Mechanics 2019 PDF

A szívizom mechanikai aktivitása Mechanical activity of the myocardium Introduction Transport Electrical activity (AP, currents) Epi Calcium signaling cAMP Receptors, signaling PKA Mechanical activity: muscle mecha...

A szívizom mechanikai aktivitása Mechanical activity of the myocardium Introduction Transport Electrical activity (AP, currents) Epi Calcium signaling cAMP Receptors, signaling PKA Mechanical activity: muscle mechanics contraction theories energy requirements myofilaments experiments contractility as a pump Excitation-contraction coupling  Basic mechanics Isometric Isotonic Work-load relationship New elastic body theory  Fenn effect Fenn (1923) Mommaerts and Carlson (1960) Evans and Matsuoka in cardiac muscle (1914,1915) Energetics E = Q + W  Isometric contraction E = QA + Wi + f(P,t) Muscle shortening E = QA + Wi + f(P,t) + QS (+ We) QS = ax We = Px  Towards the Hill equation Under isotonic shortening Extra energy = Px + ax work heat Rate of e. e. liberation = (P + a) dx/dt Rate of e. e. liberation = (P + a) v (P + a) v = b (Po - P) 2 states of active points  The Hill equation (1938) (P + a) v = b (Po - P) (P + a) (v + b) = (Po + a) b x y = constant constants Contractile proteins  Myosin (1864, 1939) MHC on Chr. 14. 200 kDa: A1 () A2 () V1 () V2 (, ) V3 () Different ATPase activity MLC on Chr. 3. 1 gene splice var. 27, 19 kDa : ALC1 VLC1, 2 Calcium binding  ~ 7 x 55 A Actin (1942) Chr. 1., 41.7 kDa  Cardiac actin 2 main functions: activates ATP-ase activity of MHC binds to myosin (possesses ATP-ase activity) Tropomyosin (1948) 2 x ~33.5 kDa 2, , 2 Heart rate x  content = constant  Troponin complex Troponin C (1965) 18.4 kDa Stabilize Ca2+, Mg2+ Ca2+ Stabilizes the binding to other troponins Troponin I Ser20 on cardiac type is the PKA P site 23.5 kDa Troponin T More than 30 alternative spliced variant 38 kDa The thin filament tropomyosin The thick filament 1.65 m total length Sarcomere The effect of calcium  Cross-bridge cycle rate-limiting step: 3 calcium dependent step: 2 dual role of ATP rigor mortis, stone heart  Experiments Isometric contractions latent period, latency relaxation + Stim.  How to eliminate series elasticity? Rest + Stim., +Stretch 1. 2. 3. Quick release experiments Length-tension relationship Ultrastructural mechanism  Experiments in cardiac muscle Isometric contractions Quick-stretch Stretch A < B Rest + S, +Stretch Stretch A = B = X A, B Stretch C, D Unloading  Length-tension relationship in cardiac muscle Isometric contractions marked differences, presence of double-overlap Potential explanations for asc. limb: 1. AP(D) changes 1. Calcium release changes 1. Calcium sensitivity How to regulate muscular performance?  Myocardial contractility Definition: “potential to do work” is load dependent Change in contractility Dependent on MHC ATP-ase activity Dependent on [Ca2+]i  Time-dependence of contractility with internal resistances Determinants of cardiac mechanical performance: I. Factors intrinsic to myocardium: 1. Po, 2. Vmax, 3. Time courses of act. and inact. 4. Initial sarcomere length II. External factors: LOAD  Regulation of contractility (players) A. Entry through Ca channels A1. Entered Ca directly activating contraction B1 B2 B1. Ca efflux via NCX A B2. Ca efflux via PMCA G C. Released Ca from SR C D. Ca uptake via SERCA mito A1 D E. Ca binding to TnC H F. Ca dissociation from TnC E F G. Ca diffusion within the SR H. Mitochondrial Ca movements  Contractility changes (examples) Ca2+ mito Bowditch staircase Post-extrasystolic potentiation  Contractility changes (examples) Na/K pump Cardiac glycosides Ca2+ Na+ Stophantus: Ouabain = Strophantin; cymarin Digitalis: Digoxin, digitoxin Ca2+ Scilla glikozid: Proscillaridin Peruvoside mito  Contractility changes (examples) B A Woodworth (negative) staircase mito Contractility changes ( adrenergic stimulation) Na+ Na/K pump P P P P mito ATP P  Contractility changes 1. pH 2. K+ 3. Isoforms of Troponin, MHC => Endocrinopathies / ratio change Hypertrophy (normal, exercise) ↑ (abnormal, overload) ↑ Aging: ↑ 4. cAMP 5. phosphorilation 6. ATP (lubricant)  The heart as a pump V = 4/3  (DA/2) (DL/2) (LM/2)  Law of Laplace T=pxR T T = (p x R) / 2h T p R p R h Disease states Work diagram Frank-Starling relationship, Starling curves Vicious cycle EDV  EDV  EDV  ESV  +VR Ejec. P  ESV  +VR Ejec. P  SV  SV   Importance of pericardium and… Isolated left heart preparation the atrium as a primer pump minute work minute work stroke work stroke work Stroke work = SV x p Stroke work = SV x p CO = SV x HR Minute work = SV x p x HR Minute work = SV x p x HR  Energetics Work = We + Wi We = PV w. + kinetic w. 90-95 % 5-10 % We = p x SV + ½ mv2 Wi = wall tension, rearrangement recovery heat Efficiency = We / Utilized energy  E = We + Wi Wi = wall tension, rearrangement recovery heat Sartorius Cardiac muscle Assessing cardiac performance Heart failure Interplay between VR and CO Equilibrium between the heart and the periphery  Microtubules in contractility Robison et al. Science. 2016; 352(6284): aaf0659. Robison P and Prosser BL J Physiol. 2017; 595(12): 3931-3937. TTL (tubulin tyrozin ligase): places tyrozin on alpha tubulin → → removes the connection between the mikrotubule and the sarcomer PTL (parthenolide): inhibits TCP, same consequence as with TTL Robison et al. Science. 2016; 352(6284): aaf0659. TTL: overexpression PTL: pharmacological approach shTTL: TTL silencing  Robison et al. Science. 2016; 352(6284): aaf0659. Sarcomer modell  Robison et al. Science. 2016; 352(6284): aaf0659. Same change in heart failure of several origins