Genesis of cardiac arrhythmias
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The document discusses the anatomy and physiology of the cardiac conduction system and the mechanisms of cardiac arrhythmias. It describes the following: 1. The location and function of the sinoatrial node, atrioventricular node, bundle of His, bundle branches and Purkinje fibers that make up the cardiac conduction system. 2. The mechanisms that can cause arrhythmias including disorders of impulse formation like abnormal automaticity and triggered activity, as well as disorders of impulse conduction like reentry. 3. Specific arrhythmias like atrial flutter and fibrillation that are caused by reentry mechanisms in the atria, and how conditions like ion channel abnormalities and electrical remodeling can contribute to these arrhythm
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Genesis of cardiac arrhythmias
- 1. Genesis of Cardiac Arrhythmias Dr Virbhan Balai NHI,Delhi
- 2. ANATOMY OF THE CARDIAC CONDUCTION SYSTEM • Sinoatrial Node • The sinoatrial node is a spindle-shaped structure • Composed of a fibrous tissue matrix with closely packed cells. • It is 10 to 20 mm long and 2 to 3 mm wide. • It lies at the junction of the SVC and RA, less than 1 mm from the epicardial surface, laterally in the right atrial sulcus terminalis.
- 3. Location of the sinus node
- 4. • The artery supplying the sinoatrial node- RCA-55% to 60% LCX- 40% to 45%
- 5. • Function. • Automaticity- • HCN ion channels. • Ca2+-sensitive ion channels.
- 6. SA node... • Densely innervated by postganglionic adrenergic and cholinergic nerve terminals. • Contains amounts of norepinephrine, acetylcholine, acetylcholinesterase & choline acetyltransferase.
- 7. • Neurotransmitters modulate the discharge rate of the SA node by stimulation of beta- adrenergic & muscarinic receptors. • Both beta1 and beta2 adrenoceptor subtypes are present in the SA node.
- 8. Atrioventricular Junctional Area and Intraventricular Conduction System • Atrioventricular Node • Just beneath the right atrial endocardium, anterior to the ostium of the coronary sinus, and directly above the insertion of the septal leaflet of the tricuspid valve. • It is at the apex of a triangle formed by the tricuspid annulus and the tendon of Todaro and eustachian valve -triangle of Koch. • Tendon of Todaro is absent in about two thirds of hearts.
- 10. • Triangle of Koch. Tendon of Todaro –superiorly Septal leaflet of the tricuspid valve- inferiorly Coronary sinus -at the base.
- 11. • The arterial supply to the AV node 85% to 90% -branch of the RCA. 10-15% br of LCX. • Function Main functionof the AV node is to delay transmission of atrial impulses to the ventricles, thereby coordinating atrial and ventricular contractions.
- 12. Bundle of His (Penetrating Portion of the Atrioventricular Bundle) • Continuation of the penetrating bundle on the ventricular side of the AV junction. • It divides to form the left and right bundles. • Branches from the anterior and posterior descending coronary arteries supply the upper muscular interventricular septum with blood, which makes the conduction system at this site more impervious to ischemic damage unless the ischemia is extensive.
- 13. Bundle Branches (Branching Portion of the Atrioventricular Bundle) • The right bundle branch continues intramyocardially as an unbranched extension. • The anatomy of the left bundle branch system can be variable.
- 14. • Terminal Purkinje Fibers • Transmit the cardiac impulse almost simultaneously to the entire right and left ventricular endocardium.
- 15. Innervation of the Atrioventricular Node, His Bundle, and Ventricular Myocardium • Pathways of Innervation. The AV node and His bundle region are innervated by a rich supply of cholinergic and adrenergic fibers with densities exceeding those found in the ventricular myocardium.
- 17. Arrhythmias and the Autonomic Nervous System • Alterations in vagal and sympathetic innervation can influence the development of arrhythmias and sudden cardiac death from ventricular tachyarrhythmias. • Damage to nerves extrinsic to the heart, such as the stellate ganglia, and to intrinsic cardiac nerves. • Viral infections- cardioneuropathy.
- 18. Intraventricular route of the sympathetic and vagal nerves to the left ventricle
- 20. BASIC ELECTROPHYSIOLOGIC PRINCIPLES • Physiology of Ion Channels • Electrical signaling in the heart involves the passage of ions through ionic channels. • The Na+, K+, Ca2+, and Cl− ions are the major charge carriers. • Their movement across the cell membrane creates a flow of current that generates excitation and signals in cardiac myocytes.
- 21. Structure of ion channels
- 22. Intracellular and Extracellular Ion Concentrations in Cardiac Muscle
- 23. Phases of the Cardiac Action Potential • The cardiac transmembrane action potential consists of five phases: • Phase 0 - upstroke or rapid depolarization • Phase 1- early rapid repolarization • Phase 2- plateau • Phase 3- final rapid repolarization • Phase 4- resting membrane potential and diastolic depolarization.
- 27. • Phase 0: Upstroke or Rapid Depolarization. • A stimulus delivered to excitable tissue evokes an action potential characterized by a sudden change in voltage caused by transient depolarization. • The action potential is conducted throughout the heart and is responsible for initiating each heartbeat.
- 28. • Mechanism of Phase 0. • An externally applied stimulus • Open the Na+ channels and depolarize the membrane • Na+ ions enter the cell down their electrochemical gradient.
- 29. • Phase 1: Early Rapid Repolarization. • The membrane repolarizes rapidly and transiently to almost 0 mV (early notch), partly because of inactivation of INa and concomitant activation of several outward currents.
- 30. • Phase 2: Plateau. • The plateau is maintained by competition between the outward current carried by K+ and Cl− ions and the inward current carried by Ca2+ moving through open L-type Ca2+ channels and Na+ being exchanged for internal Ca2+ by the Na+/Ca2+ exchanger operating in forward mode.
- 31. • Phase 3: Final Rapid Repolarization. • Repolarization proceeds rapidly at least in part because of two currents: o Time-dependent inactivation of ICa. L, with a decrease in the intracellular movement of positive charges. o Activation of repolarizing K+ currents, including the slow and rapid components of the delayed rectifier K+ currents IKs and IKr and the inwardly rectifying K+ currents IKl and IK.
- 32. • Phase 4: Diastolic Depolarization. • IKl is the current responsible for maintaining the resting potential near the K+ equilibrium potential in atrial, His-Purkinje, and ventricular cells. • IKl is the inward rectifier and shuts off during depolarization.
- 33. MECHANISMS OF ARRHYTHMOGENESIS • The mechanisms responsible for cardiac arrhythmias- Disorders of impulse formation Disorders of impulse conduction Combinations of both. • “most consistent with” or “best explained by”
- 35. Disorders of Impulse Formation • Inappropriate discharge rate of the normal pacemaker, • The SA node (e.g., sinus rates too fast or too slow for the physiologic needs of the patient). • Pacemaker discharge from ectopic sites (latent or subsidiary pacemakers).
- 36. • Ectopic pacemaker activity at one of these latent sites can become manifested when the sinus nodal discharge rate slows or block occurs at some level b/w the SA node and the ectopic pacemaker site.
- 37. • The discharge rate of the latent pacemaker can speed inappropriately and usurp control of cardiac rhythm from the SA node, which has been discharging at a normal rate- ex. PVC or a burst of VT. • Disorders of impulse formation can be caused by speeding or slowing of a normal pacemaker mechanism or by an ionically abnormal pacemaker mechanism.
- 38. • Abnormal Automaticity. • Automaticity is the property of a fiber to initiate an impulse spontaneously, without need for prior stimulation. • Purkinje cells are critical contributors to arrhythmic triggers in animal models and humans with RyR2 mutations that are linked to CPVT.
- 39. • Rhythms resulting from automaticity may be slow atrial, junctional, and ventricular escape rhythms. • Atrial tachycardias (e.g., those produced by digitalis); accelerated junctional and idioventricular rhythms & parasystole.
- 40. • Triggered Activity • Triggered activity is initiated by after depolarizations, • Triggered activity is pacemaker activity that results as a consequence of a preceding impulse or series of impulses, without which electrical quiescence occurs.
- 41. • Depolarizations can occur before or after full repolarization of the fiber and are best termed EADs or • Late afterdepolarizations or DADs when they occur after completion of repolarization.
- 43. • Delayed Afterdepolarizations. • DADs and triggered activity demonstrated in Purkinje fibers, specialized atrial fibers and ventricular muscle fibers exposed to digitalis preparations, pulmonary veins. • DADs- arrhythmias precipitated by digitalis.
- 44. Major Role of Intracellular Ca2+-Handling Abnormalities in the Generation of Delayed Afterdepolarizations. • DADs result from the activation of a calcium- sensitive inward current →spontaneous increases in the intracellular free calcium concentration. • Acquired or inherited abnormalities in the properties of the SR calcium release channels. • Rapid mobilization of Ca2+ from the SR into the cytosol is mediated by the opening of ryanodine-sensitive Ca2+ release channels.
- 45. • During cardiac systole, the small influx of calcium ions through L-type Ca channels triggers a massive release of Ca2+ from the SR via synchronous opening of RyR2 channels, a process called Ca2+-induced Ca2+ release. • Mutations in RYR2 & CASQ2 gene- linked to CPVT.
- 46. Structure of the cardiac ryanodine receptor monomer subunit RyR2.
- 47. Pathway for efflux of Ca2+ from the SR lumen through IP3 receptor
- 48. Arrhythmogenic spontaneous Ca2+ elevations in a Purkinje myocyte.
- 49. Ventricular arrhythmia in heart failure.
- 50. Induction of a DAD by the application of caffeine
- 51. DADs and triggered tachyarrhythmia
- 53. Long-QT Syndrome • The genesis of LQTS-associated VT/VF is uncertain. • Action potential prolongation may increase influx of Ca2+ through L-type Ca2+ channels during a cardiac cycle and cause excessive accumulation of Ca2+ in the SR and spontaneous release of Ca2+ from the SR. • Elevation of intracellular free calcium depolarizes cardiomyocyte membrane potential, thereby evoking EADs→ VT.
- 54. Disorders of Impulse Conduction • Conduction delay & block can result in bradyarrhythmias or tachyarrhythmias. • Bradyarrhythmias occur when the propagating impulse is blocked & is followed by asystole or a slow escape rhythm. • Tachyarrhythmias occur when the delay and block produce reentrant excitation.
- 55. • Deceleration-Dependent Block – Diastolic depolarization - cause of conduction block at slow rates, so-called bradycardia- or deceleration-dependent block.
- 56. • Tachycardia-Dependent Block • Impulses are blocked at rapid rates as a result of incomplete recovery of refractoriness caused by incomplete time. • Decremental Conduction Stimulating efficacy of the propagating action potential diminishes progressively.
- 57. • Reentry – Various names—reentry, reentrant excitation, circus movement, reciprocal or echo beat, or reciprocating tachycardia. • Entrainment – Entrainment represents capture or continuous resetting of the reentrant circuit of the tachycardia by the pacing-induced activation.
- 58. • The criteria of entrainment can be used to prove the reentrant mechanism of a clinical tachycardia. • Basis for localizing the pathway traveled by the tachycardia wave front. • Localization is essential for ablation therapy.
- 59. Anatomic Reentry • The two pathways have different electrophysiological properties- Shorter refractory period and slower conduction in one pathway. Longer refractory period and faster conduction of the other.
- 60. • The impulse is first blocked in one pathway with a longer refractory period and then propagates slowly in the adjacent pathway whose refractory period is shorter. • If conduction in this alternative route is sufficiently depressed, the slowly propagating impulse excites tissue beyond the blocked pathway and returns in a reversed direction along the pathway initially blocked to reexcite tissue proximal to the site of block. • A clinical arrhythmia caused by anatomic reentry is most likely to have a monomorphic contour.
- 64. Conditions for Reentry • Conditions that depress conduction velocity or abbreviate the refractory period promote the development of reentry, whereas prolonging refractoriness and speeding conduction velocity can hinder it.
- 65. • Anatomic reentry occurs in patients with- 1. Wolff- Parkinson-White syndrome 2. AV nodal reentry 3. some atrial flutters 4. some ventricular tachycardias 5. VF.
- 66. Functional Reentry • Occurs in contiguous fibers that exhibit functionally different electrophysiologic properties (e.g., Purkinje-myocyte transition). • Infarct border zone.
- 67. Tachycardias Caused by Reentry • Atrial Flutter • Reentry is the most likely cause of the usual form of atrial flutter. • Reentrant circuit being confined to the right atrium in typical atrial flutter. • An area of slow conduction is present in the posterolateral to posteromedial inferior area of the right atrium. • This area of slow conduction is constant and represents the site of successful ablation of atrial flutter.
- 68. Atrial Fibrillation • Spatiotemporal Organization and Focal Discharge. • Multiple-wavelet hypothesis - AF is characterized by fragmentation of the wave front into multiple daughter wavelets. • They wander randomly throughout the atrium and give rise to new wavelets that collide with each other and are mutually annihilated or that give rise to new wavelets in a perpetual activity.
- 69. • Fibrillatory activity was maintained by intramural reentry centered on fibrotic patches. • Delivery of radiofrequency energy to discrete sites in the distal pulmonary veins - reduces recurrence of AF.
- 70. • AF from the pulmonary veins- combination of both reentrant and nonreentrant mechanisms (automaticity and triggered activity). • The role of dysfunction of calcium-handling proteins (e.g., Na+/Ca2+ exchanger, ryanodine receptor calcium release channels) in AF awaits further investigation.
- 71. The patterns of propagation are highly recurrent in the control in comparison to HF
- 72. Ion Channel Abnormalities in Atrial Fibrillation • Monogenic (Familial) Atrial Fibrillation. • Familial forms of AF are relatively rare • Most mutations linked to familial AF have been located in genes that encode sodium or potassium channel subunits. • Mutations in the GJA5 gene have been linked to familial AF.
- 73. Genome-Wide Association Studies for Lone Atrial Fibrillation • Multiple genomic regions are associated with lone AF. These regions encode ion channels (e.g., the calcium-activated potassium channel gene KCNN3 and the HCN channel gene HCN4), Transcription factors related to cardiopulmonary development (e.g., the homeodomain transcription factor PRRX1), Cell-signaling molecules (e.g., CAV1, a cellular membrane protein involved in signal transduction).
- 74. Electrical Remodeling of the Atria • key determinant for maintenance of AF. • The ionic basis of shortening of the refractory period and slowing of conduction may be a significant reduction in the density of the L- type Ca2+ and the fast Na+ currents.
- 75. Sinus Reentry • The reentrant circuit can be located entirely within the SA node or involve both the SA node and atrium. • SVT caused by sinus node reentry are generally less symptomatic than other SVT because of slower rates. • Ablation of the sinoatrial node may occasionally be necessary for refractory tachycardia.
- 76. Atrial Reentry • Can be a cause of SVT. • Distinguishing atrial tachycardia caused by automaticity or afterdepolarizations from atrial tachycardia sustained by reentry over small areas is difficult.
- 77. Atrioventricular Nodal Reentry • The reentrant pathway of the slow-fast type starts counter clockwise with a block in the fast pathway. • Delay in conduction across the slow pathway to the compact AV node, exit from the AV node to the fast pathway, and rapid return to the slow pathway through atrial tissue located at the base of the triangle of Koch. • The reentrant circuit of the fast-slow type is clockwise.
- 78. In the slow-slow type, anterograde conduction is over the intermediate pathway and retrograde conduction is over the slow pathway. Because slow-pathway conduction is involved in each type of AVNRT, ablation of the slow pathway is effective for all types of AVNRT. These results also demonstrate that atrial tissue surrounding the triangle of Koch is clearly involved in all three types of AV nodal reentry.
- 80. Preexcitation Syndrome • In WPW syndrome, the accessory pathway conducts more rapidly than the normal AV node but takes a longer time to recover excitability. • Premature atrial complex that occurs sufficiently early is blocked anterogradely in the accessory pathway and continues to the ventricle over the normal AV node and His bundle. • After the ventricles have been excited, the impulse is able to enter the accessory pathway retrogradely and return to the atrium.
- 81. • A continuous conduction loop of this type establishes the circuit for the tachycardia. • Orthodromic activation in a patient with an accessory pathway occurs anterogradely over the normal AV node–His-Purkinje system and retrogradely over the accessory pathway, which results in a normal QRS complex.
- 82. Lown-Ganong-Levine syndrome (short PR interval and normal QRS complex), conduction over a James fiber (that connects the atrium to the distal portion of the AV node and His bundle) has been proposed.
- 83. Ventricular Tachycardia Caused by Reentry • Reentry in ventricular muscle is responsible for most VT in pt`s with IHD. • Surviving myocardial tissue separated by connective tissue provides serpentine routes of activation traversing infarcted areas that can establish reentry pathways. • Bundle branch reentry can cause sustained VT, particularly in pt`s with DCMP.
- 84. • Both figure-of-8 and single-circle reentrant loops. • After the infarction - the surviving epicardial border zone undergoes substantial electrical remodeling ; reduced conduction velocity and increased anisotropy → reentrant circuits & VT. • During acute ischemia - elevated [K]o & reduced pH, combine to create depressed action potentials in ischemic cells that retard conduction →reentry.
- 85. • Ventricular Tachycardias Caused by Non reentrant Mechanisms – Esp. in pt`s without CAD • Triggered Activity – Usually located in the RVOT, DADs. – EADs and triggered activity may be responsible for torsades de pointes.
- 86. • Automaticity – Responsible for some VT – Does not suppressed by adenosine.
- 87. • Brugada Syndrome Phase 2 reentry in the genesis of ventricular tachycardia-fibrillation associated with the inheritable Brugada Loss-of-function mutations in SCN5A, which encodes the pore-forming cardiac sodium channel.
- 88. Alterations in the sodium channel current →heterogeneous loss of the action potential dome during the plateau phase in the right ventricular epicardium, Leads to a marked dispersion of repolarization and refractoriness → phase 2 reentry. Ablation of right ventricular epicardium eliminated ventricular arrhythmias.
- 89. Catecholaminergic Polymorphic Ventricular Tachycardia CPVT is an inherited arrhythmogenic disease Characterized by stress-induced, adrenergically mediated polymorphic ventricular tachycardia Occurring in structurally normal hearts.
- 90. • Heterozygous missense mutations in the gene encoding the RyR2. • Mutations in the calsequestrin gene can also cause CPVT.
- 91. • Mechanism of RyR2-associated CPVT is- increased leakage of Ca2+ from the SR during diastole leading to intracellular Ca2+ waves and triggered activity. • Carvedilol and flecainide suppress CPVT via direct inhibition of cardiac ryanodine receptor– mediated Ca2+ release.
- 92. Arrhythmogenic Right Ventricular Cardiomyopathy ARVC is an inherited disease characterized by sustained monomorphic VT & sudden death. ARVC - mutations in proteins of the cardiac desmosome. ~70% of the mutations are in the gene encoding PKP2.
- 93. Ventricular Fibrillation: Initiation & Maintenance VF is maintained solely by reentry. Recent investigations- concepts of restitution kinetics, wave front, wave break, focal discharge, and rotor as replacement for the classic reentry theory.
- 94. The hallmark of cardiac fibrillation is ongoing wave break (or wave splitting). Wave break is caused by a conduction block occurring at a specific site along the wave front while the remaining portions of the front continue to propagate.
- 95. 1. Stable mother rotor theory-VF is maintained by a single, stationary, intramural stable reentrant circuit. 2. Wandering wavelet hypothesis- VF is maintained by wandering wavelets with constantly changing, evanescent, reentrant circuits.
- 97. THANKOU
Editor's Notes
- The human sinus node. This photograph, taken in the operating room, shows the location of the normal cigar-shaped sinus node along the lateral border of the terminal groove at the junction of the superior vena cava and atrium (arrowheads).
- Hyperpolarization-activated cyclic nucleotide–gated
- The failing heart exhibits fewer TH-positive nerves and markedly more CHT-positive nerves than does the nonfailing heart. tyrosine hydroxylase (TH; red) and choline transporter (CHT; green)
- Structure of ion channels. Voltage-gated Na+ and Ca2+ channels are composed of a single tetramer consisting of four covalently linked repeats of the six transmembrane–spanning motifs, whereas voltage-gated K+ channels are composed of four separate subunits, each containing a single six transmembrane– spanning motif. Inwardly rectifying K+ channels are formed by inward rectifier K+ channel pore-forming (alpha) subunits. In contrast to voltage-gated K+ channel alpha subunits, the Kir alpha subunits have only two (not six) transmembrane domains.
- Demonstration of action potentials recorded during impalement of a cardiac cell. Upper row, Shown are a cell (circle), two microelectrodes, and stages during impalement of the cell and its activation and recovery. Both microelectrodes are extracellular (A), and no difference in potential exists between them (0 potential). The environment inside the cell is negative and the outside is positive because the cell is polarized. One microelectrode has pierced the cell membrane (B) to record the intracellular resting membrane potential, which is −90 mV with respect to the outside of the cell. The cell has depolarized (C), and the upstroke of the action potential is recorded. At its peak voltage, the inside of the cell is approximately +30 mV with respect to the outside of the cell. The repolarization phase (D) is shown, with the membrane returning to its former resting potential (E).
- Some tachyarrhythmias can be started by one mechanism and be perpetuated by another. An episode of tachycardia caused by one mechanism can precipitate another episode caused by a different mechanism.
- Automacity is the ability of cardiac cells to depolarize spontaneously. Automaticity is controlled by the sinoatrial node (SAN), the so-called "Heart Pacemaker". Abnormalities in automaticity may result in rhythm disorders. Automaticity is the cardiac cell's ability to spontaneously generate an electrical impulse (depolarize). Parasystole is a kind of arrhythmia caused by the presence and function of a secondary pacemaker in the heart, which works in parallel with the SA node. Parasystolic pacemakers are protected from depolarization by the SA node by some kind of entrance block. This block can be complete or incomplete. Parasystolic pacemakers can exist in both the atrium or the ventricle. Atrial parasystolia are characterized by narrow QRS complexes Two forms of ventricular parasystole have been described in the literature, fixed parasystole and modulated parasystole. Fixed ventricular parasystole occurs when an ectopic pacemaker is protected by entrance block, and thus its activity is completely independent from the sinus pacemaker activity. Hence, the ectopic pacemaker is expected to fire at a fixed rate. Therefore, on ECG, the coupling intervals of the manifest ectopic beats will wander through the basic cycle of the sinus rhythm. Accordingly, the traditional electrocardiographic criteria used to recognize the fixed form of parasystole are: the presence of variable coupling intervals of the manifest ectopic beats; inter-ectopic intervals that are simple multiples of a common denominator; fusion beats. Depolarization, the negative internal charge of the cell becomes positive for a very brief period of time. he sinus node contains pacemaker cells that have spontaneous firing capacity. This is called normal automaticity. Abnormal automaticity occurs when other cells start firing spontaneously, resulting in premature heartbeats. Triggered activity During triggered activity heart cells contract twice, although they only have been activated once. This is often caused by so called afterdepolarizations (early or delayed afterdepolarizations EADs / DADs) caused by electrical instability in the myocardial cell membrane. A typical example of this is Torsade de Pointes. The long QT syndrome may be either genetic or acquired [6-9]. Acquired LQTS usually results from drug therapy, hypokalemia, or hypomagnesemia (table 1). As will be described below, hypokalemia, hypomagnesemia. Jervell and Lange-Nielsen (JLN) syndrome, is associated with LQTS and sensorineural deafness. Romano-Ward syndrome.
- Ordinarily kept from reaching the level of threshold because of overdrive suppression by the more rapidly firing SA node.
- Polymorphic ventricular tachycardia and sudden death in an animal model of type 4 LQTS. A, Electrocardiogram after exercise and administration of epinephrine in a mouse heterozygous for a loss-of-function mutation in the gene encoding ankyrin-B (AnkB−). Polymorphic ventricular tachycardia (torsades de pointes) occurred within about 17 minutes of epinephrine administration, followed by marked bradycardia and death 2 minutes after the arrhythmia. B, Transmembrane action potentials in single cardiomyocytes from AnkB+/− mice at the frequencies indicated. Acute exposure to isoproterenol induced both DADs and EADs, which led to extra beats.
- Structure of the cardiac ryanodine receptor monomer subunit RyR2 delineating the sites of interaction with auxiliary proteins and the phosphorylation sites (P). CaM = calmodulin; CaMKII = calmodulin-dependent kinase II; FKBP = FK506 binding protein 12.6; PKA = protein kinase A; PP = protein phosphatase. Calsequestrin, junctin, and triadin are proteins that interact with RyR2 in the SR. (From Bers DM: Macromolecular complexes regulating cardiac ryanodine receptor function.
- Structure of the IP3 receptor (IP3R). IP3Rs are intracellular membrane proteins that exist as homotetramers or heterotetramers. The Ca2+ conducting pore is believed to be created at the central axis of the tetrameric structure. The cartoon depicts three of four IP3R molecules (in different colors) in a single tetrameric channel structure. Part of the luminal loop (i.e., the loop facing the SR lumen) connecting transmembrane helices 5 and 6 of each monomer dips into the fourfold symmetrical axis and creates the pathway for efflux of Ca2+ from the SR lumen.
- Arrhythmogenic spontaneous Ca2+ elevations in a Purkinje myocyte isolated from a mouse heterozygous for a gain-of-function mutation in the RYR2 gene. Changes in intracellular free calcium (Δ[Ca2+]i, upper trace) and transmembrane action potential (Vm) were simultaneously recorded in a mutant Purkinje myocyte during electrical field stimulation (arrows) and during a spontaneous elevation in Ca2+ (triggered action potential, TA). Note that the action potential upstroke is preceded by a low-amplitude elevation in Ca2+, followed by a suprathreshold membrane depolarization that triggers a markedly prolonged action potential
- Ventricular arrhythmia in an animal model of heart failure (aortic constriction-insufficiency in the rabbit). A, Cross sections of a control and failing heart (HF) and Holter recording of nonsustained ventricular tachycardia (VT) seen in a failing heart. B, Spontaneous aftercontractions and increases in [Ca2+]i in a failing cardiomyocyte after exposure to isoproterenol.
- C, Induction of a DAD by the application of caffeine (cDAD) in a cardiomyocyte isolated from a failing rabbit heart. In normal Tyrode (NT) solution, caffeine causes rapid release of Ca2+ from the SR, thereby leading to increases in the intracellular free calcium concentration (bottom tracing), which in turn causes membrane depolarization. Blocking of the Na+/Ca2+ exchange current in Na+-free and Ca2+-free solution (0Na/0Ca) abolished DADs despite a similar increase in [Ca2+]i, whereas blocking of the Ca2+-activated Cl− current with niflumate did not prevent DADs. Em = membrane voltage.
- catecholaminergic polymorphic ventricular tachycardia [CPVT]
- Proposed scheme of events leading to DADs and triggered tachyarrhythmia. Top panel, Congenital (e.g., gain-of-function mutations in the RYR2 or CASQ2 genes) or acquired factors (e.g., ischemia, hypertrophy, increased sympathetic tone, heart failure) will cause a diastolic Ca2+ leak through RyR2 that results in localized and transient increases in [Ca2+]i in cardiomyocytes. Middle panel, Representative series of images showing changes in [Ca2+]i during a Ca2+ wave in a single cardiomyocyte loaded with a Ca2+-sensitive fluorescent dye. Images were obtained at 117-millisecond intervals. Focally elevated Ca2+ (2) diffuses to the adjacent junctional SR, where it initiates more Ca2+ release events that result in a propagating Ca2+ wave (3 to 8). Bottom panel, The Ca2+ wave, through activation of inward INa/Ca, will depolarize the cardiomyocyte (DAD). If of sufficient magnitude to overcome the source-sink mismatch, the DAD will depolarize the cardiomyocyte above threshold and result in a single or repetitive premature heartbeat (red arrows), which can trigger an arrhythmia. Downregulation of the inwardly rectifying potassium current (IK1), upregulation of INa/Ca, and shortened Ca2+ signaling refractoriness because of ryanodine receptor phosphorylation and/or oxidation can promote the generation of DAD-triggered action potentials. S = stimulus.
- If, a group of fibers not activated during the initial wave of depolarization recovers excitability in time to be discharged before the impulse dies out, the fibers may serve as a link to reexcite areas that were just discharged and have now recovered from the initial depolarization.
- Dispersion of excitability, refractoriness, or both, as well as anisotropic distributions of intercellular resistance, permit initiation and maintenance of reentry.
- It usually travels counterclockwise in a caudocranial direction in the interatrial septum and in a craniocaudal direction in the right atrial free wall.
- The patterns of propagation are highly recurrent in the control in comparison to the heart failure (HF) atrium. LIPV = left inferior pulmonary vein; LSPV = left superior pulmonary vein; RIPV = right inferior pulmonary vein; RSPV = right superior pulmonary vein.
- Reentrant circuits of different types of AVNRT. Pictures of the optical activation maps of A2 obtained from three different experiments at A2 coupling intervals of 190, 220, and 190 milliseconds, respectively, were merged with the pictures of the mapping area to show the initiation of echo beats in A (Slow/Fast), C (Fast/Slow), and E (Slow/Slow). The numbers on the maps indicate the activation times in reference to the A2 stimulus. The black arrow indicates anterograde conduction, and the asterisk and the dashed red arrow represent the site of earliest retrograde atrial activation. The corresponding locations of the lines of block (LB, green), slow anterograde conduction (SC, black arrow), and unidirectional conduction (UC, red) are shown in B, D, and F, respectively. CS = coronary sinus; FP = fast pathway; IP = intermediate pathway; SP = slow pathway.
- Wolff-Parkinson-White syndrome,
- Desmosome- component of the intercalated disc essential for mechanical coupling b/w cardiomyocytes. Intercalated discs are microscopic identifying features of cardiac muscle. Cardiac muscle consists of individual heart muscle cells (cardiomyocytes) connected by intercalated discs to work as a single functional organ or syncytium. Mutations in multiple genes, including desmoplakin, desmoglein 2, desmocollin 2, plakophilin 2, plakoglobin (JUP, also called gamma-catenin), ryanodine receptor 2, laminin receptor 1, and transforming growth factor-beta 3, have been identified in patients with ARVC.
- Action potential duration (APD) restitution slope and rotor stability. A, APD shortening and APD alternans as the pacing cycle length (PCL) decreases. B, APD restitution curves with a slope greater than 1 (solid line) or less than 1 (dashed line, obtained with 50% block of the calcium current). C, D, Spiral wave behavior several seconds after initiating a rotor in homogeneous two-dimensional tissue. All myocytes are assumed to be identical, with either a steep (C) or shallow (D) APD restitution slope. E, F, Conversion of multiple-wavelet VF to mother rotor VF. In E, multiple wave fronts move in a complex VF pattern. In F, VF has converted to ventricular tachycardia, manifested as a stable rotor. Black tracings below the color panels in E and F are corresponding electrograms. DI = diastolic interval.