Steven M. Pogwizd

Reentrant and focal mechanisms underlying ventricular tachycardia in the human heart.

BackgroundTo determine the mechanisms of ventricular tachycardia (VT) in humans, three-dimensional intraoperative mapping of up to 156 intramural sites was performed in 13 patients with healed myocardial infarction and refractory VT. Methods and ResultsMapping was of sufficient density to define the mechanism of 10 VTs in eight patients. In five of 10 cases, sustained VT was initiated in the subendocardium or epicardium by intramural reentry with marked conduction delay as well as functional and anatomic block most prominent in the subendocardium and midmyocardium. The initiating beats of reentrant VT induced by programmed electrical stimulation arose in the endocardium or midmyocardium by progressive slowing of conduction leading to unidirectional block. Multiple simultaneous reentrant circuits can be present. In contrast, five of the 10 sustained VTs were initiated by a focal mechanism as defined by the absence of electrical activity between the termination of one beat and the initiation of the next despite the presence of multiple intervening intramural electrode recording sites. Comparisons of the mapping data with results of histopathological analysis of tissue demonstrated that the location of infarction as well as that of adjacent fibrotic muscle determined sites of both fixed and functional conduction block during macroreentrant VT and that slowing of conduction occurred in a direction transverse rather than longitudinal to fiber orientation. ConclusionsBoth intramural reentry and a focal mechanism underlie sustained VT in patients with healed myocardial infarction.

Nonreentrant Mechanisms Underlying Spontaneous Ventricular Arrhythmias in a Model of Nonischemic Heart Failure in Rabbits

BACKGROUND The goal of this study was to define the mechanisms of spontaneously occurring ventricular arrhythmias in the setting of nonischemic heart failure. METHODS AND RESULTS Three-dimensional cardiac mapping from 232 intramural sites was performed in four rabbits with heart failure induced by combined aortic regurgitation and aortic stenosis and in four control rabbits. During the development of heart failure, serial echocardiographic examination demonstrated a progressive increase in left ventricular (LV) chamber dimensions and a decrease in LV systolic function over 19 +/- 2 months. Serial Holter monitoring demonstrated spontaneously occurring premature ventricular complexes (PVCs) (up to 13,000 per day) and couplets in all four rabbits with heart failure, and runs of nonsustained ventricular tachycardia (VT) up to 26 beats long in three. Mapping of spontaneous rhythm was performed for up to 60 minutes. None of the control rabbits demonstrated spontaneous arrhythmias during mapping. Three rabbits with heart failure demonstrated isolated PVCs, and two demonstrated couplets and runs of nonsustained VT up to 4 beats long. The three-dimensional activation sequence of 50 sinus beats (42 from rabbits with heart failure; 8 from control rabbits), 19 PVCs, and 37 beats of couplets and nonsustained VT was determined and the mechanism of arrhythmia defined for all ventricular ectopic beats analyzed. Normal sinus beats from the failing rabbits activated rapidly, with a total activation time of 28 +/- 1 ms (P = .18 versus sinus beats from control hearts, 26 +/- 1 ms). Sinus beats preceding PVCs in the rabbits with heart failure activated in a similar fashion, with a total activation time of 26 +/- 1 ms. In each case, these PVCs initiated in the subendocardium by a nonreentrant mechanism based on the absence of intervening electrical activity between the termination of the preceding beat and the initiation of the next (225 +/- 7 ms), despite the presence of multiple intervening electrode recording sites. Couplets and monomorphic and polymorphic VTs were due to repetitive nonreentrant activation at the same or different subendocardial sites. Total activation time of beats of VT averaged 44 +/- 1 ms and did not differ from that of isolated PVCs (43 +/- 2 ms, P = .65). Pathological analysis of tissue demonstrated myocardial fiber hypertrophy, degenerative changes, and interstitial fibrosis throughout the failing hearts. CONCLUSIONS Spontaneously occurring PVCs, couplets, and VT in a model of nonischemic heart failure are due to nonreentrant mechanisms such as triggered activity or abnormal automaticity. Approaches to the treatment of spontaneously occurring ventricular arrhythmias in patients with nonischemic heart failure should be directed at nonreentrant mechanisms.

Amphipathic lipid metabolites and their relation to arrhythmogenesis in the ischemic heart

Myocardial ischemia is associated with profound electrophysiologic derangements which occur within minutes and are rapidly reversible with reperfusion, suggesting that subtle and reversible biochemical alterations within or near the sarcolemma contribute. Our efforts have concentrated on two structurally similar amphipathic metabolites, long-chain acylcarnitine and lysophosphatidylcholine. Studies performed in vitro in isolated tissue indicate that incorporation of either metabolite into the sarcolemma at concentrations of 1-2 mole %, as verified using electron microscopic (EM) autoradiography, elicits profound electrophysiologic derangements analogous to those seen in the ischemic heart in vivo. In isolated myocytes in vitro, the electrophysiologic derangements elicited by hypoxia are associated with a marked 70-fold increase in the endogenous sarcolemmal accumulation of long-chain acylcarnitine. Inhibition of carnitine acyltransferase I (CAT-I) not only prevents the accumulation of long-chain acylcarnitine in isolated myocytes exposed to severe hypoxia, but also markedly attenuates the electrophysiologic alterations. Several lines of experimental evidence, including measurements in venous effluents as well as cardiac lymph, indicate that lysophosphatidylcholine (LPC) accumulates to a large extent in the extracellular space during ischemia. This extracellular accumulation may be secondary to release from vascular endothelium, smooth muscle or blood cell elements. In crude homogenates of myocardial tissue, the total enzymic activity for catabolism of LPC far exceeds the total activity for synthesis of LPC mediated by phospholipase A2 (PLA2) catalyzed hydrolysis of phosphatidylcholine (PC). Therefore, inhibition of catabolism would be required for net accumulation of LPC to occur. Three enzymes responsible for the catabolism of LPC are inhibited by either long-chain acylcarnitine or acidic pH. Thus, accumulation of long-chain acylcarnitine and acidosis contribute to the increase in LPC observed in ischemic tissue. In this report, we provide evidence that accumulation of long-chain acylcarnitine occurs very rapidly in ischemic myocardium in vivo, coincident with the development of electrophysiologic alterations leading to malignant arrhythmias as verified using 3-dimensional cardiac mapping procedures. Following a brief, 2-min period of ischemia, long-chain acylcarnitine content increased four-fold in the ischemic region, concomitant with the development of electrophysiologic abnormalities observed during this period. Additionally, we demonstrate that modification of intracellular lipolysis by beta-adrenergic receptor stimulation or blockade does not influence long-chain acylcarnitine accumulation following this 2-min interval of ischemia. These results suggest that production of long-chain acylcarnitine is not limited by the intracellular free fatty acid concentration early in ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Focal mechanisms underlying ventricular tachycardia during prolonged ischemic cardiomyopathy.

BackgroundThe present study was performed to define the mechanisms underlying spontaneously occurring ventricular arrhythmias in the failing heart. Methods and ResultsThree-dimensional cardiac mapping from as many as 232 intramural sites was performed in five dogs with ischemic cardiomyopathy induced by multiple intracoronary embolizations. After 5 to 10 weekly embolizations with 90-μm latex microspheres into the left anterior and circumflex coronary arteries, left ventricular ejection fraction decreased from 63±3% to 22±3%. Subsequent weekly Holter monitoring of dogs in the conscious state demonstrated frequent multiform premature ventricular complexes (PVCs) (≤2000/d), couplets, and runs of ventricular tachycardia (VT) (≤70 beats in duration and ≤560 beats per minute) in all dogs. Three-dimensional mapping of spontaneous rhythm for 60 minutes was performed an average of 6.4 weeks after the last embolization, during which time each dog demonstrated multiform PVCs, couplets, and runs of nonsustained VT at rates comparable to those in the conscious state. Mapping was of sufficient density to define the mechanism for 31 PVCs, 45 beats of ventricular couplets, and 99 beats of VT. Sinus beats preceding PVCs (n=36) initiated in the septum and spread rapidly with a total activation time (46±1 milliseconds) that did not differ from that of sinus beats not preceding PVCs or VT (46±2 milliseconds, n= 10, P=.69). PVCs and the first beat of couplets or VT were initiated primarily in the subendocardium by a focal mechanism, based on the lack of intervening electrical activity between the termination of the preceding (sinus) beat and initiation of the ectopic beat (225±23 milliseconds), despite the presence of multiple intervening intramural recording sites. All subsequent beats of VT also were initiated by a focal mechanism, and their total activation time (89±1 milliseconds) did not differ from that of the initiating ectopic beats (86±2 milliseconds, P=.14), despite acceleration of VT to a cycle length of 200 milliseconds. Monomorphic VT was due to repetitive focal activation of subendocardial sites. Polymorphic VT was due to sequential focal activation from multiple sites arising in the subendocardium and, at times, in the subepicardium. Comparison of mapping data with results of detailed anatomic analysis of tissue demonstrated that focal sites of initiation exhibited patchy nontransmural fibrosis. Functional conduction delay of a moderate degree was evident only when fibrosis extended transmurally. ConclusionsSpontaneously occurring PVCs, couplets, and VT in a model of ischemic cardiomyopathy are initiated and maintained by focal mechanisms with no evidence of macroreentry. Thus, therapeutic regimens to treat or prevent VT in the presence of ischemic cardiomyopathy will likely require interruption of these focal mechanisms.

Contribution of myocardium responsible for ventricular tachycardia to abnormalities detected by analysis of signal-averaged ECGs

BackgroundCurrent methods of signal-averaged ECG analysis interrogate the terminal 40 msec of the QRS complex and/or the ST segment and have a low positive-predictive accuracy for detecting vulnerability to sustained ventricular tachycardia (VT). The extent to which abnormalities detected during these ECG intervals are generated by myocardial tissue responsible for VT has not been well defined. The purpose of this study was to determine when, during sinus rhythm, myocardium responsible for VT is activated. Methods and ResultsThree-dimensional ventricular activation maps were analyzed during sinus rhythm and during 10 VTs in eight patients with healed myocardial infarctions undergoing arrhythmia surgery for sustained monomorphic VT. The mechanism of VT was focal in five instances and macroreentrant in five. During sinus beats, myocardium responsible for all focal VTs activated 43 ± 38 msec before the onset of the terminal 40-msec interval of the QRS complex. During sinus rhythm, activation of the myocardium critical to macroreentrant VT began 72 ± 13 msec before the onset of the terminal QRS interval and in only three instances extended 2-25 msec into the terminal 40 msec of the QRS complex. Electrograms recorded during the ST segment represented late activation of epicardial sites overlying zones of infarction that were temporally and spatially remote from tissue critical to VT. ConclusionsCurrent methods of signal-averaged ECG analysis limiting interrogation to the terminal QRS/ST segment exclude detection of >95% of the signals generated by myocardium responsible for sustained VT. These results establish a pathophysiological basis for expanding signal-averaged ECG analysis to include more of the cardiac cycle.

Three-dimensional Mapping of the Initiation of Nonsustained Ventricular Tachycardia in the Human Heart

BACKGROUND Elucidation of the electrophysiological mechanisms of nonsustained ventricular tachycardia (VT) in humans is required to define the relationship between nonsustained VT and sustained VT. This goal requires, at least in part, analysis of transmural ventricular activation in patients with both sustained and nonsustained VTs. METHODS AND RESULTS We analyzed three-dimensional intraoperative cardiac maps of extrastimuli and beats during 44 nonsustained VTs and the initiating beats of 6 sustained VTs from six patients with healed myocardial infarcts who were undergoing arrhythmia surgery. The coupling interval, total activation time, and diastolic interval of each extrastimulus and beat of nonsustained VT were compared with counterparts during sustained VT. Sites activated last during extrastimuli initiating nonsustained or sustained VTs occurred in the same region, and activation times were comparable. However, the site of earliest activation during the initial or subsequent beats of nonsustained VT was discordant from the site activated earliest during the first and subsequent beats of sustained VT in 74% of cases. The mean variance in coupling interval, but not total activation time or diastolic interval, was significantly greater for VT that terminated before the 10th cycle than for VT that sustained. When analyzed from the last extrastimulus up to the fifth VT cycle, the standard deviation of the coupling interval, but not of the total activation time, was greater for nonsustained than for sustained VTs. Electrode density was sufficient to define an arrhythmia mechanism for 36 beats of nonsustained VT. Twenty-one (58%) initiated in the subendocardium, midmyocardium, or epicardium by a macroreentrant mechanism, and 15 (42%) initiated in the subendocardium by a focal mechanism. CONCLUSIONS Compared with sustained VT, nonsustained VT initiates at discordant sites, is characterized by oscillations in coupling interval but not in total activation time, and initiates by either a macroreentrant or a focal mechanism.

Termination of Ventricular Tachycardia in the Human Heart Insights From Three-dimensional Mapping of Nonsustained and Sustained Ventricular Tachycardias

BACKGROUND To define the electrophysiological basis for the termination of ventricular tachycardia (VT), three-dimensional cardiac mapping and analysis of the terminal beats of nonsustained VT and beats of sustained VT were performed in six patients with healed myocardial infarcts. METHODS AND RESULTS Termination of VT was due to activation from multiple initiation sites that were discordant from those responsible for the maintenance of sustained VT in 45% of cases, to repetitive activation from single sites that were discordant from those responsible for the maintenance of sustained VT in 24% of cases, or to activation from sites concordant with the sites of repetitive activation during sustained VT in 31% of cases. Sustained VT was characterized by occasional shifting of initiation sites, even after the tachycardia entered the stable monomorphic phase. Mapping was of sufficient density to define the mechanisms for 21 terminating beats of VT. In 5 cases, termination was due to intramural reentry, which initiated with the total activation time of the preceding beat of 204 +/- 11 milliseconds (ms) but terminated primarily because of a decrease in total activation time (144 +/- 23 ms, P = .03) that was associated with the development of intramural conduction block or with significant changes in the activation sequence along the reentrant circuit. In 16 cases, terminal beats were initiated by a focal mechanism on the basis of the absence of intervening electrical activity from the termination of the preceding beat to the initiation of the terminating beat (172 +/- 9 ms). Focal activation was associated with less conduction delay of the preceding beat (115 +/- 6 ms) than terminating reentrant beats (P < .001) and usually terminated suddenly without oscillations in cycle length or total activation time. CONCLUSIONS Termination of VT is associated with alterations in initiation sites that are most often discordant from those maintaining sustained VT and is due to either reentrant or focal mechanisms.

Mechanisms underlying ventricular tachycardia and fibrillation in the ischemic heart : relation to nonlinear dynamics

Sudden cardiac death accounts for over 300,000 deaths annually in the United States alone,’ and is usually secondary to the development of ventricular tachycardia that degenerates to vr itricular f ibr i l la t i~n.~.~ It occurs most frequently in the setting of coronary artery disease. Autopsy studies of victims of sudden cardiac death, however, have demonstrated acute coronary artery occlusion in a minority of patients: suggesting that lethal arrhythmias may result from transient myocardial ischemia’ and/or reperfusion of ischemic myocardium.6 Strategies for treatment and prevention of these malignant tachyarrhythmias have not been very effective owing to the nonspecific actions of most antiarrhythmic drugs as well as an incomplete understanding of the underlying arrhythmogenic mechanisms. Conventional approaches to the study of the malignant arrhythmias underlying sudden cardiac death have involved investigation of electrophysiologic and biochemical membrane mechanisms contributing to the evolution of ventricular tachycardia and ventricular fibrillation during myocardial ischemia and reperfusion, both on a macroscopic as well as cellular Although this approach has increased our understanding of these lethal arrhythmias, further investigation is required not only to define the basic mechanisms and develop more rational therapeutic interventions, but also to identify patients a t risk for the development of sudden cardiac death using noninvasive procedures.

Elektrophysiologische und biochemische Mechanismen maligner ventrikulärer Arrhythmien bei früher Myokardischämie

Der akute Herztod ist fur mehr als 300 000 Todesfalle pro Jahr allein in den U.S.A. verantwortlich [111]. Am haufigsten tritt er im Zusammenhang einer diffusen koronaren Herzkrankheit auf [9], und in etwa 25% aller Falle von akutem Herztod ist dieses Ereignis die Erstmanifestation der koronaren Herzkrankheit [87]. Der Tod wird am haufigsten durch maligne ventrikulare Arrhythmien verursacht, einschlieslich komplexer ventrikularer Extrasystolen oder ventrikularer Tachykardien, die schlieslich in der Entwicklung von Kammerflimmern gipfeln [23].