• Cardiac muscle physiology overview:

  • Three major types of cardiac muscle

    1.  Atrial muscle-similar to skeletal muscle but with a longer contraction duration

    2.  Ventricular muscle-similar to skeletal muscle but with a longer contraction duration

    3.  Specialized muscle of the cardiac conducting system-few contractile fibers, hence limited contractility: important because of their central role in cardiac electrical excitation

  • Histological aspects

    • Cardiac muscle striated-similar appearance to skeletal muscle

     

    • Cardiac muscle cross-section (400X) {di Fiore's Atlas of Histology with Functional Correlations, http://www.cord.edu/faculty/todt/336/lab/muscle/cardiac.html, William L. Todt, Concordia College}

    •  Myofibrils containing (a) actin (b)  myosin filaments (extremely similar to those found in skeletal muscle)

      • Myofibril filaments interdigitate in a manner very much like that seen in skeletal muscle

  • Other anatomical aspects:

    •  Individual cardiac cells are separated from one another by "intercalated discs"

    •  Cardiac muscle fibers are composed those numerous individual cells connected in series to each other {intercalated discs do not interfere with electrical propagation (action potential propagation) through myocardial structures

    •  Because of this extensive interconnectivity without the electrical interruption, action potentials are typically propagated smoothly and progressively throughout the myocardium

    •  This "latticework" of cells is called  a syncytium, which describes cardiac muscle 

    •  The heart is composed of two syncytiums-- the atrial syncytium which includes the two atrial walls and the ventricular syncytium composed of the two ventricular walls

  • Barriers to conduction

    • Fibrous tissue between the atria and ventricles are characterized by high electrical resistance such that myocardial action potential propagated from the atrial syncytium to the ventricular syncytium through the specialized conduction system called the AV node {atrioventricular (AV) bundle}

  • Important consequence of 2 syncytium structures: the separate structures allow the atria to contract in time slightly before the ventricles -- a condition central to the cardiac pumping effectiveness

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• Myocardial Action Potential

  • Resting membrane potential

    • -85 to -90 mV for normal cardiac muscle

    • -90 to -100 mV for specialized conducting fibers, e.g. bundle of His,  AV nodal fibers

  • Action potential

    • Magnitude for ventricular muscle = about 105 mV (i.e., going from about -85 mV to + 20 mV): this abrupt change in membrane potential corresponds to the "spike"

    • Depolarization duration = about 0.2 seconds for atrial muscle & about 0.3 seconds for ventricular muscle

    • Plateau phase: extends the duration of the action potential significantly (3-15 times) relative to the action potential duration of skeletal muscle

  • Ions and the myocardial action potential:

    •  "Fast" response component -- due to activation of fast sodium channels:

      • At normal resting membrane potentials, activation of sodium channels involves large number of channels opening in a synchronous manner

      • The large number of rapidly and synchronously opening channels results in a significant inward sodium current which is the basis for typically rapid conduction & action potential propagation through the heart

    • "Slow" response component-due to activation of slow calcium channels

      • Remain open longer than sodium channels

      • Responsible for the plateau phase of the action potential

      • Ca²⁺ ions entering the cell facilitates also leading muscle  contractile process

    •  Recovery of the resting membrane potential

      • Following Na⁺ and Ca²⁺ ion channel activation and then inactivation, membrane K⁺  permeability increases

      • K⁺ efflux results in repolarization

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• Conduction Velocity

  •   Atrial/ventricular muscle fibers: 0.3-0.5 meters per second

  •  Specialized fibers for action potential propagation through the heart (e.g. Purkinje fibers): 0.02-4 m per second

• Refractory Period

  •  Definition: amount of time following an action potential during which the normal cardiac impulse cannot re-excite the previously excited tissue:  this is the absolute refractory period

    • Duration -- normal absolute refractory period = 0.25-0.3 seconds

  •  Relative refractory period:

    • Cardiac muscle may be excited, but with greater difficulty than normal.  

    • Duration: approximately 0.05 seconds (adds somewhat to the absolute refractory period)

  • Atrial refractory period (absolute refractory = 0.15 seconds; relative refractory = 0.03 seconds) -- shorter than ventricular refractory period. As a consequence, atrial contraction rates may be significantly higher than ventricular contraction rates

• Relationships between membrane depolarization and muscle contraction

  • Term: excitation contraction coupling

  • Sequence of events:

    1.  Action potential spread

       • over the surface

       • to the interior of the cardiac muscle fiber along transverse (T) tubules

    2.  T tubule action potential causes Ca²⁺ ion release from the muscle sarcoplasmic reticulum into the muscle sarcoplasmic {calcium ion are also released from the T tubules themselves, providing extra Ca²⁺ ions the lesson adding to the strength of cardiac muscle contraction. [this case is in contrast to skeletal muscle in which Ca²⁺ ions are released essentially only from the sarcoplasmic reticulum; skeletal muscle sarcoplasmic reticulum is better developed than the myocardial counterpart which stores less calcium]

    3.  Ca²⁺ ions diffuse into the myofibrils where upon binding to troponinC actin-myosin interaction and sliding are initiated.

  • Myocardial contraction strength calcium dependencies:

    • Significantly influenced by extracellular calcium concentration [Ca²⁺ ] because ends of the T tubules open extracellularly, allowing T tubule [Ca²⁺ ] equilibration with extracellular [Ca²⁺ ] .

      • This relationship between extracellular [Ca²⁺ ] and myocardial contractility explains why hypocalcemia or calcium channel antagonists would be expected to depress myocardial contractility.

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Different Forms of Cardiac Action Potential

slightly modified from: Crawford, M. H. and DiMarco, J. P, Cardiology, Mosby, St. Louis, MO. 2001

Electrophysiology: Pacemaker and Cardiac Cells 
American Association of Critical-Care Nurses (AACN)

(left to right: pacemaker cell, atrial muscle cell, ventricular muscle cell)

Figure by: Barbara McLean, MN, RN, CCRN, CRNP
Clinical Specialist in Critical Care, Grady Health System
Lecturer, Emory University School of Medicine
Clinical Faculty, Nell Hodgson Woodruff School of Nursing, Emory University
Clinical Associate, Morehouse School of Medicine
Atlanta, Georgia

Ventricular Muscle Cell Action Potential

Phase 0: Activation of fast Na+ channel-- initial depolarization; slope & magnitude of a 0 will be dependent on the resting membrane potential (A in the diagram on the right) Phase 1: Partial repolarization; K+ efflux Phase 2: Ca2+ entry with continued K+ efflux = "plateau phase".  Initial Ca2+ influx through slow L- type Ca2+ channels initiates further Ca2+ release from and sarcoplasmic reticulum stores: Free Ca2+  binds to contractile proteins (e.g. troponin C) promoting/enhancing muscle contraction  catecholamines (sympathomimetic amines e.g. epinephrine, norepinephrine (Levophed)) increase slow-inward Ca2+  currents-- a mechanism by which sympathomimetic agents enhance inotropism Phase 3 This phase is dominated by K+ efflux, i.e. repolarization. The membrane potential moves towards the original resting level. Phase 3 ccorresponds to the effective/absolute refractory period.  Restoration of ionic gradients to "pre-action potential" levels requires the action of the Na+/K+ membrane ATPase-dependent transporter Phase 4 This phase is between action potentials. In some cell types, phase 4 depolarization (diastolic depolarization) can occur {especially, for example in "pacemaker" cells}.

Cardiac Conduction System: Review

• Structure: SA node

  • disk shaped -- dimensions = 15 x 15 x 2 mm

  • Location -- in the sulcus terminalis  (junction of the superior vena cava and right atrium; posterior cardiac aspect)

  • Anatomical origin -- right-sided embryological structures {note consequence -- primarily right-vagal nerve innervation dominance}

  • Blood supply: usually (60%) from the right coronary

• Intrinsic pacemaker beats per minute (bpm)-- idioventricular pacemaker rates may be insufficient to ensure adequate cardiac output (note below)

  • SA node: 60-100 bpm

  • Atrial cells: 55-60 bpm

  • AV node: 45-50 bpm

  • HIS bundle: 40-45 bpm

  • Bundle branch: 40-45 bpm

  • Purkinje cells: 35-40 bpm

  • Myocardial cells: 30-35 bpm

• SA nodal action potential characteristics:

  • "Slow-response" type, consistent with limited fast-sodium channel activation involvement

  • Characteristic phase 4 depolarization (unstable membrane potential drifting towards threshold-- phase 4 depolarization slope influenced by sympathetic/parasympathetic stimulation as well as other factors.

Adapted from Berne and Levy (Berne, R.M and Levy, M. N. Cardiovascular Physiology,8th Edition, Mosby, St. Louis, Mo. 2001 (Fig. 2-17)

•  SA & AV nodal, slow response, fibers exhibit Ca²⁺-mediated inward currents which are responsible for depolarization

•  The channel type appears to be of the L-type Ca²⁺channel, voltage-gated, typically activated membrane potentials > -40 mV

•  L-type calcium channel inactivation is dependent on (a) cell membrane potential, [ Ca²⁺], and time

•  L-type calcium channel antagonists include: 

  •  Benzothiapines (e.g. diltiazem (Cardiazem))

  •  Dihydropyridines (e.g. nifedipine (Procardia, Adalat) & nitrendipine

  •  Phenylalkylamines (e.g. verapamil (Isoptin, Calan)

• SA nodal overdrive suppression

  •  Pacemaker cellular automaticity is suppressed following a period during which action potentials are driven (typically by external pacing) at a rate higher than the normal intrinsic pacemaker frequency

  •  Suppression of ectopic pacemakers may occur as a result of overdrive suppression, allowing the normal SA nodal pacemaker to resume control of heart rate.

  •  In "sick-sinus syndrome" rapid heart rates inhibit normal SA nodal pacemaker activity and consequently can lead to periods of asystole.

  • Mechanism: Related to the activity of Na/K ATPase

    1.  At higher heart rates enhanced sodium pump activity results in cell membrane hyperpolarization because 3 sodium ions are extruded for 2 potassium ions entering the cell

    2. As a consequence of cellular hyperpolarization, diastolic depolarization (automaticity)  will take longer to reach threshold

    3. When overdrive ends, the Na/K ATPase pump activity does not immediately returned to normal does favoring the hyperpolarized membrane potential, which is a consequence suppresses normal nodal automaticity for a brief time.

  • The relationship between cardiac output and heart rate provides the basis for rapid intervention for management of either tachycardia or bradycardia

    • Bradycardia: In the case or bradycardia, secondary to sick sinus syndrome or due to a very slow idioventricular rate {associated with complete atrioventricular block}, ventricular filling may be limited despite prolonged diastole, perhaps due to pericardial noncompliance.  This reduction in diastolic filling may be sufficient to prevent compensation by increased stroke volume

     

    • Tachycardia: With supraventricular or ventricular tachycardias, cardiac output may be dangerously low as a result of inadequate filling time

      • In tachycardic patients, the filling time may be sufficiently restricted such that a slight further reduction in filling time may have a disproportionately serious reduction in filling volume

      • Drug intervention to reduce heart rate may be effective; however in an emergency setting DC cardioversion may be more appropriate

Left Ventricular Tachycardia

• "Several features confirm this wide QRS tachycardia to be ventricular in origin. The morphology of the QRS in V1 has a distinct notch on the downstroke making it highly unlikely to be RBBB aberration. The QRS is entirely negative in lead V6. The frontal plane QRS axis is +150. The direction of ventricular activation is from left to right and posterior to anterior, suggesting a left ventricular origin" Frank G. Yanowitz, M.D. Copyright 1998 used with permission

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• Internodal pathway

  • Three internodal tracts provide input to the AV node {i.e., primary function is transmission of SA nodal pacemaker impulses to the AV node}
    • Internodal pathways are localized in the inter-atrial septum and right atrial walls
  • Three functional AV nodal zones:
    1. AN zone: joining atrium to the node
    2. N (nodal) region
    3. NH zone: joining the node to the bundle of His
  • Significance: functional AV nodal zones:
    •  Delay between atrial impulse transmission to distal conduction components-- due to "N" regions & "AN" regions
    •  This delay allows for adequate ventricular filling subsequent to atrial contraction {associated with the PR ECG interval}
• Structure: AV node
  • Button-shaped structure (22 x 10 x 3 mm)
  • Location:
    • Right posterior side of interatrial septum near coronary sinus ostium  (coronary sinus = largest cardiac vein), near the tricuspid valve septal leaflet
    • Embryological development -- left-sided, accounting for left-sided domination of AV nodal vagal innervation
  • Function: reduces atrial-ventricular conduction, thus allowing time for ventricular optimal filling
  • AV node blood supply provided by the right coronary artery

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• Bundle of His:

  • AV nodal fibers proceed to the bundle of His

  • Bundle of His extends subendocardially along the right side of the interventricular septum, then divides, continuing as the right bundle branch

  • Singular communication pathway between atria and ventricles

  • The left bundle branch also arises from the bundle of His, also passing through the interventricular septum and further dividing into a thin anterior fascicle as well as a thick posterior fascicle proceedings subendocardially along the left side of the interventricular septum. (see diagram below)

• Left bundle branch (LBB):

  • Initiation point: end of the His bundle

  • Progresses through the interventricular septum

  • LBB fibers innervate:

    1. the left ventricle

    2. the interventricular septum

  • Cardiac regions innervated by the LBB are the first to depolarize

  • Ending point: at the beginning of the left anterior and left posterior fascicles (LAF & LPF)

• The Purkinje  fiber network --deriving from the right bundle and the two left fascicles -- allows impulse conduction  throughout the ventricle

  •  Rapid impulse conduction associated with Purkinje fibers (secondary to thicker cellular diameter) permits rapid action potential propagation through the myocardium, thus coordinating contraction

• Contraction sequence, as a result of action potential propagation through Purkinje fibers

  1.  Interventricular myocardial tissue (septum) & papillary muscle

  2.  Septal contraction provides an "anchor" for the heart as the ventricular free wall begins contracting and papillary muscle tightening prevents tricuspid & mitral valve prolapse during early systole

  3.  Muscle fiber contraction proceeds outward from the endocardial region to the epicardial surface

  4.  The right ventricle contracts before the left ventricle secondary to differences in wall thickness {differences in output from the left vs. right-side are compensated in accord with Starling's Law}

Automaticity

• Overview

  • Automaticity, a  SA nodal normal characteristic and a characteristic of specialized His-Purkinje system fibers as well as some specialized atrial fibers is defined as a cardiac cellular property which causes spontaneous cell membrane depolarization.

  • This depolarization occurs during phase 4 of the action potential.

  • The primary characteristic of automaticity is that the resting membrane potential is not stable but rather decreases (towards 0 millivolts (mv)) until threshold is reached an action potential generated

  • In those normal cells which would be expected to exhibit automaticity, specific ionic currents have been identified as responsible.  These currents are:

    1. an inward  current (I_f), probably carried by Na⁺ which tends to depolarize the membrane

    2. a second inward current carried by Ca²⁺, (I_Ca²⁺), which is also depolarizing

    3. and a third outward current carried by K⁺ (I_K+), the conductance of which tends to decrease during phase 4, those leading to a net depolarizing effect. This outward current tends to oppose the inward  (I_f) and (I_Ca²⁺) currents' depolarizing influence.  Thus the time-dependent decrease in I_K+ is an important factor leading to the positive slope associated with phase 4 depolarization.

• Physiological Factors Affecting Automaticity:

  • Autonomic effects -- Adrenergic

    • Adrenergic neurotransmitters (e.g. norepinephrine) increase (I_f) and (I_Ca²⁺)  and I_K+) currents with predominant effects on (I_f) and (I_Ca²⁺). Predominant effects on the depolarizing (I_f) and (I_Ca²⁺) explains why adrenergic stimulation increases heart rate [increasing phase 4 slope means that action potential threshold is reached more frequently (per minute), thus resulting in a faster rate]

  • Autonomic effects --Cholinergic

    • Cholinergic effects, acetylcholine-mediated, result in an increase in K⁺conductance (g_K+), an effect which is hyperpolarizing (the membrane potential moves further away from threshold). Membrane hyperpolarization results in an increased length of time required for threshold to be reached during phase 4 depolarization -- a consequence of this effect is that the heart rate will be reduced.

    • In addition, acetylcholine depresses the depolarizing, (I_f) and (I_Ca²⁺) currents-- also contributing in this way to a reduced phase 4 slope, consistent with the reduced heart rate following increased vagal activity

• * ¹ hypokalemia, reduced intracellular potassium decreases outward K⁺ movement which normally counteracts phase 4 depolarization (see above). 

  • Recall that in phase 4 depolarization inward depolarizing currents are partially offset by outward potassium ion movement; therefore, in the hypokalemic state the depolarizing currents will be more dominant and as a result increased the slope of phase 4.  

  • With an increased phase 4 slope, the threshold potential is reached more easily

  • This mechanism is also partially responsible for the pro-arrhythmic activity associated with toxic digoxin (Lanoxin, Lanoxicaps)/digitoxin (Crystodigin) levels

  • Recall that in digitalis toxicity, probably due to inhibition Na/K ATPase, there's an accumulation of intracellular Na⁺and Ca²⁺.  Consequently, intracellular accumulation of  positively charged ions tends to decrease the membrane potential (less negative), bringing it closer to threshold.

Cardiovascular pharmacology module by Lee, EJD {see for more information: http://www.med.nus.edu.sg/phar/medlect/inotropes.htm)}

Both early and delayed afterdepolarizations are probably Ca²⁺ dependent

• ² Stretch-induced depolarizations are known to cause arrhythmias.  Furthermore stretch-activated ion channel have been identified and their electrophysiological properties characterized. Mechanosensitive ion channels were first discovered in skeletal muscle with subsequent identification in cardiac cells, bone, and in most other types of cells including those in bacteria and plants (see Sachs F: 1992.   Stretch sensitive Ion channels: an update. In Corey DP, Roper SD, eds. Sensory Transduction, New York, Rockefeller University press,Soc Gen Physiol. pp 241-260 and more recently GCL Bett and F. Sachs (1997) Cardiac Mechanosensitivity and Stretch-Activated Ion Channels, Trends in Cardiovascular Medicine 7: 4-8)

• ³ Injury Currents: Consider the 12-lead ECG: During an antianginal episode, ST segment depression may be observed.  Normally the ST segment is associated with phase 2 of the myocardial action potential.  Phase 2 is typically isoelectric (no  significant membrane potential change is occurring-see below)

• With ischemia, the resting membrane potential in the ischemic region is reduced compared to surrounding healthy tissue.  As a consequence of this membrane potential difference, current flows between the two regions.  This current is referred to as an injury current and is reflected by deviations in the ECG ST segment

  • For subendocardial ischemia, the ST vector is towards the ventricular cavity, resulting in surface leads reporting ST depression; however, in transmural ischemia, the ST vector is oriented towards the surface lead, causing ST segmental elevation {Biomedical Sciences 245B, Virginia Commonwealth University: Pathophysiology of Disease: Ischemic Hard Disease (Krishnan),  http://wcb.ucr.edu/wcb/school/CNAS/bmsc/lloo/11/modiules/page21.html)}

• ⁴ Acidosis: Tends to suppress normal automaticity