Genesis Of Ventricular Tachycardia Research Articles

Role of infarct scar dimensions, border zone repolarization properties and anisotropy in the origin and maintenance of cardiac reentry

Cardiac ventricular tachycardia (VT) is a life-threatening arrhythmia consisting of a well organized structure of reentrant electrical excitation pathways. Understanding the generation and maintenance of the reentrant mechanisms, which lead to the onset of VT induced by premature beats in presence of infarct scar, is one of the most important issues in current electrocardiology. We investigate, by means of numerical simulations, the role of infarct scar dimension, repolarization properties and anisotropic fiber structure of scar tissue border zone (BZ) in the genesis of VT. The simulations are based on the Bidomain model, a reaction-diffusion system of Partial Differential Equations, discretized by finite elements in space and implicit-explicit finite differences in time. The computational domain adopted is an idealized left ventricle affected by an infarct scar extending transmurally. We consider two different scenarios: i) the scar region extends along the entire transmural wall thickness, from endocardium to epicardium, with the exception of a BZ region shaped as a central sub-epicardial channel (CBZ); ii) the scar region extends transmurally along the ventricular wall, from endocardium to a sub-epicardial surface, and is surrounded by a BZ region (EBZ). In CBZ simulations, the results have shown that: i) the scar extent is a crucial element for the genesis of reentry; ii) the repolarization properties of the CBZ, in particular the reduction of IKs and IKr currents, play an important role in the genesis of reentrant VT. In EBZ simulations, since the possible reentrant pathway is not assigned a-priori, we investigate in depth where the entry and exit sites of the cycle of reentry are located and how the functional channel of reentry develops. The results have shown that: i) the interplay between the epicardial anisotropic fiber structure and the EBZ shape strongly affects the propensity that an endocardial premature stimulus generates a cycle of reentry; ii) reentrant pathways always develop along the epicardial fiber direction; iii) very thin EBZs rather than thick EBZs facilitate the onset of cycles of reentry; iv) the sustainability of cycles of reentry depends on the endocardial stimulation site and on the interplay between the epicardial breakthrough site, local fiber direction and BZ rim.

Pattern of initiation of monomorphic ventricular tachycardia and implications on tachycardia mechanism

The incidence of sudden cardiac death, predominantly caused by ventricular tachycardia and ventricular fibrillation, is high in patients with congestive heart failure. Implantable cardiac defibrillators have improved survival in this population but defibrillator shocks can lead to low quality of life and heart failure progression. The current management of recurrent ventricular tachycardia includes ablation and anti-arrhythmic drugs and both are associated with high recurrence rates. Better understanding the mechanism of ventricular tachycardia allowing individualization of treatment may improve outcomes. Re-entry is currently accepted as the mechanism of the majority of monomorphic ventricular tachycardias in patients with congestive heart failure, being responsible for more than 90% of the ventricular tachycardia in patients with ischemic cardiomyopathy. On the other hand, some studies show a greater participation of focal arrhythmias in the genesis of ventricular tachycardia in this population. The pattern of initiation of ventricular tachycardia is divided into sudden, when the first beat of the tachycardia is morphologically similar to the rest of the tachycardia, and non-sudden, when its morphology is dissimilar. An association between the pattern of the initiation and the mechanism of ventricular tachycardia has been proposed. The pattern of initiation of ventricular tachycardia is a readily available from data stored in current generation implantable cardiac defibrillators. The association with tachycardia mechanism may allow individualization of the therapy, however evidence is lacking and further research is required.

Modeling our understanding of the His-Purkinje system

The His-Purkinje System (HPS) is responsible for the rapid electric conduction in the ventricles. It relays electrical impulses from the atrioventricular node to the muscle cells and, thus, coordinates the contraction of ventricles in order to ensure proper cardiac pump function. The HPS has been implicated in the genesis of ventricular tachycardia and fibrillation as a source of ectopic beats, as well as forming distinct portions of reentry circuitry. Despite its importance, it remains much less well characterized, structurally and functionally, than the myocardium. Notably, important differences exist with regard to cell structure and electrophysiology, including ion channels, intracellular calcium handling, and gap junctions. Very few computational models address the HPS, and the majority of organ level modeling studies omit it. This review will provide an overview of our current knowledge of structure and function (including electrophysiology) of the HPS. We will review the most recent advances in modeling of the system from the single cell to the organ level, with considerations for relevant interspecies distinctions.

Letter to the editor: “The role of short QT interval and elevated LV end-diastolic pressure in the genesis of ventricular tachycardia and fibrillation”

to the editor: We read with great interest the article by Pizzuto and associates ([4][1]) in the American Journal of Physiology-Heart and Circulatory Physiology , entitled: “Dissociation of hemodynamic and electrocardiographic indexes of myocardial ischemia in pigs with hibernating myocardium and

Reply to “Letter to the editor: ‘The role of short QT interval and elevated LV end-diastolic pressure in the genesis of ventricular tachycardia and fibrillation’”

reply: We appreciate Dr. Karagueuzian's ([3][1]) insight regarding the potential role of reduced cytosolic ATP (derived from glucose and glycogen) in explaining shortening of the QT interval (through activation of the ATP-sensitive K+ channel) as well as elevations in end-diastolic pressure (through

Diminished Cardiac Fibrosis in Heart Failure is Associated with Altered Ventricular Arrhythmia Phenotype

We sought to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing ventricular myocardium. Multiple cellular events that occur during pathological remodeling of the failing ventricle are implicated in the genesis of ventricular tachycardia (VT), including interstitial fibrosis. Recent studies suggest that ventricular fibrosis is reversible, and current anti-remodeling therapies attenuate ventricular fibrosis. However, the role of interstitial fibrosis in the proarrhythmic phenotype of failing ventricular myocardium is currently not well defined. Class II histone deacetylases (HDACs) have been implicated in promoting collagen biosynthesis. As these enzymes are inhibited by protein kinase D1 (PKD1), we studied mice with cardiomyocyte-specific transgenic over-expression of a constitutively active mutant of PKD1 (caPKD). caPKD mice were compared with animals in which cardiomyopathy was induced by severe thoracic aortic banding (sTAB). Hearts were analyzed by echocardiographic and electrocardiographic means. Interstitial fibrosis was assessed by histology and quantified biochemically. Ventricular arrhythmias were induced by closed-chest, intracardiac pacing. Similar degrees of hypertrophic growth, systolic dysfunction and mortality were observed in the two models. In sTAB mice, robust ventricular fibrosis was readily detected, but myocardial collagen content was significantly reduced in caPKD mice. As expected, VT was readily inducible by programmed stimulation in sTAB mice and VT was less inducible in caPKD mice. Surprisingly, episodes of VT manifested longer cycle lengths and longer duration in caPKD mice. Attenuated ventricular fibrosis is associated with reduced VT inducibility, increased VT duration, and significantly longer arrhythmia cycle length.

Transmural Dispersion of Repolarization in Failing and Nonfailing Human Ventricle

Transmural dispersion of repolarization has been shown to play a role in the genesis of ventricular tachycardia and fibrillation in different animal models of heart failure (HF). Heterogeneous changes of repolarization within the midmyocardial population of ventricular cells have been considered an important contributor to the HF phenotype. However, there is limited electrophysiological data from the human heart. To study electrophysiological remodeling of transmural repolarization in the failing and nonfailing human hearts. We optically mapped the action potential duration (APD) in the coronary-perfused scar-free posterior-lateral left ventricular free wall wedge preparations from failing (n=5) and nonfailing (n=5) human hearts. During slow pacing (S1S1=2000 ms), in the nonfailing hearts we observed significant transmural APD gradient: subepicardial, midmyocardial, and subendocardial APD80 were 383+/-21, 455+/-20, and 494+/-22 ms, respectively. In 60% of nonfailing hearts (3 of 5), we found midmyocardial islands of cells that presented a distinctly long APD (537+/-40 ms) and a steep local APD gradient (27+/-7 ms/mm) compared with the neighboring myocardium. HF resulted in prolongation of APD80: 477+/-22 ms, 495+/-29 ms, and 506+/-35 ms for the subepi-, mid-, and subendocardium, respectively, while reducing transmural APD80 difference from 111+/-13 to 29+/-6 ms (P<0.005) and presence of any prominent local APD gradient. In HF, immunostaining revealed a significant reduction of connexin43 expression on the subepicardium. We present for the first time direct experimental evidence of a transmural APD gradient in the human heart. HF results in the heterogeneous prolongation of APD, which significantly reduces the transmural and local APD gradients.

Gender Effects on Novel Time Domain Parameters of Ventricular Repolarization Inhomogeneity

Parameters of ventricular repolarization variability are increasingly being used in an attempt to understand better and predict the occurrence of ventricular tachycardia. Nevertheless, some of the measures used have thus far not been analyzed regarding gender differences in a large group of healthy subjects. Furthermore, new parameters might give further insight. We investigated 139 healthy volunteers (mean age 41.6 +/- 15.3 years, range 20-77, median 40.0 years, 76 women) without evidence of organic cardiac disease. Mean RR interval and established time domain parameters of heart rate variability (rMSSD; SDNN) were measured for each subject. Beat-to-beat QT interval and time-domain QT interval variability were analyzed. Characteristics of the QT interval and QT interval variability were determined as hourly mean values. The standard deviation of all QT intervals/hour (SDQT) and the standard deviation of all QTc intervals/hour (SDQTc) were used to measure QT interval variability. Four novel ratios of repolarization inhomogeneity (VRI: SDQT/SDNN; VR II: SDQT/rMSSD; VR III: SDQTc/SDNN; VR IV: SDQTc/rMSSD) were introduced. Female subjects exhibited significantly higher values in all four ratios of variability. The obvious gender differences in repolarization inhomogeneity found in this study might be valuable in better understanding differences between men and women in the genesis of ventricular tachycardia.

Combined Effects of Nifekalant and Lidocaine on the Spiral-Type Re-Entry in a Perfused 2-Dimensional Layer of Rabbit Ventricular Myocardium

Spiral re-entry plays the principal role in the genesis of ventricular tachycardia and ventricular fibrillation (VT/VF). The specific I(Kr) blocker, nifekakant (NIF) has, often in combination with lidocaine (LID), recently been used in Japan to prevent recurrent VT/VF, but the combined effects of these drugs on spiral re-entry had never been investigated. A ventricular epicardial sheet was obtained from 13 Langendorff-perfused rabbit hearts by means of a cryoprocedure, and epicardial excitations were analyzed with a high-resolution optical mapping system. Nifekakant (0.5 micromol/L) caused significant prolongation of action potential duration (APD) and LID (3 micromol/L) attenuated the APD prolongation without affecting the conduction velocity. VT were induced in 6 hearts by cross-field stimulation, and single- or double-loop spirals circulating around variable functional block lines were visualized during the VT. Nifekakant reduced VT cycle length and caused early termination in association with destabilization of the spiral dynamics (prolongation of functional block line, frequent local conduction block, and extensive meandering). These modifications of spiral-type re-entrant VT by NIF were prevented by addition of LID. The effects of NIF on the spiral excitations are reversed by LID. This interaction should be taken into account when these drugs are used in combination to treat VT/VF.

Relationship between the QT indices and the microvolt-level T wave alternans in cardiomyopathy.

The relationship between the QT indices and microvolt-level T wave alternans (TWA) is unknown in cardiomyopathy, so the present study examined 86 patients with cardiomyopathy who experienced TWA during exercise testing (EXT). The QT interval (QT), duration from the Q wave to the peak of the T wave (QTp), duration from the peak to the end of the T wave and the dispersion of these parameters were measured by 12-lead electrocardiogram at rest and during EXT. In dilated cardiomyopathy (DCM), TWA was positive (TWA+) in 19 patients and negative (TWA-) in 17. No significant difference was observed between the TWA+ and TWA- groups in any parameter. In hypertrophic cardiomyopathy (HCM), TWA was positive in 24 patients and negative in 12. Max QTc, max QTpc and mean QTpc during EXT in the TWA+ group were significantly longer than those in the TWA- group. The sensitivity of TWA for ventricular tachycardia (VT) was high in DCM and HCM, and that of max QTc >500 ms during EXT for VT was high in HCM (93%). TWA is a useful predictor for VT in DCM and HCM, and prolonged max QTc during exercise has a prognostic value in HCM. Repolarization abnormality during exercise plays an important role in the genesis of VT in cardiomyopathy.

Baroreflex sensitivity predicts the induction of ventricular arrhythmias by cesium chloride in rabbits.

Previous studies have shown that the autonomic nervous system plays an important role in the genesis of ventricular tachycardia (VT) in patients with long QT syndrome, and in cesium chloride (Cs)-induced VT in animals. The present study investigated whether baroreflex sensitivity predicts the induction of VT by Cs in the rabbit in vivo. Monophasic action potentials (MAPs) of the left ventricular endocardium were recorded simultaneously with the surface ECG in 27 rabbits. Rabbits were divided into 4 groups based on the Cs-induced ventricular arrhythmias: (1) no ventricular premature contractions (No-VPC group), (2) single or paired VPC (VPC group), (3) monomorphic VT (MVT group), and (4) polymorphic VT (PVT group). Baroreflex sensitivity was significantly lower in the MVT and PVT groups than in the No-VPC and VPC groups. The plasma norepinephrine concentration before Cs injection was significantly higher in the MVT group than in the other 3 groups, and the norepinephrine concentration after Cs injection was significantly higher in the MVT and PVT groups than in the No-VPC and VPC groups. Baroreflex sensitivity was negatively correlated with the norepinephrine concentration before Cs injection. These results suggest that autonomic nervous system dysfunction, as defined by reduced baroreflex sensitivity, and elevated plasma norepinephrine concentrations predict increased susceptibility to Cs-induced VT.

Role of autonomic nervous activities in the genesis of ventricular tachycardia with non-ischemic heart diseases

Role of autonomic nervous activities in the genesis of ventricular tachycardia with non-ischemic heart diseases

Catheter Ablation of the Mitral Isthmus for Ventricular Tachycardia Associated With Inferior Infarction

Intraoperative mapping studies suggest that an isthmus of myocardium between the mitral valve annulus and the border of inferior myocardial infarction may play a role in the genesis of ventricular tachycardia. We examined the frequency with which a slow conduction zone within the mitral isthmus was critical to the maintenance of ventricular tachycardia associated with remote inferior infarction in patients undergoing catheter ablation. In 4 of 12 patients, a critical zone of slow conduction was identified within the mitral isthmus. In each of these patients, two characteristic and morphologically distinct tachycardias were induced: a left bundle (rS in V1, R in V6), left superior axis morphology and a right bundle (R in V1, QS in V6), right superior axis morphology (cycle length, 610 to 320 ms). In each patient, a zone of slow conduction, shared by both morphologies, was characterized by diastolic potentials with electrogram-QRS intervals of 85 to 161 ms (21% to 47% of tachycardia cycle length) and entrainment with concealed fusion during pacing associated with stimulus-QRS intervals of 81 to 400 ms (20% to 91% of tachycardia cycle length). In each patient, a single radiofrequency energy application at the shared site of slow conduction eliminated inducibility of both morphologies. During follow-up of 1 to 11 months, no patient had recurrent tachycardia. The mitral isthmus contains a critical region of slow conduction in some patients with ventricular tachycardia after inferior myocardial infarction, providing a vulnerable and anatomically localized target for catheter ablation. Characteristic tachycardia morphologies may provide clinical markers for this underlying mechanism.

Asymmetry of cardiac [123I] meta-iodobenzyl-guanidine scans in patients with ventricular tachycardia and a "clinically normal" heart.

Patients with exercise induced ventricular tachycardia associated with a "clinically normal" heart may have an abnormality of the regional distribution of the cardiac sympathetic nerve supply. In this study the regional distribution of the myocardial nerve supply in patients with ventricular tachycardia (VT) and control subjects was examined by [123] meta-iodobenzylguanidine (MIBG) scanning. Eight patients with exercise induced VT and seven patients with VT unrelated to exercise with "clinically normal" hearts were studied and compared with a control group of six subjects with atrioventricular reentrant tachycardia not related to exercise and eight patients with angiographically normal left ventricular function and normal coronary anatomy who had thallium scans without evidence of ischaemia or fixed perfusion deficits. Single photon emission computed tomography gamma scanning was performed in patients three hours after intravenous injection of MIBG. The left ventricular MIBG uptake data was processed into bull's-eye target plots. The inferior portion of the scan frequently showed artefact due to uptake of MIBG in the liver or spleen and was not used for statistical analysis. Asymmetry of uptake was defined as a ratio of uptake exceeding 1.25 in the upper quadrants (posterior (anterolateral free wall)/anterior (anteroseptal region)) of the MIBG scan. Patients with VT had a higher proportion of asymmetrical MIBG scans (47%) than subjects in the control groups (0%) and this was particularly obvious in the patients with exercise induced VT (62.5%). This suggests that patients with VT may have relative denervation in the septal portion of the left ventricle leading to an imbalance of the sympathetic supply to the myocardium and locally imbalanced sympathetic or parasympathetic interactions. Considerable evidence from animal experiments suggests that imbalance of the sympathetic supply to the myocardium is important in the genesis of ventricular arrhythmia. These results support the hypothesis that selective denervation of the human myocardium may be an important mechanism in the genesis of VT in "clinically normal" hearts.

Computer model of excitation and recovery in the anisotropic myocardium: III. Arrhythmogenic conditions in the simplified left ventricle

A computer model of propagated excitation and recovery in anisotropic cardiac tissue has been described in the first two reports of this series. The model consists of a large number of excitable elements whose subthreshold interactions are governed by the anisotropic bidomain theory but whose suprathreshold behavior (action potential) is largely preassigned. As described in the previous two reports, the model's performance was tested in rectangular and cubic arrays of excitable elements and in the “normal” three-dimensional simplified left ventricle with anisotropy. The present report deals with arrhythmogenic conditions in the simplified left ventricle with anisotropy and ventricular-gradient properties; specifically, we studied activation and recovery in the presence of an ischemic region and under various stimulation protocols. The aim of these simulations was to elucidate the role of reentry in the genesis of ventricular tachycardia. Our simulations produced reentrant activation as a result of appropriate endocardial stimulation.

Failure of thromboxane synthetase inhibition to protect the postinfarcted heart against the induction of ventricular tachycardia and ventricular fibrillation in a conscious canine model of sudden coronary death.

The role of thromboxane as a contributor to the genesis of ventricular tachycardia and fibrillation was examined in conscious dogs which had been subjected to myocardial infarction. CGS 12970, a thromboxane synthetase inhibitor was administered in a dose of 10 mg/kg (i.v.) every 12 h. Ex vivo thrombin-activated thromboxane synthesis, as determined by assay for thromboxane B2, was reduced to 15% of baseline 2 h after administration of CGS 12970. Drug administration was found to inhibit ex vivo platelet aggregation significantly in response to arachidonic acid, while aggregation to ADP and collagen was unaffected. CGS 12970 did not protect against the induction of ventricular tachycardia by programmed electrical stimulation of the postinfarcted heart. During provocative electrical stimulation, 9 of 11 (82%) animals continued to respond in the post-treatment period with the development of VT. Pretreatment with CGS 12970 failed to prevent the spontaneous development of ventricular fibrillation which occurred in 7 of 10 (70%) animals when a secondary ischemic event was superimposed in the region of the noninfarct-related circumflex coronary artery. The results suggest that the thromboxane synthetase inhibitor, CGS 12970, when administered in the subacute phase of recovery from myocardial infarction, does not protect against the induction of ventricular tachycardia by programmed electrical stimulation or the spontaneous development of ventricular fibrillation in the postinfarcted canine heart. The findings suggest that thromboxane may not serve a critical role in the genesis of ventricular tachyarrhythmias and ventricular fibrillation in the postinfarcted canine heart.

Alterations in norepinephrine content and beta adrenoceptor regulation in myocardium bordering aneurysm in human heart: their possible role in the genesis of ventricular tachycardia.

On the assumption that alterations in the adrenergic system may play a role in generating ventricular tachycardia in patients with myocardial post-infarction apical aneurysm, we evaluated norepinephrine concentration, number and affinity of both beta 1 and beta 2 adrenoceptors in perianeurysmatic tissue in twelve patients operated upon for congestive heart failure and recurrent sustained ventricular tachycardia. Concentration of norepinephrine in perianeurysmatic tissue was 0.1 +/- 0.05 micrograms g-1 tissue (n = 8), this value being much lower than that found in papillary muscle (n = 10) from patients with mitral valve stenosis (0.8 +/- 0.02 micrograms g-1 tissue) (P less than 0.01). The total number of beta adrenoceptors (71.4 +/- 7.8 v. 48.0 +/- 5.1 fmol mg-1 protein; P less than 0.01) and the percentage of beta 1 subtype were found to be higher in perianeurysmatic tissue (approximately 90%) than in papillary muscle (approximately 68%). Out of twelve patients with aneurysm, beta 2 adrenoceptors had considerably decreased in three patients and were absent in the remaining nine. Decrease in the neuronally released norepinephrine associated with contrasting behaviours of beta 1 and beta 2 adrenoceptors suggests the presence of a profound alteration in the sympathetic innervation of the perianeurysmatic myocardial tissue that may contribute to the genesis of sustained ventricular tachycardia in patients with postinfarction apical aneurysm.

Idiopathic paroxysmal ventricular tachycardia with a QRS pattern of right bundle branch block and left axis deviation: A unique clinical entity with specific properties

Eiectrophysiologic evaluation before and after the serial administration of verapamil, lidocaine, propranolol, and procainamide was undertaken in 4 young, asymptomatic patients with recurrent, sustained ventricular tachycardia (VT). No patient had obvious organic heart disease. The electrocardiogram during sinus rhythm showed S-T depression and T-wave inversion over the inferior and lateral precordial leads in 3 patients. QRS morphologic characteristics during episodes of VT showed a pattern of right bundle branch block and left axis deviation. In all 4 patients, VT could be both induced and terminated with electrical stimulation. Verapamil terminated VT and prevented the induction of sustained VT in 3 patients, and markedly slowed the rate of VT in 1 patient. Procainamide effectively prevented the induction of sustained VT in 2 patients, and although ineffective in preventing induction in 2 patients, it slowed the rate of tachycardia in both. Lidocaine and propranolol did not prevent the induction of VT in any patient. These findings suggest that slow-response tissues may be involved in the genesis of VT in these patients, and that VT in these patients may represent a unique clinical entity with distinct electrocardiographic, electrophysiologic, and electropharmacologic properties.

Effect of coronary occlusion on arrhythmias and conduction in the ovine heart.

The proximal left circumflex coronary artery was occluded for 1 h in 16 open-chest sheep anesthetized with pentobarbital sodium. Epicardial conduction was monitored at three or four sites within the ischemic zone and one site in the normal zone. Eight of the sheep developed ventricular fibrillation within the first 15 min of occlusion; the remaining sheep survived the 1-h observation period. In the sheep that developed spontaneous ventricular fibrillation, the circumflex perfused a significantly greater amount of the left ventricle (44 +/- 3 vs. 39 +/- 3%; P = 0.008). The occurrence of spontaneous ventricular fibrillation was invariably preceded by a period of sustained (0.5-4 min) ventricular tachycardia. Six of the surviving sheep developed episodes of sustained (2-10 min) tachycardia that were self-terminating. The ischemic zone electrograms showed continuous fractionated electrical activity during both self-terminating tachycardias and tachycardias ending in fibrillation. The continuous epicardial electrical activity did not appear to cause the tachycardias but rather occurred as a result of the tachycardias. The genesis of ventricular tachycardia and fibrillation in this model may involve mechanisms different from ischemia-induced ventricular tachycardia and fibrillation in canine and porcine hearts.

Glucose-insulin-potassium (GIK) therapy for ischemic heart disease.

In 1912 Goulston advocated glucose therapy for several different kinds of heart disease, and in 1933 Shirley-Smith recommended glucose and insulin for coronary artery disease. Thirty years later, Laborit noted that treatment of rabbits with glucose and insulin prevented ventricular fibrillation induced by potassium chloride solutions. Sodi-Pallares et al, pioneers in glucose-insulin-potassium (GIK) therapy for heart disease, showed not only that potassium may be a major excitant in the genesis of ventricular tachycardia in the ischemic heart but that GIK solution was capable of enhancing oxidative phosphorylation in the ischemic heart. Interest in GIK therapy for ischemic heart disease has been renewed as the effects of GIK solutions on myocardial infarct size, metabolism and electrical properties are better understood. In this paper, selected new information regarding the actions of GIK and the clinical applications will be reviewed.