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The development of interatrial septum (IAS) is a complicated process, which continues during postnatal life. The hypertrophic signals in developing heart are mediated among others by α-adrenergic pathways. These facts suggest the presence of specific electrophysiological features in developing IAS. This study was aimed to investigate the electrical activity in the tissue preparations of IAS from rat heart in normal conditions and under stimulation of adrenoreceptors. Intracellular recording of electrical activity revealed less negative level of resting membrane potential in IAS if compared to myocardium of left atrium. In normal conditions, non-paced IAS preparations were quiescent, but noradrenaline (10−5 M) and phenylephrine (10−5 M) induced spontaneous action potentials, which could be abolished by α1-blocker prazosin (10−5 M), but not β1-blocker atenolol (10−5 M). Optical mapping showed drastic phenylephrine-induced slowing of conduction in adult rat IAS. The α1-dependent ectopic automaticity of IAS myocardium might be explained by immunohistochemical data indicating the presence of transcription factor GATA4 and abundant α1A-adrenoreceptors in myocytes from adult rat IAS. An elevated sensitivity to adrenergic stimulation due to involvement of α1-adrenergic pathways may underlie increased proarrhythmic potential of adult IAS at least in rats. [ABSTRACT FROM AUTHOR]

Calcium ions (Ca2+) play a major role in the cardiac excitation-contraction coupling. Intracellular Ca2+ concentration increases during systole and falls in diastole thereby determining cardiac contraction and relaxation. Normal cardiac function also requires perfect organization of the ion currents at the cellular level to drive action potentials and to maintain action potential propagation and electrical homogeneity at the tissue level. Any imbalance in Ca2+ homeostasis of a cardiac myocyte can lead to electrical disturbances. This review aims to discuss cardiac physiology and pathophysiology from the elementary membrane processes that can cause the electrical instability of the ventricular myocytes through intracellular Ca2+ handling maladies to inherited and acquired arrhythmias. Finally, the paper will discuss the current therapeutic approaches targeting cardiac arrhythmias. [ABSTRACT FROM AUTHOR]

The sinoatrial node (SAN) is the dominant pacemaker of the heart. Abnormalities in SAN formation and function can cause sinus arrhythmia, including sick sinus syndrome and sudden death. A better understanding of genes and signaling pathways that regulate SAN development and function is essential to develop more effective treatment to sinus arrhythmia, including biological pacemakers. In this review, we briefly summarize the key processes of SAN morphogenesis during development, and focus on the transcriptional network that drives SAN development. [ABSTRACT FROM AUTHOR]

An editorial is presented on Atrioventricular (AV) discordance, is an uncommon form of congenital heart disease. The right atrium is connected to the morphological left ventricle through the mitral valve and the left atrium to the morphologically right ventricle through the tricuspid valve. Ventricle and mitral valve are located to the right and connected to the pulmonary artery.

In the adult heart, electrophysiological heterogeneity is present to guide activation and contraction. A change in electrophysiological heterogeneity, for example, during disease, can contribute to arrhythmogenesis. During development, spatial and temporal patterns of transcriptional activity regulate the localized expression of ion channels that cause electrophysiological heterogeneity throughout the heart. If we gain insight into the regulating processes that generate the electrophysiological characteristics and factors involved during development, we can use this knowledge in the search for new therapeutic targets. In this review, we discuss which factors guide the electrical patterning of atrioventricular conduction system and ventricles and how this patterning relates to arrhythmogenic disease in patients. [ABSTRACT FROM AUTHOR]

The ventricular conduction system represents the electrical wiring responsible for the co-ordination of cardiac contraction. Defects in the circuit produce a delay or conduction block and induce cardiac arrhythmias. Understanding how this circuit forms and identification of the factors important for its development thus provide insights into the origin of cardiac arrhythmias. Recent advances, using genetically modified mouse models, have contributed to our understanding of how the ventricular conduction system is established during heart development. Transgenic mice carrying different reporter genes have highlighted the conservation of the anatomy and development of the ventricular conduction system between mice and humans. Lineage tracing and retrospective clonal analysis have established the myogenic origin of the ventricular conduction system and determined properties of conductive progenitor cells. Finally, gene knock-out models reproducing human cardiac defects have led to the identification of transcription factors important for the development of the ventricular conduction system. These transcription factors operate at the levels of both conduction system morphogenesis and differentiation by controlling the expression of genes responsible for the electrical activity of the heart. In summary, defects in the ventricular conduction system are a major cause of arrhythmias, and deciphering the molecular pathways responsible for conduction system morphogenesis and the differentiation of conductive myocytes furthers our understanding of the mechanisms underlying heart disease. [ABSTRACT FROM AUTHOR]

Aims Human congenital heart disease linked to mutations in the homeobox transcription factor, NKX2-5, is characterized by cardiac anomalies, including atrial and ventricular septal defects as well as conduction and occasional defects in contractility. In the mouse, homozygous germline deletion of Nkx2-5 gene results in death around E10.5. It is, however, not established whether Nkx2-5 is necessary for cardiac development beyond this embryonic stage. Because human NKX2-5 mutations are related to septum secundum type atrial septal defects (ASD), we hypothesized that Nkx2-5 deficiency during the processes of septum secundum formation may cause cardiac anomalies; thus, we analysed mice with tamoxifen-inducible Nkx2-5 ablation beginning at E12.5 when the septum secundum starts to develop. Methods and results Using tamoxifen-inducible Nkx2-5 gene-targeted mice, this study demonstrates that Nkx2-5 ablation beginning at E12.5 results in embryonic death by E17.5. Analysis of mutant embryos at E16.5 shows arrhythmias, contraction defects, and cardiac malformations, including ASD. Quantitative measurements using serial section histology and three-dimensional reconstruction demonstrate growth retardation of the septum secundum and enlarged foramen ovale in Nkx2-5-ablated embryos. Functional cardiac defects may be attributed to abnormal expression of transcripts critical for conduction and contraction, including cardiac voltage-gated Na+ channel pore-forming α-subunit (Nav1.5-α), gap junction protein connexin40, cardiac myosin light chain kinase, and sarcolipin within 4 days after tamoxifen injection. Conclusion Nkx2-5 is necessary for survival after the mid-embryonic stage for cardiac function and formation by regulating the expression of its downstream target genes. [ABSTRACT FROM AUTHOR]

Ventricular Tachycardia and Restitution. Introduction:Action potential duration restitution (APDR) plays a role in initiation and maintenance of ventricular tachycardia (VT)/ventricular fibrillation (VF). We hypothesized that the steeply sloped APDR and its spatial heterogeneity contribute to VT/VF inducibility in patients with ventricular arrhythmia.Method and Results:After programmed ventricular stimulation (PVS) for evaluation of clinically documented VT, patients (n= 20, 15 male, age 52.5± 9.5 years) were divided into two groups: inducible sustained VT/VF (IVT, n= 10) and noninducible VT/VF (NVT, n= 10). Data were compared with the corresponding results obtained from normal controls (C, n= 10). Right ventricular (RV) monophasic action potential duration at 90% repolarization (APD90) and ventricular effective refractory period (VERP) in the right ventricular apex (RVA) and right ventricular outflow tract (RVOT) were determined. APDR was acquired by scanning diastole with premature ventricular beats during a pacing cycle length of 600 msec (S1-S2) in all patients and by rapid pacing at the cycle lengths that induced APD alternans in three patients. Maximal slopes (Smax) of the APDR curves andΔAPD90 (APD90 at S2 400 ms– APD90 at the shortest S2) were measured. VERP and APD90 at each RV site did not differ among the three groups. Smax obtained by S1-S2 (1.6± 0.6) did not differ from Smax obtained by rapid pacing (1.2± 0.7), with a significant correlation noted between these values (r= 0.92, P<0.01). The IVT group had a higher spatial dispersion of Smax (Smax at RVOT– Smax at RVA) compared to the C group (P<0.05), with no difference between the NVT group and the IVT or C groups. The IVT group had a higher spatial dispersion ofΔAPD90 compared to the NVT and C groups (P<0.01, respectively). Smax at the RVOT (2.7± 1.9) was steeper than that at the RVA (1.9± 1.2, P<0.05). Inducibility of sustained VT/VF was greater at the RVOT (83.3%) than at the RVA (50.0%, P<0.05).Conclusion:In patients with ventricular arrhythmia, VT/VF is highly inducible under conditions of greater spatial dispersion of ventricular refractoriness and APDR.(J Cardiovasc Electrophysiol, Vol. 15, pp. 1-7, December 2004) [ABSTRACT FROM AUTHOR]

Background: Stem cell based replacement therapy is envisioned as a method to repair failing hearts suffering from cardiomyocyte loss. To prevent potentially lethal arrhythmias, the donor cellular electrophysiological make-up should match with the acceptor tissue. To engineer the desired electrophysiological phenotype, the underlying molecular regulation of ion channels and gap-junction proteins should be clarified first. Methods: We established the expression of seven main cardiac ion channel α-subunits and four β-subunits using semiquantitive RT-PCR and two major cardiac gap-junction proteins by immunohistochemistry during the differentiation process of murine ES cells into cardiomyocytes. Results: Ion channel mRNA expression profiles display sequential upregulation. Connexin-40 and -43 expression is low in early cardiomyocytes, increased expression rates were found in subsequent differentiation phases. Conclusion: Cardiac differentiation of mouse embryonic stem cells is characterized by a sequential upregulation of the main cardiac ion channels and connexins. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the spatial and temporal expression of various pro-inflammatory cytokines in the peri-sinoatrial nodal area after atrial infarction. Rats were subjected to permanent atrial infarction, in particular, sinoatrial node (SAN) infarction and sacrificed at various time points up to 7 days. Real-time polymerase chain reaction analysis demonstrated that mRNA levels of tumor necrosis factor alpha (TNF-α), interleukin-1β, interleukin-6, and transforming growth factor beta 1 (TGF-β1) were upregulated in the peri-sinoatrial nodal area after atrial infarction. Immunostaining for TNF-α and TGF-β1 proteins revealed that both cytokines were expressed persistently up to 7 days after atrial infarction around the peri-sinoatrial nodal area. Furthermore, the infiltrating inflammatory cells immunoreactive for both cytokines were predominant within the infarct SAN. In situ hybridization analysis showed that TNF-α gene expression was enhanced in the inflammatory cells and myocardium within the peri-sinoatrial nodal area in response to the infarction. These results provide evidence for the local expression of cytokines in the post-ischemic peri-sinoatrial nodal area, suggesting that the upregulation of the cytokines might be associated with the atrial arrhythmia observed after acute myocardial infarction. [ABSTRACT FROM AUTHOR]

Studies the mechanism of atrioventricular (AV) node reentry. Perspectives pertaining to future refinement of the technical aspects involved in the ablative treatment of AV node reentrant tachycardia; Anatomical characteristics of the AV junction and AV node; Cellular electrophysiology characteristics of the AV node; Tissue components of the AV node reentrant circuit.

Introduction: Gap junctions connect cardiac myocytes allowing propagation of action potentials. They contain intercellular channels formed by multiple different connexin proteins. The arrangement and type of gap junctions and the types, function, and interaction of connexin proteins determine intercellular resistance and can thereby influence conduction velocity and the potential for reentrant arrhythmias. Our goal was to develop genetically maniputable models to test the effects of altering expression of a major cardiac connexin (connexin43) on intercellular coupling and expression of other connexin proteins. Methods and Results: BHK cells that are poorly coupled and BWEM cells that are well coupled were stably transfected with plasmids containing connexin43 cDNA in antisense and sense orientations. RNA blots confirmed expression of the transfected transcripts. Immunoblots showed that connexin43 protein was reduced in the BHK antisense transfectants and increased in the BHK sense transfectants compared to the parental cells. It was not detectably changed in the BWEM antisense transfectant line compared to the BWEM parental cells. Transfection of connexin43 cDNA did not affect production of connexin45 mRNA and protein nor did transfection induce expression of other previously unexpressed connexin mRNAs. Cell coupling was assessed by intercellular diffusion of microinjected Lucifer yellow in confluent cell populations. Lucifer yellow passed to a mean of 3 ± 3 neighboring parental BHK cells, to 8 ± 8 neighbors in the sense connexin43 transfected BHK cells, and to only 2 ± 2 neighbors in the antisense connexin43 transfected BHK cells (P < 0.05). In contrast, dye transfer did not differ significantly between the parental BWEM cells (mean transfer = 19 ± 14 cells) and the BWEM connexin43 antisense transfectants (mean transfer = 15 ± 12 cells) (P = 0.20). Conclusions: These data demonstrate that stable transfection with connexin43 cDNA constructs can result in detectable changes in connexin43 expression and cellular coupling without inducing compensatory changes in the cells connexin phenotype and, therefore, may provide a basis for future attempts at specifically modulating connexin expression and intercellular resistance in cardiac tissues. [ABSTRACT FROM AUTHOR]