Arrhythmias In Animal Models Research Articles

Animal Models to Study Cardiac Arrhythmias.

Cardiac arrhythmias are a significant cause of morbidity and mortality worldwide, accounting for 10% to 15% of all deaths. Although most arrhythmias are due to acquired heart disease, inherited channelopathies and cardiomyopathies disproportionately affect children and young adults. Arrhythmogenesis is complex, involving anatomic structure, ion channels and regulatory proteins, and the interplay between cells in the conduction system, cardiomyocytes, fibroblasts, and the immune system. Animal models of arrhythmia are powerful tools for studying not only molecular and cellular mechanism of arrhythmogenesis but also more complex mechanisms at the whole heart level, and for testing therapeutic interventions. This review summarizes basic and clinical arrhythmia mechanisms followed by an in-depth review of published animal models of genetic and acquired arrhythmia disorders.

Short‐Term Variability of the QT Interval Can be Used for the Prediction of Imminent Ventricular Arrhythmias in Patients With Primary Prophylactic Implantable Cardioverter Defibrillators

BackgroundShort‐term variability of the QT interval (STVQT) has been proposed as a novel electrophysiological marker for the prediction of imminent ventricular arrhythmias in animal models. Our aim is to study whether STVQT can predict imminent ventricular arrhythmias in patients.Methods and ResultsIn 2331 patients with primary prophylactic implantable cardioverter defibrillators, 24‐hour ECG Holter recordings were obtained as part of the EU‐CERT‐ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter Defibrillators) study. ECG Holter recordings showing ventricular arrhythmias of >4 consecutive complexes were selected for the arrhythmic groups (n=170), whereas a control group was randomly selected from the remaining Holter recordings (n=37). STVQT was determined from 31 beats with fiducial segment averaging and calculated as ∑Dn+1‐Dn/30×2, where Dn represents the QT interval. STVQT was determined before the ventricular arrhythmia or 8:00 am in the control group and between 1:30 and 4:30 am as baseline. STVQT at baseline was 0.84±0.47 ms and increased to 1.18±0.74 ms (P<0.05) before the ventricular arrhythmia, whereas the STVQT in the control group remained unchanged. The arrhythmic patients were divided into three groups based on the severity of the arrhythmia: (1) nonsustained ventricular arrhythmia (n=32), (2) nonsustained ventricular tachycardia (n=134), (3) sustained ventricular tachycardia (n=4). STVQT increased before nonsustained ventricular arrhythmia, nonsustained ventricular tachycardia, and sustained ventricular tachycardia from 0.80±0.43 ms to 1.18±0.78 ms (P<0.05), from 0.90±0.49 ms to 1.14±0.70 ms (P<0.05), and from 1.05±0.22 ms to 2.33±1.25 ms (P<0.05). This rise in STVQT was significantly higher in sustained ventricular tachycardia compared with nonsustained ventricular arrhythmia (+1.28±1.05 ms versus +0.24±0.57 ms [P<0.05]) and compared with nonsustained ventricular arrhythmia (+0.34±0.87 ms [P<0.05]).ConclusionsSTVQT increases before imminent ventricular arrhythmias in patients, and the extent of the increase is associated with the severity of the ventricular arrhythmia.

Animal models of arrhythmia: classic electrophysiology to genetically modified large animals.

Arrhythmias are common and contribute substantially to cardiovascular morbidity and mortality. The underlying pathophysiology of arrhythmias is complex and remains incompletely understood, which explains why mostly only symptomatic therapy is available. The evaluation of the complex interplay between various cell types in the heart, including cardiomyocytes from the conduction system and the working myocardium, fibroblasts and cardiac immune cells, remains a major challenge in arrhythmia research because it can be investigated only in vivo. Various animal species have been used, and several disease models have been developed to study arrhythmias. Although every species is useful and might be ideal to study a specific hypothesis, we suggest a practical trio of animal models for future use: mice for genetic investigations, mechanistic evaluations or early studies to identify potential drug targets; rabbits for studies on ion channel function, repolarization or re-entrant arrhythmias; and pigs for preclinical translational studies to validate previous findings. In this Review, we provide a comprehensive overview of different models and currently used species for arrhythmia research, discuss their advantages and disadvantages and provide guidance for researchers who are considering performing in vivo studies.

Sympathetic Nervous System Activation and Its Modulation: Role in Atrial Fibrillation.

The autonomic nervous system (ANS) has a significant influence on the structural integrity and electrical conductivity of the atria. Aberrant activation of the sympathetic nervous system can induce heterogeneous changes with arrhythmogenic potential which can result in atrial tachycardia, atrial tachyarrhythmias and atrial fibrillation (AF). Methods to modulate autonomic activity primarily through reduction of sympathetic outflow reduce the incidence of spontaneous or induced atrial arrhythmias in animal models and humans, suggestive of the potential application of such strategies in the management of AF. In this review we focus on the relationship between the ANS, sympathetic overdrive and the pathophysiology of AF, and the potential of sympathetic neuromodulation in the management of AF. We conclude that sympathetic activity plays an important role in the initiation and maintenance of AF, and modulating ANS function is an important therapeutic approach to improve the management of AF in selected categories of patients. Potential therapeutic applications include pharmacological inhibition with central and peripheral sympatholytic agents and various device based approaches. While the role of the sympathetic nervous system has long been recognized, new developments in science and technology in this field promise exciting prospects for the future.

Intercalated Disk Extracellular Nanodomain Expansion in Patients With Atrial Fibrillation.

Aims: Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous evidence in animal models suggests that the gap junction (GJ) adjacent nanodomain – perinexus – is a site capable of independent intercellular communication via ephaptic transmission. Perinexal expansion is associated with slowed conduction and increased ventricular arrhythmias in animal models, but has not been studied in human tissue. The purpose of this study was to characterize the perinexus in humans and determine if perinexal expansion associates with AF.Methods: Atrial appendages from 39 patients (pts) undergoing cardiac surgery were fixed for immunofluorescence and transmission electron microscopy (TEM). Intercalated disk distribution of the cardiac sodium channel Nav1.5, its β1 subunit, and connexin43 (C×43) was determined by confocal immunofluorescence. Perinexal width (Wp) from TEM was manually segmented by two blinded observers using ImageJ software.Results: Nav1.5, β1, and C×43 are co-adjacent within intercalated disks of human atria, consistent with perinexal protein distributions in ventricular tissue of other species. TEM revealed that the GJ adjacent intermembrane separation in an individual perinexus does not change at distances greater than 30 nm from the GJ edge. Importantly, Wp is significantly wider in patients with a history of AF than in patients with no history of AF by approximately 3 nm, and Wp correlates with age (R = 0.7, p < 0.05).Conclusion: Human atrial myocytes have voltage-gated sodium channels in a dynamic intercellular cleft adjacent to GJs that is consistent with previous descriptions of the perinexus. Further, perinexal width is greater in patients with AF undergoing cardiac surgery than in those without.

SAFETY OF THORACIC MAGNETIC RESONANCE IMAGING IN PATIENTS WITH PACEMAKERS AND DEFIBRILLATORS

During magnetic resonance imaging (MRI), pacemaker and defibrillator leads can focus energy onto the myocardium causing heating and arrhythmias in animal models. Direct exposure of the devices to the magnetic field in thoracic MRI could potentially augment this risk. However no data is currently

MAPPING REGIONAL REPOLARISATION GRADIENTS IN THE FAILING HUMAN VENTRICLE USING CARDIAC SLICES

Regional differences in repolarisation have been shown to contribute to ventricular arrhythmias in animal models of heart failure, however little is known about their presence and role in the human heart. In this study we investigated regional electrophysiological properties in the failing human ventricle using cardiac slices prepared from the left ventricular free wall (LV) and from the left side of the ventricular septum (LVS). Cardiac slices (300 µm thick) were prepared from ventricular biopsies obtained from heart failure patients undergoing heart transplant. Slices were point-stimulated at cycle lengths (CL) ranging from 500 ms to 4000 ms, and analysed using a multi-electrode array system. Field potential duration (FPD), an index of action potential duration, was measured. FPD was significantly longer in slices from the LVS versus slices from the LV at all pacing cycle lengths (CL 500 ms: 368±13 ms in LVS vs 330±7 ms in LV, n=7 slices/2 hearts, p

Striatin: a novel regulator of cardiomyocyte calcium homeostasis and contraction (864.3)

Although cardiac arrhythmias are still a major health threat for human, there is paucity of information on the molecular mechanisms involved in this pathology. Striatin (STRN) is a multivalent protein with dynamic domains including caveolin (Cav), Calmodulin (CaM), and Protein Phosphatase 2A (PP2A) binding sites, all of which are important regulatory units of the L‐type Calcium Channels (LCC) in cardiomyocytes. Previous studies indicate that mutations/deletions of the striatin gene correlate with the development of cardiac arrhythmias in animal models. We aimed to investigate whether STRN regulates calcium homeostasis and cardiomyocyte contraction rate. Data indicate that STRN is highly expressed in atrial myocardium when compared to the ventricles. Overexpression of STRN elevated the contraction rate (~ 3 fold) and resulted in sustained levels of KCl‐induced increases in intracellular calcium in neonatal rat cardiomyocytes. Conversely, silencing (&gt;80%) the STRN gene using shRNA was associated with decreased contraction rate (~50%) of cardiomyocytes. Interestingly, pharmacological challenge with isoproterenol (β‐adrenergic agonist) failed to improve the contraction rate of cardiomyocytes with low levels of striatin (shRNA‐STRN). Biochemical analysis (CaM pull down) revealed that the interaction between CaM/PP2A/Cav‐3/LCC was increased in shRNA‐STRN cardiomyocytes and reduced when overexpressing STRN. Collectively our data indicate that striatin is a novel regulator of cardiomyocyte calcium homeostasis and contraction rate by modulating the CaM/PP2A/Cav‐3/LCC complex and influencing the activity of the LCC in the myocardium.Grant Funding Source: King Faisal Specialist Hospital and Research Center

In Vivo Human Left-to-Right Ventricular Differences in Rate Adaptation Transiently Increase Pro-Arrhythmic Risk following Rate Acceleration

Left-to-right ventricular (LV/RV) differences in repolarization have been implicated in lethal arrhythmias in animal models. Our goal is to quantify LV/RV differences in action potential duration (APD) and APD rate adaptation and their contribution to arrhythmogenic substrates in the in vivo human heart using combined in vivo and in silico studies. Electrograms were acquired from 10 LV and 10 RV endocardial sites in 15 patients with normal ventricles. APD and APD adaptation were measured during an increase in heart rate. Analysis of in vivo electrograms revealed longer APD in LV than RV (207.8±21.5 vs 196.7±20.1 ms; P<0.05), and slower APD adaptation in LV than RV (time constant τs = 47.0±14.3 vs 35.6±6.5 s; P<0.05). Following rate acceleration, LV/RV APD dispersion experienced an increase of up to 91% in 12 patients, showing a strong correlation (r2 = 0.90) with both initial dispersion and LV/RV difference in slow adaptation. Pro-arrhythmic implications of measured LV/RV functional differences were studied using in silico simulations. Results show that LV/RV APD and APD adaptation heterogeneities promote unidirectional block following rate acceleration, albeit being insufficient for establishment of reentry in normal hearts. However, in the presence of an ischemic region at the LV/RV junction, LV/RV heterogeneity in APD and APD rate adaptation promotes reentrant activity and its degeneration into fibrillatory activity. Our results suggest that LV/RV heterogeneities in APD adaptation cause a transient increase in APD dispersion in the human ventricles following rate acceleration, which promotes unidirectional block and wave-break at the LV/RV junction, and may potentiate the arrhythmogenic substrate, particularly in patients with ischemic heart disease.

A stimulating environment for the atrial kick: Spinal cord stimulation can inhibit atrial fibrillation

Although the heart has an innate ability to generate its own electrical impulses, proper cardiac function is heavily dependent on hormonal and neuronal modulations. The extensive innervation of the heart by afferent and efferent neurons 1 Armour J.A. Functional anatomy of intrathoracic neurons innervating the atria and ventricles. Heart Rhythm. 2010; 7: 994-996 Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar stress the important role of the autonomic nervous system (ANS) in controlling its proper function under dynamic changes in the environment. The direct effects of sympathetic and parasympathetic transmitters on the physiological properties of cardiac cells have been known for many years and are relatively well described. However, the integrative function and delicate balance between complex ANS networks innervating the heart have only lately been substantiated. There is increasing evidence that abnormal ANS function may have an important role in various cardiac pathologies. Moreover, autonomic modulation emerges as a new paradigm that may effectively treat challenging conditions such as drug-refractory vasovagal syncope and severe heart failure. 2 Yao Y. Shi R. Wong T. et al. Endocardial autonomic denervation of the left atrium to treat vasovagal syncope: an early experience in humans. Circ Arrhythm Electrophysiol. 2012; 5: 279-286 Crossref PubMed Scopus (83) Google Scholar , 3 De Ferrari G.M. Crijns H.J. Borggrefe M. et al. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J. 2011; 32: 847-855 Crossref PubMed Scopus (377) Google Scholar Along these lines, numerous pieces of recent evidence indicate that neuronal mechanisms are critical determinants of atrial arrhythmogenesis. 4 Shen M.J. Choi E.K. Tan A.Y. et al. Neural mechanisms of atrial arrhythmias. Nat Rev Cardiol. 2012; 9: 30-39 Crossref Scopus (119) Google Scholar Spinal cord stimulation protects against atrial fibrillation induced by tachypacingHeart RhythmVol. 9Issue 9PreviewSpinal cord stimulation (SCS) has been shown to modulate atrial electrophysiology and confer protection against ischemia and ventricular arrhythmias in animal models. Full-Text PDF

Spinal cord stimulation protects against atrial fibrillation induced by tachypacing.

Spinal cord stimulation (SCS) has been shown to modulate atrial electrophysiology and confer protection against ischemia and ventricular arrhythmias in animal models. To determine whether SCS reduces the susceptibility to atrial fibrillation (AF) induced by tachypacing (TP). In 21 canines, upper thoracic SCS systems and custom cardiac pacing systems were implanted. Right atrial and left atrial effective refractory periods were measured at baseline and after 15 minutes of SCS. Following recovery in a subset of canines, pacemakers were turned on to induce AF by alternately delivering TP and searching for AF. Canines were randomized to no SCS therapy (CTL) or intermittent SCS therapy on the initiation of TP (EARLY) or after 8 weeks of TP (LATE). AF burden (percent AF relative to total sense time) and AF inducibility (percentage of TP periods resulting in AF) were monitored weekly. After 15 weeks, echocardiography and histology were performed. Effective refractory periods increased by 21 ± 14 ms (P = .001) in the left atrium and 29 ± 12 ms (P = .002) in the right atrium after acute SCS. AF burden was reduced for 11 weeks in EARLY compared with CTL (P <.05) animals. AF inducibility remained lower by week 15 in EARLY compared with CTL animals (32% ± 10% vs 91% ± 6%; P <.05). AF burden and inducibility were not significantly different between LATE and CTL animals. There were no structural differences among any groups. SCS prolonged atrial effective refractory periods and reduced AF burden and inducibility in a canine AF model induced by TP. These data suggest that SCS may represent a treatment option for AF.

Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 4th communication: influence on experimentally induced ventricular arrhythmia in dogs.

Influence of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]- 1,2,5,6,-tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013) and vesnarinone (CAS 81840-15-5) on the arrhythmia experimentally induced by three different methods was investigated in dogs. In digitalis-induced arrhythmia, SCH00013 (3 mg/kg i.v.) showed a tendency to improve the arrhythmia with a decrease in the arrhythmic ratio and an increase in the conducted beats (CB), though these changes did not reach a significant level; it decreased significantly the blood pressure (BP) with no change in the total heart rate (THR) and atrial rate (AR). Vesnarinone (3 mg/kg i.v.) did not affect these parameters except for BP that was decreased significantly. In two-stage coronary ligation-induced arrhythmia, SCH00013 (1 and 3 mg/kg i.v.) did not change the arrhythmic ratio, CB, AR and BP, while the THR being slightly decreased; the arrhythmic ratio showed a tendency to decrease with SCH00013 when examined at 24 h after coronary ligation. Vesnarinone (3 mg/kg i.v.) did not affect these parameters at 24 and 48 h after ligation. In epinephrine (adrenaline)-induced arrhythmia, both SCH00013 and vesnarinone showed exacerbation of arrhythmia. SCH00013 at 1 mg/kg i.v. did not elicit ventricular fibrillation (VF) in five dogs examined, but at 3 mg/kg i.v. it elicited VF in two of three dogs. Vesnarinone at 1 mg/kg i.v. induced VF in all of three dogs examined. Incidence of VF induced by optical isomers of SCH00013 was not significantly different from each other: both isomers elicited VF in two of six dogs at 1 mg/kg i.v. and at 3 mg/kg i.v. each of them induced VF in two dogs examined. The present results indicate that SCH00013 is a cardiotonic agent that is equivalent to or less arrhythmogenic than vesnarinone in animal models of arrhythmia, such as adrenaline- and digitalis-induced arrhythmia and the two-stage coronary ligation-induced arrhythmia. Optical isomers of SCH00013 were essentially equieffective in eliciting exacerbation of adrenaline-induced arrhythmia in the dog.

The Electrophysiological Properties of Ranolazine: A Metabolic Anti-Ischemic Drug or an Energy-Efficient Antiarrhythmic Agent?

Ranolazine, a newer anti-ischemic agent that appears to induce a more efficient utilization of adenosine triphosphate at the cellular level, has been shown to be clinically beneficial in patients with chronic stable angina. More recently, the antiarrhythmic effects of the drug have been described in patients with acute coronary syndromes, as well as in those with atrial fibrillation, when combined with other agents. Experimentally, the predominant inhibitory effects on late I(Na), I(Ca), I(Na-Ca), and I(Ks), with little or no effect on I(to) or I(K1), have been demonstrated. Different experimental models have shown the potential beneficial effect of the drug in both supraventricular and ventricular arrhythmias. Interestingly, despite its potential prolongation of the QT interval, ranolazine does not appear to induce ventricular arrhythmias in animal models. Whether the antiarrhythmic effect is secondary to a more efficient energy production by the cardiac cell or by its direct effect on ion channels is still unclear. The effect of ranolazine on other ionic currents, as well as its potential as a clinically relevant antiarrhythmic agent, still needs to be studied.

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.

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. 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 and hypertension, following exercise and exposure to air pollutants, as well as determination of the antiarrhythmic efficacy of pharmacological agents. 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, and results in mortality in 20% of cases. Many individuals survive the SE, but die within 30 days. 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. 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). 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. 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. 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.

Electrophysiological Properties of HBI-3000: A New Antiarrhythmic Agent With Multiple-channel Blocking Properties in Human Ventricular Myocytes

HBI-3000 (sulcardine sulfate) has been shown to suppress various ventricular arrhythmias in animal models. The electrophysiological properties of HBI-3000 were investigated using standard microelectrode and patch-clamp techniques in single human ventricular myocytes. HBI-3000 led to concentration-dependent suppression of dofetilide-induced early afterdepolarizations in single nonfailing human ventricular myocytes and early afterdepolarizations seen in failing ventricular myocytes. The concentration-dependent prolongation of action potential duration (APD) by HBI-3000 was bell shaped with maximum response occurring around 10 μM. Interestingly, HBI-3000 at the concentration of 10 μM modestly prolonged the APD at all 3 basic cycle lengths. The slope of APD-cycle length curve of HBI-3000 was only slightly steeper than that of control (88.8 ± 7.7 ms/s vs. 78.9 ± 5.2 ms/s in control, n = 8, P > 0.05). HBI-3000 only showed a minimal use-dependent prolongation of the APD in human ventricular myocytes. HBI-3000 inhibited fast sodium current (INa-F), late sodium channel (INa-L), L-type calcium current (ICa-L), and rapidly activating delayed rectifier K current (IKr) in single human ventricular myocytes. The estimated half-maximal inhibitory concentration values of INa-F, INa-L, ICa-L, and IKr were 48.3 ± 3.8, 16.5 ± 1.4, 32.2 ± 2.9, and 22.7 ± 2.5 μM, respectively. The ion channel profile and electrophysiological properties of HBI-3000 are similar to those of ranolazine and chronic amiodarone (reduced INa-F, INa-L, ICa-L, and IKr). HBI-3000 may be a promising antiarrhythmic agent with low proarrhythmic risk.

CaMKII Inhibition in Heart Failure Makes Jump to Human

See related article, pages 1150–1161 In this issue of Circulation Research , Sossalla et al1 show that acute inhibition of Ca2+/calmodulin-dependent protein kinase (CaMK)II in failing human myocardium causes functional improvement in contractility by restoring a positive force–frequency relationship (FFR) in cardiac trabeculae. The loss of this normal positive FFR (and often an induction of a negative FFR) is a functional hallmark of failing human myocardium2 and has been seen as an intrinsic limitation of the failing heart to enhance contractility appropriately at higher heart rates. This failure of positive FFR also constitutes a reduction in functional cardiac reserve. So, why might CaMKII inhibition be beneficial in heart failure (HF)? For several years, evidence has been accumulating that CaMKII is increased in both expression level and activity in both animal models of HF and in failing human hearts.3,–,9 It has also come to light that CaMKII has many different functional effects in cardiac myocytes, including alterations in ion channels, Ca2+ handling proteins, myofilaments, and transcriptional regulation.10,–,12 Moreover, many of these CaMKII effects on myocyte properties have been implicated in hypertrophy, HF, and arrhythmias in animal models. Indeed, CaMKII inhibition (or knockout of the dominant cardiac isoform CaMKIIδ) can improve cardiac function and delay the onset of maladaptive aspects of the hypertrophic/HF phenotype in animal models, resulting in beneficial functional effects.13,–,15 Sossalla et al1 provide important novel data that acute CaMKII inhibition in human HF myocardium causes functional improvement. This is an important validation step with respect to consideration of cardiac CaMKII inhibition as therapeutic strategy in human HF. So, what are some key acute functional effects of CaMKII that can alter cardiac Ca2+ handling and excitability? CaMKII phosphorylates …

Aconitine blocks HERG and Kv1.5 potassium channels

Ethnopharmacological relevance Aconitum has been widely used to treat various diseases in China for a long time. However, improper use of this drug results in severe intoxication. Aconitine (ACO), a diterpenoid alkaloid from aconitum, mainly contributes to cardio-toxic effects of aconitum and has also been commonly known to induce arrhythmias in animal models. However, its pro-arrhythmic mechanisms are not clear. Aim of the study The effects of ACO on HERG and Kv1.5 channels were investigated. Materials and methods HERG and Kv1.5 channels were expressed in Xenopus laevis oocytes, and the resulting currents were recorded using a two-microelectrode voltage clamp technique. Results In HERG channels, ACO exhibited a blockade in a voltage- and time-dependent manner. The blockade was enhanced by further activation of currents, which were consistent with an open-channel blockade. In Kv1.5 channels, ACO produced a voltage-, time-, and frequency-dependent inhibition. The blockade was enhanced by higher rates of stimulation, consistent with preferential binding of the drug to the open state. In addition, ACO blocked Kv1.5 and HERG channels in a concentration-dependent manner with an IC 50 of 0.796 ± 0.123 and 1.801 ± 0.332 μM, respectively. Conclusions ACO blocks HERG and Kv1.5 potassium channels in the open state. Blockade of potassium channels, particular the HERG channel, may be one of the important mechanisms of how ACO induces arrhythmias.

Assessment of Efficacy of Pharmacotherapy for Ventricular Tachycardia

The presence and sinister prognosis of sustained ventricular tachycardia was recognised early in the twentieth century in patients with serious cardiac disease. Treatment was difficult and evolved slowly. The development of antiarrhythmic drug therapy was frequently based on chance clinical observations and on the assessment of drug effects in animal models of arrhythmia that bore little resemblance to the actual clinical scenarios in which the drugs were to be employed. Even early reports of antiarrhythmic drug use were tempered by awareness of serious adverse side effects. Many drugs were brought into wide-spread clinical use without the background of large randomised trials of efficacy. Assessment of drug efficacy for ventricular tachycardia was frequently based on the effects of an administered drug on inducibility of tachycardia with invasive electrophysiologic techniques. Suppression of inducibility was suggested to be a marker of drug efficacy. Similarly, suppression of spontaneously occurring ventricular ectopic beats was also used as a predictor of drug effect. However, both predictive techniques were hindered by inherent baseline variability. It was subsequently demonstrated that mode of induction of ventricular tachycardia could vary widely at repeat inductions. Antiarrhythmic drugs rarely suppressed inducibility of VT but could alter mode of induction. Techniques were developed to estimate true drug effects by quantitating and allowing for random variability in mode of tachycardia induction. In particular, reproducibility of tachycardia induction was enhanced when baseline and drug studies were performed at short intervals. Even with these techniques, prediction of long-term drug efficacy in individual patients remained difficult and acute drug testing served principally to demonstrate the fact that drug therapy was more likely to facilitate induction of tachycardia than to suppress it (pro-arrhythmic effect). Large clinical trials also demonstrated the potent pro-arrhythmic effects of drug therapy especially when sodium-channel blocking drugs were used. By the end of the twentieth century, antiarrhythmic drugs were used primarily as adjuncts to device therapy for patients at risk of life-threatening ventricular arrhythmias.

Acute subendocardial ischaemia leads to homogenous prolongation in ventricular repolarization

Acute transmural ischaemia often shortens ventricular repolarization and increases repolarization dispersion, leading to life threatening ventricular arrhythmias in animal models and human subjects. Experimental studies and clinical observations have shown that acute subendocardial ischaemia rarely causes serious ventricular arrhythmia. We hypothesized that the different arrhythmia outcomes between transmural and subendocardial ischaemia are largely due to the homogenous prolongation in ventricular repolarization after acute subendocardial ischaemia. Further experimental studies on a subendocardial model are required to assess the changes in ventricular repolarization and its spatial dispersion, and to investigate the role of these changes in the pathogenesis of ventricular arrhythmias. These studies will facilitate our understanding on the mechanisms of life-threatening ventricular arrhythmias during acute myocardial ischaemia.