Electromechanical vortex filaments during cardiac fibrillation.

The self-organized dynamics of vortex-like rotating waves, which are also known as scroll waves, are the basis of the formation of complex spatiotemporal patterns in many excitable chemical and biological systems. In the heart, filament-like phase singularities that are associated with three-dimensional scroll waves are considered to be the organizing centres of life-threatening cardiac arrhythmias. The mechanisms that underlie the onset, maintenance and control of electromechanical turbulence in the heart are inherently three-dimensional phenomena. However, it has not previously been possible to visualize the three-dimensional spatiotemporal dynamics of scroll waves inside cardiac tissues. Here we show that three-dimensional mechanical scroll waves and filament-like phase singularities can be observed deep inside the contracting heart wall using high-resolution four-dimensional ultrasound-based strain imaging. We found that mechanical phase singularities co-exist with electrical phase singularities during cardiac fibrillation. We investigated the dynamics of electrical and mechanical phase singularities by simultaneously measuring the membrane potential, intracellular calcium concentration and mechanical contractions of the heart. We show that cardiac fibrillation can be characterized using the three-dimensional spatiotemporal dynamics of mechanical phase singularities, which arise inside the fibrillating contracting ventricular wall. We demonstrate that electrical and mechanical phase singularities show complex interactions and we characterize their dynamics in terms of trajectories, topological charge and lifetime. We anticipate that our findings will provide novel perspectives for non-invasive diagnostic imaging and therapeutic applications.

Lidocaine converts acute vagally associated atrial fibrillation to sinus rhythm in German Shepherd dogs with inherited arrhythmias.

BACKGROUND: Lidocaine is most frequently used to treat ventricular arrhythmias. However, lidocaine may have an antiarrhythmic effect for certain supraventricular arrhythmias. HYPOTHESIS: We hypothesized that lidocaine would be effective in converting experimentally induced atrial fibrillation (AF) to sinus rhythm and that a decrease in the dominant frequency (DF) and an increase in the organization as judged by the spectral entropy (SE) would occur over the course of the conversion. ANIMALS: Seven German Shepherd (GS) Dogs. METHODS: Dogs were anesthetized with fentanyl and pentobarbital. AF was induced with standard pacing protocols while left and right atrial monophasic action potentials (MAP) were recorded. The power spectra from the MAP recordings were analyzed to determine DF and SE during treatment with boluses of 2 mg/kg lidocaine. RESULTS: Lidocaine converted AF to sinus rhythm in all dogs and all episodes (n = 19). Conversion time was 27-87 seconds. After atropine, sustained AF was not induced; however, 5 episodes of atrial tachycardia resulted, and 3 were converted with lidocaine. Frequency domain analysis of 12 conversion sequences showed that left and right DF of the MAP signals decreased from the time of injection to conversion to sinus rhythm (P < .001). Mean SE indicated a gradient between the left and right atria (P = .003) that did not change during conversion. CONCLUSIONS AND CLINICAL IMPORTANCE: Vagally associated AF in GS dogs is terminated with lidocaine. Lidocaine is likely an effective treatment in clinical dogs with vagally associated AF.

Depolarization and decreased surface expression of K+ channels contribute to NSAID-inhibition of intestinal restitution.

Non-steroidal anti-inflammatory drugs (NSAIDs) contribute to gastrointestinal ulcer formation by inhibiting epithelial cell migration and mucosal restitution; however, the drug-affected signaling pathways are poorly defined. We investigated whether NSAID inhibition of intestinal epithelial migration is associated with depletion of intracellular polyamines, depolarization of membrane potential (E(m)) and altered surface expression of K(+) channels. Epithelial cell migration in response to the wounding of confluent IEC-6 and IEC-Cdx2 monolayers was reduced by indomethacin (100 microM), phenylbutazone (100 microM) and NS-398 (100 microM) but not by SC-560 (1 microM). NSAID-inhibition of intestinal cell migration was not associated with depletion of intracellular polyamines. Treatment of IEC-6 and IEC-Cdx2 cells with indomethacin, phenylbutazone and NS-398 induced significant depolarization of E(m), whereas treatment with SC-560 had no effect on E(m). The E(m) of IEC-Cdx2 cells was: -38.5+/-1.8 mV under control conditions; -35.9+/-1.6 mV after treatment with SC-560; -18.8+/-1.2 mV after treatment with indomethacin; and -23.7+/-1.4 mV after treatment with NS-398. Whereas SC-560 had no significant effects on the total cellular expression of K(v)1.4 channel protein, indomethacin and NS-398 decreased not only the total cellular expression of K(v)1.4, but also the cell surface expression of both K(v)1.4 and K(v)1.6 channel subunits in IEC-Cdx2. Both K(v)1.4 and K(v)1.6 channel proteins were immunoprecipitated by K(v)1.4 antibody from IEC-Cdx2 lysates, indicating that these subunits co-assemble to form heteromeric K(v) channels. These results suggest that NSAID inhibition of epithelial cell migration is independent of polyamine-depletion, and is associated with depolarization of E(m) and decreased surface expression of heteromeric K(v)1 channels.

Subungual melanoma: Management in the modern era.

Subungual melanoma is a rare subtype of cutaneous melanoma that arises from the structures of the nail apparatus. It presents most commonly in older patients and at an advanced stage. A retrospective review of all patients with subungual melanoma in a single institution over a 15-year period was performed. In total, 54 patients were included (26 males, average age 62.9 years), of which 28 cases involved the upper limb. Median tumour thickness was 4.5 mm. Eighteen patients had lymph node metastasis at diagnosis, including 11 of 36 patients with positive sentinel lymph node biopsy. Median survival was 4.6 years. Subungual melanoma has a poor prognosis that is strongly associated with presence of nodal disease at diagnosis. Sentinel lymph node biopsy should be considered to determine stage and prognosis.

Triggered activity as a mechanism for inherited ventricular arrhythmias in German shepherd Dogs.

OBJECTIVES: This study sought to determine whether early afterdepolarization-induced triggered activity is responsible for the initiation of ventricular arrhythmias in dogs with an inherited predisposition to sudden death. BACKGROUND: We have identified a colony of German shepherd dogs that display inherited ventricular ectopic activity and sudden cardiac death. The arrhythmias in these animals are pause dependent but are not associated with a prolonged QT interval, suggesting that they might be initiated by early afterdepolarization-induced triggered activity in Purkinje fibers. METHODS: Cardiac Purkinje fibers obtained from dogs that either did or did not exhibit ventricular tachyarrhythmias at the time of study were superfused in vitro with normal Tyrode solution (extracellular potassium ion concentration 4 mmol/liter) and were studied using standard microelectrode techniques. RESULTS: Early afterdepolarizations and triggered activity occurred spontaneously in Purkinje fibers obtained from affected dogs (n = 7) but not in fibers obtained from unaffected dogs (n = 13). Exit conduction block of triggered responses occurred to varying degrees within the Purkinje fiber but not at the Purkinje-muscle junction. Overdrive pacing suppressed triggered activity. The reemergence of triggered activity after cessation of pacing was both time and rate dependent. Triggered activity in fibers obtained from affected dogs was potentiated by phenylephrine and epinephrine and was suppressed by isoproterenol. Triggered activity was not induced by phenylephrine or epinephrine in fibers obtained from unaffected dogs. CONCLUSIONS: These results support the hypothesis that early afterdepolarization-induced triggered activity in Purkinje fibers is responsible for the initiation of ventricular arrhythmias in this canine model of inherited sudden death.

Evidence for prejunctional and postjunctional antagonism of the sympathetic neuroeffector junction by acetylcholine in canine cardiac Purkinje fibers.

This study determined whether acetylcholine inhibited changes in action potential duration and developed tension in canine Purkinje fibers produced by norepinephrine released during field stimulation more than it inhibited changes produced by superfusion with norepinephrine. Field stimulation increased action potential duration measured at 75% of repolarization by 9.6 ms and increased active tension by 35.5%. Acetylcholine (10(-6) M) almost completely inhibited changes in action potential duration and developed tension during field stimulation. Norepinephrine (10(-8) M to 5 X 10(-8) M) superfusion during normal pacing increased developed tension by 40.6%. Acetylcholine (10(-6) M) reduced this increase to 19.7%. Thus, acetylcholine inhibited the increase in tension during field stimulation by 90.7%, whereas it inhibited equivalent increases in tension produced by superfusion with norepinephrine by only 51.4% (p less than 0.01). These data suggest that acetylcholine antagonizes the effects of adrenergic stimulation by pre- and postjunctional inhibitory actions in canine cardiac Purkinje fibers.

Time- and rate-dependent alterations of the QT interval precede the onset of torsade de pointes in patients with acquired QT prolongation.

OBJECTIVES: The purpose of this study was to determine whether the QT interval dynamics that precede torsade de pointes are consistent with the initiation of this arrhythmia by early afterdepolarization-induced triggered activity. BACKGROUND: Early afterdepolarization-induced triggered activity has been suggested as an electrophysiologic mechanism for torsade de pointes. Consequently, the initiation of torsade de pointes should involve time- and rate-dependent alterations of ventricular repolarization similar to those known to modulate the development of early afterdepolarizations. METHODS: RR and QT intervals were measured in digitized 24-h ambulatory electrocardiographic recordings obtained from seven patients with acquired prolongation of ventricular repolarization. Each patient had one or more episodes of torsade de pointes. The relation between RR and QT intervals was determined before, during and after multiple episodes of torsade de pointes. RESULTS: In patients with multiple episodes of ventricular arrhythmias, the onset of the arrhythmias was associated with a critical prolongation of the QT interval. In some episodes, prolongation of the QT interval was associated with sudden prolongation of the sinus cycle length, whereas in other episodes, the QT interval prolonged progressively at a constant cycle length. CONCLUSIONS: The association between a critically prolonged QT interval and the onset of ventricular arrhythmias suggests that the initial complex of torsade de pointes is an early afterdepolarization-induced triggered response. However, prolongation of the QT interval itself was not sufficient to account for the initiation of torsade de pointes, suggesting that other, as yet unidentified factors are required.

Duchenne's cardiomyopathy in a canine model: electrocardiographic and echocardiographic studies.

Thirteen dogs affected with X-linked Duchenne's muscular dystrophy and 11 female carrier dogs were studied by electrocardiography (ECG) and echocardiography. Twelve of the affected dogs were studied as immature animals and followed at 1 to 6 month intervals until they were 7 to 46 months of age. Compared with control dogs, affected dogs had significantly increased (p less than 0.02) Q/R ratios in ECG leads II, III, aVF, CV6LL (V2) and CV6LU (V4). Carrier dogs had significantly increased (p less than 0.02) Q/R ratios in leads V2 and V4. The Q/R ratio increased in three of six dogs followed up from age 6 months to greater than 2 years. The PR intervals were significantly shorter (p less than 0.02) in affected dogs. Ventricular arrhythmias were identified in four of six mature affected dogs. Two-dimensional echocardiography revealed distinctive hyperechoic lesions in 12 of the 13 affected dogs and in 6 of the 11 carrier dogs. Hyperechoic lesions corresponded to calcified myocardium and surrounding dense connective tissue. This study establishes the dog affected with Duchenne's muscular dystrophy as an animal model of Duchenne's cardiomyopathy and demonstrates that the heart in carrier dogs is affected by the dystrophic process.

Electrophysiological characteristics of rodent myocardium damaged by adrenaline.

Myocardial cell injury was produced in rats and guinea pigs by injecting 3.0 mg.kg-1 1-adrenaline subcutaneously. Ventricular myocardium removed from animals 24 h after the injection exhibited marked electrophysiological alterations when studied in vitro. These alterations included: (1) reduced resting membrane potential, action potential amplitude and duration, and dV/dt; (2) conduction disturbances such as delay, unidirectional block, summation and inhibition; (3) abnormal automatic activity including triggered sustained rhythmic activity and post-overdrive acceleration. Conduction disturbances were affected by stimulus intensity, duration, rate and site of pacing. Isoprenaline (10(-7) mol.litre-1) improved conduction. Automatic activity was modified by changes in entrance and exit block and depolarising or hyperpolarising current pulses. These data indicate that diverse abnormal electrophysiological alterations occur in myocardium damaged by adrenaline.

Age dependence of the development of ventricular arrhythmias in a canine model of sudden cardiac death.

OBJECTIVES: The age-dependence of the development of ventricular arrhythmias was studied in German shepherd dogs with inherited ventricular arrhythmias and sudden death. BACKGROUND: A colony of German shepherd dogs has been established that exhibit inherited ventricular arrhythmias and sudden death. The incidence of arrhythmias increases with age. Because ventricular tachycardia is associated with bradycardia, it was hypothesized that the increased incidence of arrhythmias was related to age-dependent slowing of heart rate. METHODS: Arrhythmia counts and RR intervals were measured from serial ambulatory ECG recordings obtained in 71 dogs (1-48 weeks). In addition, 19 dogs were challenged with phenylephrine (10 micrograms/kg i.v.) at 15, 28, and 45 weeks of age, 10 dogs were challenged with epinephrine (1 microgram/kg i.v.) at 3, 5, 7, 9, 11, 18, and 28 weeks of age, and 10 dogs were challenged at 28 weeks with epinephrine (2.5 micrograms/kg i.v.), before and after propranolol (0.5 mg/kg i.v.). RESULTS: The incidence and severity of ventricular arrhythmias increased between 7 and 28 weeks of age and decreased between 28 and 44 weeks of age. The age-dependent increase in the incidence of ventricular tachycardia was associated with age-dependent reductions in sinus rate. Baroreflex-mediated slowing of the heart rate unmasked arrhythmias in young animals that did not spontaneously display arrthythmias and exacerbated existing arrhythmias in older animals. However, the magnitude of baroreflex-induced bradycardia was similar from 7-18 weeks of age, yet the incidence of arrhythmias increased progressively. Moreover, the waning of ventricular arrhythmias in older animals was not associated with more rapid sinus rates. CONCLUSION: The risk for sudden death in dogs with inherited ventricular arrhythmias increases with age in part because of age-dependent slowing of heart rate and in part because of other heart-rate-independent factors. The correspondence between the development of ventricular tachycardia and sinus pauses is consistent with the hypothesis that ventricular arrhythmias are initiated by early afterdepolarization-induced triggered activity.

Depressant effects of fast sodium channel blockade on the electrical activity of ischaemic canine ventricle: mediation by the sympathetic nervous system.

In this study we examined the possibility that local anaesthetic agents such as tetrodotoxin may exacerbate electrical changes during acute myocardial ischaemia by inhibiting fast sodium channels, both in cardiac cells and in sympathetic nerve terminals. Bipolar electrograms were recorded during serial 2 to 5 min occlusions of the left anterior descending coronary artery in open-chest, anaesthetised dogs. Tetrodotoxin (1 or 2 micrograms X kg-1 iv) given prior to occlusion did not affect activation times or electrograms in normal myocardium but exacerbated activation delay and loss of electrogram amplitude during ischaemia. Bilateral stellectomy reversed the effects of tetrodotoxin during ischaemia. Tetrodotoxin (1 microgram X kg-1 iv) reduced changes in heart rate and mean arterial blood pressure produced by stellate ganglia stimulation. Intracoronary infusion of tetrodotoxin (10(-5) mol X litre-1) during normal perfusion lengthened mean effective ventricular refractory periods and propranolol (0.5 mg X kg-1 iv) or bilateral stellectomy prevented this effect. Thus, tetrodotoxin appeared to increase ventricular refractoriness and exacerbate ischaemia-induced activation delay by inhibiting sympathetic nerve activity. Other agents with local anaesthetic properties may have similar effects.

Effect of ethanol on electrogram changes and regional myocardial blood flow during acute myocardial ischaemia.

Acute occlusion of the left anterior descending coronary artery in dogs produced delayed conduction and diminished amplitude of bipolar electrograms recorded from ischaemic zones. Intravenous infusion of ethanol (1.2 g . kg-1), before coronary artery occlusion, delayed conduction and reduced the amplitude of electrograms recorded in normal myocardium, but attenuated ischaemia-induced electrogram changes produced by the subsequent occlusion. Ethanol (0.6 g . kg-1 iv) did not significantly alter activation of electrograms recorded from normal myocardium, but reduced ischaemia-induced electrogram changes and decreased the incidence of ventricular fibrillation elicited by rapid ventricular pacing from five of eight to one of eight dogs. Infusion of 10 or 30% (V/V) ethanol directly into a non-occluded coronary artery significantly increased conduction time and reduced electrogram amplitude recorded in the epicardium perfused by that coronary artery. These effects were more pronounced when ethanol was infused into an occluded coronary artery distal to the site of occlusion. Ethanol did not alter regional myocardial blood flow determined by labelled microspheres during ischaemia. Thus, despite a direct depressant effect on extracellular electrical activity recorded from normal and ischaemic myocardium, ethanol reduced the severity of ischaemia-induced electrogram alterations and decreased the incidence of ventricular fibrillation when given intravenously prior to coronary artery occlusion.

Modulation of the excitability of avian peripheral nerves by vitamin D: relation to calbindin-D28k, calcium status and lipid composition.

Calbindin-D28k (CaBP), previously localized in some of the cell bodies of ganglia of the avian intestinal (Remark's) nerve, was shown to be vitamin D-dependent. In the present studies, the effect of vitamin D3 on electrophysiological properties of this nerve was examined in vitro. Electrical stimulation of the nerve yielded a compound action potential with two primary components, Peaks I and II. Peak II, suppressed by hexamethonium bromide or Ca(2+)-free buffer, is synaptically mediated. The transit time between the two peaks was unaffected by vitamin D3. The apparent conduction velocity, defined as [(activation time + transit time)/nerve length], was increased by vitamin D-deficiency and decreased by vitamin D3 repletion, the latter decrease due entirely to an increase in activation time. Activation time after vitamin D-repletion was correlated with an increase in CaBP and plasma Ca2+ levels. However, normalization of plasma Ca2+ by supplementation of vitamin D-deficient diets with excess calcium (2.5 and 4.0%) also resulted in an increase in activation time, without affecting neuronal CaBP levels. Vitamin D3 also decreased the conduction velocity and increased CaBP of the vagus nerve and, by lipid analysis, was shown to increase and decrease its phosphatidylcholine and phosphatidylethanolamine content, respectively, and to decrease its phospholipid/cholesterol ratio. Modulation of peripheral nerve activity by vitamin D3 is related to calcium status and perhaps to changes in lipid composition. The functional role of CaBP in the behaviour of this complex nerve remains unknown.

Myocardial uptake of Tc-99m skeletal agents in the rat after experimental induction of microscopic foci of injury.

The cardiac uptake of Tc-99m tagged skeletal agents was studied after myocardial injury produced by subcutaneous catecholamine injection and random foot-shock stress. Rats stressed for 2 hr developed microfocal myocardial injury, without gross change, whereas those stressed for 12 hr sustained more confluent and sometimes grossly visible damage. Tc-99m MDP and Tc-99m PPi concentrations in these hearts were significantly above control (undamaged) heart levels, producing positive gamma-camera images. Subcutaneous epinephrine injections resulted in grossly visible lesions, with tracer concentrations higher than those previously reported in vasoocclusive infarcts. We postulate that the stress-induced scattered microfocal lesions may accumulate radiopharmaceutical on a per-gram basis in the same way as the larger catecholamine-induced lesions, since tracer delivery to the injured areas in each case is probably less impeded than in frankly vasoocclusive models. Such microfoci, then, could provide an explanation for some of the "false positive" myocardial scans observed clinically.

Slow inward current and cardiac arrhythmias.

The slow inward current contributes to the normal electrical and contractile activity of several cardiac and vascular tissues and also may mediate the electrical abnormalities responsible for certain cardiac arrhythmias. The slow inward current differs from the fast inward sodium current in that it is carried primarily by calcium rather than sodium, requires a more positive level of membrane potential to be activated, has slower activation and inactivation kinetics, is responsible for normal depolarization in sinus and atrioventricular (AV) nodal cells and is blocked by a rather specific group of agents that includes verapamil, diltiazem and nifedipine. Recent data suggest that slow-channel openings occur in bursts, separated by silent periods, and that less negative membrane potentials and beta-adrenergic stimulation increase the probability that the channels will open. Inactivation of the channels is associated with a lower probability of channel opening. Slow-channel blocking agents such as verapamil, diltiazem and nifedipine appear to bind to activated, rather than rested, slow channels. Therefore, their effects are more prominent at faster pacing rates and at less negative membrane potentials. Clinically occurring cardiac arrhythmias dependent on the slow inward current include primarily sinus and AV nodal reentry and reciprocating tachycardia in the Wolff-Parkinson-White syndrome when one of the pathways incorporates the AV node. Damaged atrial, ventricular and specialized tissue also can generate slow response-mediated reentry or forms of automaticity that may be clinically important under certain circumstances.

Cellular electrophysiologic abnormalities of diseased human ventricular myocardium.

Using standard microelectrode techniques, the cellular electrophysiologic features of ventricular myocardium resected from 8 patients with refractory arrhythmias were studied in vitro. Action potentials from damaged myocardium compared with normal myocardium had reduced resting membrane potential, amplitude, and maximal upstroke velocity. Tetrodotoxin, but not verapamil, suppressed 3 action potentials with resting potentials of -60 to -64 mV and Vmax less than 70 V/s. Verapamil, but not tetrodotoxin, suppressed 4 action potentials with resting potentials of -44 to -57 mV and Vmax less than 20 V/s. Unidirectional block, Wenckebach block, and summation occurred in damaged zones. Exit block from and frequency-dependent entrance block into an ectopic focus were noted. Subthreshold responses in the focal area induced by action potentials in the surrounding myocardium and by subthreshold current pulses injected through the recording microelectrode altered the spontaneous discharge rate of the focus, as previously described for modulated parasystole. Pulses early in the spontaneous cycle delayed the next expected discharge, and later pulses accelerated the subsequent discharge. Pulses injected at the singular point completely suppressed automaticity (annihilation). Tetrodotoxin and verapamil suppressed automaticity in some fibers. Single action potentials induced in quiescent fibers triggered and terminated sustained rhythmic activity. These data suggest that depressed fast responses, slow responses, and subthreshold potentials can generate and modulate ectopic activity in damaged human ventricle and that fast- and slow-channel blocking agents and single premature stimuli can terminate such activity.

Basic electrophysiologic mechanisms for the development of arrhythmias. Clinical application.

The mechanisms responsible for the genesis of cardiac arrhythmias are frequently divided into categories of disorders of impulse formation, disorders of impulse propagation, or combinations of both. Classification of arrhythmias into these categories is based largely on the results of experimental studies, where the initiation and perpetuation of an arrhythmia can be studied in some detail in a relatively controlled environment.

Primary hydronephrosis. Assessment of diuretic renography, pelvis perfusion pressure, operative findings, and renal and ureteral histology.

Hydronephrosis generally implies ureteropelvic junction obstruction, but may be mimicked by a variety of other disorders. The authors have attempted to determine the relative diagnostic value of diuretic renography and the pelvis perfusion test in children with hydronephrosis by correlating the results with operative findings, renal and ureteral histology, and postoperative results.

Inhibition of epinephrine-induced myocardial necrosis in rats by administration of single doses of ethanol.

The oral administration of single doses (0.5-6.0 g/kg) of ethanol to rats, shortly before injecting them with a large dose (3.0 mg base/kg) of epinephrine subcutaneously, significantly reduced the severity of the myocardial damage produced by the epinephrine. The larger the dose of ethanol, the greater was the protective effect. The results were the same, regardless of the method used to determine the degree of cardiac injury. Experiments employing various agents to determine the mechanisms of ethanol action have tentatively suggested that a platelet de-aggregating or an osmotic effect of alcohol may be involved.

Cellular basis for cardiac arrhythmias.

The authors summarize current concepts of the cellular electrophysiologic basis for cardiac arrhythmias. The cellular mechanisms for abnormal formation and propagation of impulses and selected interactions between the two are reviewed. The clinical significance of these phenomena is also discussed.