Slow conduction through an arc of block: A basis for arrhythmia formation postmyocardial infarction.

INTRODUCTION: The electrophysiologic basis for characteristic rate-dependent, constant-late-coupled (390 + 54 milliseconds) premature ventricular beats (PVBs) present 4-5 days following coronary artery occlusion were examined in 108 anesthetized dogs. METHODS AND RESULTS: Fractionated/double potentials were observed in injured zone bipolar and composite electrograms at prolonged sinus cycle lengths (1,296 ± 396 milliseconds). At shorter cycle lengths, conduction of the delayed potential decremented, separating from the initial electrogram by a progressively prolonged isoelectric interval. With sufficient delay of the second potential following an isoelectric interval, a PVB was initiated. Both metastable and stable constant-coupled PVBs were associated with Wenckebach-like patterns of delayed activation following an isoelectric interval. Signal-averaging from the infarct border confirmed the presence of an isoelectric interval preceding the PVBs (N = 15). Pacing from the site of double potential formation accurately reproduced the surface ECG morphology (N = 15) of spontaneous PVBs. Closely-spaced epicardial mapping demonstrated delayed activation across an isoelectric interval representing "an arc of conduction block." Rate-dependent very slow antegrade conduction through a zone of apparent conduction block (N = 8) produced decremental activation delays until the delay was sufficient to excite epicardium distal to the original "arc of conduction block," resulting in PVB formation. CONCLUSION: The present experiments demonstrate double potential formation and rate-dependent constant-coupled late PVB formation in infarcted dog hearts. Electrode recordings demonstrate a prolonged isoelectric period preceding PVB formation consistent with very slow conduction (<70 mm/s) across a line of apparent conduction block and may represent a new mechanism of PVB formation following myocardial infarction.

Slow antegrade excitation and delayed retrograde activation through an "inexcitable zone": A basis for arrhythmia formation in infarcted myocardium ex vivo.

INTRODUCTION: The electrophysiologic mechanism for rate-dependent PVBs associated with double potentials (DPs) was investigated in infarcted canine hearts using bipolar and intracellular microelectrode recordings. METHODS AND RESULTS: Dogs exhibiting rate-related ventricular ectopic beats (coupling interval, 390 ± 54 milliseconds) during sinus rhythm or atrial pacing were studied 4-5 days (N = 63) or 25 days (N = 16) following anterior descending coronary artery ligation. Sites of DP and rate-dependent arrhythmia formation were identified in vivo using bipolar recordings for subsequent ex vivo studies. Rate-dependent conduction delays with increasing duration isoelectric intervals representing very slow conduction were observed at sites of DP formation, frequently provoking both manifest and concealed reentry (non-stimulated beats) over a narrow range of paced cycle lengths. Both slow antegrade and retrograde activation across an inexcitable gap (reflection) were integral components of extrasystole formation. Retrograde reflection to a region of very slow conduction (mid-potential) during antegrade activation was routinely observed at 4-5 days (42 of 63 preparations, 67%) and 25 days (22 of 26 preparations, 85%) postcoronary artery ligation. Reflection and premature re-activation of the proximal site was then observed in 6 of 63 (9%), and 3 of 26 preparations (12%). CONCLUSION: The present experiments demonstrate DP formation and rate-dependent constant-coupled late epicardial premature beats in infarcted dog hearts. Microelectrode recordings at DP sites demonstrating prolonged isoelectric intervals display very slow conduction preceding distal activation and "reentrant" re-activation of more proximal sites, representing reflection as an arrhythmia mechanism in ischemically injured epicardium during subacute myocardial infarction.

Extra- and intracellular recordings from the avjunction: discerning the mechanisms for irregular ventricular responses during supraventricular arrhythmias.

INTRODUCTION: There has been a long-standing controversy regarding the mechanism(s) to explain the irregular ventricular response during atrial tachycardia (AT) or atrial fibrillation (AF) and where the site of block, if any, resides in the atrioventricular (AV) junction. METHODS: We studied 12 Langendorff preparations perfused with modified Tyrode's solution containing 5-10 mM diacetyl monoxime which suppressed contractility but allowed the use of intracellular action potential (AP) recordings. Octapolar catheters (2-mm rings, 2-mm spacing) were secured along the tricuspid annulus from the apex to the base of the triangle of Koch and along the anterior limbus of the fossa ovalis to record extracellular, slow pathway, fast pathway, His bundle (Hb) and AV nodal (AVN) extracellular potentials as well as intracellular action potentials. RESULTS: AT or AF induced by rapid atrial pacing showed a variety of irregular responses due to: (1) Wenckebach conduction showing decrement within the AVN and progressive diminution of extracellular AVN potentials (n = 5); (2) repetitive concealed conduction proximal to the AVN (n = 3); (3) ectopic beats arising within the AVN (n = 2); (4) ectopic beats arising at the Hb (n = 2). CONCLUSIONS: In this experimental preparation, extracellular and intracellular recordings provided presumptive evidence for the mechanisms causing the irregularities of the ventricular response such as repetitive concealed conduction, enhanced automaticity or electrotonically triggered activity. Also more definitive determinations of the site of block in the AV junction were also obtained.

Opposing cardiac effects of autoantibody activation of ß-adrenergic and M2 muscarinic receptors in cardiac-related diseases.

BACKGROUND: Activating autoantibodies to ß-adrenergic receptors (AAß1/2AR) and M2 muscarinic receptors (AAM2R) have been reported in several cardiac diseases and may have pathophysiologic relevance. However, the interactions and relative effects of AAß1AR, AAß2AR and AAM2R on contractile function have not been characterized. METHODS: The inotropic effects of IgG from 18 selected patients with cardiomyopathy and/or atrial tachyarrhythmias positive by ELISA for antibodies to ß1/2AR were studied using an isolated canine Purkinje fiber contractility assay. M2R-blockade was tested using atropine while selective ß1AR and ß2AR blockade used CGP-20712A and ICI-118551 respectively. RESULTS: Fifteen of the 18 anti-ß1/2AR ELISA-positive samples demonstrated evidence for negative inotropic muscarinic effects which were blocked using atropine. Atropine failed to uncover a positive inotropic response in 2 of the 18 IgG samples (false positive ELISA for AAßAR). In the remaining 16 AAßAR true-positive subjects, the ß1AR-induced increase in contractility (concurrent M2/ß2 blockade) was augmented to 140.5±12.2% of baseline compared to 127.4±7.2% of baseline with M2 blockade (atropine) only (p<0.001, n=16). The ß2AR-induced increase in contractility (concurrent M2/ß1 blockade) was only 114.5±4.3% of baseline (p<0.001, n=16). Combined M2 and ß1/ß2 blockade eliminated any increase in contractility. CONCLUSIONS: The inherently positive inotropic effect of AAß1AR was negatively modulated by AAM2R and AAß2AR. These opposing effects of receptor-activating autoantibodies may alter cardiac performance and influence clinical outcome depending on their receptor type and relative contractile activity.

Stable patterns of AH block arising from longitudinal dissociation and reentry within the superfused rabbit AV junction.

INTRODUCTION: Multiple forms of antegrade AH Wenckebach block (WB) observed in 14 of 221 superfused rabbit AV junctions. METHODS: Bipolar and microelectrode recordings were used to examine the mechanism of multiple forms of AH WB. RESULTS: Each of the 14 preparations demonstrated typical 3:2 and 2:1 AV block, but also demonstrated longitudinal dissociation within the slow pathway input (N = 11) or compact AV node (N = 3). A 3:2 WB in one pathway and 1:1 conduction in a parallel pathway summated to provide antegrade conduction of the third atrial beat. Retrograde conduction (reentry) blocked conduction of the fourth impulse (4:3 block). A 5:4 block was similarly observed, with summation providing for antegrade AH activation of the third and fourth atrial beats. Retrograde activation observed with the fourth beat, terminated antegrade conduction of the fifth beat. CONCLUSIONS: The studies demonstrate multiple AH WB patterns consistent with rate-dependent longitudinal dissociation, summation of dissociated AV conduction pathways, and retrograde conduction block within the AV junction.

Pathophysiologic basis of autonomic ganglionated plexus ablation in patients with atrial fibrillation.

The intrinsic cardiac autonomic nervous system (ganglionated plexuses [GP]) plays a significant role in the initiation and maintenance of atrial fibrillation (AF) in both experimental models and AF patients. Left atrial GP, located in epicardial fat pads and the ligament of Marshall, contain afferent neurons from the atrial myocardium and the central autonomic nervous system, efferent neurons (cholinergic and adrenergic neurons), and interconnecting neurons, which allow communication between GP. Stimulation of the GP produces both parasympathetic stimulation (markedly shortens action potential duration) and sympathetic stimulation (increases calcium transient) in the pulmonary vein (PV) myocardium and atrial myocardium. In a canine model, GP stimulation resulted in early afterdepolarizations, and calcium transient triggered firing in the adjacent PV and initiated AF. Fractionated atrial potentials (FAP) were consistently located in the left atrium close to the stimulated GP. Ablation of the stimulated GP eliminated the FAP surrounding the GP. In patients with paroxysmal AF, epicardial and endocardial high-frequency stimulation produced a positive vagal response (transient AV block during AF and hypotension), allowing the identification and localization of five major left atrial GP (superior left GP, inferior left GP, Marshall tract GP, anterior right GP, inferior right GP). High-density electroanatomic maps of the left atrium and PVs obtained during AF showed the FAP are located in four main left atrial areas (left atrial appendage ridge FAP area, superior-left FAP area, inferoposterior FAP area, anterior-right FAP area). All five GP are located within one of the four FAP areas. In 63 patients with paroxysmal AF, GP ablation alone (before PV antrum isolation) significantly decreased the occurrence of PV firing (47/63 patients before ablation vs 9/63 patients after ablation, P <.01). GP ablation also decreased the inducibility of sustained AF (43/63 patients vs 23/63 patients, P <.01) and markedly reduced or eliminated the left atrial FAP areas.

An acute experimental model demonstrating 2 different forms of sustained atrial tachyarrhythmias.

BACKGROUND: The objective of this study was to develop an acute experimental model showing both focal and macroreentrant sustained atrial fibrillation (AF). METHODS AND RESULTS: In 31 anesthetized dogs, bilateral thoracotomies allowed the attachment of electrode catheters at the right and left superior pulmonary veins, atrial free walls, and atrial appendages. Acetylcholine, 100 mmol/L, was applied topically to either appendage. Sequential radiofrequency ablation was achieved for the ganglionated plexi (GP), found adjacent to the 4 pulmonary veins. In 12 separate studies, a propafenone bolus, 2 mg/kg, was given before and after GP ablations at the start of acetylcholine-induced AF. Acetylcholine caused abrupt onset of AF (n=22) or induced AF by burst pacing (n=9) that lasted > or = 10 minutes. Rapid, regular, or fractionated atrial electrograms were consistently seen (average cycle length, 37+/-7 ms) at the appendages versus cycle lengths of 114+/-23 ms at other atrial sites. After ablations of GP, AF abruptly terminated (n=25). In 6 dogs, sustained atrial tachyarrhythmias continued. Pacing at specific atrial sites organized electrograms of one atrium or also captured the other atrium. The latter resulted in termination when pacing was stopped in 4 of these 6 experiments. Propafenone did not change the duration of focal AF before GP ablation (17+/-9 versus 14+/-8 minutes; control, P=0.6) but terminated reentrant atrial tachyarrhythmias (12+/-3 versus 2+/-1 minutes, P=0.0009). CONCLUSIONS: Before GP ablation, acetylcholine (100 mmol/L) induced sustained AF characterized by rapid, focal firing. GP ablations were associated with loss of focal firing and regularization of electrograms in both atria before termination. Propafenone failed to terminate focal AF but rapidly terminated entrainable macroreentrant atrial tachyarrhythmias.

Activating autoantibodies to the beta-1 adrenergic and m2 muscarinic receptors facilitate atrial fibrillation in patients with Graves' hyperthyroidism.

OBJECTIVES: We studied activating autoantibodies to beta-1 adrenergic receptors (AAbeta1AR) and activating autoantibodies to M2 muscarinic receptors (AAM2R) in the genesis of atrial fibrillation (AF) in Graves' hyperthyroidism. BACKGROUND: Atrial fibrillation frequently complicates hyperthyroidism. Both AAbeta1AR and AAM2R have been described in some patients with dilated cardiomyopathy and AF. We hypothesized that their copresence would facilitate AF in autoimmune Graves' hyperthyroidism. METHODS: Immunoglobulin G purified from 38 patients with Graves' hyperthyroidism with AF (n=17) or sinus rhythm (n=21) and 10 healthy control subjects was tested for its effects on isolated canine Purkinje fiber contractility with and without atropine and nadolol. Immunoglobulin G electrophysiologic effects were studied using intracellular recordings from isolated canine pulmonary veins. Potential cross-reactivity of AAbeta1AR and AAM2R with stimulating thyrotropin receptor (TSHR) antibodies was evaluated before and after adsorption to Chinese hamster ovary cells expressing human TSHRs using flow cytometry and enzyme-linked immunosorbent assays. RESULTS: The frequency of AAbeta1AR and/or AAM2R differed significantly between patients with AF and sinus rhythm (AAbeta1AR=94% vs. 38%, p<0.001; AAM2R=88% vs. 19%, p<0.001; and AAbeta1AR+AAM2R=82% vs. 10%, p<0.001). The copresence of AAbeta1AR and AAM2R was the strongest predictor of AF (odds ratio: 33.61, 95% confidence interval: 1.17 to 964.11, p=0.04). Immunoglobulin G from autoantibody-positive patients induced hyperpolarization, decreased action potential duration, enhanced early afterdepolarization formation, and facilitated triggered firing in pulmonary veins by local autonomic nerve stimulation. Immunoadsorption studies showed that AAbeta1AR and AAM2R were immunologically distinct from TSHR antibodies. CONCLUSIONS: When present in patients with Graves' hyperthyroidism, AAbeta1AR and AAM2R facilitate development of AF.

Autonomic elements within the ligament of Marshall and inferior left ganglionated plexus mediate functions of the atrial neural network.

OBJECTIVES: We sought to systematically investigate the role of the ligament of Marshall (LOM) and inferior left ganglionated plexi (ILGP) in modulating electrophysiological functions. METHODS: The following structures were exposed in 36 dogs: (1) LOM, (2) superior left GP (SLGP) near the junction of left superior pulmonary vein (LSPV) and left atrium, (3) ILGP near the left inferior pulmonary vein-atrial junction, (4) anterior right GP (ARGP) near the sino-atrial node, and (5) inferior right GP (IRGP) at the junction of inferior vena cava and atria. High frequency stimulation (HFS; 0.6-8.0 V, 20 Hz, 0.1 msec in duration) was applied to the LOM, SLGP, ILGP, ARGP, IRGP, or vagosympathetic trunk. Ventricular rate (VR) during atrial fibrillation (AF) was compared before and after ablation of GP in different sequences. RESULTS: ARGP + ILGP ablation but not ARGP ablation alone eliminated the VR slowing response induced by LOM stimulation, suggesting that all the autonomic innervation from the LOM to AV node passes the ILGP. LOM ablation attenuated the VR slowing response caused by SLGP or left vagosympathetic stimulation, suggesting that LOM modulates the autonomic innervation between the AV node and the left vagosympathetic trunk or SLGP. ARGP attenuated while ARGP + ILGP ablation eliminated the VR slowing response induced by left vagosympathetic stimulation, suggesting that both ARGP and ILGP modulate the AV nodal innervation of the extrinsic and intrinsic cardiac autonomic nervous system (ANS). CONCLUSION: The LOM and ILGP function as the "integration centers" that modulate the autonomic interactions between extrinsic and intrinsic cardiac ANS on AV nodal function.

Targeting proteasomes for cardioprotection.

The ubiquitin-proteasome system (UPS) plays a central role in intracellular protein degradation and regulates many cellular processes, including cell proliferation, inflammation, adaptation to stress, cell death, and the removal of damaged or misfolded proteins. Numerous studies have demonstrated that altered UPS function is involved in the pathogenesis of a wide range of cardiac diseases including hypertrophy and failure, myocardial ischemia, atherosclerosis, and diabetic cardiovascular disease. Impairment of proteasome function is a common feature of cardiac disease; however several studies have also demonstrated increased proteasome activity in models similar but not identical with those having decreased function. Recent studies have shown that use of proteasome inhibitors before or following production of the model of cardiac disease may confer cardioprotection under certain conditions.

Development of cardiomyopathy and atrial tachyarrhythmias associated with activating autoantibodies to beta-adrenergic and muscarinic receptors.

A 71-year-old male with well-controlled hypertension developed atrial tachyarrhythmias in 2002 and a restrictive cardiomyopathy in 2006 to 2007. Sera from 1992, 2001, and 2006 to 2008 demonstrated activating autoantibodies against beta-adrenergic (AAbetaAR) and M2 muscarinic receptors (AAM2R). These sera have been characterized for bioactivity using in vitro assays of cardiac contractility and automaticity using a canine cardiac Purkinje fiber assay as well as protein kinase assay activation in H9c2 cells. These assays demonstrated concurrent positive betaAR and inhibitory M2R effects that were blocked by nadolol and atropine, respectively. In a canine pulmonary vein atrial sleeve preparation, sera diluted 1:100 produced atrial hyperpolarization that was blocked by atropine. Atrial tachyarrhythmias developed in 2002 in the presence of a persistent bradycardia. Serial echocardiograms demonstrated progressive diastolic dysfunction in the absence of cardiac hypertrophy between 2006 and 2007. A dual-chamber pacemaker was installed with combined betaAR (nadolol) and M2<3R (oxybutynin) blockade, resulting in marked suppression of atrial ectopy and improved diastolic function. The estimated pulmonary artery pressure decreased and exercise tolerance returned. Blood pressure has remained normal with beta-blockade. AAbetaAR and AAM2R prospectively influenced atrial and ventricular function in this patient, and specific receptor blockade was associated with improved cardiac function.

The Autonomic Nervous System and Atrial Fibrillation:The Roles of Pulmonary Vein Isolation and Ganglionated Plexi Ablation.

After the sequential successes of catheter ablation for the treatment of pre-excitation syndromes (WPW), junctional reentry (AVNRT) atrial flutter (AFL) and ventricular arrhythmias, clinical electrophysiologists have focused on the myocardial basis of atrial fibrillation (AF). Thus, the strategy for ablation of drug and cardioversion refractory AF was to isolate the myocardial connections from the focal firing pulmonary veins (PVs) in addition to altering the atrial substrate maintaining AF. However, the overall success rates have not achieved those of the other types of ablation procedures. In this review we have summarized the favorable aspects and drawbacks of pulmonary vein isolation (PVI). As for the role of the Intrinsic Cardiac Autonomic Nervous System (ICANS), both basic and clinical evidence has shown that ganglionated plexi (GP) stimulation promotes initiation and maintenance of AF, and that GP ablation reduces recurrence of AF following catheter or surgical ablation of these structures. Based on these findings, the GP Hyperactivity Hypothesis has been proposed to explain, at least in part, the mechanistic basis for the focal form of AF. For example, PV isolation may not always be necessary for elimination of AF, as in the early stages of paroxysmal AF. GP ablation alone, in these cases, may suffice for focal AF termination. In the persistent and long standing persistent forms the substrate for AF may be more extensive and therefore require GP ablation plus PV isolation and/or CFAE ablations. Clinical reports, both catheter based as well as minimally invasive surgical procedures, which include PVI plus GP ablation have shown relatively long-term success rates much closer to or equal to those achieved by myocardial ablation procedures in patients with WPW, AVNRT and AFL.

Inducibility of atrial and ventricular arrhythmias along the ligament of marshall: role of autonomic factors.

BACKGROUND: The mechanism(s) underlying atrial fibrillation (AF) initiation along the ligament of Marshall (LOM) remains controversial. OBJECTIVES: We sought to examine the role of the autonomic nervous system in arrhythmogenesis along the LOM. METHODS: In 31 anesthetized dogs, a left thoracotomy exposed the LOM. During atrial pacing, high-frequency stimulation (HFS: 200 Hz, 0.1 ms pulse width, 40 ms duration, 0.6-12 V) was delivered during atrial refractoriness to different sites of LOM (LOM(CS)= near coronary sinus; LOM(LIPV)= near left inferior pulmonary vein; LOM(LS-LIPV)= between LIPV and left superior pulmonary vein (LSPV); LOM(LSPV)= near LSPV). HFS was repeated after intravenous administration of esmolol (1 mg/kg; n = 9) or atropine (2 mg; n = 12). Norepinephrine (10(-7) M, 0.4 cc) was injected into LOM(LSPV) (n = 5). RESULTS: The median voltages for HFS to induce AF were 3.2 V, 3.2 V, 8.0 V*(,double dagger), and 12 V*(,double dagger) at LOM(CS), LOM(LIPV), LOM(LS-LIPV), and LOM(LSPV), respectively (*P < 0.01, compared with LOM(CS) and double dagger P < 0.01, compared with LOM(LIPV)). Esmolol or atropine markedly increased the threshold for AF induction. Ventricular tachycardias (VT) and accelerated junctional rhythm were induced in 8 of 12 and 6 of 12 dogs after atropine administration, respectively. Sustained VT occurred within minutes in 5 of 5 dogs receiving norepinephrine injection into the LOM(LSPV.) CONCLUSION: HFS induced AF along LOM with a gradient of stimulation thresholds from LOM(CS) (lowest) toward LOM(LSPV) (highest). This response was inhibited by esmolol or atropine. These data suggest an autonomic basis for AF initiation in LOM, and both sympathetic and parasympathetic neural elements play an important role in AF initiation. Hyperactivity of the sympathetic neural elements in LOM may be crucial in the initiation of ventricular tachyarrhythmias.

Antifibrillatory properties of mivacurium in a canine model of atrial fibrillation.

The electrophysiologic actions of the competitive neuromuscular blocker mivacurium (0.05-0.8 mg/kg IV; N = 10) and atropine sulfate [0.01-0.16 mg/Kg intravenously (IV), N = 6] were determined under control conditions, during right vagus nerve stimulation, and during anterior right ganglionated plexus stimulation. Both drugs suppressed shortening of right atrial monophasic action potential (MAP) duration, right atrial refractoriness, and right superior pulmonary vein sleeve refractoriness produced by vagus nerve or ganglionated plexus stimulation and suppressed the induction of atrial fibrillation. Suppression of atrial fibrillation by atropine was accompanied by improved sinus and atrioventricular (AV) nodal function, increasing the ventricular heart rate observed during sinus rhythm and atrial fibrillation and eliminating the depressant actions of vagus nerve stimulation on sinoatrial (SA) and AV nodal function. Unlike atropine, mivacurium selectively antagonized the effects of vagus nerve and ganglionated plexus stimulation on atrial and pulmonary vein sleeve myocardium (shortening of action potential duration/refractoriness and increased atrial vulnerability) without altering sinus or AV nodal function under control conditions or during vagus nerve stimulation. The selective inhibition of parasympathetic nervous system effects in atrium versus sinus and AV nodes by mivacurium may represent a selective mechanism for the suppression of atrial fibrillation without altering SA and AV nodal function.

Antifibrillatory actions of cisatracurium: an atrial specific M2 receptor antagonist.

INTRODUCTION: Muscarinic receptor antagonists are proposed to prevent atrial fibrillation (AF), but also facilitate AV conduction, limiting clinical usefulness. METHODS: Cisatracurium, a neuromuscular blocker, was administered to anesthetized dogs (0.05-0.8 mg/kg IV) and was administered to superfused pulmonary vein (PV) tissues in vitro. RESULTS: Dose-dependent suppression of AF induced by premature atrial stimuli was observed under control conditions (n = 3), right vagus nerve stimulation (n = 7), and anterior right ganglionated plexus stimulation (n = 3). AF was prevented (P < 0.0001) concurrent with suppression of the decreased atrial MAP duration/ERP accompanying vagus nerve stimulation without altering AH intervals or sinus cycle length. Although atropine (0.001-0.016 mg/kg, n = 4) suppressed AF (P < 0.04) in association with suppression of atrial MAP shortening induced by vagus nerve stimulation, atropine also prevented sinus cycle length and AH interval prolongation with vagus nerve stimulation, and decreased AV effective and functional refractory periods. In vitro, both cisatracurium and atropine prevented (1) action potential shortening produced by acetylcholine administration and (2) action potential shortening and arrhythmia triggering within PV sleeves produced by local autonomic nerve stimulation, atropine producing competitive inhibition, and cisatracurium producing noncompetitive M(2) muscarinic receptor blockade. CONCLUSIONS: Cisatracurium demonstrates a dose-dependent (1) suppression of AF and atrial action potential shortening accompanying vagus nerve stimulation without facilitating sinus or atrioventricular nodal function and (2) noncompetitive blockade of action potential shortening and triggered firing induced in isolated PVs by local autonomic nerve stimulation. The data are consistent with allosteric binding of cisatracurium to the M(2) muscarinic receptor in canine atrium.

An acute model for atrial fibrillation arising from a peripheral atrial site: evidence for primary and secondary triggers.

BACKGROUND: We previously demonstrated that acetylcholine (Ach) injected into cardiac ganglionated plexi (GP) causes pulmonary vein (PV) ectopy initiating atrial fibrillation (AF). OBJECTIVE: To determine the effects of Ach applied at non-PV sites. METHODS: Overall, 54 dogs were anesthetized with Na-pentobarbital. A right and left thoracotomy allowed the placement of multielectrode catheters to record from the superior PVs, mid portion of the atrium and the atrial appendages (AA). A monophasic action potential (MAP) was recorded from the AA. Ach (1, 10, 100 mM) was applied sequentially to the AA. RESULTS: In 19 of 26 animals, Ach 100 mM on the right (n = 15) or left (n = 4) AA induced focal, sustained AF (>or=10 minutes) with rapid regular firing (cycle length = 37 +/- 7 ms) at the AA. A clamp with teeth placed across the AA caused arrest in the AA. However, AF was sustained only when PV sites adjacent to the GP manifested complex fractionated atrial electrograms (CFAE). Clamping the AA prior to Ach (100 mM) application resulted in focal AF arising at the PVs but not at the AA. When a clamp without teeth was applied prior to Ach application, no AF at either AA or PV site could be induced. CONCLUSION: Isolation of the focal AF at the AA (primary trigger) by clamping caused cessation of activity in the AA, but AF continued due to secondary triggers arising from PVs. The possible mechanism(s) responsible for these findings are discussed, and various ancillary experiments (n = 28) were added to help elucidate mechanisms.

Proteasome inhibition 1 h following ischemia protects GRK2 and prevents malignant ventricular tachyarrhythmias and SCD in a model of myocardial infarction.

Arrhythmia-prone epicardial border zone (EBZ) tissues demonstrate decreased G protein-coupled receptor kinase-2 (GRK2) activity and increased sensitivity to isoproterenol 6-24 h after coronary artery ligation in the dog. We previously demonstrated that the ischemia-mediated decrease in GRK2 in cardiac ischemic tissue was largely blocked by proteasome blockade initiated 1 h before the onset of ischemia, and this was associated with significant cardioprotection against malignant ventricular tachyarrhythmias. For application to clinical circumstances, it is desirable to determine whether a clinical window exists following the onset of ischemia for such a protective effect. The treatment of six dogs with the selective proteasome inhibitor bortezomib 1 h after the surgical induction of left coronary artery ischemia provided 80% (EBZ) and 42% (infarct) protection (by immunoblot) against the loss of GRK2 at 24 h. There was no significant increase of heat shock protein 70(72) in the EBZ of bortezomib-treated animals compared with control. There was a striking absence of rapid (>300 beats/min) and very rapid (>360 beats/min) ventricular triplets that is highly predictive of sudden cardiac deaths (SCDs) during electrocardiogram monitoring of the first 24 h in the bortezomib-treated animals in contrast with nontreated infarcted animals. There were no SCDs in the 6 treated animals (0%) and five SCDs in the 14 control animals (36%). Assay of whole blood proteasome activity demonstrated the expected decrease over the 24-h observation period. These data support the concept that proteasome inhibition within a window of time following myocardial infarction may be of use in suppressing malignant tachyarrhythmias and SCD.

Autonomic mechanism to explain complex fractionated atrial electrograms (CFAE).

OBJECTIVE: To simulate complex fractionated atrial electrograms (CFAE) during sustained atrial fibrillation (AF) in experimental animals. BACKGROUND: The mechanism(s) underlying CFAE has not been fully elucidated. METHODS: Twenty-two dogs were subjected to a right and/or left thoracotomy. A gauze patch soaked with acetylcholine (ACh) was placed on the right atrial appendage (RAA) to induce sustained AF. During AF, varying concentrations of ACh (1, 10, 100 mM) were "painted" on the RA where electrograms showed regular organized activity. In another six dogs, anterior right ganglionated plexi (ARGP) near the sino-atrial node and inferior right GP (IRGP) at the junction of inferior vena cava and atria were sequentially ablated. In five dogs, ACh was injected into ARGP to induce CFAE. RESULTS: During sustained AF, local "painting" with ACh 1 mM and 10 mM induced intermittent CFAE in 1 of 11 and 10 of 11 dogs, respectively. With 100 mM ACh, all 11 showed CFAE (two intermittent, nine continuous). In six other dogs, continuous CFAE induced by topical application of 100 mM ACh were markedly attenuated by ARGP + IRGP ablation. In another five of five dogs, ACh injection into ARGP induced a gradient of CFAE with the continuous CFAE always occurring near the ARGP and CFAE also occurring at left pulmonary vein-atrial junctions. During ARGP ablation, AF was terminated in all five dogs immediately after regularization of the rotor-like electrograms or continuous CFAE. CONCLUSIONS: This study demonstrates an autonomic basis for CFAE formation, suggesting that graded hyperactive states of the autonomic nervous system (ANS) may induce various types of CFAE observed clinically.

Electrophysiologic actions of d,l-sotalol and GLG-V-13 in ischemically injured canine epicardium.

The electrophysiologic actions of the class III antiarrhythmic agents, GLG-V-13 and d,l-sotalol, were examined in superfused normal and ischemically injured epicardium. Both drugs produced concentration and reverse-use dependent prolongation of the action potential duration in normal myocardium without altering resting potential, action potential amplitude, or Vmax. Both drugs increased the slope of restitution curves in normal epicardium but prevented action potential alternans at short cycle lengths. The response of superfused ischemically injured left ventricular epicardium to drug 4 days after coronary artery ligation was determined by the extent of ischemic injury, with no electrophysiologic changes produced within epicardial cells characterized by prominent action potential shortening and no further action potential shortening with pacing. Cells demonstrating less severe injury (as evidenced by less severely depressed action potential amplitudes, Vmax, and action potential durations) retained a limited ability to respond to drug administration with action potential prolongation. A concentration-dependent, increased disparity of action potential duration was observed concurrent with the ability of single premature stimuli to induce monomorphic tachycardia. The present data demonstrate a variable response of ischemically injured canine epicardial cells to action potential prolongation with GLG-V-13 and d,l-sotalol, facilitating localized reentry in vitro, despite a failure of the same drugs to facilitate reentrant tachycardia in vivo.