Cardiac Electrophysiology: Promises And Contributions
1329JACC Vol. 13, No. 6May 1989:1329-52PLENARY LECTURECardiac Electrophysiology: Promises and ContributionsDOUGLASIndianapolis,P. ZIPES,MD, FACCIndianaIntroductionPatient J.D. is a 53 year old man who was recoveringuneventfully in a coronary care unit 5 days after having anacute inferior myocardial infarction. Fifteen seconds afterbeing told that his mother died, J.D. developed ventricularfibrillation (Fig. 1).In this presentation, I discuss concepts that relate to theonset of ventricular tachyarrhythmia in patients like J.D. Ido this by reviewing some of the clinically relevant contributions made by cardiac electrophysiology and the promisesthat the future offers in understanding and treating patientswith cardiac arrhythmias. Selected aspects of four areas willbe discussed: pathogenesis, treatment, prognosis and futuredirections.Pathogenesis of Cardiac ArrhythmiasMechanisms responsible for cardiac arrhythmias are generally divided into three major categories: disorders ofimpulse formation, disorders of impulse conduction andcombinations of both causes (Table 1) (l-5). The classification is limited and contains some inconsistencies. For example, reentry is not actually a mechanism, but rather is apathway traveled by the cardiac impulse. The mechanism isreally a circus movement of excitation (2). Abnormalities incell to cell coupling and excitability (6), effects of anisotrophy (7) and other factors are lumped under single, simpleheadings. Nevertheless, it serves as a useful framework inwhich to discuss arrhythmogenesis.Disordersof Impulse FormationAutomaticity, triggered activity and afterdepolarizations.Normal automaticity relates to the normal diastolic depolarization of pacemakers found in the normal sinus node,From the Department of Medicine, Krannert Institute of Cardiology andthe Roudebush Veterans Administration Medical Center, Indianapolis, Indiana. This study was supported in part by the Herman C. Krannert Fund; byGrants HL-06308and HL-07182from the National Heart, Lung, and BloodInstitute, National Institutes of Health, Bethesda, Maryland and by theAmerican Heart Association, Indiana Affiliate, Inc., Indianapolis, Indiana. Itwas presented in part as the Opening Plenary Lecture at the 36th AnnualScientific Sessions, American College of Cardiology, Atlanta, Georgia, March1988.Address fo reorints: Douglas P. Zipes, MD, Krannert Institute ofCardiology, 100rlW. 10th Street, Indianapolis, Indiana 46202.01989 by the American College of CardiologyPurkinje fibers and some other areas in the heart. Abnormalautomaticity may occur in many of these fibers subjected tothe effects of ischemia, drugs or other interventions. Bothnormal and abnormal forms of automaticity can generatearrhythmias (l-5,8).Triggered activity. This concept has been emphasizedrecently (3), though it is not new (9). It refers to a transientmembrane oscillation triggered by cardiac depolarization.When this oscillation occurs early, before repolarization iscompleted, it is called an early afterdepolarization; when itoccurs late, after repolarization is completed, it is called adelayed afterdepolarization (3). Slow heart rates generallyincrease the amplitude of early afterdepolarizations,whereas fast heart rates, within limits, increase the amplitude of delayed afterdepolarizations. In this example of atransmembrane cardiac action potential recording (Fig. 2),depolarization during the upstroke of the cardiac actionpotential (arrow) corresponds to the QRS complex in thescalar electrocardiogram (ECG) (10). During repolarization,when the T wave would be present, additional depolarizations occur (arrowheads). These early afterdepolarizations,produced in this example by superfusing an isolated Purkinjefiber with cesium, can prolong repolarization (lengthen theQT interval in the scalar ECG) and can give rise to premature complexes or tachycardia (Table 1) (11-14).Afterdepolarizations.Early afterdepolarizations resultfrom a reduced repolarizing current in comparison with thedepolarizing current. This may be caused by a reducedoutward current, an increased inward current or both (3).Because interventions that act through different mechanismscan abolish early afterdepolarizations (such as the calciumchannel blockers, verapamil, D-600 and nitrendipine [ 151;the sodium channel blockers like tetrodotoxin and lidocaine[16] and increasing rate or increasing external potassium[K ]) and because a variety of substances can induce earlyafterdepolarizations (such as quinidine [ 161and related drugs[3], a sea anemone polypeptide [17], calcium current agonists [18], acidosis [19], low extracellular Kf concentration[20], hypoxia and catecholamines), a diversity of currentshave been suggested as causes. These include a calciumcurrent through L-type calcium channels (18), the sodium“window” or slowly inactivating current (21), sodium channel exchange mechanisms (22), the transient inward current0735.1097/89/ 3.50
1330ZIPESCARDIAC’ ELECTROPHYSIOLOGY:ANDPROMISESJACC Vol. 13. No. 6May 1989: 1329-52CONTRIBUTIONSFigure 1. Monitor recording from patient J.D., showingthe onset of ventricular fibrillation.MONITORsimilarities to both the acquired and the idiopathic (congen-activated by elevated intracellular calcium (23) intracellularpotassium accumulation (21) and the I,, current (24).Cesium blocks inward-rectifyingpotassiumital) long QT syndromes (see below). Magnesium suppressesthese early afterdepolarizations and associated ventriculartachyarrhythmias (10,27), possibly by blocking the calciumcurrent (28), whereas ansae subclaviae stimulation and norepinephrine infusion stimulates them.Alpha-l adrenoceptor stimulation, by provoking intracellular calcium accumulation, has been implicated in thegenesis of ventricular arrhythmias associated with ischemia(29). Alpha-l adrenoceptor stimulation has also been showncurrents andHowever, the ionic basis ofcesium-induced early afterdepolarizations is still unclear.Some early afterdepolarizations may be due to electrotonicmembrane events (11). A calcium current through L-typecalcium channels may be involved (l&26). Cesium producesearly afterdepolarizations in canine cardiac Purkinje fibers(10,12) and in the intact heart (lo,1 1). The latter exhibitsdelaysrepolarization(2.5).Table 1. Mechanisms of ArrhythmogenesisI. Disordersof impulseformationA. AutomaticityI. Normalautomaticitya. Experimentalb. Clinicalexamples-normalexamples-sinusventricular2. Abnormalinappropriatefibers.othersfor the clinicalsituation,possiblyfibers or maricityventricularrhythmsin Purkinjeafter myocardialinfarctionactivity1. Earlyafterdepolarizationsa. Experimental(EADs)example-EADsdrugs such as sotalol.b. Clinical2. Delayedproducedexamples-possiblyb. Clinicalacquiredhypoxia.high concentrationsof catecholamines.cesiumlong QT syndromeand producedexample-possiblyof impulseby barium,N-acetylprocainamide,afterdepolarizationsa. ExperimentalII. Disordersor bradycardiaparasystolea. ExperimentalB. Triggeredin vivo or in vitro sinus node. Purkinjetachycardiain Purkinjesome digitalis-inducedfibers by digitalisarrhythmiasconductionA. BlockI. Bidirectionalor unidirectionala. Experimentalb. Clinicalexample--GSA2. Unidirectionalbundlereentrynode, AV node. bundlenode. AV node ck with reentrya. Experimentalb. Clinicalwithoutexample-SAexamples-AVnode, Purkinjeexamples-reciprocatingbranchreentry,muscle junction,tachycardiain WPWinfarctedsyndrome.myocardium.AV nodal reentry,othersVT due toothers3. Reflectiona. Experimentalb. ClinicalIII.Combinedexample-Purkinjefiber with area of inexcitabilityexample-unknowndisorders.4. InteractionsbetweenI. Experimentaldischarge2. ClinicalB. Interactionsautonomicfociexamples-depolarizingor hyperpolarizingsubthresholdstimulispeed or slow automaticrateexample-modulatedbetweenI. Experimentalparasystoleautomaticityand rdrivesuppressionof conduction.entranceand exit block2. ClinicalAVsyndrome.examples-similar atrioventricular:ReproducedSAto experimental sinoatrial;with permissionVTexamples ventricularfrom Zipes (176).tachycardia;WPW Wolff-Parkinson-White
JACC Vol. 13, No. hMa\, AND CONTRIHt:i-IONS1331Cs 5mMCs 5mM Mci5mMCs 5mMRVMAPI50mVFigure 3. Recording of monophasic action potential from the right5 SCFigure 2. Transmembrane potential recordings showing the effectof magnesium chloride on early afterdepolarizations induced bycesium in a spontaneously discharging canine cardiac Purkinje fiber.Top, Several repetitive early afterdepolarizations were induced by 5mM cesium (Cs) in 2.7 potassium chloride Tyrode’s solution.Middle, Five minutes after superfusion with 5 mhl magnesiumchloride added to the cesium-low potassium Tyrode’s solution, earlyafterdepolarizations were abolished. Bottom, Four minutes afterwashout of magnesium chloride and resumption of superfusion withcesium-low potassium Tyrode’s solution, early afterdepolarizationsrecurred. Reproduced with permission from the American HeartAssociation. Inc. t IO).to produce delayed afterdepolarizationsin Purkinje fibersremoved from cats with previous myocardial infarction, butnot in normal feline Purkinje fibers unless the extracellularcalcium concentration is raised (30). Alpha- 1 adrenoceptorstimulation leads to an increase in cytosolic free calcium(31), which could increase the net inward current. Thiswould magnify the amplitude of early afterdepolarizationsand exacerbate the prevalence of ventricular tachyarrhythmias related to them. Alpha-l adrenoceptor blockade mightbe expected to exert opposite effects (32).Long QT syndromes. Just as the Wolff-Parkinson-Whitesyndrome serves the clinical electrophysiologist as the Rosetta stone of reentry, so may the long QT syndrome be theRosetta stone for an entirely different class of arrhythmias.In patients with acquired and idiopathic (congenital) long QTsyndromes (33,341, early afterdepolarizations may be responsible for the prolonged repolarization and the associatedventricular arrhythmias such as torsade de pointes (14.35).The example illustrated in Figure 3 was recorded in an intactdog with use of a special catheter electrode that produces aventricle (RVMAP) along with electrocardiographic (ECG) lead IIand right atrial electrogram (RA). Panel A, Control. No earlyafterdepolarization present. Panel B. Immediately after administration of cesium (intravenously). Early afterdepolarization is indicatedby the arrow. Panel C, After continued administration of cesium.premature ventricular complexes and ventricular tachycardia result.Note the large early afterdepolarization occurring after a pause inthe cycle (arrow).monophasic action potential (36) resembling the intracellularrecording in Figure 2. Early afterdepolarizations (Fig. 3,arrow) develop shortly after cesium injection. Early afterdepolarizations can occur at a reduced (Fig. 2) or a morenegative (Fig. 3) membrane potential. When sufficient cesium is administered, ventricular tachyarrhythmias similarto torsade de pointes result. Note the long-short cycle lengthin Figure 3 before the onset of the ventricular tachycardia(Fig. 4). Magnesium has been reported to suppress torsadede pointes in patients with the acquired long QT syndromedue to quinidine and other antiarrhythmic agents (37). It alsosuppresses cesium-induced early afterdepolarizations (Fig.2) (10.27) and ventricular tachyarrhythmias in the dog (10).Idiopathic long QT syndrome: role of left stellate stimulation. In patients with the idiopathic long QT syndrome, leftstellate stimulation, possibly due to sympathetic imbalance,has been postulated as a possible cause of ventriculararrhythmias (38). This animal model produced by cesiumadministration simulated many aspects of the acquired andidiopathic long QT syndromes and provided the opportunityto test this hypothesis. We found that dogs treated withcesium had larger amplitude early afterdepolarizations and agreater prevalence of ventricular tachycardia during leftstellate stimulation compared with right stellate stimulation(Fig. 5) (39). Left sympathetic stimulation may be arrhyth-
1332ZIPESCARDIACELECTROPHYSIOLOGY:JACC Vol. 13, No. 6May 1989: 1329-52PROMISES AND CONTRIBUTIONSFigure 4. Polymorphic ventricular tachycardia resembling torsadede pointes. The ventricular tachycardia shown during its onset inFigure 3 continues as polymorphic ventricular tachycardia resembling torsade de pointes. Finally, it terminates at the end of thecontinuous recording of electrocardiographic lead II. Reproducedwith permission from the American Heart Association, Inc. (175).mogenic because it exerts a quantitatively greater adrenergicinfluence on the ventricles, particularly the left ventricle,than does the right stellate ganglion. We postulate that leftsympathetic stimulation, which results in a larger ventricularmass being affected by more norepinephrine being released,rather than qualitative differences between the stellate gan-glia or right-left stellate imbalance, may be the basis for thearrhythmogenic potential of the left stellate ganglion. It alsomay account for the beneficial effects of surgical interruptionof the left stellate ganglion.One can hypothesize that patients with the idiopathic longQT syndrome have a primary myocardialmembranedefectmanifested during repolarization (for example, involving anoutward repolatizing potassium current or an inward calcium current) that creates early afterdepolarizations and thelong QT interval. Autonomic imbalance is not necessary.Sympathetic stimulation, primarily left, could periodicallyincrease the amplitude of the early afterdepolarizations toreach threshold and produce ventricular tachyarrhythmias.The fact that left stellate ganglion interruption reduces theincidence of syncope and sudden death in some patients withthe idiopathic long QT syndrome in whom beta-adrenoceptor blocking drugs are ineffective (40) underscores thepotential importance of alpha-adrenoceptor stimulation ofearly afterdepolarizations (32). In patients with the long QTsyndrome after surgery, the long QT interval generally doesnot shorten, although ventricular tachyarrhythmias cease,possibly because early afterdepolarizations are still present,though subthreshold. Left stellate ganglion interruption hasalso been shown to reduce sudden death in patients afteranterior myocardial infarction (41) and, thus, its stimulationmay be arrhythmogenic during ischemia in patients like J.D.(Fig. 1).Causes of delayed afterdepolarizations.Delayed afterdepolarizations have been reported (42-44) experimentally inFigure 5. Differential response of early afterdepolarizations during each intervention inthe same dog. Panel A was recorded duringcontrol; no early afterdepolarizations or anyvoltage deflections exist during phase 3 or 4.One minute after cesium injection, panels B,C, D and E were recorded during cesiumalone (panel B) or with right (RAS) (panel C),left (LAS) (panel D) and bilateral (BAS) (panelE) ansae subclaviae stimulation. The numberswithin the monophasic action potential (MAP)recordings represent the early afterdepolarization amplitude as a percentage of the monophasic action potential amplitude. Panel Fshows the effect of left stellate stimulation(LAS) on the same dog 25 s after panel D wasrecorded; after an atria1 paced beat, a short runof nonsustained ventricular tachycardia (VT)occurred. Note the decreased amplitude of theearly afterdepolarization in the right ventricle(RV) compared with the high take-off potentialof the early afterdepolarization in the left ventricle (LV), initiating the ventricular tachycardia. LVMAP left ventricular monophasicaction potential recording; -0, -5 indicate 0 to5 mV. LVEG left ventricular electrogram;other abbreviations as in Figure 3. Reproducedwith permission of the American Heart Association, Inc. (39).
JACC Vol. 13, No. 6May 1989: 1329-52CARDIAC ELECTROPHYSIOLOGY:several settings, such as in digitalis-treated hearts, duringcatecholamine stimulation of the coronary sinus, sympathetic neural stimulation and 24 h after myocardial infarctionin dogs (Table 1). Digitalis poisons sodium-potassium adenosine triphosphate, which leads to an increase in intracellular sodium that then exchanges for calcium. The elevatedintracellular calcium concentration causes more calcium tobe released from the sarcoplasmic reticulum (calciuminitiated calcium release), which triggers a transient inwardcurrent carried by sodium that causes the delayed afterdepolarizations (45). Delayed afterdepolarizations may be responsible for some of the clinical arrhythmias that are foundin situations resembling the experimental conditions inwhich they have been produced (for example. arrhythmiasdue to digitalis or occurring after myocardial infarction).Delayed afterdepolarizations could be recorded in endocardium resected from a patient with recurrent episodes ofventricular tachycardia due to coronary artery disease (Fig.6) (46). In this example, during initial electrical stimulation(filled circles). the preparation developed a gradual increasein the amplitude of the delayed afterdepolarizations(arrows). The depolarization phase of the action potential isnot clearly seen because of the rapid upstroke, whereasrepolarization is obvious. After cessation of stimulation (lastfilled circle), a large delayed afterdepolarization results andtriggers the sustained short run of spontaneous action potentials, probably comparable with ventricular tachycardia in anintact heart. A subthreshold delayed afterdepolarization(arrow) terminates the burst. Accelerated atrioventricular(AV) junctional escape complexes may be due to delayedafterdepolarizations (47).Disorders of Impulse ConductionZIPESPROMISES AND CONTRIBUTIONS1333OXlA? ?Figure 6. Triggered sustained rhythmic activity and delayed afterdepolarizations in diseased human ventricle. A, Spontaneous activity triggered by a series of driven action potentials (dots)at recordingsite X,. Note the gradual increase in the size of the delayedafterdepolarizations (arrows) until the afterdepolarization reachesthreshold and maintains sustained rhythmic activity after cessationof pacing. The sustainedrhythmic activity finallyterminates whenthe last afterdepolarization fails to reach threshold (third arrow). B,Initiation of triggered activity by intracellular current injection (dotsbeneath the respective action potential recordings) at sites X, andX,, which lie along the same trabeculum. Although sites X, and XIwere only about 4 mm apart, triggered sustained rhythmic activityfrom one site did not propagate to the other site. indicating completedissociation between these two sites. For current pulses, cyclelength 2,000 ms; pulse duration 10 ms; pulse intensity 200 na.Vertical calibration: 50 mV; horizontal calibration: IO s. Reproduced with permission from Gilmour et al. (46).Reentrant tachyarrhythmias. The presence of unidirectional block is the basis for reentry and has been demon-strated experimentally in many preparations, including AVnode1 tissue, ischemic/infarcted ventricular muscle, the bundle branches (491, Purkinje-muscle junctions and at othercardiac sites (49-52). Determinants of conduction patternsthat produce reentry are multiple and complex, includingchanges in cellular excitability and cell to cell coupling (6),anisotropic propagation (7) and rate of rise of action potential depolarization. Calcium concentration (53), pH (54) andautonomic influences (55) affect cell to cell coupling, whichin turn modulates conduction.Reentry curt occur over anatomically or functionallydejined pathways and is basically of three types: 1) reentrantcircuits created by separate anatomic pathways, such as inthe Wolff-Parkinson-White syndrome (56,57); 2) functionallydete
Cardiac Electrophysiology: Promises and Contributions DOUGLAS P. ZIPES, MD, FACC . disorders of impulse conduction and combinations of both causes (Table 1) (l-5). . ple, reentry is not actually a mechanism, but rather is a pathway traveled by the cardiac impulse. The mechanism is really a circus movement of excitation (2). .
CARDIAC ELECTROPHYSIOLOGY, ARRHYTHMIAS AND PACING Medical Knowledge Goals and Objectives PF EF MF LF Aspirational Know the protocols and diagnostic value of invasive X studies of cardiac conduction including sinus node function test and studies of intra-atrial, AV nodal and
Electrophysiology Biomechanics An inherent and rhythmic electrical activity is the reason for the heart’s lifelong beat. The primary function of cardiac myocytes is to contract. Electrical changes within the myocytes initiate this contraction. Cardiac cells, like all living cells in the bod
3) Blockage in normal conduction pathway (e.g., disease) Cardiac Electrophysiology Cardiovascular System –Heart Cardiac Electrophysiology Conduction velocity (speed at which APs propagate in tissues) differs among myocardial tissues Only connection: atria ventricles Costanzo (Physiology, 4th ed.) –Figure 4.14
Supraventricular Tachycardia —(1)5 min consult William L. Discepolo, M.D. Cardiac Electrophysiology. Pomona Valley Hospital
Personalization of Cardiac Electrophysiology Models for Prediction of Ischaemic Ventricular Tachy-cardia. Interface Focus, Royal Society publishing, 2011, 1 (3), pp.396-407. 10.1098/rsfs.2010.0041 . . eters of a biophysical model, the Mitchell-Schaeffer (MS) model. Additional parameters related to Action Potential
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