James Coromilas

Disturbed Connexin43 Gap Junction Distribution Correlates With the Location of Reentrant Circuits in the Epicardial Border Zone of Healing Canine Infarcts That Cause Ventricular Tachycardia

BACKGROUND Slow, nonuniform conduction caused by abnormal gap-junctional coupling of infarct-related myocardium is thought to be a component of the arrhythmogenic substrate. The hypothesis that changes in gap-junctional distribution in the epicardial border zone (EBZ) of healing canine infarcts define the locations of reentrant ventricular tachycardia (VT) circuits was tested by correlating activation maps of the surviving subepicardial myocardial layer with immunolocalization of the principal gap-junctional protein, connexin43 (Cx43). METHODS AND RESULTS The EBZ overlying 4-day-old anterior infarcts in three dogs with inducible VT and three noninducible dogs was mapped with a high-resolution electrode array and systematically examined by standard histology and confocal immunolocalization of Cx43. The thickness of the EBZ was significantly less in the hearts with (538 +/- 257 microns) than without (840 +/- 132 microns; P < .05) VT. At the interface with the underlying necrotic cells, the EBZ myocardium showed a marked disruption of gap-junctional distribution, with Cx43 labeling abnormally arrayed longitudinally along the lateral surfaces of the cells. In the EBZ of all hearts, the disrupted Cx43 labeling extended part of the way to the epicardial surface, with the most superficial epicardial myocytes having the normal transversely orientated pattern. Only in the hearts with inducible VT did the disorganization extend through the full thickness of the surviving layer at sites correlating with the location of the central common pathways of the figure-of-8 reentrant VT circuits. CONCLUSIONS Altered gap-junctional distribution is part of the early remodeling of myocardium after infarction, and by defining the location of the common central pathway of the reentrant VT circuits, it may be a determinant of VT susceptibility.

Electrophysiologic Testing to Identify Patients with Coronary Artery Disease Who Are at Risk for Sudden Death

BACKGROUND The mortality rate among patients with coronary artery disease, abnormal ventricular function, and unsustained ventricular tachycardia is high. The usefulness of electrophysiologic testing for risk stratification in these patients is unclear. METHODS We performed electrophysiologic testing in patients who had coronary artery disease, a left ventricular ejection fraction of 40 percent or less, and asymptomatic, unsustained ventricular tachycardia. Patients in whom sustained ventricular tachyarrhythmias could be induced were randomly assigned to receive either antiarrhythmic therapy guided by electrophysiologic testing or no antiarrhythmic therapy. The primary end point was cardiac arrest or death from arrhythmia. Patients without inducible tachyarrhythmias were followed in a registry. We compared the outcomes of 1397 patients in the registry with those of 353 patients with inducible tachyarrhythmias who were randomly assigned to receive no antiarrhythmic therapy in order to assess the prognostic value of electrophysiologic testing. RESULTS Patients were followed for a median of 39 months. In a Kaplan-Meier analysis, two-year and five-year rates of cardiac arrest or death due to arrhythmia were 12 and 24 percent, respectively, among the patients in the registry, as compared with 18 and 32 percent among the patients with inducible tachyarrhythmias who were assigned to no antiarrhythmic therapy (adjusted P<0.001). Overall mortality after five years was 48 percent among the patients with inducible tachyarrhythmias, as compared with 44 percent among the patients in the registry (adjusted P=0.005). Deaths among patients without inducible tachyarrhythmias were less likely to be classified as due to arrhythmia than those among patients with inducible tachyarrhythmias (45 and 54 percent, respectively; P=0.06). CONCLUSIONS Patients with coronary artery disease, left ventricular dysfunction, and asymptomatic, unsustained ventricular tachycardia in whom sustained ventricular tachyarrhythmias cannot be induced have a significantly lower risk of sudden death or cardiac arrest and lower overall mortality than similar patients with inducible sustained tachyarrhythmias.

Electrical Storm Presages Nonsudden Death

Background—Electrical storm, multiple temporally related episodes of ventricular tachycardia (VT) or ventricular fibrillation (VF), is a frequent problem among recipients of implantable cardioverter defibrillators (ICDs). However, insufficient data exist regarding its prognostic significance. Methods and Results—This analysis includes 457 patients who received an ICD in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial and who were followed for 31±13 months. Electrical storm was defined as ≥3 separate episodes of VT/VF within 24 hours. Characteristics and survival of patients surviving electrical storm (n=90), those with VT/VF unrelated to electrical storm (n=184), and the remaining patients (n=183) were compared. The 3 groups differed in terms of ejection fraction, index arrhythmia, revascularization status, and baseline medication use. Survival was evaluated using time-dependent Cox modeling. Electrical storm occurred 9.2±11.5 months after ICD implantation, and most episodes (86%) were ...

Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias

Catecholaminergic polymorphic ventricular tachycardia is a form of exercise-induced sudden cardiac death that has been linked to mutations in the cardiac Ca2+ release channel/ryanodine receptor (RyR2) located on the sarcoplasmic reticulum (SR). We have shown that catecholaminergic polymorphic ventricular tachycardia-linked RyR2 mutations significantly decrease the binding affinity for calstabin-2 (FKBP12.6), a subunit that stabilizes the closed state of the channel. We have proposed that RyR2-mediated diastolic SR Ca2+ leak triggers ventricular tachycardia (VT) and sudden cardiac death. In calstabin-2-deficient mice, we have now documented diastolic SR Ca2+ leak, monophasic action potential alternans, and bidirectional VT. Calstabin-deficient cardiomyocytes exhibited SR Ca2+ leak-induced aberrant transient inward currents in diastole consistent with delayed after-depolarizations. The 1,4-benzothiazepine JTV519, which increases the binding affinity of calstabin-2 for RyR2, inhibited the diastolic SR Ca2+ leak, monophasic action potential alternans and triggered arrhythmias. Our data suggest that calstabin-2 deficiency is as a critical mediator of triggers that initiate cardiac arrhythmias.

Analysis of implantable cardioverter defibrillator therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial

Introduction: The implantable cardioverter defibrillator (ICD) is commonly used to treat patients with documented sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Arrhythmia recurrence rates in these patients are high, but which patients will receive a therapy and the forms of arrhythmia recurrence (VT or VF) are poorly understood.

Left ventricular function and rapid release of creatine kinase MB in acute myocardial infarction. Evidence for spontaneous reperfusion.

Intracoronary thrombolysis during acute myocardial infarction in human beings is associated with rapid release of creatine kinase and improvement of the cardiac ejection fraction. To examine the phenomenon of spontaneous coronary-artery recanalization, we studied the release of creatine kinase MB and sequential radionuclide ventriculograms in 52 patients with transmural myocardial infarction. Patients were divided into two groups according to whether the release of creatine kinase MB (time from base-line to peak serum level) was rapid (n = 24) or slow (n = 28). Patients with slow release had no significant change in global or regional ejection fraction from the time of admission to discharge. However, global ejection fraction in patients with rapid release improved from 0.38 +/- 0.09 (mean +/- S.D.) to 0.48 +/- 0.08 (P less than 0.001). The regional ejection fraction of Q-wave regions also improved, from 0.33 +/- 0.11 to 0.43 +/- 0.13 (P less than 0.001). A negative correlation (r = -0.52, P less than 0.001) existed between time to peak enzyme level and degree of improvement in ejection fraction. With increasing left ventricular damage, patients with rapid release had greater increments in creatine kinase MB than comparable patients with slow release (P = 0.03), suggesting enzyme washout. These data are consistent with the idea that spontaneous reperfusion, leading to altered enzyme release and improvement in ventricular function, is not uncommon after acute myocardial infarction.

Prediction of Sustained Ventricular Tachycardia Inducible by Programmed Stimulation in Patients With Coronary Artery Disease Utility of Clinical Variables

BACKGROUND Cardiologists often use clinical variables to determine the need for electrophysiological studies to stratify patients for risk of sudden death. It is not clear whether this is rational in patients with coronary artery disease, left ventricular dysfunction, and nonsustained ventricular tachycardia. METHODS AND RESULTS We analyzed the first 1721 patients enrolled in the Multicenter UnSustained Tachycardia Trial to determine whether clinical variables could predict which patients would have inducible sustained monomorphic ventricular tachycardia. The rate of inducibility of sustained ventricular tachycardia was significantly higher in patients with a history of myocardial infarction and in men compared with women. There was a progressively increased rate of inducibility with increasing numbers of diseased coronary arteries. There was a significantly lower rate of inducibility in patients with prior coronary artery bypass surgery and in patients who also had noncoronary cardiac disease. The rate of inducibility was higher in patients of white race, patients with recent (</=6 weeks) angina, left ventricular dyskinesis, and in patients with greater numbers of fixed thallium defects. Inducibility was more likely in patients who had a prior myocardial infarction complicated by congestive heart failure, ventricular tachycardia, or fibrillation </=48 hours after the onset of infarction. Although these associations are statistically significant, the accuracy of the clinical variables in discriminating between patients with and those without inducible ventricular tachycardia is only modest (receiver operator characteristic area <0.70). CONCLUSIONS Multiple clinical variables are independently associated with inducible sustained ventricular tachycardia. However, they have limited utility to guide clinical decisions regarding the use of electrophysiological testing for risk stratification in this patient population.

Effect of β-blocking therapy on outcome in the Multicenter UnSustained Tachycardia Trial (MUSTT)

Background—&bgr;-Blockers are known to reduce total mortality and sudden death in survivors of recent myocardial infarction. The effects of these agents in patients at high risk for sudden death with remote infarction are not clear. Methods and Results—We analyzed the effect of &bgr;-blockers on outcomes in 2096 patients with coronary artery disease, ejection fraction ≤40%, and spontaneous nonsustained ventricular tachycardia enrolled in the Multicenter UnSustained Tachycardia Trial (MUSTT). Forty-five percent of 702 patients with inducible sustained ventricular tachyarrhythmia and 35% of 1394 patients without inducible tachycardia were discharged from hospital receiving &bgr;-blockers. Patients treated with &bgr;-blockers were younger and had higher ejection fractions, higher rates of recent angina, and more recent infarction. &bgr;-Blockers were associated with decreased total mortality for the entire study population (5-year mortality 50% with &bgr;-blockers versus 66% without &bgr;-blockers; adjusted P =0.0001). The mortality benefit associated with &bgr;-blockers was present in patients with and without inducible tachycardia, except those treated with implantable defibrillators. There was no significant effect of &bgr;-blocker therapy on the rate of arrhythmic death or cardiac arrest (adjusted P =0.2344). Conclusions—&bgr;-Blocking agents have beneficial effects on survival of patients having characteristics of those enrolled in the MUSTT trial. These effects do not appear to be due to a specific antiarrhythmic effect of &bgr;-blockers. The beneficial effects of &bgr;-blockers were demonstrable in all patients except those treated with implantable defibrillators.

Mechanisms Causing Sustained Ventricular Tachycardia With Multiple QRS Morphologies Results of Mapping Studies in the Infarcted Canine Heart

BACKGROUND Sustained reentrant ventricular tachycardias (VTs) with different QRS morphologies have been observed to occur spontaneously and during programmed stimulation in human hearts. We determined mechanisms that can cause tachycardias with multiple morphologies in a canine model of myocardial infarction by mapping reentrant circuits. METHODS AND RESULTS Reentrant VT with multiple QRS morphologies was induced in 11 canine hearts with 4-day-old infarcts. Comparison of activation maps of the reentrant circuits in the epicardial border zone associated with each morphology indicated two basic mechanisms. Less frequently, VTs of different morphologies in the same heart were caused by reentrant circuits in different regions of the infarct. Most commonly, the reentrant circuits associated with different morphologies were in the same region. Three different factors caused different exit routes from circuits in the same region, leading to the multiple morphologies. (1) The reentrant wave front for each morphology rotated around the same line of block but in different directions. (2) Reentrant circuits associated with each morphology were similar, but there were small changes in the extent of the central line of block. (3) Reentrant circuits with completely different sizes and shapes caused different morphologies. CONCLUSIONS In this canine model, tachycardias with multiple morphologies most commonly arise from reentrant circuits in the same region of the infarct, suggesting that most often only one area has electrophysiological properties necessary to sustain reentry.

Anisotropic reentry in the epicardial border zone of myocardial infarcts.

In a currently used classification of arrhythmogenic mechanisms, there are two major classes of reentry-anatomical and functional. The former is dependent on anatomically defined reentrant pathways that may course around an obstacle as originally shown in Mines”-* and Garrey’s3 studies on excised rings of cardiac muscle. It is exemplified in the intact heart by bundle branch reentry,4 reentry utilizing an accessory AV pathway in the preexcitation syndrome5 and reentry in the ring of muscle around the tricuspid valve causing atrial flutter.6 On the other hand, functional reentry is dependent on heterogeneities of the electrophysiological properties of the cardiac fibers caused by local differences in the transmembrane action potentials, for example, resting potentials, time course of repolarization, and recovery of excitability. It does not require an anatomically defined reentrant pathway. The mechanism for functional reentry that has been characterized in the most detail is the “leading circle mechanism” that can occur in normal atrial tissue.’ Recent studies indicate that the anatomy of cardiac muscle may be important for reentry in a way other than simply providing a road over which the reentrant impulse travels. Anatomy may participate in determining functional properties of cardiac muscle, since the structural characteristics of heart muscle can influence both conduction and refractor ine~s.~.~ These structural characteristics include the orientation of the myocardial fibers and the way the fibers or bundles of fibers are connected to each other. The influence of structure on functional properties is described by the concept of anisotropy (see paper by Spach et al., this volume).