The Heart

1. The Heart Gregory Shen (沈啸), MD Department of Physiology Room 516, Research Building C School of Medicine, Zijingang Campus Email: shenx@zju.edu.cn

2. Functions of the heart • Pumping（泵血） • Endocrine（内分泌） • Atrial natriuretic peptide (ANP) • Other bioactivators

4. Valves of the heart

5. The general route of the blood through the body is shown, including passage through the heart (colored box).

6. Cardiac muscle • The major types of cardiac muscle: • Atrial muscle • Ventricular muscle • Specialized excitatory and conductive muscle Contractile cells （收缩细胞） Autorhythmic cells （自律细胞）

7. Cardiac muscle metabolism • At rest, cardiac muscle consumes fatty acids to supply most of its energy (70% fatty acids vs. 30% carbohydrates). • Under fasting state, almost all of the energy comes from fatty acid oxidation. • Under anaerobic or ischemic conditions, glycolysis is required, which consumes tremendous amounts of blood glucose and forms large amount of lactic acids.

8. Conducting system of the heart

9. Innervation Norepinephrine Acetylcholine β1 adrenergic receptor M acetylcholine receptor Epinephrine Adrenal gland Kidney

10. Cardiac cells’ gap junction • Cardiac cells are electrically coupled through gap junctions. • Is an electrical synapse that permits electrical current to flow between neighboring cells. .

11. Gap junction One gap junction channel is composed of two connexons (or hemichannels), which connect across the intercellular space.

12. Sequence of cardiac excitation

13. Sinoatrial node (SA node) • Located in the right artium. • Fire off action potentials at a regular and intrinsic rate. • Both parasympathetic and sympathetic neural input can modulate its pacemaker activity, or automaticity. • The existence of discrete conducting pathways in the atria is still disputed. The signal arrives to the left atrium and atrioventricular node (AV node).

14. Transmembrane potentials recorded in different heart regions

15. The membrane currents underlying cardiac action potentials • The Na+ current (INa): is responsible for the rapid depolarizing phase of the action potential in cardiac muscle cells and in Purkinje fibers. • The Ca2+ current (ICa): is responsible for the rapid depolarizing phase of the action potential in the SA node and AV node; also triggers contraction in all cardiomyocytes. • The K+ current (IK): is responsible for the repolarizing phase of the action potential in all cardiomyocytes. • The pacemaker (Funny) current (If): is responsible, in part, for pacemaker activity in SA nodal cells, AV nodal cells and Purkinju fibers; is mediated by a nonselective cation channel.

16. Transmembrane potential of ventricular cells and its ionic mechanisms Resting Potential: -90 mV Action Potential • Phase 0: Depolarization • Phase 1: Early phase of rapid repolarization • Phase 2: Plateau • Phase 3: Late phase of rapid repolarization • Phase 4: Resting phase

17. The action potential of a myocardial pumping cell. • Resting potential (-90mV) • K+ Channel leaking 0 • Phase 0 (rapid depolarization) • Threshold potential (-70mV) • Opening of Na+ channel (Na+ current is the largest current in the heart) • K+ Channel starts to close

18. 1 2 • Phase 1 (rapid repolarization) • Fast shut of Na+ channel • K+ current stays below the resting value • Ca2+ channel starts to open for Ca2+ inflow • Phase 2 • The long-lasting L(long-lasting)-type Ca2+ channel open and Ca2+ enters

19. Phase 3 (repolarization) • Inactivation of Ca2+ channel • Outward K+ current dominates • * The repolarizing K+ current turns on slowly. 3 4 • Phase 4 • Sarcolemmal Ca2+ pump • Na+-K+ pump • * In conducting system, the electrical diastolic phase

20. 0 3 4 Sinoatrial node is the primary pacemaker of the heart • Intrinsic pacemaking tissues: SA node, AV node and Purkinje fibers. • Pacemaker activity: spontaneous time-dependent depolarization of the cell membrane that leads to an action potential in an otherwise quiescent cells. • Only composed of Phases 0, 3 and 4. • The pacemaker with the highest frequency will trigger action potential. • A decreasing outward current of IK and two increasing inward currents (of Ica and If) control the Phase 4 depolarization and intrinsic rhythmicity of the SA node. • The membrane currents are under the control of neural and circulating agents (acetylcholine, norepinephrine and epinephrine).

21. ICa in the SA and AV nodes • The inward Ca2+ is the current source for the upstroke/depolarization (Phase 0). • There is no Na+ channels. • Their upstroke is slower than those in the cardiac muscle cells. • The speed of the conducted action potential is much slower that that of any other cardiac tissue. • This feature in the AV node leads to an electrical delay between atrial contraction and ventricular contraction.

22. 0 3 4 Sinoatrial cells: Slow response autorhythmic cells • Maximal repolarization potential -60mV • Threshold potential -40mV • Phase 0, 3, 4

23. The action potential of anautorhythmic cardiac cell. • Phase 4： • Ik decay • Inactivated when repolarized to -60mV • If • Depolarizing Na+ current • T(transient)-type, ICa • Activated when depolarized to -50mV

24. Ionic mechanism • Phase 0: ICa (ICa,L) • Phase 3: • Inactivation of L-type Ca2+ channel • Outward K+ current (Ik)

25. Contractile cellsAutorhythmic cells Phase 4 stable potentialPhase 4 spontaneous depolarization Phase 0 INa –mediated deporalizationPhase 0 ICa –mediated deporalization No pacemaker activity Pacemaker activity Phase 4 resting potential -80mV Phase 4 maximum diastolic potential -65mV Threshold potential -70mV Threshold potential -40mV

26. Ectopic pacemakers Normally, other cells of the conducting system have slower inherent pacemaker rates, they are driven to threshold by action potentials from the SA node and do not manifest their own rhythm. However, they can do so under certain circumstances and are then called ectopic pacemakers.

27. Three ways the SA node slow the firing rate of its pacemaker

28. Acetylcholine and catecholamine modulation • The vagus nerve, which is parasympathetic, releases acetylcholine onto the SA node and slows the intrinsic pacemaker activity and onto the AV node and slows conduction velocity. • Sympathetic innervation to the heart releases norepinephrine and adrenal medulla releases epinephrine into the circulation. • Both of norepinephrine and epinephrine act through β1—adrenergic receptor and increase heart rate. • Both of norepinephrine and epinephrine cause an increase in the strength of contraction

29. Electrocardiogram (ECG)（心电图） The electrocardiogram (ECG) measures changes in skin electrical voltage/potential caused by electrical currents generated by the heart

30. I aVR aVL V1 V2 V3 V4 V5 V6 III II aVF The standard 12 lead ECG Einthoven’s Triangle Standard Limb leads (I, II, III) Augmented limb leads (aVR, aVL, aVF) Chest (precordial) leads (V1, V2, V3, V4, V5, V6) Willem Einthoven: Dutch physiologist. He won a 1924 Nobel Prize for his contributions to electrocardiography.

32. • P wave − atrial depolarization • QRS complex − ventrical depolarization • T wave − ventrical repolarization

33. PR interval: time interval from onset of atrial depolarization (P wave) to onset of ventricular depolarization (conduct through AV node) • QRS duration: how long it takes for the wave of depolarization to spread throughout the ventricles • QT interval: duration of ventricular depolarization and repolarization (overall ventricular action potential) • ST segment: the time period between the end of the QRS complex and the beginning of the T wave,  during which each myocyte is in the plateau phase (phase 2) of the action potential 

34. 0.04 sec • ECG interpretation • Measurements • Rhythm analysis • Conduction analysis • Waveform description • Comparison with previous ECG (if any)

36. Physiological properties of cardiac cells • Excitability • Autorhythmicity • Conductivity • Contractility Electrophysiological properties （电生理特性） Mechanical property （机械特性）

37. Excitability（兴奋性） • Factors affecting excitability • Resting potential • Threshold potential • Status of Na+ or Ca2+ channels

38. Periodic excitability: absolute refractory period

39. Autorhythmicity（自律性）

40. Normal pacemaker（正常起搏点） • SA node • Latent pacemaker （潜在起搏点） • (Ectopic pacemaker [异位起搏点] under pathophysiological conditions) • AV node • Bundle of His • Purkinje fibers

41. Maximal repolarization potential • Threshold potential • The rate of phase 4 spontaneous depolarization Factors Affecting SA Autorhythmicity

42. Conductivity（传导性）

43. Gap junction

44. Conducting velocity SA node Atria A-V node 0.05 m/s 0.4 m/s 0.02~0.05 m/s His bundle Purkinje fiber Ventricle 1.2~2.0 m/s 2.0~4.0 m/s1.0 m/s Atrioventricular delay（房室延搁）: Asynchronization of atrial and ventricular depolarization to provide adequate cardiac output

45. Cardiac arrhythmias • Conduction abnormalities are a major cause of arrhythmias. • Altered automaticity can originate from the sinus node or from an ectopic locus.

47. Excitation-Contraction Coupling In Cardiac Muscle The mechanism that couples excitation – an action potential in the plasma membrane of the muscle cell – and contraction of heart muscle Skeletal muscle: the initial event is the arrival of an action potential at the neuromuscular junction, the release of acetylcholine. Cardiac muscle: action potentials in adjacent myocytes depolarize the target cell through gap junction.

48. Calcium ions regulate the contraction of cardiac muscle: the entry of extracellular calcium ions causes the release of calcium from the sarcoplasmic reticulum (calcium-induced calcium release [钙诱导的钙释放]), the source of about 95% of the calcium in the cytosol. Excitation-contraction coupling in cardiac muscle

49. Cardiac cycle（心动周期） • The cardiac events occur from beginning of one heartbeat to the beginning of the next are called the cardiac cycle. • The cycle is divided into systole and diastole. 60 (s/min) Duration (s/beat) = Heart rate (beats/min) *The pacemaker in the SA node determine the duration of cardiac cycle.

50. The closing and opening of the cardiac valves define four phases of the cardiac cycle (1) Inflow phase: the inlet valve is open and the outlet valve is closed. (terminates on AV valve closure) (2) Isovolumetric contraction: both valves are closed with no blood flow. (terminates on semilunar valves openness) (3) Outflow phase: the outlet valve is open and the inlet valve is closed. (terminates on semilunar valves closure) (4) Isovolumetric relaxation: both valves are closed with no blood flow. (terminates on AV valve openess)