Methods for ECG Evaluation of Indicators of Cardiac Risk,and Susceptibility to Aconitine-induced Arrhythmias in Rats Following Status Epilepticus

Lethal cardiac arrhythmias contribute to mortality in a number of pathological conditions. Several parameters obtained from a non-invasive, easily obtained electrocardiogram (ECG) are established, well-validated prognostic indicators of cardiac risk in patients suffering from a number of cardiomyopathies. Increased heart rate, decreased heart rate variability (HRV), and increased duration and variability of cardiac ventricular electrical activity (QT interval) are all indicative of enhanced cardiac risk ^1-4. In animal models, it is valuable to compare these ECG-derived variables and susceptibility to experimentally induced arrhythmias. Intravenous infusion of the arrhythmogenic agent aconitine has been widely used to evaluate susceptibility to arrhythmias in a range of experimental conditions, including animal models of depression ⁵ and hypertension ⁶, following exercise ⁷ and exposure to air pollutants ⁸, as well as determination of the antiarrhythmic efficacy of pharmacological agents ^9,10.It should be noted that QT dispersion in humans is a measure of QT interval variation across the full set of leads from a standard 12-lead ECG. Consequently, the measure of QT dispersion from the 2-lead ECG in the rat described in this protocol is different than that calculated from human ECG records. This represents a limitation in the translation of the data obtained from rodents to human clinical medicine.Status epilepticus (SE) is a single seizure or series of continuously recurring seizures lasting more than 30 min ^{11,12 11,12}, and results in mortality in 20% of cases ¹³. Many individuals survive the SE, but die within 30 days ^14,15. The mechanism(s) of this delayed mortality is not fully understood. It has been suggested that lethal ventricular arrhythmias contribute to many of these deaths ^14-17. In addition to SE, patients experiencing spontaneously recurring seizures, i.e. epilepsy, are at risk of premature sudden and unexpected death associated with epilepsy (SUDEP) ¹⁸. As with SE, the precise mechanisms mediating SUDEP are not known. It has been proposed that ventricular abnormalities and resulting arrhythmias make a significant contribution ^18-22.To investigate the mechanisms of seizure-related cardiac death, and the efficacy of cardioprotective therapies, it is necessary to obtain both ECG-derived indicators of risk and evaluate susceptibility to cardiac arrhythmias in animal models of seizure disorders ^23-25. Here we describe methods for implanting ECG electrodes in the Sprague-Dawley laboratory rat (Rattus norvegicus), following SE, collection and analysis of ECG recordings, and induction of arrhythmias during iv infusion of aconitine.These procedures can be used to directly determine the relationships between ECG-derived measures of cardiac electrical activity and susceptibility to ventricular arrhythmias in rat models of seizure disorders, or any pathology associated with increased risk of sudden cardiac death. Download video file.^{(52M, mov)}     

Loss of consciousness and convulsion induced by a ventricular tachycardia mimicking epilepsy in a patient with noncompaction cardiomyopathy: a case report

Convulsions and loss of consciousness can be caused by, among other things, arrhythmias, conduction disorders or epilepsy. In clinical practice it can be difficult to distinguish between these causes of syncope, even for well-trained specialists. Patients with cardiac syncope have a substantial risk of subsequent sudden death. We present a patient with previously unknown noncompaction cardiomyopathy in whom syncope induced by ventricular tachycardia was misinterpreted as epilepsy. We present this case report in order to underline the necessity for cardiological assessment in patients with assumed mild epilepsy or syncope of unknown origin.     

Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias

Phosphodiesterases (PDEs) regulate the local concentration of 3',5' cyclic adenosine monophosphate (cAMP) within cells. cAMP activates the cAMP-dependent protein kinase (PKA). In patients, PDE inhibitors have been linked to heart failure and cardiac arrhythmias, although the mechanisms are not understood. We show that PDE4D gene inactivation in mice results in a progressive cardiomyopathy, accelerated heart failure after myocardial infarction, and cardiac arrhythmias. The phosphodiesterase 4D3 (PDE4D3) was found in the cardiac ryanodine receptor (RyR2)/calcium-release-channel complex (required for excitation-contraction [EC] coupling in heart muscle). PDE4D3 levels in the RyR2 complex were reduced in failing human hearts, contributing to PKA-hyperphosphorylated, "leaky" RyR2 channels that promote cardiac dysfunction and arrhythmias. Cardiac arrhythmias and dysfunction associated with PDE4 inhibition or deficiency were suppressed in mice harboring RyR2 that cannot be PKA phosphorylated. These data suggest that reduced PDE4D activity causes defective RyR2-channel function associated with heart failure and arrhythmias.     

Altered Cardiac Electrophysiology and SUDEP in a Model of Dravet Syndrome

Objective

Dravet syndrome is a severe form of intractable pediatric epilepsy with a high incidence of SUDEP: Sudden Unexpected Death in epilepsy. Cardiac arrhythmias are a proposed cause for some cases of SUDEP, yet the susceptibility and potential mechanism of arrhythmogenesis in Dravet syndrome remain unknown. The majority of Dravet syndrome patients have de novo mutations in SCN1A, resulting in haploinsufficiency. We propose that, in addition to neuronal hyperexcitability, SCN1A haploinsufficiency alters cardiac electrical function and produces arrhythmias, providing a potential mechanism for SUDEP.

Methods

Postnatal day 15-21 heterozygous SCN1A-R1407X knock-in mice, expressing a human Dravet syndrome mutation, were used to investigate a possible cardiac phenotype. A combination of single cell electrophysiology and in vivo electrocardiogram (ECG) recordings were performed.

Results

We observed a 2-fold increase in both transient and persistent Na⁺ current density in isolated Dravet syndrome ventricular myocytes that resulted from increased activity of a tetrodotoxin-resistant Na⁺ current, likely Na_v1.5. Dravet syndrome myocytes exhibited increased excitability, action potential duration prolongation, and triggered activity. Continuous radiotelemetric ECG recordings showed QT prolongation, ventricular ectopic foci, idioventricular rhythms, beat-to-beat variability, ventricular fibrillation, and focal bradycardia. Spontaneous deaths were recorded in 2 DS mice, and a third became moribund and required euthanasia.

Interpretation

These data from single cell and whole animal experiments suggest that altered cardiac electrical function in Dravet syndrome may contribute to the susceptibility for arrhythmogenesis and SUDEP. These mechanistic insights may lead to critical risk assessment and intervention in human patients.     

FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death

Arrhythmias, a common cause of sudden cardiac death, can occur in structurally normal hearts, although the mechanism is not known. In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum releases the calcium required for muscle contraction. The FK506 binding protein (FKBP12.6) stabilizes RyR2, preventing aberrant activation of the channel during the resting phase of the cardiac cycle. We show that during exercise, RyR2 phosphorylation by cAMP-dependent protein kinase A (PKA) partially dissociates FKBP12.6 from the channel, increasing intracellular Ca(2+) release and cardiac contractility. FKBP12.6(-/-) mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that cause sudden cardiac death. Mutations in RyR2 linked to exercise-induced arrhythmias (in patients with catecholaminergic polymorphic ventricular tachycardia [CPVT]) reduced the affinity of FKBP12.6 for RyR2 and increased single-channel activity under conditions that simulate exercise. These data suggest that "leaky" RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT.     

Reduced Incidence of Cardiac Arrhythmias in Walkers and Runners

Purpose

Walking is purported to reduce the risk of atrial fibrillation by 48%, whereas jogging is purported to increase its risk by 53%, suggesting a strong anti-arrhythmic benefit of walking over running. The purpose of these analyses is to compare incident self-reported physician-diagnosed cardiac arrhythmia to baseline energy expenditure (metabolic equivalent hours per day, METhr/d) from walking, running and other exercise.

Methods

Proportional hazards analysis of 14,734 walkers and 32,073 runners.

Results

There were 1,060 incident cardiac arrhythmias (412 walkers, 648 runners) during 6.2 years of follow-up. The risk for incident cardiac arrhythmias declined 4.4% per baseline METhr/d walked by the walkers, or running in the runners (P = 0.0001). Specifically, the risk declined 14.2% (hazard ratio: 0.858) for 1.8 to 3.6 METhr/d, 26.5% for 3.6 to 5.4 METhr/d, and 31.7% for ≥5.4 METhr/d, relative to <1.8 METhr/d. The risk reduction per METhr/d was significantly greater for walking than running (P<0.01), but only because walkers were at 34% greater risk than runners who fell below contemporary physical activity guideline recommendations; otherwise the walkers and runners had similar risks for cardiac arrhythmias. Cardiac arrhythmias were unrelated to walking and running intensity, and unrelated to marathon participation and performance.

Conclusions

The risk for cardiac arrhythmias was similar in walkers and runners who expended comparable METhr/d during structured exercise. We found no significant risk increase for self-reported cardiac arrhythmias associated with running distance, exercise intensity, or marathon participation. Rhythm abnormalities were based on self-report, precluding definitive categorization of the nature of the rhythm disturbance. However, even if the runners’ arrhythmias include sinus bradycardia due to running itself, there was no increase in arrhythmias with greater running distance.     

The impact of diagnostic tests in evaluating patients with syncope

We reviewed the charts of 100 patients admitted to the hospital for evaluation of syncope. The charts were examined with special attention given to the causes of syncope, the frequency and benefit of diagnostic tests, and the relative cost of these tests. In 39 patients no etiology for syncope was found, and another 18 were felt to have had a vasovagal episode. Twelve patients had arrhythmias as the cause for syncope. Most of the patients underwent a variety of diagnostic tests including cardiac enzyme determinations, brain scans, electroencephalograms, head CAT scans, and Holter monitoring. In most instances, these tests added little useful information to the initial history and physical exam and were done at great expense to the patient. Our data suggest that extensive neurologic testing in patients with "routine" syncope is not warranted and that the focus of hospitalization should be to rule out potentially life-threatening arrhythmias.     

Cardiac arrhythmias in myocardial infarction as an extension of lesions to the myocardium and the state of circulatory efficiency

The study involved 55 patients with the acute myocardial infarction aged between 34 and 69 years (mean 53 years) in whom the relation of cardiac arrhythmias incidence to the extension of myocardial involvement and circulatory efficiency was assessed. All patients were examined clinically, a 24-hour ECG with Holter technique (in the first day, 21st day and 6th months after myocardial infarction) and echocardiographic (Echo-2D) tests were registered. Echocardiography was performed during hospital phase and 6 months after myocardial infarction. Cardiac arrhythmias were evaluated with classification into classes described by Lown. Close relation of serious cardiac arrhythmias with extension of myocardial involvement was noted especially in the acute phase of myocardial infarction. High risk arrhythmias--class IVA, IVB and V were noted in nearly 100% of patients in this phase with cardiac aneurysm, extensive akinesis of apex and anterior wall of the heart. Mean value of the ejection fraction was 31% in this group. Incidence of cardiac arrhythmias did not exceed 40%, ejection fraction was 56% in the group of patients with limited lesions to the heart, e.g. akinesis of the lower wall. Incidence of late cardiac arrhythmias (6 months) did not differ significantly in particular groups of patients. The value of ejection fraction remained, however, on the same level as in the hospital phase of the myocardial infarction.     

Programmed electrical stimulation-induced arrhythmias in isolated hearts from adult and senescent rats

In isolated hearts from normal rats, we previously demonstrated an age-related increase of spontaneous ventricular arrhythmias. The aim of the present experiments was to test the possible effect of aging on ventricular arrhythmias induced by programmed electrical stimulation. Experiments were performed in isolated cardiac preparations of 6- and 24-month-old normal Wistar rat hearts. Programmed electrical stimulation (single or double premature stimuli following a stimuli train) was tested in isolated Langendorff perfused hearts during control perfusion, after left anterior descending coronary artery ligature and during global hypoxia. No significant differences were observed between adult and senescent hearts in the incidence of programmed electrical stimulation-induced ventricular arrhythmias during these three different situations. These experiments demonstrate that the cardiac "physiological" aging process is not associated with a greater propensity to programmed electrical stimulation-induced arrhythmias.     

Arrhythmia in patients with mitral valve prolapse]

An incidence of cardiac arrhythmias was evaluated in 119 patients with mitral valve prolapse. The disease was made basing on the results of clinical symptoms, echo-, angio- and phonocardiography. Electrocardiograms were recorded from the standard 12 lead and Holter technique for 24 hours in each patient to assess present arrhythmias. It was found that the most frequent cardiac arrhythmias accompanying mitral valve prolapse are ventricular extrasystolic contractions of Lown's class 1a and 1b. Only examination of strictly selected groups of patients (age groups with or without co-existing mitral valve insufficiency for adequate period of time) will facilitate precise evaluation of an incidence of different cardiac arrhythmias accompanying the underlying disease.     

Iron does not cause arrhythmias in the guinea pig model of transfusional iron overload

Cardiac events, including heart failure and arrhythmias, are the leading cause of death in patients with beta thalassemia. Although cardiac arrhythmias in humans are believed to result from iron overload, excluding confounding factors in the human population is difficult. The goal of the current study was to determine whether cardiac arrhythmias occurred in the guinea pig model of secondary iron overload. Electrocardiograms were recorded by using surgically implanted telemetry devices in guinea pigs loaded intraperitoneally with iron dextran (test animals) or dextran alone (controls). Loading occurred over approximately 6 wk. Electrocardiograms were recorded for 1 wk prior to loading, throughout loading, and for approximately 4 wk after loading was complete. Cardiac and liver iron concentrations were significantly increased in the iron-loaded animals compared with controls and were in the range of those reported for humans with thalassemia. Arrhythmias were rare in both iron-loaded and control guinea pigs. No life-threatening arrhythmias were detected in either group. These data suggest that iron alone may be insufficient to cause cardiac arrhythmias in the iron-loaded guinea pig model and that arrhythmias detected in human patients with iron overload may be the result of a complex interplay of factors.     

Cardiac arrhythmias during phenol face peeling

Thirty-nine percent of 54 phenol face peel patients treated rapidly developed some form of cardiac arrhythmia. When half the face was treated on consecutive days, only 22 percent of 100 patients developed cardiac arrhythmias and these were less severe. Serum phenol levels varied from 4.4 to 337.1 mg/L. Neither age, sex, nor previous cardiac history were accurate predictors of cardiac arrhythmia susceptibility. There was no predictable relationship between serum phenol level and the appearance of cardiac arrhythmia. The duration of the cardiac arrhythmias (2 to 19 minutes) suggests that the risk of cardiac arrhythmia in phenol peeling can be reduced by dividing the face into several units and spacing the application of phenol to each unit 20 minutes apart.     

Myocardial remodeling and arrhythmogenesis in moderate cardiac hypertrophy in rats

In 47 male adult Wistar rats with 4-wk aortic coarctation (AC) and 39 age-matched sham-operated rats (SO) chronically instrumented for telemetry electrocardiogram recording, we investigated the mechanisms of arrhythmogenesis in moderate cardiac hypertrophy, with an approach from "in vivo" toward the cellular level, analyzing 1) stress-induced cardiac arrhythmias in all rats and 2) myocardial fibrosis in 35 animals and action potential duration and density of hyperpolarization-activated current in 19 others at the ventricular level. Aortic banding increased arterial blood pressure, cardiac weight, and ventricular myocyte volume by 11, 25, and 14%, respectively (P < 0.001-0.05). Ventricular arrhythmias occurred at similar rates in AC and SO rats throughout the stress procedure. Action potential duration and hyperpolarization-activated current were about twice as great and myocardial fibrosis about four times greater in AC animals (P < 0.005-0.05). Electrocardiogram data also revealed more supraventricular arrhythmias in AC rats during the baseline period and after stress and fewer atrioventricular block episodes after stress (P < 0.05). Thus stress-induced supraventricular and atrioventricular nodal, but not ventricular, arrhythmias were affected in moderate cardiac hypertrophy when ventricular morphofunctional alterations were evident.     

Effect of Heparin on Serum Free-fatty-acids,Plasma Catecholamines,and the Incidence of Arrhythmias following Acute Myocardial Infarction

The effect of intravenous heparin in a therapeutic dosage on cardiac arrhythmias in patients with indubitable acute myocardial infarction was investigated. The value of serum free-fatty-acids (F.F.A.s) and plasma catecholamines in the prediction of patients vulnerable to serious arrhythmias was also studied.Heparin produced a significant rise in F.F.A., maximal within 10 minutes of injection, but did not increase the incidence of cardiac arrhythmias.No relationship was found between the incidence of arrhythmias and the initial levels of F.F.A. or adrenaline. No correlation was obtained between F.F.A. and plasma catecholamine levels. Heparin did not have a consistent effect on plasma catecholamines. Initial control plasma noradrenaline concentrations, however, were found to be significantly correlated with the incidence of subsequent arrhythmias. It is suggested that the level of plasma noradrenaline may be a valuable predictive guide to those patients likely to develop significant arrhythmias after acute myocardial infarction.     

Immediate Effects of Intravenous Verapamil in Cardiac Arrhythmias

Verapamil was administered by intravenous injection to 181 patients with various cardiac arrhythmias. The automaticity of the cardiac pacemaker was slowed in sinus, idionodal, and idioventricular tachycardia. In atrial fibrillation the drug usually slowed the ventricular response and often made it regular. In some cases atrial flutter was converted to sinus rhythm, the ventricular response being reduced in the remainder. Conversion of paroxysmal supraventricular tachycardia to sinus rhythm was consistently achieved. A favourable response occurred in four patients in whom arrhythmias were associated with pre-excitation syndromes. There were no adverse clinical side effects.     

Clinical characterisation and risk stratification of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy ≥50 years of age

Purpose

With the increased use of genetic testing for arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), this disease is being increasingly recognised among elderly patients. However, elderly ARVD/C patients were underrepresented in prior cohorts. We aimed to describe the phenotypical characteristics and outcomes among ARVD/C patients surviving ≥50 years.

Methods

We assessed detailed phenotypical data of 29 patients who (1) presented at ≥50 years of age; and (2) fulfilled 2010 Task Force Criteria (TFC) for ARVD/C by last follow-up. Primary outcome was the occurrence of a major ventricular arrhythmia (sudden cardiac death, resuscitated sudden cardiac arrest or sustained ventricular tachycardia).

Results

The majority (55?%) of elderly ARVD/C subjects were male, with a mean age of 59.0 ± 5.8 years at presentation. Study participants fulfilled a median of six (IQR 5–8) TFC criteria by last follow-up, of which arrhythmia criteria were most frequent (97?%), followed by structural criteria (83?%), depolarisation criteria (72?%) and repolarisation criteria (69?%). By last follow-up, 15 (52?%) patients had experienced major ventricular arrhythmias. Most patients (n = 12) presented with this arrhythmia, while three experienced the event during 5.4 ± 3.2 years of follow-up. Compared with patients without an arrhythmic event, patients with major arrhythmias were more likely to be proband (p < 0.001) and male (p = 0.042). Likewise, survival free from sustained ventricular arrhythmia was lower among probands and males.

Conclusion

Phenotypic characteristics of elderly ARVD/C patients are characterised by depolarisation abnormalities and structural cardiac changes. Ventricular arrhythmias in this elderly cohort are associated with male gender and proband status.

     

Cardiac arrhythmias during rewarming of patients with accidental hypothermia.

Accidental hypothermia has a high mortality and is associated with cardiac arrhythmias. To determine the incidence of arrhythmias and their importance 22 patients with accidental hypothermia (core temperature less than 35 degrees C) were studied by 12 lead electrocardiography and continuous recording of cardiac rhythm. Although 14 of the patients died (64%), only six died while hypothermic. Prolongation of the Q-T interval and the presence of J waves were related to the severity of the hypothermia. Supraventricular arrhythmias, including atrial fibrillation, were common (nine cases) and benign. Ventricular extrasystoles were also common (10 cases), but ventricular tachycardia or fibrillation did not occur during rewarming. In eight patients who died while being monitored the terminal rhythm was asystole. There was no correlation between the severity of hypothermia or the rate of rewarming and the clinical outcome. In the absence of malignant arrhythmias there is no indication for using prophylactic antiarrhythmic treatment in patients with accidental hypothermia. The presence or absence of severe underlying disease is the main determinant of prognosis.     

The Role of Quantum Tunneling of Ions in the Pathogenesis of the Cardiac Arrhythmias Due to Channelopathies,Ischemia, and Mechanical Stretch

Biophysics - Cardiac arrhythmias cause considerable morbidity and mortality among patients and many pathological disorders have been identified to be related to the cardiac arrhythmias....     

冠心病合并脑梗死患者心率变异性及心律失常的变化分析

目的：研究冠心病合并脑梗死患者的心率变异性情况,和心律失常的发生率,分析它们的变化规律,为患者疾病的治疗及预后提供更好的治疗指导。方法：研究对象为2012年2月~2012年12月我院心内科及神经内科的患者,其中Ⅰ组：冠心病合并脑梗死患者40例、Ⅱ组：单纯冠心病患者40例、Ⅲ组：单纯脑梗死患者40例、以及Ⅳ组：健康成人50例,统计全部患24 h心率变异性及心律失常发生情况,并进行对比分析。结果：Ⅰ组患者的心率变异性和心律失常发生明显高于其它组患者,差异均具有统计学意义（P〈0.05）。且心率变异性时域参数下降,心律失常发生率升高。结论：冠心病合并脑梗死患者的心率变异性和心律失常发生率增高,为避免冠心病合并脑梗死的患者突然心律失常及猝死,应积极改变治疗措施。     

Electrocardiogram abnormalities in captive chimpanzees (Pan troglodytes)

Although cardiovascular disease is the leading cause of death in the captive chimpanzee population, little is known about the prevalence and etiology of heart disease in this species. We reviewed the physical exam records of 265 common chimpanzees (Pan troglodytes) for electrocardiogram abnormalities. During the 24-mo period reviewed (August 2003 through August 2005), 34 animals were diagnosed with cardiac arrhythmias consisting of ventricular arrhythmias, supraventricular arrhythmias, conduction disturbances, mixed arrhythmias, and bradycardia. The incidence of cardiac arrhythmia was significantly higher in male animals, chimpanzees 20 to 39 y old, and those with structural heart disease. Incidence of cardiac arrhythmia was not significantly higher in animals with hypertension, hyperlipidemia, or chronic viral infections. During the retrospective period, 7 animals with cardiac arrhythmias died or were euthanized. Mortality was significantly higher in animals with ventricular arrhythmias compared with those without ventricular arrhythmias. We conclude that in the common chimpanzee, age, male gender, and structural heart disease are risk factors for developing cardiac arrhythmias and that ventricular arrhythmias are risk factors for mortality.