Effects of coupled pacing on cardiac performance during acute atrial tachycardia and fibrillation: an old therapy revisited for a new reason

Atrial tachycardia (AT) and fibrillation (AF) result in rapid ventricular rates that are detrimental to optimal cardiac function. The purpose of this study was to determine whether the application of a coupled pacing (CP) regimen would improve ventricular function by decreasing the ventricular rate of mechanical contractions (VRMCs). We simulated AT by pacing either atrium at a rate that resulted in a rapid but regular ventricular rate in seven anesthetized dogs. AF was induced by increasing the atrial pacing rate until atrial activation did not follow the pacing. After the induction of either AT or AF, we applied CP after each intrinsic ventricular activation. We measured the VRMCs and left ventricular (LV) pressures and volumes via a pressure-conductance catheter. The marked reductions in VRMCs during CP resulted in increases in LV end-diastolic volume. The CP resulted in virtually no mechanical contractions, whereas the strength of contractions from the normal electrical activation increased. The increases in the positive LV rate of pressure development over time and LV ejection fraction during CP were the result of postextrasystolic potentiation. The average stroke work (area of the pressure-volume loops) increased as a result of CP during both AT and AF. Despite the large increases in stroke volume (approximately 2x) during CP, the changes in cardiac output were moderate because the VRMCs markedly decreased (approximately 1/2). We conclude that CP therapy may be a viable therapy for slowing the heart rate and improving cardiac performance in patients with AT and AF.     

Selective AV nodal vagal stimulation improves hemodynamics during acute atrial fibrillation in dogs

Although the atrioventricular node (AVN) plays a vital role in blocking many of the atrial impulses from reaching the ventricles during atrial fibrillation (AF), a rapid irregular ventricular rate nevertheless persists. The goals of the present study were to explore the feasibility of novel epicardial selective vagal nerve stimulation for slowing of the ventricular rate during AF and to characterize the hemodynamic benefits in vivo. Electrophysiological-echocardiographic experiments were performed on 11 anesthetized open-chest dogs. Hemodynamic measurements were performed during three distinct periods: 1) sinus rate, 2) AF, and 3) AF with vagal nerve stimulation. AF was associated with significant deterioration of all measured parameters (P < 0.025). The vagal nerve stimulation produced slowing of the ventricular rate, significant reversal of the pressure and contractile indexes (P < 0.025), and a sharp reduction in one-half of the abortive ventricular contractions. The present study provides comprehensive evidence that slowing of the ventricular rate during AF by selective ganglionic stimulation of the vagal nerves that innervate the AVN successfully improved the hemodynamic responses.     

The usefulness of ventricular pacing during atrial fibrillation ablation in a persistent left superior vena cava: A case report

A 69-year-old woman with palpitations was referred to our hospital for a second session of atrial fibrillation (AF) catheter ablation. She had a history of AF ablation including pulmonary vein (PV) isolation and persistent left superior vena cava (PLSVC) isolation. Electrophysiologic studies showed the veno-atrial connections that had recovered. After PV isolation was performed, AF was induced by atrial premature contraction (APC) from the PLSVC, and AF storm occurred. During PLSVC isolation, AF was not induced by APC from the PLSVC. PLSVC isolation continued during sinus rhythm. The elimination of the PLSVC potential was difficult to confirm because of the far-field potential of the left ventricle. Then, we performed right ventricular pacing. The remaining PLSVC potential was identified. After that, the PLSVC isolation was successful during right ventricular pacing. Complications were not observed. The patient had no recurrence of AF thereafter.     

Comparison of contractile function of diaphragm and cardiac muscle in response to paired electrical stimulation

Paired pacing has been shown to potentiate contractile function of cardiac muscle, and it has been suggested that this may enhance contractile function of diaphragmatic muscle. The primary goal of this study was to study the effect of paired pacing on potentiation of contractile function of diaphragmatic muscle compared to atrial and ventricular myocardium. Diaphragmatic muscle was isolated from mouse and rat, and atrial and ventricular myocardium from dogs. Potentiation was induced by isolated extrastimuli (equal in duration and intensity to the pacing stimulus) and by repetitive extrastimuli (i.e. paired pacing) at a paced rate of 12, 30 and 60 beats/min. Baseline studies were performed while preparations were isometrically contracting at L(max) in oxygenated Krebs-Henseleit solution at 28 degrees C. Maximal force generation in response to a premature stimulus was determined at each rate by scanning the coupling interval between paced beats. Under baseline conditions, diaphragmatic muscle contracted faster than atrial and ventricular muscle. In all tissues, maximum potentiation (increase in force above baseline) was approximately 100% of baseline force, and peak potentiation occurred at shorter coupling intervals with increasing rates of stimulation. Single and paired pacing of diaphragm potentiated the contraction during which the extrastimuli were introduced, while in cardiac muscle, extrastimuli potentiated the contraction following the extrastimulus. The maximum potentiated response occurred when the extrastimulus was introduced prior to the development of peak force in diaphragmatic muscle. In contrast, in atrial and ventricular muscle, a single or paired premature stimulus potentiated the subsequent beat when delivered late during relaxation. In cardiac muscle, maximal potentiation gradually occurred following several repetitive stimuli. Following cessation of single and paired pacing, the beat following the potentiated response immediately returned to baseline in diaphragmatic muscle, while a gradual decline was evident over several subsequent beats in cardiac muscle. Increasing the bath temperature from 28 to 37 degrees C resulted in a leftward shift in the peak potentiated force vs. coupling interval curve without a decline in the magnitude of potentiated force in diaphragmatic muscle. In diaphragm muscle, exposure to ryanodine markedly decreased baseline force and maximal potentiation. We conclude that closely timed extrastimuli applied to diaphragmatic muscle can potentiate developed force in a given contraction, while in cardiac tissue a delayed stimulus potentiates the subsequent beat. These differences in contractile responsiveness are not due to differences in loading conditions, but appear to reflect intrinsic differences in calcium handling.     

Atrial electrogram quality in single-pass defibrillator leads with floating atrial bipole in patients with permanent atrial fibrillation and cardiac resynchronization therapy

Many patients receiving cardiac resynchronization therapy (CRT) suffer from permanent atrial fibrillation (AF). Knowledge of the atrial rhythm is important to direct pharmacological or interventional treatment as well as maintaining AV-synchronous biventricular pacing if sinus rhythm can be restored. A single pass single-coil defibrillator lead with a floating atrial bipole has been shown to obtain reliable information about the atrial rhythm but has never been employed in a CRT-system. The purpose of this study was to assess the feasibility of implanting a single coil right ventricular ICD lead with a floating atrial bipole and the signal quality of atrial electrograms (AEGM) in CRT-defibrillator recipients with permanent AF.

N-terminal Pro-Brain Natriuretic Peptide And Atrial Fibrillation

NT-proBNP is produced from both atria and ventricles. The primary regulation of production is at the synthesis level. The plasma half-life of NT-proBNP is 60-120 min. Cutoff value of NT-proBNP for diagnosis of heart failure is 125 pg/ml in the age group below 75 years and 450 pg/ml in the age group above 75 years. It increases in atrial fibrillation and drops after successful cardioversion. High levels predict development of atrial fibrillation (AF) in healthy persons with sinus rhythm (SR). Some studies concluded that baseline level predicts maintenance of SR after cardioversion of AF while some others found that it did not. Many studies have proven that it is useful in monitoring rhythm stability after cardioversion of AF. Since it is increased in many other conditions, out of which some may also cause AF, care must be taken before ascribing changes in its level to AF alone.     

Decreased sarcolipin protein expression and enhanced sarco(endo)plasmic reticulum Ca2+ uptake in human atrial fibrillation

Sarcolipin (SLN), a key regulator of cardiac sarco(endo)plasmic reticulum (SR) Ca(2+) ATPase, is predominantly expressed in atria and mediates β-adrenergic responses. Studies have shown that SLN mRNA expression is decreased in human chronic atrial fibrillation (AF) and in aortic banded mouse atria; however, SLN protein expression in human atrial pathology and its role in atrial SR Ca(2+) uptake are not yet elucidated. In the present study, we determined the expression of major SR Ca(2+) handling proteins in atria of human AF patients and in human and in a mouse model of heart failure (HF). We found that the expression of SR Ca(2+) uptake and Ca(2+) release channel proteins are significantly decreased in atria but not in the ventricles of pressure-overload induced HF in mice. In human AF and HF, the expression of SLN protein was significantly decreased; whereas the expressions of other major SR Ca(2+) handling proteins were not altered. Further, we found that the SR Ca(2+) uptake was significantly increased in human AF. The selective downregulation of SLN and enhanced SR Ca(2+) uptake in human AF suggest that SLN downregulation could play an important role in abnormal intracellular Ca(2+) cycling in atrial pathology.     

Direction-dependent conduction abnormalities in a canine model of atrial fibrillation due to chronic atrial dilatation

Chronic rapid atrial pacing (RAP) leads to changes that perpetuate atrial fibrillation (AF). Chronic atrial dilatation due to mitral regurgitation (MR) also increases AF inducibility, but it is not clear whether the underlying mechanism is similar. Therefore, we have investigated atrial electrophysiology in a canine MR model (mitral valve avulsion, 1 mo) using high-resolution optical mapping and compared it with control dogs and with the canine RAP model (6-8 wk of atrial pacing at 600 beats/min, atrioventricular block, and ventricular pacing at 100 beats/min). At followup, optical action potentials were recorded using a 16 x 16 photodiode array from 2 x 2-cm left atrial (LA) and right atrial (RA) areas in perfused preparations, with pacing electrodes around the field of view to study direction dependency of conduction. Action potential duration at 80% repolarization (APD(80)) was not different between control and MR but was reduced in RAP atria. Conduction velocities during normal pacing were not different between groups. However, the MR LA showed increased conduction heterogeneity during pacing at short cycle lengths and during premature extrastimuli, which frequently caused pronounced regional conduction slowing. Conduction in the MR LA during extrastimulation also displayed a marked dependence on propagation direction. These phenomena were not observed in the MR RA and in control and RAP atria. Thus both models form distinctly different AF substrates; in RAP dogs, the decrease in APD(80) may stabilize reentry. In MR dogs, regional LA conduction slowing and increased directional dependency, allowing unidirectional conduction block and preferential paths of conduction, may account for increased AF inducibility.     

Changes in regional myocardial volume during the cardiac cycle: implications for transmural blood flow and cardiac structure

Although previous studies report a reduction in myocardial volume during systole, myocardial volume changes during the cardiac cycle have not been quantitatively analyzed with high spatiotemporal resolution. We studied the time course of myocardial volume in the anterior mid-left ventricular (LV) wall of normal canine heart in vivo (n = 14) during atrial or LV pacing using transmurally implanted markers and biplane cineradiography (8 ms/frame). During atrial pacing, there was a significant transmural gradient in maximum volume decrease (4.1, 6.8, and 10.3% at subepi, midwall, and subendo layer, respectively, P = 0.002). The rate of myocardial volume increase during diastole was 4.7 +/- 5.8, 6.8 +/- 6.1, and 10.8 +/- 7.7 ml.min(-1).g(-1), respectively, which is substantially larger than the average myocardial blood flow in the literature measured by the microsphere method (0.7-1.3 ml.min(-1).g(-1)). In the early activated region during LV pacing, myocardial volume began to decrease before the LV pressure upstroke. We conclude that the volume change is greater than would be estimated from the known average transmural blood flow. This implies the existence of blood-filled spaces within the myocardium, which could communicate with the ventricular lumen. Our data in the early activated region also suggest that myocardial volume change is caused not by the intramyocardial tissue pressure but by direct impingement of the contracting myocytes on the microvasculature.     

Adverse effects of atrioventricular synchronous right ventricular pacing on left ventricular sympathetic activity, efficiency, and hemodynamic status

Right ventricular (RV) pacing is now recognized to play a role in the development of heart failure in patients with and without underlying left ventricular (LV) dysfunction. We used the cardiac norepinephrine spillover method to test the hypothesis that RV pacing is associated with cardiac sympathetic activation. We studied 8 patients with normal LV function using temporary right atrial and ventricular pacing wires. All measurements were carried out during a fixed atrial pacing rate. The radiotracer norepinephrine spillover technique was employed to measure total body and cardiac sympathetic activity while changes in LV performance were evaluated with a high-fidelity manometer catheter. Atrioventricular synchronous RV pacing, compared with atrial pacing alone, was associated with a 65% increase in cardiac norepinephrine spillover, an increase in LV end-diastolic pressure, and a reduction in myocardial efficiency. These responses may play a role in the development of heart failure and poor outcomes that are associated with chronic RV pacing.     

Effect of atrio-ventricular conduction on the appearance of supraventricular arrhythmia and thrombotic complications in patients with chronic stimulation of cardiac ventricles in sick sinus syndrome]

Two hundred three patients with sick sinus node disease were treated with continuous ventricular stimulation between 1981 and 1985. To 1988, 168 patients aged between 26 and 88 years were followed-up for 5.1 years on the average. All these patients were divided into two groups: I (93 patients) with sinusal bradycardia, and group II (93 patients) with brady-tachycardia. Ventriculo-atrial conduction was seen in 82.61% of patients of group I in whom the implantation of electric stimulator produced the attacks of atrial fibrillation, and in 44.23% of patients without such attacks (p < 0.01); in 80.77% of patients of group II in whom atrial fibrillation became stable with time, and in 50.57% with intermittent atrial fibrillation (p < 0.01) ventriculo-atrial conduction was noted. It may be concluded, that the presence of ventriculo-atrial conduction in patients with prolonged stimulation of the cardiac ventricles favor the occurrence and stabilization of the paroxysmal atrial fibrillation and thrombotic complications.     

Disrupted Calcium Release as a Mechanism for Atrial Alternans Associated with Human Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, but our knowledge of the arrhythmogenic substrate is incomplete. Alternans, the beat-to-beat alternation in the shape of cardiac electrical signals, typically occurs at fast heart rates and leads to arrhythmia. However, atrial alternans have been observed at slower pacing rates in AF patients than in controls, suggesting that increased vulnerability to arrhythmia in AF patients may be due to the proarrythmic influence of alternans at these slower rates. As such, alternans may present a useful therapeutic target for the treatment and prevention of AF, but the mechanism underlying alternans occurrence in AF patients at heart rates near rest is unknown. The goal of this study was to determine how cellular changes that occur in human AF affect the appearance of alternans at heart rates near rest. To achieve this, we developed a computational model of human atrial tissue incorporating electrophysiological remodeling associated with chronic AF (cAF) and performed parameter sensitivity analysis of ionic model parameters to determine which cellular changes led to alternans. Of the 20 parameters tested, only decreasing the ryanodine receptor (RyR) inactivation rate constant (ki_Ca) produced action potential duration (APD) alternans seen clinically at slower pacing rates. Using single-cell clamps of voltage, fluxes, and state variables, we determined that alternans onset was Ca²⁺-driven rather than voltage-driven and occurred as a result of decreased RyR inactivation which led to increased steepness of the sarcoplasmic reticulum (SR) Ca²⁺ release slope. Iterated map analysis revealed that because SR Ca²⁺ uptake efficiency was much higher in control atrial cells than in cAF cells, drastic reductions in ki_Ca were required to produce alternans at comparable pacing rates in control atrial cells. These findings suggest that RyR kinetics may play a critical role in altered Ca²⁺ homeostasis which drives proarrhythmic APD alternans in patients with AF.     

Characterization of fibrillatory rhythms by ensemble vector directional analysis

Recent studies have demonstrated that fibrillatory rhythms are not random phenomena but have definable patterns. However, standard mapping techniques may have limitations in their ability to identify the organization of fibrillation. The purpose of this study was to develop and apply a method, "ensemble vector mapping," for characterizing the spatiotemporal organization of fibrillation. Ventricular fibrillation was induced by burst pacing in normal mongrel dogs. In a separate protocol, atrial fibrillation was induced by epicardial aconitine application. Epicardial electrograms were recorded from a 112-electrode plaque array using a computerized mapping system. Vectors were created by summing orthogonal bipolar electrograms. The magnitude of the vectors was transformed using a logarithmic function, integrated over time, and normalized for local electrogram amplitude to produce an "ensemble vector" index whose magnitude is high when beat-to-beat activation direction is consistent and low when activation direction is variable. The mean index was 137 +/- 36 mV/s during ventricular pacing at a cycle length of 300 ms but only 39 +/- 23 mV/s during ventricular fibrillation (P < 0.001). The ensemble vector index was also lower during atrial fibrillation (60 +/- 54 mV/s) than during atrial pacing (115 +/- 27 mV/s, P < 0.01 vs. atrial fibrillation) but not as low as during ventricular fibrillation (P < 0.05, atrial vs. ventricular fibrillation). The index was also capable of distinguishing atrial tachycardia from atrial fibrillation. Ensemble vector mapping produces an objective assessment of the consistency of myocardial activation during fibrillation. The consistency of activation direction differs in different models of fibrillation and is higher during atrial than ventricular fibrillation. This technique has the potential to rapidly characterize repetitive activation patterns in fibrillatory rhythms and may help distinguish among different characteristics of fibrillatory rhythms.     

Decreased sarcolipin protein expression and enhanced sarco(endo)plasmic reticulum Ca uptake in human atrial fibrillation

Sarcolipin (SLN), a key regulator of cardiac sarco(endo)plasmic reticulum (SR) Ca²⁺ ATPase, is predominantly expressed in atria and mediates β-adrenergic responses. Studies have shown that SLN mRNA expression is decreased in human chronic atrial fibrillation (AF) and in aortic banded mouse atria; however, SLN protein expression in human atrial pathology and its role in atrial SR Ca²⁺ uptake are not yet elucidated. In the present study, we determined the expression of major SR Ca²⁺ handling proteins in atria of human AF patients and in human and in a mouse model of heart failure (HF). We found that the expression of SR Ca²⁺ uptake and Ca²⁺ release channel proteins are significantly decreased in atria but not in the ventricles of pressure-overload induced HF in mice. In human AF and HF, the expression of SLN protein was significantly decreased; whereas the expressions of other major SR Ca²⁺ handling proteins were not altered. Further, we found that the SR Ca²⁺ uptake was significantly increased in human AF. The selective downregulation of SLN and enhanced SR Ca²⁺ uptake in human AF suggest that SLN downregulation could play an important role in abnormal intracellular Ca²⁺ cycling in atrial pathology.     

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.     

Ventricular Pacing on the Prognosis of Patients with Pacemaker Implantation

Excessive right ventricular apex pacing has significant adverse effects on the cardiac function and hence, it is necessary to clinically optimize pacing parameters and advocate suitable physiological pacing to safeguard the cardiac function after pacemaker implant. Minimizing ventricular pacing is an atrioventricular node priority function, to encourage ventricular self conduction and to reduce unnecessary right ventricular pacing. Minimized ventricular pacing reduces ventricular pacing by encouraging self atrioventricular conduction function and extending the AV interval. This study is a prospective cohort study to evaluate the changes of cardiac function in patients and serum amino-terminal natriuretic peptide (NT-proBNP) before and after pacing, and the risk of atrial fibrillation with different CUM% VP. The study has shown that the cardiac function will deteriorate with an increase in pacing rate.     

Effects of aldosterone and mineralocorticoid receptor antagonism on cardiac ion channels in the view of upstream therapy of atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia in man. Over the past years, importance of the renin-angiotensin-aldosterone system in AF pathophysiology has been recognized. Lately, the role of aldosterone in AF pathophysiology and mineralocorticoid receptor (MR) antagonism in "upstream" AF treatment is discussed with special regards concerning the effects on AF-induced structural remodeling. However, there is more and more evidence that MR antagonism also influences atrial electrophysiology and, respectively, AF-induced electrical remodeling, whereas the molecular mechanisms are almost unknown. The aim of this mini-review is to give an overview about the role of aldosterone in AF pathophysiology in principle and to summarize current available data concerning affection of cardiac ion channels by aldosterone and MR antagonism. Finally, as modulation of oxidative stress is discussed as one main therapy principle of "upstream" treatment of AF, potential mechanisms how modulation of oxidative stress by aldosterone and accordingly MR antagonism might alter atrial ion currents are delineated. Summarized, publications concerning potential mechanisms of aldosterone- and MR antagonism-modulated cardiac ion channels in various experimental settings are almost exclusively limited to the ventricular level and, partly, they are also contradictorily. Translation of these data to the atria is problematic because atrial and ventricular electrophysiology exhibit remarkable differences. It can be concluded that further research on the "atrial level" is needed in order to clarify the potential impact of the affection of atrial ion channels by aldosterone and accordingly MR antagonism in "upstream" therapy of AF.     

Altered function and regulation of cardiac ryanodine receptors in cardiac disease

In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum (SR) releases the calcium required for muscle contraction. The magnitude of Ca²⁺ release by RyR2, which is subject to regulation by several physiological mediators, determines cardiac contractility. In heart failure, chronic stimulation of the β-adrenergic signaling pathway leads to hyperphosphorylation of RyR2 by protein kinase A, which dissociates calstabin2 (FKBP12.6) from the receptor. Calstabin2-depleted channels display altered channel gating and can cause diastolic Ca²⁺ release from the SR. This release depletes the SR Ca²⁺ stores, leading to reduced myocardial contractility. Mutant RyR2, found in patients with catecholaminergic polymorphic ventricular tachycardia, has decreased calstabin2 binding affinity, which can trigger ventricular arrhythmias and sudden cardiac death after stress and exercise. Thus, defects in RyR2 have been linked to heart failure and exercise-induced sudden cardiac death and might provide novel therapeutic targets for the treatment of these common diseases of the heart.     

Ginsenoside Re suppresses electromechanical alternans in cat and human cardiomyocytes

Ginseng botanicals are increasingly used as complementary or alternative medicines for a variety of cardiovascular diseases, yet little is known about their cellular actions in cardiac muscle. Electromechanical alternans (EMA) is a proarrhythmic cardiac abnormality that results from disturbances of intracellular Ca(2+) homeostasis. This study sought to determine whether a purified ginsenoside extract of ginseng, Re, exerts effects to suppress EMA and to gain insight into its mechanism of action. Alternans was induced by electrically pacing cardiomyocytes at room temperature. Re (> or = 10 nM) reversibly suppressed EMA recorded from cat ventricular and atrial myocytes and Langendorff-perfused cat hearts. In cat ventricular myocytes, Re reversibly suppressed intracellular Ca(2+) concentration ([Ca(2+)](i)) transient alternans. Re exerted no significant effects on baseline action potential configuration or sarcolemmal L-type Ca(2+) current (I(Ca,L)), Na(+) current, or total K(+) conductance. In human atrial myocytes, Re suppressed mechanical alternans and exerted no effect on I(Ca,L). In cat ventricular myocytes, Re increased [Ca(2+)](i) transient amplitude and decreased sarcoplasmic reticulum (SR) Ca(2+) content, resulting in an increase in fractional SR Ca(2+) release. In SR microsomes isolated from cat ventricles, Re had no effect on SR Ca(2+) uptake. Re increased the open probability of ryanodine receptors (RyRs), i.e., SR Ca(2+)-release channels, isolated from cat ventricles and incorporated into planar lipid bilayers. We concluded that ginsenoside Re suppresses EMA in cat atrial and ventricular myocytes, cat ventricular muscle, and human atrial myocytes. The effects of Re are not mediated via actions on sarcolemmal ion channels or action potential configuration. Re acts via a subcellular mechanism to enhance the opening of RyRs and thereby overcome the impaired SR Ca(2+) release underlying EMA.