G1 hb 2011 2012 23 excitation-contraction coupling (steendijk)
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G1HB - Hart & Bloedsomloop - April 2012 Cardiac mechanics Paul Steendijk, PhD Associate Professor Cardiovascular Physiology Department of Cardiology, LUMC [email protected]
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Transcript of G1 hb 2011 2012 23 excitation-contraction coupling (steendijk)
G1HB - Hart & Bloedsomloop - April 2012
Cardiac mechanics
Paul Steendijk, PhD
Associate Professor Cardiovascular PhysiologyDepartment of Cardiology, LUMC
Determinants of cardiac performance
• Myocardial contractility (inotropy & lusitropy)- contraction, relaxation
• Loading conditions- preload, afterload, geometry
• Chronotropy- heart rate
• Temporal and spatial (non)-uniformity- dyssynchrony
Stiffness (Elastance) = dP/dVCompliance = dV/dP
Intrinsic propertiesby load-independent characterization
early compartmentlate compartmentdt = 0.010 s
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t=0.22
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Time-varying elastance (stiffness)
Senzaki, Circulation 1996
Reduced cardiac output (stroke volume)
increased afterloadreduced preload
reduced contractility reduced
compliance
Effects of load changes(preload, afterload)
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Systolic vs. Diastolic Heart Failure
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Pre
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Systolic Heart Failure Diastolic Heart Failure
Volume
Systolic and diastolic PV relationsDobutamine vs. Baseline
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Steendijk et al. J Am Coll Cardiol 1998; 32: 816-26
2.2: Contraction mechanisms
2.3:Excitation-contraction coupling
2.4: Pump function
G1HB - Hart & Bloedsomloop - April 2012
Cardiac mechanics
Cross-bridge cycling & calcium
Calcium & cross-bridge cycling
Calcium concentrationsExtracellular Ca concentration: [Ca]o ~ 1.2 mM (1200 μM) Intracellular Ca concentration: [Ca]i ~ 100 nM (0.1 μM)- 104-fold concentration gradient
During action potential:- Ca enters via L-type Ca channels- Free [Ca]i increases ~10-fold
[Ca]o , [Ca]i and Force
- [Ca]i depends on [Ca]o
- Developed force is dependent on free [Ca]i
Calcium-induced calcium release from SR- Ca influx is not sufficient to raise [Ca]i and initiate contraction- Sarcoplasmic reticulum stores large amounts of Ca- Ca entry (L-type Ca channels) triggers Ca release from SR via Ryanodine receptors
Calcium re-uptake into the SR- Ca is sequestered into SR by SERCA pump (SR Ca-ATPase)- Phospholamban regulates SERCA; phosphorylation removes its inhibitory effect- Calsequestrin is a SR Ca-binding protein
Calcium removal initiates relaxation
Species differences: Humans ≈ Rabbit
- Ca must be removed from the cytosol to lower [Ca]i and allow relaxation- Routes: SERCA (SR-ATPase), Na/Ca exchange (NCX), SL-ATPase
Cave:Na (“natrium”) = SodiumK (“kalium”) = Potassium
Calcium handling
Beta-receptor stimulation & ECC- Sympathetic activation >> release norepinephrine >> stimulate beta- receptors on SL >> stimulates cAMP production >> protein kinase A- Phosphorylation of L-type Ca-channels: positive inotropic effect (improves contraction)- Phosphorylation of phospholamban (PLB) and troponin-I (TnI): positive lusitropic effect (improves relaxation)
- Myofilaments (Actine-Myosine)- Myofibrils- Mitochondria (ATP)
-Sarcolemma, T-tubule- Sarcoplasmic reticulum- Cisterna
Anatomy & E-C coupling
Sarcomere length and intracellular calcium control force
Isometric force is increased by:
Increased intracellular calcium- binding to Tn-C >> actine-myosin interaction
Increased sarcomere length(“Starling’s Law of the Heart”)- Optimal actine-myosine overlap- Reduced lattice spacing- Altered myosin head orientation
Interaction of two mechanisms- Increased calcium sensitivity at increased sarcomere length
Mechanical dyssynchrony (Heart failure and LBBB)Cardiac Resynchronization Therapy (CRT)
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LV Volume (ml)
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Steendijk et al. Eur Heart J Suppl 2004; 6: D35-42
Cardiac Resynchronization Therapy (CRT)Acute effects
Nelson et al., Circulation 2000
Myocardial Oxygen Consumption (MVO2)LV Pacing vs. Dobutamine
Steendijk et al. Circulation 2006; 113: 1295-1304
Cessation of biventricular pacingafter 6 months of CRT
Asynchronous mechanical activation
McVeigh, Magn Res Med 1998
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