Physiology of the Heart Conduction System Cardiac Cellular Electrophysiology Electromechanic Coupling Assoc. Prof. MUDr. Markéta Bébarová, PhD Department of Physiology Faculty of Medicine Masaryk University ORGANIZATION OF CARDIOVASCULAR SYSTEM Roles of the Cardiovascular System • primary role - distribution of dissolved gases and other nutrients • several secondary roles, for example: - fast chemical signalling to the cells (circulating hormones and neurotransmitters) - thermoregulation (delivery of heat from the core to the surface of the body) - immune reaction • roles of the heart: - primary role - pumping of blood - endocrinne organ (natriuretic peptides) ORGANIZATION OF CARDIOVASCULAR SYSTEM RIGHT ATRIUM RIGHT VENTRICLE LEFT ATRIUM LEFT VENTRICLE LUNGS PULMONARY ARTERY PERIPHERAL ORGANS AORTA RIGHT HEART LEFT HEART TWO PUMPS INTERCONNECTED IN SERIES SUPERIOR VENA CAVA AORTA PULMONARY ARTERY INFERIOR VENA CAVA RIGHT ATRIUM LEFT ATRIUM LEFT VENTRICLE RIGHT VENTRICLE RIGHT ATRIUM AORTA PULMONARY ARTERY SUPERIOR VENA CAVA INFERIOR VENA CAVA LEFT ATRIUM LEFT VENTRICLE RIGHT VENTRICLE ORGANIZATION OF CARDIOVASCULAR SYSTEM Two Main Phases of the Cardiac Cycle DIASTOLE PHASE OF FILLING of the ventricles SYSTOLE EJECTION PHASE ONE WAY VALVES DIASTOLE SYSTOLE ATRIOVENTRICULAR (mitral and tricuspid) open closed SEMILUNAR (aortal and pulmonary) closed open - mechanical connections - electrical connections - gap junctions ORGANIZATION OF CARDIOVASCULAR SYSTEM Two Major Types of Cardiac Cells • cardiomyocytes of the working myocardium - specialized for contraction (atrial and ventricular myocytes) cell 1 cell 2 sarcomere FUNCTIONAL SYNCYTIUM ORGANIZATION OF CARDIOVASCULAR SYSTEM Two Major Types of Cardiac Cells • cardiomyocytes of the working myocardium - specialized for contraction (atrial and ventricular myocytes) • cardiomyocytes of the cardiac conduction system - specialized for: - automatic excitation (pacemaker activity) - conduction of excitation The cardiac conduction system ensures: 1) generation of automatic electrical activity of the heart (pacemaker activity) that initiates its mechanical activity 2) optimal timing of the mechanical activity of the heart as a pump ECG CARDIAC CONDUCTION SYSTEM SA node atrial muscle AV node bundle branches bundle of His Purkinje fibres ventricular muscle HIERARCHY OF PACEMAKERS SA AV CARDIAC CONDUCTION SYSTEM Conduction velocity in atrial and ventricular muscle: 1 m/s SINOATRIAL (SA) NODE PRIMARY pacemaker (60-100 impulses/min) INTERNODAL PREFERENTIAL PATHWAYS 1 m/s ATRIOVENTRICULAR (AV) NODE SECONDARY pacemaker (40-55 impulses/min) TERCIARY pacemaker (25-40 impulses/min) PURKINJE FIBRES BUNDLE OF HIS BUNDLE BRANCHES (LEFT AND RIGHT) 0.05 m/s 1 m/s 1 m/s 4 m/s 0.05 m/s CARDIAC CELLULAR ELECTROPHYSIOLOGY Ionic Currents Underlying Action Potential Configuration SA node AV node atrial muscle ventricular muscle bundle of His bundle branches Purkinje fibres time CARDIAC CELLULAR ELECTROPHYSIOLOGY Ionic Currents Underlying Action Potential Configuration initial/fast depolarization (equilibrium between depolarizing and repolarizing currents) 0 mV 1 2 3 4 0 transpolarization _+ -80 mV early repolarization plateau phase final/late repolarization resting membrane voltage (Emr) CARDIAC CELLULAR ELECTROPHYSIOLOGY Ionic Currents Underlying Action Potential Configuration Na+ repolarization INa depolarization threshold voltage ICa -35 mV Ca2+ K+ Ito plateau -65 mV Emr ENa ECa 0 mV + _ EK IK + IK1 100 ms CARDIAC CELLULAR ELECTROPHYSIOLOGY Ionic Currents Underlying Action Potential Configuration INa OPEN STATE (depolarization over threshold voltage) ACTIVATION INACTIVATION (at maintained membrane depolarization) RESTING STATE (closed) inactivation gate activation gate INACTIVATED STATE (closed) CARDIAC CELLULAR ELECTROPHYSIOLOGY Refractory Period – Suppression of Excitability RELATIVE ABSOLUTE contraction action potential CARDIAC CELLULAR ELECTROPHYSIOLOGY Refractory Period - Mechanism INa OPEN STATE (depolarization over threshold voltage) ACTIVATION INACTIVATION (at maintained membrane depolarization) INACTIVATED STATE (closed) RESTING STATE (closed) inactivation gate activation gate RECOVERY FROM INACTIVATION (at repolarization) ICa CARDIAC CELLULAR ELECTROPHYSIOLOGY Pacemaker Activity - Mechanism CARDIAC CELLULAR ELECTROPHYSIOLOGY Pacemaker Activity - Mechanism maximal diastolic voltage threshold voltage ICa-L FACTORS DETERMINING THE HEART RATE: 1) maximal diastolic voltage 2) steepness of diastolic depolarization 3) threshold voltage for activation of ICa-L CARDIAC CELLULAR ELECTROPHYSIOLOGY Pacemaker Activity - Mechanism COMPLEX PROCESS resulting from an INTERPLAY between • REPOLARIZING CURRENTS, namely IK (including IK,Ach) • DEPOLARIZING CURRENTS, namely If and ICa-T maximal diastolic voltage threshold voltage ICa-T ICa-L IK If CARDIAC CELLULAR ELECTROPHYSIOLOGY Pacemaker Activity - Mechanism ICa-T ICa-L IK If SYMPATHETIC STIMULATION •  cAMP  If and ICa-T  rate of diastolic depolarization  threshold voltage for activation of ICa-L ( excitability)    CARDIAC CELLULAR ELECTROPHYSIOLOGY Pacemaker Activity - Mechanism ICa-T ICa-L IK If PARASYMPATHETIC STIMULATION • activation of IK,Ach  maximal diastolic voltage  threshold voltage for activation of ICa-L ( excitability)  (IK,Ach) •  cAMP  If and ICa-T  rate of diastolic depolarization     ECG SPREADING OF EXCITATION IN THE HEART SA node atrial muscle AV node bundle branches bundle of His Purkinje fibres ventricular muscle +++++ +++++ ----- ----- +++++ +++++ ----- ----- electric field (magnitude, direction) ELECTROMECHANICAL COUPLING Excitation-Contraction Coupling Z-line Z-lineCa2+ TERMINAL CISTERNS OF SR LONGITUDINAL TUBULES OF SR TRANSVERSE TUBULE Ca2+-ATPase myosin filaments actin filaments SIMILAR ARRANGEMENT IN SKELETAL AND CARDIAC MUSCLE CELLS SARCOTUBULAR SYSTEM ELECTROMECHANICAL COUPLING Excitation-Contraction Coupling in Cardiomyocytes CALSEQUESTRIN Ca2+ buffer in SR Na+/Ca2+ Ca2+-ATPase action potentials Ca2+-ATPase Ca2+-ATPase CONTRACTION [Ca2+]i 200 ms ICa Ca2+-RELEASE channels in SR (Ca2+-sensitive) voltage-dependent Ca2+ channels in the cell membrane (both the surface membrane and membrane of t-tubules) EXCITATION ELECTROMECHANICAL COUPLING Molecular Mechanism of Contraction Z-line Z-line myosin filaments actin filaments MECHANISM IDENTICAL IN SKELETAL AND CARDIAC MUSCLE CELLS FORMATION OF CROSS BRIDGES BETWEEN ACTIN AND MYOSIN FILAMENTS Ca2+ ELECTROMECHANICAL COUPLING Molecular Mechanism of Contraction RESTING MUSCLE TROPONIN-TROPOMYOSIN COMPLEX CONTRACTING MUSCLE ELECTROMECHANICAL COUPLING Molecular Mechanism of Contraction ELECTROMECHANICAL COUPLING Molecular Mechanism of Contraction