 beats/min in Group I, versus 124 ± 18 beats/min in Group II (P < 0.001). In Group I, 4 patients were excluded from analysis, due to high noise level or frequent ectopy during exercise. Out of the remaining 46 patients, TWA was present in 28 patients (61%), and absent in 18 (39%). In group II, TWA was present in four subjects (7%), and absent in 51 (93%). HR at the onset of TWA was 91 ± 11/min in Group I, and 119 ± 12/min in Group II (P < 0.001). Receiver operated characteristics curves demonstrated that a HR of 115 beats/min was the cutoff with the best sensitivity and specificity for TWA (100 and 96%, respectively). None of the patients in Group I developed TWA at HR > 115 beats/min, while two out of four in Group II had TWA at HR > 115/minutes. However, 13 patients in Group I who had no TWA were unable to exercise to a peak HR > 115 beats/min, compared to nine subjects in Group II. Conclusions: A target HR of 115 beats/min was highly sensitive and specific for determination of exercise-induced TWA as an index of risk of malignant ventricular tachyarrhythmias. However, a significant number of patients may not be able to achieve this target HR, resulting in an indeterminate test. The value of pharmacologic testing in this group should be assessed. A.N.E. 2001;6(2):123-128 [ABSTRACT FROM AUTHOR]

Introduction: After a myocardial infarction (MI), the heart undergoes a remodeling process that includes hypertrophy of noninfarcted left ventricular myocytes. Alterations in the genetic expression, including reexpression of fetal isogene patterns, can result in electrophysiologic changes that contribute to the arrhythmogenicity of post-MI heart. The present study investigated possible alterations in gene expression of Na+ channel subtypes, as well as the kinetics of the Na+ current (INa), in 3- to 4-week-old post-MI rat remodeled left ventricular myocardium. Methods and Results: Using a macropatch technique, we showed increased Na+ channel bursting activity during sustained depolarization in post-MI remodeled myocytes resulting in a large slow component of the INa decay. A tetrodotoxin-sensitive current contributed 18% to the prolonged APD90 of isolated post-MI myocytes compared with 6% in control myocytes . Our molecular studies revealed that, in addition to the rat heart I (rH I) subtype, thought to be the predominant subtype that encodes a tetrodotoxin-resistant isoform, the brain subtypes NaCh I and NaCh Ia also are expressed in the rat myocytes. Post-MI remodeled myocardium showed increased expression of NaCh I protein with reversion of the NaCh Ia/NaCh I isoform ratio toward the fetal phenotype. Conclusion: Our findings raise the possibility that the increase in the slow component of INa in post-MI remodeled myocytes is secondary to the increased expression of NaCh I. Additional studies are required to address these questions and to characterize the functional role of the NaCh I subtypes in cardiac myocytes. [ABSTRACT FROM AUTHOR]