Abstract 18272: Aggravation of Myofibroblast Arrhythmogeneicity by Mechanical Stress
INTRODUCTION: Owing to their modest membrane polarization, cardiac myofibroblasts (MFBs) induce arrhythmogenic slow conduction and ectopic activity by causing partial depolarization of electrotonically coupled cardiomyocytes (CMCs) in-vitro. We hypothesize that mechanical stress may aggravate this condition by activation of stretch activated channels (SACs) in MFBs that accentuate MFB depolarization.
METHODS: The effects of acutely blocking SACs with streptomycin (SM) on single MFB and CMC membrane polarization (Vm) were assessed by patch clamp. Modulation of impulse conduction velocity (θ) by SM and by stretch was investigated in strands of neonatal rat ventricular CMCs or CMCs coated with MFBs using optical recording techniques. For stretch experiments, cell strands were cultured on silicon membranes.
RESULTS: Whereas SM (50 µmol/L) had no effect on Vm of CMCs (control: -75.1±2.62mV; SM: -75.3±2.59mV, n=8 each), it caused MFBs to hyperpolarize from -33.7 ± 11.2 mV to -37.7±11.4 mV (n=8) suggesting the presence of active SACs in MFBs under control conditions. In accordance with these findings, SM exerted no effects on θ in CMC cell strands (control: 335.4±23.3 cm/sec; SM: 328.0±19.8 cm/sec; n=36 each; n.s.) but increased θ from 173.8±68.2 cm/sec to 224.9±63.3 cm/sec (n=54 each; p<0.0001) in CMC-MFB strands. Direct proof for the modulation of θ by MFB-SACs was obtained by subjecting cell strands to acute length changes. In CMC-only strands, θ was positively correlated with strand length (8% relaxation: 323.6±19.1 cm/s; control: 332.6±22.8 cm/s; 10% stretch: 340.6±22.7 cm/s; n=14) which is likely explained by changes in cell geometry. In contrast, θ of hybrid CMC-MFB strands decreased with increasing strand length (8% relaxation: 270.8±36.9; control: 248.4±48.1 cm/s; 10% stretch: 237.6±40.1, n=5) suggesting that stretch caused activation of SACs in MFBs that ultimately led to partial depolarization of coupled CMCs.
CONCLUSION: The results demonstrate that acute stretch differentially affects θ depending on the cellular composition of cardiac tissue. Slowing of conduction is observed only in presence of MFBs which suggests that arrhythmogenic consequences of mechanical stress may be aggravated by MFBs in fibrotically remodelled myocardia.
- © 2012 by American Heart Association, Inc.