Abstract-Roughly half of the cells of the heart consist of nonmyocardial cells, with fibroblasts representing the predominant cell type. It is well established that individual cardiomyocytes and fibroblasts in culture establish gap junctional communication at the single cell level (short-range interaction). However, it is not known whether such coupling permits activation of cardiac tissue over extended distances (long-range interaction). Long-range interactions may be responsible for electrical synchronization of donor and recipient tissue after heart transplantation and may play a role in arrhythmogenesis. This question was investigated using a novel heterocellular culture model with strands of cardiomyocytes interrupted by cardiac fibroblasts over defined distances. With use of optical recording techniques, it could be shown that impulse propagation along fibroblast inserts was successful over distances up to 300 m and was characterized by length-dependent local propagation delays ranging from 11 to 68 ms (apparent local "conduction velocities" 4.6Ϯ1.8 mm/s, nϭ23). Involvement of mechanical stretch in this phenomenon was excluded by showing that inserts consisting of communication-deficient HeLa cells were incapable of supporting propagation. In contrast, HeLa cells expressing connexin43 permitted impulse conduction over distances as long as 600 m. Immunocytochemistry showed that fibroblasts and cardiomyocytes expressed connexin43 and connexin45, whereas connexin40 was absent. These results illustrate that fibroblasts of cardiac origin are capable of synchronizing electrical activity of multicellular cardiac tissue over extended distances through electrotonic interactions. This synchronization is accompanied by extremely large local conduction delays, which might contribute to the generation of arrhythmias in fibrotic hearts.

Abstract-Connexin43 (Cx43) is a major determinant of the electrical properties of the myocardium. Closure of gap junctions causes rapid slowing of propagation velocity (), but the precise effect of a reduction in Cx43 levels due to genetic manipulation has only partially been clarified. In this study, morphological and electrical properties of synthetic strands of cultured neonatal ventricular myocytes from Cx43 ϩ/ϩ (wild type, WT) and Cx ϩ/Ϫ (heterozygote, HZ) mice were compared. Quantitative immunofluorescence analysis of Cx43 demonstrated a 43% reduction of Cx43 expression in the HZ versus WT mice. Cell dimensions, connectivity, and alignment were independent of genotype. Measurement of electrical properties by microelectrodes and optical mapping showed no differences in action potential amplitude or minimum diastolic potential between WT and HZ. However, maximal upstroke velocity of the transmembrane action potential, dV/dt max , was increased and action potential duration was reduced in HZ versus WT. was similar in the two genotypes. Computer simulation of propagation and dV/dt max showed a relatively small dependence of on gap junction coupling, thus explaining the lack of observed differences in between WT and HZ. Importantly, the simulations suggested that the difference in dV/dt max is due to an upregulation of I Na in HZ versus WT. Thus, heterozygote-null mutation of Cx43 produces a complex electrical phenotype in synthetic strands that is characterized by both changes in ion channel function and cell-to-cell coupling. The lack of changes in in this tissue is explained by the dominating role of myoplasmic resistance and the compensatory increase of dV/dt max . Key Words: synthetic cardiac strands Ⅲ neonatal mouse cardiomyocytes Ⅲ connexin43 expression Ⅲ conduction velocity P ropagation of the cardiac impulse is a complex process that depends on the active electrical properties of myocyte membranes and the passive properties of the cellular network. The connexin proteins form the electrical connections between myocytes, and are therefore important determinants of the myocardial electrical properties. The most abundant connexin in ventricular myocardium of both mice and humans is connexin43 (Cx43). 1 The overall electrical conductance between cardiac cells can be changed in two basic ways: (1) by affecting gap junctional conductance (drugs 2,3 and myocardial ischemia 4 ), or (2) by changing connexin expression. 5 Computer simulations 6 and experimental studies 7 have shown that a large reduction in gap junctional conductance can result in reduction of to values of a few centimeters per second, an extreme degree of slowing that cannot be achieved with suppression of current flow through ion channels. 8 More moderate changes in gap junctional conductance due to a change of connexin expression have been shown to occur in ventricular hypertrophy and failure 9,10 and after application of mediators of hypertrophy 11 and mechanical stretch. 12 Mice with a targeted deletion of Cx43 have reduced expression o...

Adequate catheter-tissue contact facilitates efficient heat energy transfer to target tissue. Tissue contact is thus critical to achieving lesion transmurality and success of radiofrequency (RF) ablation procedures, a fact recognized more than 2 decades ago. The availability of real-time contact force (CF)-sensing catheters has reinvigorated the field of ablation biophysics and optimized lesion formation. The ability to measure and display CF came with the promise of dramatic improvement in safety and efficacy; however, CF quality was noted to have just as important an influence on lesion formation as absolute CF quantity. Multiple other factors have emerged as key elements influencing effective lesion formation, including catheter stability, lesion contiguity and continuity, lesion density, contact homogeneity across a line of ablation, spatiotemporal dynamics of contact governed by cardiac and respiratory motion, contact directionality, and anatomic wall thickness, in addition to traditional ablation indices of power and RF duration. There is greater appreciation of surrogate markers as a guide to lesion formation, such as impedance fall, loss of pace capture, and change in unipolar electrogram morphology. In contrast, other surrogates such as tactile feedback, catheter motion, and electrogram amplitude are notably poor predictors of actual contact and lesion formation. This review aims to contextualize the role of CF sensing in lesion formation with respect of the fundamental principles of biophysics of RF ablation and summarize the state-of-the-art evidence behind the role of CF in optimizing lesion formation.