Determinants of myocardial conduction velocity: implications for arrhythmogenesis

Abstract

Slowed myocardial conduction velocity (θ) is associated with an increased risk of re-entrant excitation, predisposing to cardiac arrhythmia. θ is determined by the ion channel and physical properties of cardiac myocytes and by their interconnections. Thus, θ is closely related to the maximum rate of action potential (AP) depolarization [(dV/dt)max], as determined by the fast Na(+) current (I Na); the axial resistance (r a) to local circuit current flow between cells; their membrane capacitances (c m); and to the geometrical relationship between successive myocytes within cardiac tissue. These determinants are altered by a wide range of pathophysiological conditions. Firstly, I Na is reduced by the impaired Na(+) channel function that arises clinically during heart failure, ischemia, tachycardia, and following treatment with class I antiarrhythmic drugs. Such reductions also arise as a consequence of mutations in SCN5A such as those occurring in Lenègre disease, Brugada syndrome (BrS), sick sinus syndrome, and atrial fibrillation (AF). Secondly, r a, may be increased due to gap junction decoupling following ischemia, ventricular hypertrophy, and heart failure, or as a result of mutations in CJA5 found in idiopathic AF and atrial standstill. Finally, either r a or c m could potentially be altered by fibrotic change through the resultant decoupling of myocyte-myocyte connections and coupling of myocytes with fibroblasts. Such changes are observed in myocardial infarction and cardiomyopathy or following mutations in MHC403 and SCN5A resulting in hypertrophic cardiomyopathy (HCM) or Lenègre disease, respectively. This review defines and quantifies the determinants of θ and summarizes experimental evidence that links changes in these determinants with reduced myocardial θ and arrhythmogenesis. It thereby identifies the diverse pathophysiological conditions in which abnormal θ may contribute to arrhythmia.

Keywords: arrhythmia; conduction velocity; fibrosis; gap junction; sodium channel.

Figure 1

The relationships between θ and re-entrant arrhythmia. A diagram illustrating a typical re-entry circuit, consisting of a pathway of slow conducting myocardium [A(i) path 1, light gray] passing through non-conducting myocardium (dark gray), bordered by a second pathway of normal myocardium [A(i) path 2, white]. (A) An electrical impulse (blue arrow) originating from the SAN, (i) propagates along path 2 (white) and path 1 (light gray) pathways. As the impulse conducts, the myocardium becomes refractory (yellow in path 2 or orange in path 1) (ii) The impulse that travels along path 2 reaches the end of the circuit resulting in a normal AP. The impulse that conducts along 1 cannot exit the circuit as it collides with the refractory tissue of path 2. (B) An abnormal impulse originating from an ectopic focus is triggered immediately following the sinus impulse (i). It cannot conduct down path 1 which remains refractory; it therefore conducts along path 2. (ii) When the impulse reaches the distal end of path 2 it splits, conducting retrogradely along path 1 and orthogradely along path 2. (C) The impulse conducting retrogradely along path 1 then activates the beginning of path 2 (i) without the need of any further stimuli, thereby creating a self-perpetuating re-entrant rhythm (ii). Such re-entry is more likely to occur following reductions in conduction velocity (θ) and/or the effective refractory period (ERP) that reduce the wavelength of excitation (λ), given by the product of the θ and ERP, to values smaller than the dimensions of the available circuits.

Figure 2

Quantification of the determination of θ in a computer model. The cable equation identifies r_a, c_m, and i_i as the determinants of θ, but does not clearly demonstrate the magnitudes of their influences. Computer modeling of a skeletal muscle fiber (Fraser et al., 2011) shows the influence of r_a (panel A), c_m (panel B), and i_Na(max) (panel C) on AP waveform (i), dV/dt (ii), and θ (iii). In panels i and ii, three representative APs are shown, each stimulated at 1s and recorded 2.5 mm further along the cable, such that increased times to the AP peaks denote slowed conduction. In panel iii, the velocities of these APs are labeled 1, 2, and 3. It will be noted that r_a influences θ but not AP waveform, whereas c_m and i_Na(max) each influence AP waveform and θ. Note that in panel C(iii), θ is plotted against both i_Na(max) (upper scale, squares) and P_Na(max) (lower scale, triangles). The simple quantitative relationships between these parameters that emerge from this analysis are given in the text.

Figure 3

Physiological influences on the determinants of θ. Three diagrams illustrating the mechanisms by which (a) membrane excitability, (b) cell coupling and (c) fibrotic change influence current. Transmembrane current (dark blue arrow) enters through open Na_v1.5 (green rectangle) and intercellular current (light blue arrow) passes through open Cxs (green ladder). (A) Abnormal membrane excitability results from reductions in either (i) Na_v1.5 function through increases in extracellular [K⁺] and pH and by increases in [Ca²⁺]_i and phosphorylation, or (ii) Na_v1.5 expression by mutations in SCN5A (Brugada syndrome) and through Ca²⁺ mediated down regulation of the channel. (B) Abnormal cell coupling results from reductions in either (i) Cx function through increases in [Ca²⁺]_i and dephosphorylation or (ii) Cx expression by mutations in either CJA1 or CJA5 (idiopathic AF). (C) Abnormal fibrosis produces either (i) increased myocyte-myocyte decoupling, resulting in increased r_a,. or (ii) Cx-mediated myocyte-fibroblast coupling, resulting in increased c_m.