Mechano-Electric Feedback PDF

Mechano-Electric Feedback (Mechano-electric Coupling) 1 Tamas Banyasz  The concept Electrical dynamics a a’ Ca2+ dynamics b b’ Contractile...

Mechano-Electric Feedback (Mechano-electric Coupling) 1 Tamas Banyasz  The concept Electrical dynamics a a’ Ca2+ dynamics b b’ Contractile dynamics 2  Early observations: commotio cordis & sudden cardiac death 3 Schematic representation of the location of impact sites, sustained during various sports activities, that led to sudden cardiac death by Commotio cordis 4 Kohl, P. et al. Cardiovasc Res 2001 50:280-289; doi:10.1016/S0008-6363(01)00194-8 Rebecca Burger (1984-2017)  ECG (lead I, top) and left ventricular pressure recording (LVP, bottom), obtained from an anaesthetised pig, subjected to a pre-cordial impact that coincided with the upstroke of the T- wave 6 Kohl, P. et al. Cardiovasc Res 2001 50:280-289; doi:10.1016/S0008-6363(01)00194-8 Schematic representation of the effects of pre-cordial mechanical stimulation on cardiac rhythm Labels above the ECG pattern illustrate the number and timing of interventions; markers below denote the type and number of rhythm disturbances caused. Key: CHB, complete heart block; ST , ST segment elevation; LBBB, left branch bundle block; VF, ventricular fibrillation; NSVT, non-sustained ventricular tachycardia. 7 Kohl, P. et al. Cardiovasc Res 2001 50:280-289; doi:10.1016/S0008-6363(01)00194-8  Clinical observations: Blood Pressure & Cardiac Action Potential 8 Relationship between pressure in radial artery and AP length in human patient 9 Taggart et al, Cardiac mechano-electric feedback in…1999 Progress in Biophysics & Molecular Biology Acute obstruction of the right ventricular outfow tract by balloon catheter induces defections resembling early afterdepolarisations 10 Taggart et al, Cardiac mechano-electric feedback in…1999 Progress in Biophysics & Molecular Biology  Incremental left ventricular volume pulses in an isolated rabbit heart preparation with heart block. 11 Taggart et al, Cardiac mechano-electric feedback in…1999 Progress in Biophysics & Molecular Biology Comparison of the effects of stretch and altered calcium handling 12 Taggart et al, Cardiac mechano-electric feedback in…1999 Progress in Biophysics & Molecular Biology  Schematic representation of the potential arrhythmogenic effects of mechanical activation of cation-selective channels during early repolarisation (upstroke of the T-wave, see top ECG trace) 13 Kohl, P. et al. Cardiovasc Res 2001 50:280-289; doi:10.1016/S0008-6363(01)00194-8 Effect of increased venous return on heart rate and blood pressure 14 P. Kohl et al. / Progress in Biophysics & Molecular Biology 71 (1999) 91±138 Summary of electrophysiological effects of diastolic and systolic stretch on normal cardiac electrophysiology. 15 P. Kohl et al. / Progress in Biophysics & Molecular Biology 71 (1999) 91±138 The physics behind mechanical stretch 16 Strain versus stress 17 Viscoelasticity 18 Stress Types in Mechanics 19 Mechanical stress in a cardiac myocyte Strain ≈ Δl/l0 Stress ≈ F/A 20  Mechanical Stress is inhomogeneous Surface Traction 21 What is the mechanism? Early observations 22 Gadolinium suppresses stretch induced arrhythmia 23 Taggart et al, Cardiac mechano-electric feedback in…1999 Progress in Biophysics & Molecular Biology Extracellular potassium reverses stretch induced depolarization 24 Max Lab / Progress in Biophysics & Molecular Biology 71 (1999) 3-5 Patch clamp recording of an isolated cardiac myocyte before and during application of axial stretch (10% of resting length) 25 Kohl, P. et al. Cardiovasc Res 2001 50:280-289; doi:10.1016/S0008-6363(01)00194-8 Mechanically Induced Potential (MIP) in cardiac fibroblasts 0.2 mM Cytochalasin D 0.2 mM Colchicine 26 Kamkin et al. / Progress in Biophysics & Molecular Biology (2003)  Events of the surface: Stretch-activated/modulated currents in ventricular myocytes amplitude and arrhythmogenic effects increase with hypertrophy 27 Two mechanisms accounting for the mechanotransduction in living cells 28  Recording of spontaneous pacemaker activity in an isolated rabbit sinoatrial node (SAN) cell in the absence (light curve) and presence (dark curve) of stretch (7% of resting length). Stretch was applied using 2 carbon fibers attached to opposite ends of the cell. Calibration bar = 10 µm. 29 J Appl Physiol 89: 2099-2104, 2000; Stretch-induced changes of key electrophysiological parameters of spontaneously beating rabbit SAN pacemaker cells Control (absolute values) Stretch, % of control Recovery, % of control Cycle length 290.2 ± 22.3 ms 95.0 ± 0.7* 99.8 ± 0.9 Maximum systolic potential 45.2 ± 3.6 mV 97.8 ± 0.4* 100.6 ± 0.4 Maximum diastolic potential 54.3 ± 3.2 mV 97.6 ± 0.4* 99.6 ± 0.3 Spontaneous depolarization rate 0.115 ± 0.015 V/s 111.2 ± 3.3 106.7 ± 3.4 Maximum upstroke velocity 22.98 ± 7.56 V/s 89.0 ± 1.8* 94.6 ± 2.7 Early repolarization velocity 0.50 ± 0.06 V/s 105.6 ± 1.9* 102.3 ± 1.4 Late repolarization velocity 1.59 ± 0.17 V/s 96.3 ± 0.9* 99.7 ± 1.0 Spontaneous depolarization time 137.0 ± 4.6 ms 92.7 ± 1.4* 102.7 ± 1.8 Threshold to peak time 14.8 ± 0.9 ms 109.3 ± 2.9* 100.6 ± 2.3 Repolarization time 141.0 ± 3.4 ms 97.1 ± 0.7* 99.2 ± 0.6 Values are means ± SE; n = 8 cells. Early repolarization velocity, rate of initial fast repolarization; late repolarization velocity, rate of secondary slow phase of repolarization; spontaneous depolarization time, time from maximum diastolic potential (MDP) to threshold; threshold to peak time, time from threshold to maximum systolic potential (MSP); repolarization time, time from MSP to MDP. SAN, sinoatrial node. * P < 0.05 (ANOVA). 30 J Appl Physiol 89: 2099-2104, 2000; Mechanical stress modulates the AP profile Mechano-electric feedback in fish heart 31 Action potential recordings from single cells and from the surface of myocardium 32 Effect of filling pressure on hemodynamics 33  Effect of praeload and afterload on Ventricular Electric Remodeling (VER) 34 Stretch induces membrane depolarization, prolongation of the action potential and extra-systoles Failing human heart Healthy guinea pig heart Healthy guinea pig heart with 8 µm stretch Kamkin, A et al. Cardiovasc Res 2000 48:409-420; doi:10.1016/S0008-6363(00)00208-X 35 Copyright restrictions may apply. Electrophysiologic analysis of the currents generated by MSC 36  Mechanical stimulation: local stretch of a ventricular myocyte from the guinea pig (VMGP) Kamkin, A et al. Cardiovasc Res 2000 48:409-420; doi:10.1016/S0008-6363(00)00208-X 37 Copyright restrictions may apply. The mechanosensitive currents of heart 38 Whole cell current response to stretch. 39 J Appl Physiol 89: 2099-2104, 2000;  Stretch-sensitivity of ISAC SHR 15 mo GP 3 mo Human End Stage WKY 15 mo WKY 3 mo On-line pen records, IK1 suppressed. Ventricular myocytes from (A) humans with end-stage cardiac failure, (B) healthy guinea-pigs (3 months) or (C) rats. WKY, Wistar Kyoto rats; SHR, spontaneously hypertensive rats, age of 2–3 (2 mo) or of 15 months (15 mo). Extent of stretch is labeled by numbers, duration is marked by horizontal bar on top of each figure. (D) Stretch sensitivity. Amplitude of ISAC was measured at –45 mV and plotted versus extent of stretch. Filled symbols: Ventricular myocytes from rats, WKY 3 months (circles), WKY 15 months (squares) and SHR 15 months (triangles). Empty symbols: myocytes from humans with end-stage failure (squares) and from guinea pigs 3 months (circles). 40 Known channels are mechanosensitive too 41 Nav channel mechanosensitivity 42 Morris et al, Biophysical Journal 2007, 93(3):822-833 Models for MSC 43 Two mechanisms accounting for the mechanotransduction in living cells 44  Chemical–mechanical synergism via PLC and PLA2 pathways EET: epoxyeicosatrienoic acid HETE: 20-hydroxyeicosatrienoic acid 45 MSCC: mechanosensitive cation channel  Events of the deep cytoplasm 1. Mechanosensitivity of calcium dynamics 46  Myocyte contraction - Knockdown factor in gel Aspect ratio=0.16, Length=109.4µm, Cell-in- Load-free Gel SL (µm) Gel dissolved Cell-in-Gel contraction show smaller fractional shortening (FS) and slower relaxation than load-free cell. 47  Knock-down Factor in myocyte contraction Alternans Samples Cell-in- Gel dissolved Load-free Gel Sarcomere Length Cell-1 (µm) Time (0.5 Hz pacing) 48 Enhanced length-dependent Ca2+ activation in fish cardiomyocytes permits a large operating range of sarcomere lengths 49 Active tension development and calcium sensitivity of rat and trout 50 JMCC 48 (2010) 917–924 Passive tension determines calcium sensitivity in cardiac myocytes 51 JMCC 48 (2010) 917–924 Differences in passive tension are resulted by different titin isoform expression and phosphorylation Intact Skinned Titin phosphorylation 0.8 (arbitrary units) 0.6 * * 0.4 0.2 0.0 Rat Fish 52 Supplemental Fig. S2. 53 Spontaneous Calcium Release is Translated to Afterdepolarization 54 Sarcomere length determines electric stability of cardiac myocytes CRU Ca2+ release current (pA) unstable c b a stable z-line distance (um) 55 Events of the deep cytoplasm 2. Mechanochemical sensing 56 57  Mechano-Chemo Transduction Preload increase – by stretching myocyte 58  A B C F/Fo wt wt wt (-eNOS) (-nNOS) L-Nio L-NPA D E F nNOS-/- eNOS-/- eNOS-/- (-nNOS) L-NPA G wt H wt I nNOS-/- J eNOS-/- NS -1 NS *** Spark # (100m* s) *** *** *** *** CaT peak (F/F0) 4 *** ** 15 *** *** 15 30 3 10 10 20 2 NS 1 5 5 NS 10 NS 0 0 0 0 NA l o L- E A in e o e l A o ee L- l A L- E o in e NA l A L- e Ge e L- e M e Ni NP fre Ni M Ni e Ni NP NP -G NP -G -G -fr -fr -fr L- - L- L- L- in - in L- ad d ad ad oa Lo Lo Lo L 59 A Cell OH OH HO OH OH OH PVA 4-boronate-PEG Cell-in-Gel crosslinker B Electric field excitation Perfusion Imaging 60 Cell contracting under mechanical load 3-D Elastic Matrix Collaboration with Prof. Kit Lam’s lab and Prof. Tingrui Pan’s lab 61  Long Term Effects The role of mechanical stress in Ventricular Electric Remodeling (VER) 62  Anatomic segmentation of the LV Jeyaraj, D. et al. Circulation 2007;115:3145-3155 63 Copyright ©2007 American Heart Association Action potential changes in Ventricular Electric Remodelling (VER) APD Remodeling in Epicardial, Midmyocardial, and Endocardial Cells with anterior segment pacing Anterior segment Lateral segment Posterior segment Control VER ∆APD Control VER ∆APD Control VER ∆APD * Epicardial, ms 213±12 237±12 24 211±10 200±11 –11 219±12 272±37 53 * Midmyocardial, ms 241±11 266±13 25 243±6 219±9 –24 240±8 302±34 62 * Endocardial, ms 235±11 256±11 21 239±8 210±11 –29 232±9 289±24 57 *P