Background-Purkinje cells (PCs) comprise the most distal component of the cardiac conduction system, and their unique electrophysiological properties and the anatomic complexity of the Purkinje fiber network may account for the prominent role these cells play in the genesis of various arrhythmic syndromes. Methods and Results-Differential transcriptional profiling of murine Purkinje fibers and working ventricular myocytes was performed to identify novel genes expressed in PCs. The most highly enriched transcript in Purkinje fibers encoded Contactin-2 (Cntn2), a cell adhesion molecule critical for neuronal patterning and ion channel clustering. Endogenous expression of Cntn2 in the murine ventricle was restricted to a subendocardial network of myocytes that also express ␤-galactosidase in CCS-lacZ transgenic mice and the connexin40 gap junction protein. Key Words: cell adhesion molecules Ⅲ electrophysiology Ⅲ genetics Ⅲ Purkinje fiber P urkinje fibers (PFs) are the most distal component of the cardiac conduction system (CCS), first described by Purkinje in 1839 as gray, flat, gelatin-like ramifications, running under the endocardium. 1 Some 70 years later, Tawara 2 more fully characterized the Purkinje system, identifying the left (anterior, septal, and posterior) and right fascicular strands, which served to connect the distal PFs to the bundle branches proper. Tawara was also the first to correctly suggest the functional role of the Purkinje system in rapidly transmitting the electric wave of excitation to the ventricular muscle. Clinical Perspective on p 194PFs appear to play a prominent role in the genesis of ventricular arrhythmias, (reviewed in Reference 3). 3 PF and anterior or posterior left fascicular triggers have been implicated in the initiation of monomorphic ventricular tachycardia in post-myocardial infarction patients, as demonstrated by cure after focal ablation of Purkinje fiber or fascicular potentials. 4 -6 PF-based triggers have also been described in patients with ventricular tachycardia associated with dilated forms of cardiomyopathy, 7 as well as idiopathic ventricular fibrillation (VF), in which ablation of premature beats arising from the PF network resulted in significant reductions in the recurrence of VF. 8 PF-dependent triggering of arrhythmias has also been proposed in inherited syndromes including catecholaminergic polymorphic VT, 9 Brugada syndrome, and long-QT syndrome. 10 Despite growing evidence implicating PFs in ventricular arrhythmogenesis, our understanding of the cellular mechanisms underlying PF-dependent diseases is hampered by the lack of knowledge of the developmental biology of individual Purkinje cells (PCs), their patterning into a network of highly coupled cells, and their adaptive and maladaptive responses to pathological stimuli. To some extent, this gap in knowledge reflects the anatomic complexity of the PF network, which includes branching cells that couple not only with neighboring PCs but also with working myocytes at Purkinje- In recent years, a number of "...

Abstract-The mechanisms that govern the capacity of the bone marrow stem cells to generate cardiac myocytes are stillunknown. Herein we demonstrate that the cardiomyogenic potential of bone marrow-derived Oct3/4 ϩ

Abstract-The directed generation of cardiac myocytes from endogenous stem cells offers the potential for novel therapies for cardiovascular disease. To facilitate the development of such approaches, we sought to identify and exploit the pathways directing the generation of cardiac myocytes from adult rodent bone marrow cells (BMCs). In vitro cultures supporting the spontaneous generation of functional cardiac myocytes from murine BMCs demonstrated induced expression of platelet-derived growth factor (PDGF)-A and -B isoforms with ␣-and ␤-myosin heavy chains as well as connexin43. Supplementation of PDGF-AB speeded the kinetics of myocyte development in culture by 2-fold. In a rat heart, myocardial infarction pretreatment model PDGF-AB also promoted the derivation of cardiac myocytes from BMCs, resulting in a significantly greater number of islands of cardiac myocyte bundles within the myocardial infarction scar compared with other treatment groups. However, gap junctions were detected only between the cardiac myocytes receiving BMCs alone, but not BMCs injected with PDGF-AB. Echocardiography and exercise testing revealed that the functional improvement of hearts treated with the combination of BMCs and PDGF-AB was no greater than with injections of BMCs or PDGF-AB alone. These studies demonstrated that PDGF-AB enhances the generation of BMC-derived cardiac myocytes in rodent hearts, but suggest that alterations in cellular patterning may limit the functional benefit from the combined injection of PDGF-AB and BMCs. Strategies based on the synergistic interactions of PDGF-AB and endogenous stem cells will need to maintain cellular patterning in order to promote the restoration of cardiac function after acute coronary occlusion. The full text of this article is available online at

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