Electrophysiological Effects of Remodeling Cardiac Gap Junctions and Cell Size

Abstract

The increased incidence of arrhythmias in structural heart disease is accompanied by remodeling of the cellular distribution of gap junctions to a diffuse pattern like that of neonatal cardiomyocytes. Accordingly, it has become important to know how remodeling of gap junctions due to normal growth hypertrophy alters anisotropic propagation at a cellular level (V(max)) in relation to conduction velocities measured at a macroscopic level. To this end, morphological studies of gap junctions (connexin43) and in vitro electrical measurements were performed in neonatal and adult canine ventricular muscle. When cells enlarged, gap junctions shifted from the sides to the ends of ventricular myocytes. Electrically, normal growth produced different patterns of change at a macroscopic and microscopic level. Although the longitudinal and transverse conduction velocities were greater in adult than neonatal muscle, the anisotropic velocity ratios were the same. In the neonate, mean V(max) was not different during longitudinal (LP) and transverse (TP) propagation. However, growth hypertrophy produced a selective increase in mean TP V(max) (P<0.001), with no significant change in mean LP V(max). Two-dimensional neonatal and adult cellular computational models show that the observed increases in cell size and changes in the distribution of gap junctions are sufficient to account for the experimental results. Unexpectedly, the results show that cellular scaling (cell size) is as important (or more so) as changes in gap junction distribution in determining TP properties. As the cells enlarged, both mean TP V(max) and lateral cell-to-cell delay increased. V(max) increased because increases in cell-to-cell delay reduced the electric current flowing downstream up to the time of V(max), thus enhancing V(max). The results suggest that in pathological substrates that are arrhythmogenic, maintaining cell size during remodeling of gap junctions is important in sustaining a maximum rate of depolarization.

Novel anisotropic engineered cardiac tissues: Studies of electrical propagation

“…Average velocity anisotropy ratios of 2 obtained after 2 weeks of culture (Fig. 2C) are in agreement with those previously measured in neonatal ventricles [18,19], but lower than those measured in adult ventricles (due to the differences in shape and gap junction distribution of adult vs. neonatal cardiomyocytes [19]). …”

Connexin30.2 containing gap junction channels decelerate impulse propagation through the atrioventricular node

“…The myocytes of the SA node and AV node differ with respect to their morphology and connexin expression pattern from the fast conducting working myocytes of atria and ventricles and cardiomyocytes of the His-Purkinje system (17). Cell and tissue geometry and action potential parameters (e.g., dV͞dt) have been described to influence the conduction velocity during cardiac impulse propagation (18)(19)(20)(21). Furthermore, the extent of intercellular coupling and the intrinsic electrophysiological properties of the gap junction channels expressed in the different compartments of the heart are thought to contribute to the corresponding distinctive conduction velocities (17,19,22).…”

Defining the major health modifiers causing atrial fibrillation: a roadmap to underpin personalized prevention and treatment

“…Both AF itself and various clinical conditions associated with AF, such as inflammation, hypertension, cardiac hypertrophy, or mitral valve disease, can cause increased atrial fibrosis resulting in different fibrotic patterns 21,23 . In addition, the ageing heart is constantly losing cardiomyocytes (estimated at 0.5-1.0% cardiomyocyte-loss per year [52][53][54] ), and fibrous tissue often forms in lieu of cardiomyocytes in older individuals. Impaired electrical coupling between myocytes within the epicardial layer, as well as between the epicardial layer and the endocardial bundle network, fosters three-dimensional, temporospatial conduction events (breakthroughs) 55 , thereby maintaining AF.…”