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4/25/13 BENG 230C Cardiovascular Physiology Lecture 8 Development of the Heart – 2 Cardiac ConducGon System Mark Mercola, PhD Professor of Bioengineering, UCSD Professor and Director, Muscle Development and RegeneraGon Program, Sanford-­‐Burnham Medical Research InsGtute Lecture ObjecGves •  Understand basic funcGon of the cardiac conducGon system and its components •  Understand sympatheGc and parasympatheGc effects on the heart •  Understand the developmental origin of cardiac conducGng cells Cardiac ConducGng System 1.  SAN fires 2.  Propagates quickly to LA via Bachman’s bundle 3.  Propagates slowly across RA and LA 4.  Delay in AVN (~0.1 sec) 5.  PropagaGon to ventricles via AVN to Bundle of His 6.  Ventricle propagaGon via R and L bundle branches and into Purkinjee fibers Bachman’s bundle
1 4/25/13 SA Node Pacemaker •  Pacemaker channels acGvate when membrane hyperpolarizes (more negaGve than -­‐35mV). + influx causes slow depolarizaGon •  Ca2+ channels open at -­‐40mV. Low density of the L-­‐
type Ca2+ channels makes for gradual upstroke •  Ca2+ channel inacGvaGon •  AcGvaGon of voltage-­‐gated K+ channels causes repolarizaGon; K+ channels inacGvated upon repolarizaGon Electrophysiological heterogeneity of the sinoatrial node (SAN).
Park D S , and Fishman G I Circulation 2011;123:904-915
Copyright © American Heart Association
AV Node Delay •  Shallow phase 4 (slow depolarizing) •  Shallow phase 0 (upstroke); decreases conducGon velocity •  ~0.1 sec delay 2 4/25/13 Atrioventricular Bundle •  A.K.A. Bundle of His –  From the AV node, impulses travel through to the right and lef bundle branches –  These branches extend to the right and lef sides of the septum and bohom of the heart. Purkinje Fibers –  The lef and right bundle branchs fork repeatedly to form the Purkinje fibers that transmit the impulses to working cardiomyocytes –  The bundle of His, bundle branches and Purkinje fibers transmit impulses quickly to coordinate L and R ventricular contracGon Intercellular Impulse PropagaGon • 
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Intercalated discs: gap juncGons and desmosomes. Gap juncGons permit Ca2+ and Na+ transfer between cells. Desmosomes provide structural integrity. During wave propagaGon, Na+ and Ca2+ entering a cardiomyocyte raise membrane potenGal and acGvate Na channels to fire the acGon potenGal T-­‐tubule network increases effecGve surface area for Ca2+ entry that sGmulates Ca2+-­‐induced Ca2+ release from sarcoplasmic reGculum, amplifying Ca2+ release, and acGvaGng contracGon 3 4/25/13 Electrocardiogram •  Method developed by Wilhelm Einthoven –  Dutch Elektrokardiogram (EKG) –  Now usually ECG. •  Records ion movement in heart. –  VariaGons in electrical potenGal radiate from heart; detectable at wrists, ankles. Electrocardiogram •  P wave –  DepolarizaGon of atria –  Followed by contracGon •  QRS complex –  3 waves (Q, R, & S) –  DepolarizaGon of ventricles –  Followed by contracGon •  T wave –  RepolarizaGon of ventricles •  P-­‐Q interval •  Q-­‐T interval Electrocardiogram •  P-­‐Q interval (or P-­‐R) –  Time atria depolarize & remain depolarized •  Q-­‐T interval –  Time ventricles depolarize & remain depolarized 4 4/25/13 Impulse PropagaGon and ECG Long QT syndrome •  Long QT interval, increase AcGon PotenGal DuraGon •  Causes syncope, sudden death and potenGally fatal arrhythmia •  Common mutaGons: –  LQT1, slow delayed recGfier K channel (KCNQ1) –  LQT2, rapid delayed recGfier K channel (hERG) –  LQT3, Na channel alpha subunit (SCN5A) –  LQT8, L-­‐type Ca channel (Cav1.2) •  Drug-­‐induced LQT –  Common concern and reason for drug failures during development in pharma Wolff-­‐Parkinson-­‐White and Artrioventricular Bypass Tract •  Accessory pathways form and fail to disappear during fetal development •  Formed near the mitral or tricuspid valves or interventricular septum •  An AV bypass tract is someGmes referred to as the bundle of Kent 5 4/25/13 Artrioventricular Bypass Tract • 
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From SA node directly to AV node AND to ventricular myocardium ParGally bypassing the bundle of His and purkinje fibers Accessory Pathways Atrioventricular Heart Blocks Degree
AV Conduction Pattern
1St Degree Block
Uniformly prolonged PR
interval
2nd Degree, Mobitz Type I
Progressive PR interval
prolongation
2nd Degree, Mobitz Type II
Sudden conduction failure
3rd Degree Block
No AV conduction
6 4/25/13 SchemaGc Overview of ConducGng System Development Christoffels V M , and Moorman A F Circ Arrhythm
Electrophysiol 2009;2:195-207
Copyright © American Heart Association
Figure 2. Development of chambers and ECG. A, Left-sided view of embryonic hearts of
embryonic day (E) 8 to 8.5 and E9.5 to 10.5, respectively.
Christoffels V M , and Moorman A F Circ Arrhythm
Electrophysiol 2009;2:195-207
Copyright © American Heart Association
Electrophysiological Changes in Pacemaker FuncGon During Development During development, iniGally the enGre sinus venosus myocardium is capable of generaGng the iniGal electrical acGvaGon. Later in development the right sided SAN will become the definiGve pacemaker. (a) RepresentaGve example of an ex ovo electrophysiological recording of an embryonic chick heart (stage HH21), demonstraGng lef atrial acGvaGon (LAc) preceding the right atrial acGvaGon (RAc) with 4,6 ms. (b) and (c) Electrical acGvaGon pahern as obtained with opGcal mapping, dorsal view, showing the iniGaGon of the electrical signal (indicated in red) in the LA. d. RepresentaGve example of an ex ovo electrophysiological recording of an embryonic chick heart (stage HH29), demonstraGng RA acGvaGon preceding the LA acGvaGon with 3,1 ms. (e) and (f): Electrical acGvaGon pahern as obtained with opGcal mapping, dorsal view, showing the iniGaGon of the electrical signal (indicated in red) in the RA. AbbreviaGons: SV: sinus venosus, OFT: ouolow tract, V: ventricle. 7 4/25/13 Progressive ContracGle and ConducGve MaturaGon during Cardiogenesis Lineage RelaGonship Between the Working and ConducGng Myocytes • 
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Lineage labelling in transgenic mice by random acGvaGon of LacZ transgene demonstrates both mixed and unmixed working and conducGng myocytes. The finding of mixed clusters indicates that conducGng cells share a common origin with working myocytes. The relaGvely small numbers of conducGng cells in the clusters indicates that they proliferate much less than working myoyctes Lineage RelaGonship Between the Working and ConducGng Myocytes • 
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Common lineage for conducGng and working myocytes Greater proliferaGon of working myoycte progenitors Control by neuregulin (NG) and endothelin (ET) Christoffels V M , and Moorman A F Circ Arrhythm Electrophysiol 2009;2:195-­‐207 Mikawa et al., Seminars in Cell & Developmental Biology; 18, Issue 1 2007 90 -­‐ 100 8 4/25/13 Development of the Purkinje fiber system (PVCS) Christoffels V M , and Moorman A F Circ Arrhythm
Electrophysiol 2009;2:195-207
Copyright © American Heart Association
Development of the AVC and AVN. Depicted factors control formation of the atrioventricular
(AV) canal and atrial or ventricular working myocardium (chamber), respectively, or are
involved in establishing boundaries.
Christoffels V M , and Moorman A F Circ Arrhythm
Electrophysiol 2009;2:195-207
Copyright © American Heart Association
Model for Influence of Hemodynamic Forces on Purkinje Fiber FormaGon 9 4/25/13 Autonomic RegulaGon of Cardiac Output •  ParasympatheGc Nervous System –  decreases HR and SV –  dominant at rest •  SympatheGc Nervous System –  increases HR and SV –  dominant during exercise/stress Autonomic Nervous System SchemaGc ParasympatheGc Effects •  Vagal nerves release acetylcholine at SA and A-­‐V nodes •  sGmulates muscarinic receptors •  increased K+ channel opening •  decreased sinus node rhythm •  decreased A-­‐V node transmission •  ventricular escape”, a form of arrhythmia that creates an ectopic beat in the absence of failure to transmit SA or AV node signals 10 4/25/13 SympatheGc Effects •  SympatheGc nerves release norepinephrine throughout heart •  sGmulates adrenergic receptors •  increased Ca+ and Na+ channel opening •  increased SA node rhythm •  increased A-­‐V node transmission •  increased force of atrial and ventricular contracGon Baroreceptor Reflex •  rapid control of CVS funcGon •  sensory baroreceptors in caroGd sinus and aorGc arch detect BP changes •  increased BP detected, increased vagal firing, decreased CO •  decreased BP detected, increased sympatheGc firing, increased CO Key Points •  Pacemaker cells exhibit automaGcity. •  ConducGng cells exhibit faster conducGon velociGes than do working myocytes, so impulses propagate in an appropriate and Gmely fashion across the muscle •  AVN causes a ~0.1 sec delay in impulse propagaGon necessary for Gming atrial and ventricle beats •  A and V bundle branches fork into Purkinje fibers, propagaGng impulse to working myocytes in R and L ventricles in a coordinated fashion •  Wolf-­‐Parkinson-­‐White is an example of atrioventricular bypass •  ConducGng and working myocytes arise from a common developmental lineage through disGnct programs of gene expression •  SympatheGc sGmulaGon (adrenergic) increases SA node rhythm and A-­‐V node transmission •  ParasympatheGc sGmulaGon (cholinergic) decreases sinus node rhythm and A-­‐V node transmission 11