Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a

Voltage-gated sodium channels drive the initial depolarization phase of the cardiac action potential and therefore critically determine conduction of excitation through the heart. In patients, deletions or loss-of-function mutations of the cardiac sodium channel gene, SCN5A, have been associated with a wide range of arrhythmias including bradycardia (heart rate slowing), atrioventricular conduction delay, and ventricular fibrillation. The pathophysiological basis of these clinical conditions is unresolved. Here we show that disruption of the mouse cardiac sodium channel gene, Scn5a, causes intrauterine lethality in homozygotes with severe defects in ventricular morphogenesis whereas heterozygotes show normal survival. Whole-cell patch clamp analyses of isolated ventricular myocytes from adult Scn5a(+/-) mice demonstrate a approximate to50% reduction in sodium conductance. Scn5a(+/-) hearts have several defects including impaired atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation. These findings reconcile reduced activity of the cardiac sodium channel leading to slowed conduction with several apparently diverse clinical phenotypes, providing a model for the detailed analysis of the pathophysiology of arrhythmias.

Amiodarone - waxed and waned and waxed again

Amiodarone has been used as an anti-arrhythmic drug since the 1970s and has an established role in the treatment of ventricular tachyarrhythmias. Although considered to be a class III anti-arrhythmic, amiodarone also has class I, II and IV actions, which gives it a unique pharmacological and anti-arrhythmic profile. Amiodarone is a structural analogue of thyroid hormone and some of its anti-arrhythmic properties and toxicity may be attributable to interactions with nuclear thyroid hormone receptors. The lipid solubility of amiodarone gives it an exceptionally long half-life. Oral amiodarone takes days to work in ventricular tachyarrhythmias, but iv. amiodarone has immediate effect and can be used in life threatening ventricular arrhythmias. Intravenous amiodarone administered after out-of-hospital cardiac arrest due to ventricular fibrillation improves survival to hospital admission. Many survivors of myocardial infarction (MI) die during the subsequent year, probably due to ventricular arrhythmia. Amiodarone reduces sudden death after MI and this benefit is predominantly observed in patients with preserved cardiac function. Sudden cardiac death, predominantly due to ventricular arrhythmias, is also commonly seen in patients with heart failure. The Grupo de Estudio de la Sobrevida en lsuficiencia Cardiaca en Argentina (GESICA) and Estudio Piloto Argentino de Muerte Subita y Amiodarona (EPAMSA) trials showed survival benefit of amiodarone in heart failure, whereas Congestive Heart Failure-Survival Trial of Anti-arrhythmic Therapy (CHF-STAT) did not. Subsequent meta-analysis established a survival benefit of amiodarone in heart failure. Implanted Cardioverter Defibrillators (ICDs) also give survival benefit to patients at risk of sudden death. In patients with a history of ventricular fibrillation or haemodynamically-compromising ventricular tachycardia, ICDs have been shown to be superior to anti-arrhythmic drugs, principally amiodarone. Further analysis has been undertaken to ascertain which patients are most likely to benefit from ICDs, as these are more expensive than treatment with amiodarone. Patients with severely depressed ejection fractions should be the first to be considered for ICDs. A new indication for amiodarone is atrial fibrillation or flutter. Amiodarone is effective in chronic and recent onset atrial fibrillation and orally or iv. for atrial fibrillation after heart surgery. In atrial fibrillation amiodarone is more than or equi-effective with flecainide, quinidine, racemic sotalol, propafenone and diltiazem and therefore should be considered for first line therapy. Amiodarone is also safe and effective in controlling refractory tachyarrhythmias in infants and is safe after cardiac surgery.

Long QT syndrome in dogs with tick toxicity (Ixodes holocyclus)

Objective To evaluate cardiac electrical function in dogs with tick toxicity. Design A prospective clinical investigation of 39 client-owned dogs treated for naturally occurring tick toxicity. Procedure An ECG was performed on each dog on several occasions; at admission to hospital with tick toxicity, 24 h later, at discharge from hospital when clinically normal and approximately 12 months later. Results The mean QT interval corrected for heart rate (QTc) was prolonged at admission, 24 h and at discharge compared to the QTc measured 12 months later. T wave morphology was altered in dogs at admission. All other parameters were within normal limits. Conclusions The prolonged QTc interval and altered T wave morphology of dogs with tick toxicity reflects delayed cardiac repolarisation and is comparable with long QT syndrome (LQTS) in people who are predisposed to polymorphic ventricular tachycardia and sudden death. Resolution of ECG changes lagged behind clinical recovery.

Effects of the paralysis tick, Ixodes holocyclus, on the electrocardiogram of the Spectacled Flying Fox, Pteropus conspicillatus

Objective To evaluate cardiac electrical function in the Spectacled Flying Fox (bat) infested with Ixodes holocyclus. Design Prospective clinical investigation of bats treated for naturally occurring tick toxicity. Procedure ECGs were performed on bats with tick toxicity (n = 33), bats that recovered slowly (n = 5) and normally (n = 5) following treatment for tick toxicity, and on normal bats with no history of tick toxicity (n = 9). Results Bats with tick toxicity had significantly prolonged corrected QT intervals, bradycardia and rhythm disturbances which included sinus bradydysrhythmia, atrial standstill, ventricular premature complexes, and idioventricular bradydysrhythmia. Conclusions The QT prolongation observed on ECG traces of bats with tick toxicity reflected delayed ventricular repolarisation and predisposed to polymorphic ventricular tachycardia and sudden cardiac death in response to sympathetic stimulation. The inability to document ventricular tachycardia in bats shortly before death from tick toxicity may be explained by a lack of sympathetic responsiveness attributable to the unique parasympathetic innervation of the bat heart, or hypothermiainduced catecholamine receptor down-regulation. Bradycardia and rhythm disturbances may be attributable to hypothermia.

Cardiovascular actions of the venom from the Irukandji (Carukia barnesi) jellyfish: Effects in human, rat and guinea-pig tissues in vitro and in pigs in vivo

1. We have investigated the cardiovascular pharmacology of the crude venom extract (CVE) from the potentially lethal, very small carybdeid jellyfish Carukia barnesi, in rat, guinea-pig and human isolated tissues and anaesthetized piglets. 2. In rat and guinea-pig isolated right atria, CVE (0.1-10 mu g/mL) caused tachycardia in the presence of atropine (I mu mol/L), a response almost completely abolished by pretreatment with tetrodotoxin (TTX; 0.1 mu mol/L). In paced left atria from guinea-pig or rat, CVE (0.1-3 mu g/mL) caused a positive inotropic response in the presence of atropine (1 mu mol/L). 3. In rat mesenteric small arteries, CVE (0.1-30 mu g/mL) caused concentration-dependent contractions that were unaffected by 0.1 mu mol/L TTX, 0.3 mu mol/L prazosin or 0.1 mu mol/L co-conotoxin GVIA. 4. Neither the rat right atria tachycardic response nor the contraction of rat mesenteric arteries to CVE were affected by the presence of box jellyfish (Chironex fleckeri) antivenom (92.6 units/mL). 5. In human isolated driven right atrial trabeculae muscle strips, CVE (10 mu g/mL) tended to cause an initial fall, followed by a more sustained increase, in contractile force. In the presence of atropine (I mu mol/L), CVE only caused a positive inotropic response. In separate experiments in the, presence of propranolol (0.2 mu mol/L), the negative inotropic effect of CVE was enhanced, whereas the positive inotropic response was markedly decreased. 6. In anaesthetized piglets, CVE (67 mu g/kg, i.v.) caused sustained tachycardia and systemic and pulmonary hypertension. Venous blood samples demonstrated a marked elevation in circulating levels of noradrenaline and adrenaline. 7. We conclude that C. barnesi venom may contain a neural sodium channel activator (blocked by TTX) that, in isolated atrial tissue (and in vivo), causes the release of transmitter (and circulating) catecholamines. The venom may also contain a 'direct' vasoconstrictor component. These observations explain, at least in part, the clinical features of the potentially deadly Irukandji syndrome.

Cardiac chymase: pathophysiological role and therapeutic potential of chymase inhibitors

On release from cardiac mast cells, alpha-chymase converts angiotensin I (Ang I) to Ang II. In addition to Ang II formation, alpha-chymase is capable of activating TGF-beta 1 and IL-1 beta, forming endothelins consisting of 31 amino acids, degrading endothelin-1, altering lipid metabolism, and degrading the extracellular matrix. Under physiological conditions the role of chymase in the mast cells of the heart is uncertain. In pathological situations, chymase may be secreted and have important effects on the heart. Thus, in animal models of cardiomyopathy, pressure overload, and myocardial infarction, there are increases in both chymase mRNA levels and chymase activity in the heart. In human diseased heart homogenates, alterations in chymase activity have also been reported. These findings have raised the possibility that inhibition of chymase may have a role in the therapy of cardiac disease. The selective chymase inhibitors developed to date include TY-51076, SUN-C8257, BCEAB, NK320, and TEI-E548. These have yet to be tested in humans, but promising results have been obtained in animal models of myocardial infarction, cardiomyopathy, and tachycardia-induced heart failure. It seems likely that orally active inhibitors of chymase could have a place in the treatment of cardiac diseases where injury-induced mast cell degranulation contributes to the pathology.

Response of heart rate and cloacal ventilation in the bimodally respiring freshwater turtle, Rheodytes leukops to experimental changes in aquatic PO2

Changes in heart rate (f(H)) and cloacal ventilation frequency (f(C)) were investigated in the Fitzroy turtle, Rheodytes leukops, under normoxic (17.85 kPa) and hypoxic (3.79 kPa) conditions at 25 degrees C. Given R. leukops' high reliance on aquatic respiration via the cloacal bursae, the objective Of this Study was to examine the effect of varying aquatic PO2 levels upon the expression of a bradycardia in a freely diving, bimodally respiring turtle. In normoxia, mean diving f(H) and f(C) for R. leukops remained constant with increasing submergence length, indicating that a bradycardia failed to develop during extended dives of up to 3 days. Alternatively, exposure to aquatic hypoxia resulted in the expression of a bradycardia as recorded by a decreasing mean diving f(H) with increasing dive duration. The observed bradycardia is attributed to a hypoxic-induced metabolic depression, possibly facilitated by a concurrent decrease in f(C). Results suggest that R. leukops alters its strategy from aquatic O-2 extraction via cloacal respiration in normoxia to O-2 conservation when exposed to aquatic hypoxia for the purpose of extending dive duration. Upon surfacing, a significant tachycardia was observed for R. leukops regardless of aquatic PO2, presumably functioning to rapidly equilibrate blood and tissue gas tensions with alveolar gas to reduce surfacing duration.