Effects of lysophosphoglycerides on cardiac arrhythmias

The accumulation of lysophosphoglycerides has been implicated as an important biochemical factor for cardiac arrhythmias. Recently, we demonstrated that lysophosphatidylcholine caused cardiac arrhythmias in the isolated hamster heart. In this study, the arrhythmogenic nature of various lysophosphoglycerides with respect to acyl chain lengths and base groups were assessed. We demonstrated that all naturally occurring lysolipids tested were arrhythmogenic at 0.05-0.10 mM. Arrhythmias were also observed with Triton X-100 or sodium laurylsulfate at 0.05-0.10 mM. Our data suggests that no correlation exists between the arrhythmogenic nature of the lysolipids and their critical micelle concentrations. We postulate that arrhythmias are produced by the detergent effect of lysophosphoglycerides.     

Significance of ATP-sensitive K(+)-channel in the mechanism of antiarrhythmic and cardioprotective effect of adaptation to intermittent hypobaric hypoxia

Adult male Wistar rats were exposed to intermittent hypobaric hypoxia (5000 m, 6 h/day, 6 weeks). It has been found that such mode of adaptation increased cardiac tolerance to arrhythmogenic action of a 45-min coronary artery occlusion but did not change an infarct size/area at risk (IS/AAR) ratio. In a separate series, rats were exposed to stronger intermittent hypobaric hypoxia (7000 m, 8 h/day, 6 weeks) and subjected to 20-min coronary artery occlusion and 3-h reperfusion on the day after the last hypoxic exposure. It has been established that in this case adaptation decreased the IS/AAR ratio, increased cardiac tolerance to arrhythmogenic action of reperfusion but had no effect on the incidence of ventricular arrhythmias occurred during ischemic period. We found that cardioprotective and antiarrhythmic effect of adaptation to the "altitudes" of 7000 m and antiarrhythmic effect of adaptation to the "altitude" of 5000 m is mediated via K(ATP)-channel activation.     

Role of delta opioid receptors and their ligands in the development of adaptive heart protection against arrhythmogenesis

It has been found that stimulation of delta-1 opioid receptors by intravenous administration of DPDPE (0.5 mg/kg) decreases the incidence of ischemic and reperfusion-induced arrhythmias and also increases myocardial tolerance to the arrhythmogenic action of epinephrine in rats. Pretreatment with a selective delta-2 agonist, DSLET, had no antiarrhythmic effect. The inhibition of the enzymatic breakdown of endogenous enkephalins by intravenous administration of acetorphan decreased the incidence of epinephrine-induced arrhythmias. Pretreatment with a selective delta opioid receptor antagonist, ICI-174.868, completely abolished this antiarrhythmic effect. Adaptation of rats to repeated immobilization stress during 12 days increased myocardial tolerance to the arrhythmogenic action of coronary artery occlusion (10 min) and reperfusion (10 min). Pretreatment with a selective delta opioid receptor antagonist, TIPP(Psy), did not abolish the antiarrhythmic effect of adaptation to immobilization stress. It seems that endogenous agonists of delta opioid receptors are not involved in the antiarrhythmic effect resulting from adaptation to stress.     

Changes in cardiac resistance to arrhythmogenic effects during ATP-dependent K+ channel activation

It has been found that pretreatment with ATP-dependent potassium channel (KATP-channel) opener, BMS 180448 (3 mg/kg, intravenously), increases cardiac resistance against arrhythmogenic action of coronary artery occlusion and reperfusion in anaesthetized rats. However, BMS 180448 induced a decrease in ventricular fibrillation threshold in rats postinfarction cardiac fibrosis. This effect was completely abolished by administration of the KATP-channel inhibitor, glibenclamide. By contrast, coadministration of BMS 180448 and selective sarcolemmal KATP-channel inhibitor, HMR 1098, promoted an increase in ventricular fibrillation threshold in rats with postinfarction cardiac fibrosis before normal value. The selective mitochondrial KATP-channel opener, diazoxide, also exacerbated a decrease in ventricular fibrillation threshold induced by postinfarction cardiac sclerosis. But after depletion of endogenous catecholamine storage by pretreatment with guanthidine, diazoxide, on the contrary, elevated the ventricular fibrillation threshold. It has been suggested that stimulation of mitochondrial ATP-sensitive potassium channels promotes an elevation in electrical stability of the heart, whereas opening of sarcolemmal KATP-channel increases a possibility of ventricular arrhythmias.     

The vagal involvement in the antiarrhythmic and arrhythmogenic effects of prostaglandin F2 alpha on ouabain-induced cardiac arrhythmias in cats

The effects of prostaglandin F2 alpha (PGF2 alpha) on ouabain-induced cardiac arrhythmias were investigated in chloralose-anaesthetized cats. Bilateral vagotomy and atropine intervention were employed to elucidate the involvement of vagal neural influences. PGF2 alpha (2-16 micrograms/kg i.v. bolus) predominantly suppressed the ouabain-induced ventricular and supraventricular arrhythmias and less commonly aggravated them in vagi-intact cats. The antiarrhythmic effect of PGF2 alpha was considerably, but not statistically significantly, decreased while its arrhythmogenic effect was significantly (p less than 0.05) increased in atropine-pretreated group. In vagotomised group PGF2 alpha failed to abolish the arrhythmias but it aggravated them to a degree comparable to that observed in vagi-intact group. It is concluded that the PGF2 alpha exhibits both antiarrhythmic and arrhythmogenic properties and these are largely due to elicitation of two opposing neural reflexes - one being protective and another being deleterious to ouabain-induced arrhythmias.     

Thromboxane A2-induced arrhythmias in the anesthetized rabbit

Experiments were conducted in the anesthetized rabbit to investigate mechanisms for arrhythmias that occur after left atrial injection of the thromboxane A(2) (TxA(2)) mimetic U-46619. Arrhythmias were primarily of ventricular origin, dose dependent in frequency, and TxA(2) receptor mediated. The response was receptor specific since arrhythmias were absent after pretreatment with a specific TxA(2) receptor antagonist (SQ-29548) and did not occur in response to another prostaglandin, PGF(2alpha). Alterations in coronary blood flow were unlikely the cause of these arrhythmias because coronary blood flow (as measured with fluorescent microspheres) was unchanged after U-46619, and there were no observable changes in the ECG-ST segment. In addition, arrhythmias did not occur after administration of another vasoconstrictor (phenylephrine). The potential involvement of autonomic cardiac efferent nerves in these arrhythmias was also investigated because TxA(2) has been shown to stimulate peripheral nerves. Pretreatment of animals with the beta-adrenergic receptor antagonist propranolol did not reduce the frequency of these arrhythmias. Pretreatment with atropine or bilateral vagotomy resulted in an increased frequency of arrhythmias, suggesting that parasympathetic nerves may actually inhibit the arrhythmogenic activity of TxA(2). These experiments demonstrate that left atrial injection of U-46619 elicits arrhythmias via a mechanism independent of a significant reduction in coronary blood flow or activation of the autonomic nervous system. It is possible that TxA(2) may have a direct effect on the electrical activity of the heart in vivo, which provides significant implications for cardiac events where TxA(2) is increased, e.g., after myocardial ischemia or administration of cyclooxygenase-2 inhibitors.     

Neuromodulation targets intrinsic cardiac neurons to attenuate neuronally mediated atrial arrhythmias

Our objective was to determine whether atrial fibrillation (AF) results from excessive activation of intrinsic cardiac neurons (ICNs) and, if so, whether select subpopulations of neurons therein represent therapeutic targets for suppression of this arrhythmogenic potential. Trains of five electrical stimuli (0.3-1.2 mA, 1 ms) were delivered during the atrial refractory period to mediastinal nerves (MSN) on the superior vena cava to evoke AF. Neuroanatomical studies were performed by injecting the neuronal tracer DiI into MSN sites that induced AF. Functional studies involved recording of neuronal activity in situ from the right atrial ganglionated plexus (RAGP) in response to MSN stimulation (MSNS) prior to and following neuromodulation involving either preemptive spinal cord stimulation (SCS; T(1)-T(3), 50 Hz, 200-ms duration) or ganglionic blockade (hexamethonium, 5 mg/kg). The tetramethylindocarbocyanine perchlorate (DiI) neuronal tracer labeled a subset (13.2%) of RAGP neurons, which also colocalized with cholinergic or adrenergic markers. A subset of DiI-labeled RAGP neurons were noncholinergic/nonadrenergic. MSNS evoked an ～4-fold increase in RAGP neuronal activity from baseline, which SCS reduced by 43%. Hexamethonium blocked MSNS-evoked increases in neuronal activity. MSNS evoked AF in 78% of right-sided MSN sites, which SCS reduced to 33% and hexamethonium reduced to 7%. MSNS-induced bradycardia was maintained with SCS but was mitigated by hexamethonium. We conclude that MSNS activates subpopulations of intrinsic cardiac neurons, thereby resulting in the formation of atrial arrhythmias leading to atrial fibrillation. Stabilization of ICN local circuit neurons by SCS or the local circuit and autonomic efferent neurons with hexamethonium reduces the arrhythmogenic potential.     

Lipid metabolites and their differential pro-arrhythmic profiles: of importance in the development of a new anti-arrhythmic pharmacology

Arrhythmias have been treated for a long time with drugs that mainly target the ionic pumps and channels. These anti-arrhythmic regimens per se introduce new arrhythmias, which can be detrimental to patients. Advances in development of novel pharmacology without introduction of iatrogenic arrhythmias are thus favorable for an effective treatment of arrhythmias. Electrophysiological stability of the heart has been shown to be closely associated with cardiac metabolism. The present effective anti-arrhythmic drugs such as beta-blockers and amiodarone have profound beneficial effects in regulating myocardial metabolism. Aiming at decreasing production of toxic metabolites or preventing accumulation of arrhythmogenic lipids perhaps is a good strategy to effectively control arrhythmias. Therefore, a better understanding of the pro-arrhythmic profiles of cardiac metabolites helps to explore a new generation of metabolically oriented anti-arrhythmic medications. In this review, we present several lipid metabolites and summarize their arrhythmogenic characteristics.     

Arrhythmogenic effect of sympathetic histamine in mouse hearts subjected to acute ischemia

The role of histamine as a newly recognized sympathetic neurotransmitter has been presented previously, and its postsynaptic effects greatly depended on the activities of sympathetic nerves. Cardiac sympathetic nerves become overactivated under acute myocardial ischemic conditions and release neurotransmitters in large amounts, inducing ventricular arrhythmia. Therefore, it is proposed that cardiac sympathetic histamine, in addition to norepinephrine, may have a significant arrhythmogenic effect. To test this hypothesis, we observed the release of cardiac sympathetic histamine and associated ventricular arrhythmogenesis that was induced by acute ischemia in isolated mouse hearts. Mast cell-deficient mice (MCDM) and histidine decarboxylase knockout (HDC(-/-)) mice were used to exclude the potential involvement of mast cells. Electrical field stimulation and acute ischemia-reperfusion evoked chemical sympathectomy-sensitive histamine release from the hearts of both MCDM and wild-type (WT) mice but not from HDC(-/-) mice. The release of histamine from the hearts of MCDM and WT mice was associated with the development of acute ischemia-induced ventricular tachycardia and ventricular fibrillation. The incidence and duration of induced ventricular arrhythmias were found to decrease in the presence of the selective histamine H(2) receptor antagonist famotidine. Additionally, the released histamine facilitated the arrhythmogenic effect of simultaneously released norepinephrine. We conclude that, under acute ischemic conditions, cardiac sympathetic histamine released by overactive sympathetic nerve terminals plays a certain arrhythmogenic role via H(2) receptors. These findings provided novel insight into the pathophysiological roles of sympathetic histamine, which may be a new therapeutic target for acute ischemia-induced arrhythmias.     

Alpha-adrenoceptor blockade modifies neurally induced atrial arrhythmias

Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by alpha-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (alpha(1)-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (alpha(2)-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined alpha-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by alpha(1,2)-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal alpha-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that alpha-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system.     

Is Cardiac Resynchronisation Therapy Proarrhythmic?

It is well established that cardiac resynchronisation therapy (CRT) using biventricular pacing prolongs survival by its effects on pump failure. The rate of sudden cardiac death in patients undergoing CRT, however, remains high. Animal and human studies have shown that reversal of normal sequence of myocardial activation during epicardial pacing, as applied during CRT, increases the transmural dispersion of repolarisation (TDR), a substrate for ventricular arrhythmias. Cohort studies in humans suggest that CRT has a differential effect on the arrhythmogenic substrate, antiarrhythmic in some and proarrhythmic in others. This review the focuses on the possibility that CRT may, under certain circumstances, promote arrhythmogenesis.     

Cardiac mechano-electric feedback in man: clinical relevance

Clinical conditions associated with sudden cardiac death due to arrhythmia are frequently accompanied by abnormalities of mechanical loading and wall stretch. These arrhythmias may result from several mechanisms including secondary depolarisations during or following the action potential or from a combination of conduction slowing and action potential shortening. Mechanical perturbations have been shown to reproduce these electrophysiological effects experimentally. However the effect of mechanical intervention is complex depending on the timing and intensity of the stimulus and the interplay between effects mediated via stretch activated channels and calcium cycling. Studies in patients during cardiac catheterisation or cardiac surgery using monophasic action potentials have shown alteration in the time course and shape of action potential repolarisation in response to changes in ventricular loading. Although stretch in experimental preparations has been shown to be arrhythmogenic, particularly in pathological conditions, the role of mechanically induced electrophysiological changes in important clinical ventricular arrhythmias remains to be established.     

Lysophosphatidylcholine metabolism and cardiac arrhythmias

The ability of exogenous lysophosphatidylcholine (LPC) to produce electrophysiological abnormalities in cardiac tissues and cardiac arrhythmias in isolated hearts has been well documented. In this study, the arrhythmogenic nature of LPC in the rat, rabbit, and guinea pig hearts was studied. The rat heart was found to be the most susceptible to LPC-induced arrhythmias, while the guinea pig heart was the least susceptible. Perfusion with labelled LPC revealed that the severity of arrhythmias correlates well with the amount of labelled LPC found in the microsomal membrane. The biochemical basis for the differences in the accumulation of LPC in the microsomal membrane of different animal species was investigated. Our results strongly indicate that the LPC level in the microsomal membrane may be regulated by the activity of microsomal lysophospholipase.     

Alpha-adrenergic receptor modulation of the intrathoracic efferent sympathetic nervous system regulating the canine heart

The augmentation of ventricular inotropism induced by electrical stimulation of acutely decentralized efferent sympathetic preganglionic axons was reduced, but still present, following administration of hexamethonium (10 mg/kg i.v.). While hexamethonium continued to be administered, the cardiac augmentations so induced were enhanced significantly following administration of the alpha-adrenergic receptor blocking agent, phentolamine myselate (1 mg/kg i.v.). Stimulation of the sympathetic efferent postganglionic axons in cardiopulmonary nerves induced cardiac augmentations that were unchanged following administration of these agents singly or together. The cardiac augmentations induced by stimulation of efferent preganglionic sympathetic axons were unchanged when phentolamine was administered alone. The augmentations of cardiac inotropism induced by efferent postganglionic sympathetic axonal stimulation were decreased following local administration of the beta-adrenergic antagonist timolol into the ipsilateral stellate and middle cervical ganglia. Thereafter, these augmentations were unchanged following the subsequent intravenous administration of phentolamine. It is concluded that the activation of cardiac neurons in the stellate and middle cervical ganglia by stimulation of efferent preganglionic sympathetic axons can be modified by alpha-adrenergic receptors and that these effects are dependent upon beta-adrenergic receptors, not nicotinic ones, in intrathoracic ganglia.     

Cell–cell junction remodeling in the heart: Possible role in cardiac conduction system function and arrhythmias?

Anchoring cell-cell junctions (desmosomes, fascia adherens) play crucial roles in maintaining mechanical integrity of cardiac muscle cells and tissue. Genetic mutations and/or loss of critical components in these macromolecular structures are increasingly being associated with arrhythmogenic cardiomyopathies; however, their specific roles have been primarily attributed to effects within the working (ventricular) cardiac muscle. Growing evidence also points to a key role for anchoring cell-cell junction components in cardiac muscle cells of the cardiac conduction system. This is not only evidenced by the molecular and ultra-structural presence of anchoring cell junctions in specific compartments/structures of the cardiac conduction system (sinoatrial node, atrioventricular node, His-Purkinje system), but also because conduction system-related arrhythmias can be found in humans and mouse models of cardiomyopathies harboring defects and/or mutations in key anchoring cell-cell junction proteins. These studies emphasize the clinical need to understand the molecular and cellular role(s) for anchoring cell-cell junctions in cardiac conduction system function and arrhythmias. This review will focus on (i) experimental findings that underline an important role for anchoring cell-cell junctions in the cardiac conduction system, (ii) insights regarding involvement of these structures in age-related cardiac remodeling of the conduction system, (iii) summarizing available genetic mouse models that can target cardiac conduction system structures and (iv) implications of these findings on future therapies for arrhythmogenic heart diseases.     

Peptidergic modulation of efferent sympathetic neurons in intrathoracic ganglia regulating the canine heart

When either substance P or vasoactive intestinal peptide was injected into an acutely decentralized intrathoracic sympathetic ganglion, short-lasting augmentation of cardiac chronotropism and inotropism was induced. These augmentations were induced before the fall in systemic arterial pressure occurred which was a consequence of these peptides leaking into the systemic circulation in enough quantity to alter peripheral vascular resistance directly. When similar volumes of normal saline were injected into an intrathoracic ganglion, no significant cardiac changes were induced. When substance P or vasoactive intestinal peptide was administered into an intrathoracic ganglion, similar cardiac augmentations were induced either before or after the intravenous administration of hexamethonium. In contrast, when these peptides were injected into an intrathoracic ganglion in which the beta-adrenergic blocking agent timolol (0.1 mg/0.1 ml of normal saline) had been administered no cardiac augmentation occurred. These data imply that in the presence of beta-adrenergic blockade intraganglionic administration of substance P or vasoactive intestinal peptide does not modify enough intrathoracic neurons to alter cardiac chronotropism and inotropism detectably. When neuropeptide Y was injected into an intrathoracic ganglion, no cardiac changes occurred. However, when cardiac augmentations were induced by sympathetic preganglionic axon stimulation these were enhanced following the intraganglionic administration of neuropeptide Y. As this effect occurred after timolol was administered into the ipsilateral ganglia, but not after intravenous administration of hexamethonium, it is proposed that the effects of neuropeptide Y are dependent upon functioning intrathoracic ganglionic nicotinic cholinergic synaptic mechanisms. Intravenous administration of either morphine or [D-ala2,D-leu5]enkephalin acetate did not alter the capacity of the preganglionic sympathetic axons to augment the heart when stimulated. Following the intravenous administration of naloxone, the positive inotropic cardiac responses induced by efferent preganglionic sympathetic axonal stimulation were enhanced minimally in control states and significantly following hexamethonium administration. Thus, it appears that enkephalins are involved in the modulation of intrathoracic ganglion neurons regulating the heart, perhaps via modification of beta-adrenergic receptors. Taken together these data indicate that substance P, vasoactive intestinal peptide, neuropeptide Y, or enkephalins modify intrathoracic ganglionic neurons which are involved in efferent sympathetic cardiac regulation.     

Normal and abnormal development of the cardiac conduction system; implications for conduction and rhythm disorders in the child and adult

The cardiac conduction system is a specialized network that initiates and closely coordinates the heart beat. Cardiac conduction system development is intricately related to the development and maturation of the embryonic heart towards its four-chambered form, as is indicated by the fact that disturbed development of cardiac structures is often accompanied by a disturbed formation of the CCS. Electrophysiological studies have shown that selected conduction disturbances and cardiac arrhythmias do not take place randomly in the heart but rather at anatomical predilection sites. Knowledge on development of the CCS may facilitate understanding of the etiology of arrhythmogenic events. In this review we will focus on embryonic development of the CCS in relation to clinical arrhythmias, as well as on specific cardiac conduction abnormalities that are observed in patients with congenital heart disease.     

Arrhythmogenic dysplasia of the right ventricle-- clinical picture in view of the literature and personal experience

The author discusses arrhythmogenic dysplasia of the right ventricle, a disease of unclear etiology characterized by the replacement of right ventricular muscle with the connective tissue and ventricular cardiac arrhythmias. Clinical symptoms, available diagnostic techniques and treatment are reviewed. Four case reports illustrate arrhythmogenic dysplasia of the right ventricle.     

Increase of the heart arrhythmogenic resistance and decrease of the myocardial necrosis zone during activation of cannabinoid receptors

We have found that intravenous administration of cannabinoid receptor (CB) agonist HU-210 (0.05 mg/kg), increases cardiac resistance against arrhythmogenic effect of epinephrine, aconitine, coronary artery occlusion and reperfusion in rats. Pretreatment with CB2-receptor antagonist, SR144528 (1 mg/kg), completely abolished the antiarrhythmic effect of HU-210. However this effect of HU-210 was not attenuated by pretreatment with CB1-receptor antagonist, SR141716A (3 mg/kg). We also found that HU-210 (0.05 mg/kg) decreased the relationship between infarction size and area of ischemia. It is concluded that CB2 receptor stimulation promotes an increase in the cardiac resistance against arrhythmogenic influences and probably increases myocardial tolerance of both ischemic and reperfusion damages in rats.     

Anti-arrhythmia effect of digoxin antibodies in experimental myocardial infarct (arrhythmogenic action of endogenous digoxin-like factor)]

Suggesting endogenous digoxin-like factor (EDLF) to display arrhythmogenic activities in myocardial ischemia (MI), we studied the effect of anti-digoxin antiserum (ADS) on the ventricular fibrillation threshold (VFT) after the coronary ligation in cats and ventricular arrhythmias caused by MI in rats and chloroform-induced hypoxia in mice. Intravenous administration of ADS (5 mg/kg) enhanced VFT in cats with MI from 11.3 +/- 1.6 to 53.3 +/- 8.1 V (M +/- m; p less than 0.01) and significantly reduced ventricular arrhythmias in rats and mice. Our experiments on the isolated electro-stimulated rat atria demonstrated that EDLF is likely not to be an adrenergic cotransmitter in the heart. Possible mechanisms of the arrhythmogenic action of EDLF are discussed.