224The progression towards heart failure exposes the heart to a mechano-arrhythmic response related to the cellular membrane compliance

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Abstract

After myocardial infarction (MI), structural remodelling and mechanical stress may be arrhythmogenic. We tested the hypothesis that, in hypertrophic cardiomyocytes (CMs) from infarcted hearts, local nanometre mechanical perturbation of the sarcolemma initiates and potentiates abnormal Ca2+ activity. We use a unique combination of scanning ion conductance microscopy (SICM) modified for applying local nanometre hydrojets, in conjunction with optical recording of cytoplasmic Ca2+ levels. The SICM's nano-pipette scans the membrane of healthy adult rat CMs and CMs derived from adult rats 4, 8 and 16 weeks after coronary ligation (compensated post MI hypertrophy (MI-LVH)) superfused with HBSS at 36 C. SICM produces a high-resolution topographical image and via the same pipette, a 20kPa hydro-jet of HBSS is applied to a restricted 400nm2 area targeting selected locations for a 2 second pulse. During the pulse, and the subsequent 6 seconds, we monitor Ca2+ levels. Hydro-jets applied to crests in healthy rat CMs did not activate Ca2+; but over the Z-grooves produced short Ca2+ activations (197 ± 29 ms in 16% of CMs, n=20) confined to the jet site. Membrane compliance (MemC) during jets was 0.032 ± 0.01 μm/kPa on crest and 0.012 ± 0.005 μm/kPa over Z-grooves. Jets applied to unstriated part of MI-LVH-CMs activated longer intracellular Ca2+, initiated by a ripple effect from the jet site (25% of cells MI-LVH 4 weeks n=16; 58% of cells MI-LVH 8 weeks n=20; 67% of cells MI-LVH 16 weeks n=14). MemC in MI-LVH CMs were reduced (0.009 ± 0.001 on crest and 0.007 ± 0.001 μm/kPa on groove MI-4 weeks, 0.008 ± 0.00 on crest and 0.0015 ± 0.00 μm/kPa on groove MI-8-weeks, 0.010 ± 0.006 on crest and 0.010 ± 0.007 μm/kPa on groove MI-16-weeks). We observed two different patterns of activation, depending on the severity of MI: in the majority of cases Ca2+ activated from the pressure site and propagated throughout the cell by a ripple effect (velocity of Ca2+ propagation 131 ± 57 μm/sec); however a in MI-LVH (33% of cell 8 weeks, 28% of cell 16 weeks) Ca2+ further activated from two independent locations subsequent the initiation starting at the pressure site. This triplet collided in ∼1ms resulted in fast fused propagation throughout the cells (3939 ± 2795 μm/sec). This effect was abolished by targeting mechano-sensitive channels by 100 μmol/L streptomycin. In conclusion, MI-LVH-CMs are prone to abnormal Ca2+ activations induced by local mechanical membrane perturbation, whereas normal CMs are not; these findings support the concept of mechano-arrhythmia and suggest that monitoring cardiac stiffness, elasticity may aid arrhythmia risk profiling.

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