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Overexpression of calcineurin in transgenic mouse heart results in massive cardiac hypertrophy followed by sudden death. Sudden deaths are caused by abrupt transitions from sinus rhythm to heart block (asystole) in calcineurin-overexpressing (CN) mice. Preliminary studies showed decreased maximum change in potential over time (dV/dtmax) of phase 0 of the action potential. Accordingly, the hypothesis was tested that decreased activity of the sodium channel contributes to heart block. Profound decreases in activity of sodium currents (INa) paralleled the changes in action potential characteristics. Progressive age-dependent decreases were observed such that at 42-50 days of life little sodium channel function existed. However, this was not paralleled by decreased protein expression as assessed by immunocytochemistry or by Western blot. Since calcineurin can interact with the ryanodine receptor, we assessed whether chronic in vitro treatment with BAPTA-AM, thapsigargin, and ryanodine could rescue the decrease of INa. All of these treatments rescued INa to levels indistinguishable from wild type. The nonspecific PKC inhibitor bisindolylmaleimide I also rescued the decrease of INa. To assess whether decreased sodium channel activity contributes to sudden death in vivo, the response to encainide (20 mg/kg) was assessed: 6 of 10 young CN mice died because of asystole, whereas 0 of 10 wild-type mice died (P < 0.01). Moreover, encainide produced exaggerated prolongation of the QRS width in sinus beats before the heart block. Catecholamine tone appears necessary to support life in older CN mice because propranolol (1 mg/kg) triggered asystolic death in five of six CN mice. We conclude that decrease in sodium channel activity is in the common final pathway to asystole in CN mice. [ABSTRACT FROM AUTHOR]

Combination therapy with mexiletine and quinidine has been shown to be more effective than either monotherapy in treating patients with ventricular tachycardia. This enhanced efficacy was associated with prolongation of ventricular refractoriness and conduction time in the infarct zone. As sodium channel activity is a determinant of both conduction time and refractoriness we formed the hypothesis that the mexiletine-quinidine interaction was due at least in part to interactions involving the sodium channel. To assess the role of sodium channel blockade in the enhanced anti-arrhythmic activity of mexiletine-quinidine combination we determined whether the electrophysiological and anti-arrhythmic effects of tetrodotoxin combined with mexiletine or quinidine mimicked the effect seen with mexiletine combined with quinidine. Eighty isolated perfused rabbit hearts were treated with mexiletine, quinidine and tetrodotoxin either alone or in combination before and after circumflex occlusion-reperfusion. Ventricular fibrillation occurred in response to single extrastimuli in all 24 hearts treated with a saline control infusion. Combinations of mexiletine and quinidine at concentrations which alone had little electrophysiological activity produced anti-arrhythmic activity greater than that seen with high concentrations of mexiletine or quinidine alone. The combination of similarly low concentrations of tetrodotoxin and quinidine also produced enhanced anti-arrhythmic efficacy and enhanced prolongation of ventricular refractoriness and conduction which mimicked the effect of mexiletine and quinidine in combination. In contrast, the combination of mexiletine and tetrodotoxin did not produce enhanced anti-arrhythmic and electrophysiological activity.Since tetrodotoxin is a highly specific sodium channel blocker, these data suggest that the enhanced antiarrhythmic activity of mexiletine-quinidine combination therapy involves, at least in part, blockade of the cardiac sodium channel. [ABSTRACT FROM PUBLISHER]

Dual-chamber pacing is a promising treatment for patients with very frequent vasovagal syncope, but its cost utility is unknown. We report that the incremental cost per quality-adjusted life-year gained is $13,159 Canadian dollars (about $8,600 US dollars), and therefore this pacemaker therapy for vasovagal syncope has a favorable cost-utility ratio. [ABSTRACT FROM AUTHOR]

The follow-up prevalence of electrogram-confirmed spontaneous ventricular tachycardia with a cycle length of >280 ms (53%) exceeds the prevalence of ventricular fibrillation (23%) in patients whose only spontaneous arrhythmia before implantable cardioverter defibrillator implantation was ventricular fibrillation. Antitachycardia pacing therapy safely terminates most (89%) of these slower ventricular tachycardia episodes, recommending the use of tiered-therapy devices and anticipatory activation of ventricular tachycardia detection and treatment algorithms for ventricular fibrillation patients who receive an implantable cardioverter defibrillator. [ABSTRACT FROM AUTHOR]

Overexpression of calcineurin in transgenic mouse heart results in massive cardiac hypertrophy followed by sudden death. Sudden deaths are caused by abrupt transitions from sinus rhythm to heart block (asystole) in calcineurin-overexpressing (CN) mice. Preliminary studies showed decreased maximum change in potential over time (dV/dt(max)) of phase 0 of the action potential. Accordingly, the hypothesis was tested that decreased activity of the sodium channel contributes to heart block. Profound decreases in activity of sodium currents (I(Na)) paralleled the changes in action potential characteristics. Progressive age-dependent decreases were observed such that at 42-50 days of life little sodium channel function existed. However, this was not paralleled by decreased protein expression as assessed by immunocytochemistry or by Western blot. Since calcineurin can interact with the ryanodine receptor, we assessed whether chronic in vitro treatment with BAPTA-AM, thapsigargin, and ryanodine could rescue the decrease of I(Na). All of these treatments rescued I(Na) to levels indistinguishable from wild type. The nonspecific PKC inhibitor bisindolylmaleimide I also rescued the decrease of I(Na). To assess whether decreased sodium channel activity contributes to sudden death in vivo, the response to encainide (20 mg/kg) was assessed: 6 of 10 young CN mice died because of asystole, whereas 0 of 10 wild-type mice died (P < 0.01). Moreover, encainide produced exaggerated prolongation of the QRS width in sinus beats before the heart block. Catecholamine tone appears necessary to support life in older CN mice because propranolol (1 mg/kg) triggered asystolic death in five of six CN mice. We conclude that decrease in sodium channel activity is in the common final pathway to asystole in CN mice.

Background: Overexpression of calcineurin in transgenic (TG) mice results in cardiac hypertrophy and unexpected deaths., Methods and Results: None of the TG survived beyond 24 weeks (n=38) whereas all of the wildtype (WT, n=47) survived. Prolongation of repolarization preceded the development of sustained pleomorphic ventricular tachycardia and high degree atrioventricular block, which occurred during spontaneous sudden deaths. Since depolarization-activated K(+) channels contribute dominantly to repolarization in mice, we hypothesized that the TG would decrease these K(+) currents and that the in vivo administration of cyclosporin A (CsA), a calcineurin inhibitor, would reduce this effect. CsA reversed cardiac hypertrophy: capacitance measurements of WT left ventricular myocytes (127+/-7 pF; n=45) and CsA-treated TG (129+/-14 pF; n=17) were significantly lower than in placebo-treated TG (220+/-11 pF; n=41; P<0.001 by ANOVA). Independent of whether the data fit a bi- or a tri-exponential model, the density of I(tof) was significantly reduced in TG versus WT and CsA reversed this effect. While I(tos) and I(Kslow) were also reduced in TG, CsA does not reverse this change because long-term in vivo CsA treatment of WT also reduces I(tos) and I(Kslow.) To assess whether the decreased 'repolarization reserve' contributed to arrhythmogenesis, the residual I(Kr) was blocked by dofetilide precipitating pleomorphic ventricular tachycardias., Conclusion: Since the downregulation of I(tof) was observed with overexpression of calcineurin and was also reversed by the calcineurin inhibitor CsA, we conclude that downregulation of I(tof) is a consequence of calcineurin overexpression.

The implantable cardioverter-defibrillator (ICD) has become a highly effective, but expensive therapy for sudden cardiac death due to ventricular tachyarrhythmias. ICD use has been increasing at 20-30% per year, and is expected to rise at a faster rate. Clinical trials have now shown that the ICD can be effective for the secondary prevention, and more recently for the primary prevention, of sudden cardiac death in selected populations. Despite the high quality trial evidence that is currently available, several issues pertaining to ICD use remain unresolved. These relate to the management of patient groups who were not included in the clinical trials, optimizing the selection of patients who will benefit from an ICD, determining the duration of survival benefit from an ICD, assessing and optimizing a patient's quality of life with an ICD, and determining the cost-effectiveness and cost-impact of the ICD. These considerations are discussed in this article.

The implantable cardioverter-defibrillator (ICD) has emerged as an effective, but expensive, therapy for arrhythmic sudden cardiac death. ICD use has been increasing by 20% to 30% per year. Clinical trials have shown that the ICD can be effective for both the primary prevention and the secondary prevention of sudden cardiac death in selected populations. Despite the available trial evidence, several issues pertaining to ICD use remain unresolved, including the treatment of patients not represented in clinical trials, the optimal selection of patients who will benefit from an ICD, the duration of benefit from an ICD, the quality of life for patients with an ICD, and both the cost-effectiveness and the cost impact of the ICD. These considerations are discussed in this article., (Copyright 2001 by W.B. Saunders Company)

Objective: Our purpose was to evaluate whether baseline characteristics predictive of implantable cardioverter defibrillator (ICD) efficacy in the Canadian Implantable Defibrillator Study (CIDS) are predictive in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial., Background: ICD therapy is superior to antiarrhythmic drug use in patients with life-threatening arrhythmias. However, identification of subgroups most likely to benefit from ICD therapy may be useful. Data from CIDS suggest that 3 characteristics (age > or =70 years, ejection fraction [EF] < or =0.35, and New York Heart Association class >II) can be combined to reliably categorize patients as likely (> or =2 characteristics) versus unlikely to benefit (<2 characteristics) from ICD therapy., Methods: The utility of the CIDS categorization of ICD efficacy was assessed by Kaplan-Meier analysis and Cox hazards modeling. The accuracy of the CIDS score was formally tested by evaluating for interaction between categorization of benefit and treatment in a Cox model., Results: ICD therapy was associated with a significantly lower risk of death in the 320 patients categorized as likely to benefit (relative risk [RR] 0.57, 95% confidence interval [CI] 0.37-0.88, P =.01) and a trend toward a lower risk of death in the 689 patients categorized as unlikely to benefit (RR 0.70, 95% CI 0.48-1.03, P =.07). Categorization of benefit was imperfect, as evidenced by a lack of statistical interaction (P =.5). Although 32 of the 42 deaths prevented by ICD therapy in AVID were in patients categorized as likely to benefit, all 42 of these patients had EF values < or =0.35. Neither advanced age nor poorer functional class predicted ICD efficacy in AVID., Conclusion: Of the 3 characteristics identified to predict ICD efficacy in CIDS, only depressed EF predicted ICD efficacy in AVID. Thus physicians faced with limited resources might elect to consider ICD therapy over antiarrhythmic drug use in patients with severely depressed EF values.

Prior clinical research indicates that conduction slowing is the primary mechanism leading to the spontaneous termination of reentrant tachycardia in humans. Yet, some experimental models indicate that cycle length oscillations and enhanced conduction are important prerequisites. The role of oscillations in conduction times and enhanced conduction in the spontaneous termination of human reentrant tachycardia has not been adequately investigated. The electrophysiologic features preceding the spontaneous termination of orthodromic atrioventricular (AV) reciprocating tachycardia (RT) were evaluated in 21 patients, each of whom had a sustained (>60 seconds) and a spontaneously terminating (>/=10 beats and

Background: Patients surviving ventricular fibrillation (VF) or sustained ventricular tachycardia (VT) are at a high risk of death due to a recurrence of arrhythmia. The implantable cardioverter defibrillator (ICD) terminates VT or VF, but it is not known whether this device prolongs life in these patients compared with medical therapy with amiodarone., Methods and Results: A total of 659 patients with resuscitated VF or VT or with unmonitored syncope were randomly assigned to treatment with the ICD or with amiodarone. The primary outcome measure was all-cause mortality, and the secondary outcome was arrhythmic death. A total of 328 patients were randomized to receive an ICD. A thoracotomy was done in 33, no ICD was implanted in 18, and the rest had a nonthoracotomy ICD. All 331 patients randomized to amiodarone received it initially. At 5 years, 85.4% of patients assigned to amiodarone were still receiving it at a mean dose of 255 mg/day, 28.1% of ICD patients were also receiving amiodarone, and 21.4% of amiodarone patients had received an ICD. A nonsignificant reduction in the risk of death was observed with the ICD, from 10.2% per year to 8.3% per year (19.7% relative risk reduction; 95% confidence interval, -7.7% to 40%; P=0.142). A nonsignificant reduction in the risk of arrhythmic death was observed, from 4.5% per year to 3.0% per year (32.8% relative risk reduction; 95% confidence interval, -7.2% to 57.8%; P=0.094)., Conclusions: A 20% relative risk reduction occurred in all-cause mortality and a 33% reduction occurred in arrhythmic mortality with ICD therapy compared with amiodarone; this reduction did not reach statistical significance.

We propose that heart period sequences are organized similarly to sentences, with a lexicon of recurrent, similarly shaped words. These words should fulfill four criteria: universality, nonrandomness, central statistical tendencies, and specific associated physiology. Here we describe a large-magnitude, transient bradycardia (LMTB) and assess whether it constitutes a word. LMTBs were seen in 11 of 12 adult female rabbits. All shape parameters were different than those of the beat-randomized and phase-randomized surrogate sequences (P < 0.05-0.001). LMTBs were 8. 4 +/- 2.9 beats and 2.64 +/- 0.87 s long and were characterized by bradycardia of 77 +/- 49 ms over 1.09 +/- 0.49 s with a recovery to baseline over 1.56 +/- 0.61 s. The LMTBs had a slower recovery than onset in 9 of 11 rabbits and were highly peaked in 10 of 11 rabbits (P < 0.05). Scalar, magnitude, and shape parameters had values with central statistical tendencies. About 76% of LMTBs were accompanied by hypotension (mean -6.1 +/- 3.9 mmHg) that lagged 2 beats behind the onset of the bradycardia and that correlated with the bradycardia (-10.5 +/- 4.1 ms/mmHg). Thus transient bradycardic events are a distinct "word" in the lexicon of heart rate variability.

Many chaos detection methods have proven inherently ambiguous in that they yield similar results for chaotic signals and correlated noise. The purpose of this work was to determine whether human resting heart period sequences have global properties characteristic of chaotic systems. We investigated the inherent global organization of heart period sequences by quantifying how the information content of the embedded sequences varied as a function of scale. We compared the information scaling characteristics of 60-min heart period sequences obtained from 10 healthy resting volunteers with those obtained from numerous periodic and chaotic control sequences. The information scaling properties of the heart period sequences were significantly different from those obtained for the controls, particularly at the coarsest scales (P = 0.0003 vs. low-dimensional periodic controls; P = 0.0005 vs. low-dimensional chaotic controls; P = 0.0003 vs. low-dimensional periodic and chaotic controls). We also showed that nondeterministic components, such as large tachycardic (or bradycardic) events or aperiodic fluctuations, can lead to scaling characteristics similar to those observed for the resting heart period sequences. This, in addition to previous evidence from spectral, nonlinear predictability and lexical studies, favors an events-based approach to understanding heart rate variability.