Akiko Shiroshita-Takeshita

Effect of Simvastatin and Antioxidant Vitamins on Atrial Fibrillation Promotion by Atrial-Tachycardia Remodeling in Dogs

Background—There is evidence for a role of oxidant stress and inflammation in atrial fibrillation (AF). Statins have both antioxidant and antiinflammatory properties. We compared the effects of simvastatin with those of antioxidant vitamins on AF promotion by atrial tachycardia in dogs. Methods and Results—We studied dogs subjected to atrial tachypacing (ATP) at 400 bpm in the absence and presence of treatment with simvastatin, vitamin C, and combined vitamins C and E. Serial closed-chest electrophysiological studies were performed in each dog at baseline and 2, 4, and 7 days after tachypacing onset. Atrioventricular block was performed to control ventricular rate. Mean duration of induced AF was increased from 42±18 to 1079±341 seconds at terminal open-chest study after tachypacing alone (P<0.01), and atrial effective refractory period (ERP) at a cycle length of 300 ms was decreased from 117±5 to 76±6 ms (P<0.01). Tachypacing-induced ERP shortening and AF promotion were unaffected by vitamin C or vitamins C and E; however, simvastatin suppressed tachypacing-induced remodeling effects significantly, with AF duration and ERP averaging 41±15 seconds and 103±4 ms, respectively, after tachypacing with simvastatin therapy. Tachypacing downregulated L-type Ca2+-channel &agr;-subunit expression (Western blot), an effect that was unaltered by antioxidant vitamins but greatly attenuated by simvastatin. Conclusions—Simvastatin attenuates AF promotion by atrial tachycardia in dogs, an effect not shared by antioxidant vitamins, and constitutes a potentially interesting new pharmacological approach to preventing the consequences of atrial tachycardia remodeling.

Pulmonary Vein Region Ablation in Experimental Vagal Atrial Fibrillation Role of Pulmonary Veins Versus Autonomic Ganglia

Background— Pulmonary vein (PV) –encircling radiofrequency ablation frequently is effective in vagal atrial fibrillation (AF), and there is evidence that PVs may be particularly prone to cholinergically induced arrhythmia mechanisms. However, PV ablation procedures also can affect intracardiac autonomic ganglia. The present study examined the relative role of PVs versus peri-PV autonomic ganglia in an experimental vagal AF model. Methods and Results— Cholinergic AF was studied under carbachol infusion in coronary perfused canine left atrial PV preparations in vitro and with cervical vagal stimulation in vivo. Carbachol caused dose-dependent AF promotion in vitro, which was not affected by excision of all PVs. Sustained AF could be induced easily in all dogs during vagal nerve stimulation in vivo both before and after isolation of all PVs with encircling lesions created by a bipolar radiofrequency ablation clamp device. PV elimination had no effect on atrial effective refractory period or its responses to cholinergic stimulation. Autonomic ganglia were identified by bradycardic and/or tachycardic responses to high-frequency subthreshold local stimulation. Ablation of the autonomic ganglia overlying all PV ostia suppressed the effective refractory period–abbreviating and AF-promoting effects of cervical vagal stimulation, whereas ablation of only left- or right-sided PV ostial ganglia failed to suppress AF. Dominant-frequency analysis suggested that the success of ablation in suppressing vagal AF depended on the elimination of high-frequency driver regions. Conclusions— Intact PVs are not needed for maintenance of experimental cholinergic AF. Ablation of the autonomic ganglia at the base of the PVs suppresses vagal responses and may contribute to the effectiveness of PV-directed ablation procedures in vagal AF.

Effects of Antiarrhythmic Drugs on Fibrillation in the Remodeled Atrium Insights Into the Mechanism of the Superior Efficacy of Amiodarone

Background—The basis of the unique effectiveness of amiodarone for atrial fibrillation (AF) is poorly understood. The present study tested the hypothesis that amiodarone blocks electrical remodeling induced by atrial tachycardia. Methods and Results—Mongrel dogs were subjected to atrial tachycardia (400 bpm for 7 days) in the absence and presence of therapy with amiodarone, the class III cardiac antiarrhythmic drug dofetilide, or the class I agent flecainide begun 3 days before the onset of tachypacing and maintained until a final electrophysiological study. AF vulnerability (percentage of sites with AF induction by single premature extrastimuli), mean AF duration, atrial effective refractory period (ERP), and conduction velocity were compared among these dogs and in unpaced dogs in the absence or presence of treatment with the same agents. Only amiodarone prevented promotion of AF duration and vulnerability by atrial tachycardia. Furthermore, only amiodarone eliminated tachycardia-induced ERP abbreviation and loss of ERP rate adaptation while obviating L-type Ca2+-current &agr;1c-subunit downregulation as determined by Western blot. In an additional series of dogs monitored with repeated electrophysiological studies, amiodarone administered after the induction of atrial tachycardia remodeling reversed remodeling within several days, despite continued atrial tachypacing during amiodarone therapy. Conclusions—Amiodarone is uniquely effective against AF promotion by atrial tachycardia remodeling in this experimental model and prevents electrophysiological and biochemical consequences of remodeling. Amiodarone also reversed remodeling established by 4 days of atrial tachycardia. The inhibition of atrial tachycardia remodeling may therefore contribute to the superior efficacy of amiodarone in AF.

Omega-3 Polyunsaturated Fatty Acids Prevent Atrial Fibrillation Associated With Heart Failure but Not Atrial Tachycardia Remodeling

Background— There is epidemiological evidence that omega-3 polyunsaturated fatty acids (PUFAs) reduce the risk of atrial fibrillation (AF), but clinical data are conflicting. The present study assessed the effects of PUFA on AF in experimental models. Methods and Results— We studied the effects of oral PUFA supplements in 2 experimental AF paradigms: electrical remodeling induced by atrial tachypacing (400 bpm for 1 week) and congestive heart failure–associated structural remodeling induced by ventricular tachypacing (240 bpm for 2 weeks). PUFA pretreatment did not directly change atrial effective refractory period (128±6 [mean±SEM] versus 127±2 ms; all effective refractory periods at 300-ms cycle lengths) or burst pacing–induced AF duration (5±4 versus 34±18 seconds). Atrial tachypacing dogs had shorter refractory periods (73±6 ms) and greater AF duration (1185±300 seconds) than shams (119±5 ms and 20±11 seconds; P<0.01 for each). PUFAs did not significantly alter atrial tachypacing effects on refractory periods (77±8 ms) or AF duration (1128±412 seconds). PUFAs suppressed ventricular tachypacing–induced increases in AF duration (952±221 versus 318±249 seconds; P<0.05) and attenuated congestive heart failure–related atrial fibrosis (from 19.2±1.1% to 5.8±1.0%; P<0.001) and conduction abnormalities. PUFAs also attenuated ventricular tachypacing–induced hemodynamic dysfunction (eg, left ventricular end-diastolic and left atrial pressure from 12.2±0.5 and 11.4±0.6 mm Hg, respectively, to 6.4±0.5 and 7.0±0.8 mm Hg; P<0.01) and phosphorylation of mitogen-activated protein kinases (extracellular-signal related and P38 kinase). Conclusions— PUFAs suppress congestive heart failure–induced atrial structural remodeling and AF promotion but do not affect atrial tachycardia–induced electrical remodeling. The beneficial effects of PUFAs on structural remodeling, possibly related to prevention of mitogen-activated protein kinase activation, may contribute to their clinical anti-AF potential.

Model-Dependent Effects of the Gap Junction Conduction–Enhancing Antiarrhythmic Peptide Rotigaptide (ZP123) on Experimental Atrial Fibrillation in Dogs

Background— Abnormal intercellular communication caused by connexin dysfunction may be involved in atrial fibrillation (AF). The present study assessed the effect of the gap junctional conduction–enhancing peptide rotigaptide on AF maintenance in substrates that result from congestive heart failure induced by 2-week ventricular tachypacing (240 bpm), atrial tachypacing (ATP; 400 bpm for 3 to 6 weeks), and isolated atrial myocardial ischemia. Methods and Results— Electrophysiological study and epicardial mapping were performed before and after rotigaptide administration in dogs with ATP and congestive heart failure, as well as in similarly instrumented sham dogs that were not tachypaced. For atrial myocardial ischemia, dogs administered rotigaptide before myocardial ischemia were compared with no-drug myocardial ischemia controls. ATP significantly shortened the atrial effective refractory period (P=0.003) and increased AF duration (P=0.008), with AF lasting >3 hours in all 6-week ATP animals. Rotigaptide increased conduction velocity in ATP dogs slightly but significantly (P=0.04) and did not affect the effective refractory period, AF duration, or atrial vulnerability. In dogs with congestive heart failure, rotigaptide also slightly increased conduction velocity (P=0.046) but failed to prevent AF promotion. Rotigaptide had no statistically significant effects in sham dogs. Myocardial ischemia alone increased AF duration and impaired conduction (based on conduction velocity across the ischemic border and indices of conduction heterogeneity). Rotigaptide prevented myocardial ischemia–induced conduction slowing and AF duration increases. Conclusions— Rotigaptide improves conduction in various AF models but suppresses AF only for the acute ischemia substrate. These results define the atrial antiarrhythmic profile of a mechanistically novel antiarrhythmic drug and suggest that gap junction dysfunction may be more important in ischemic AF than in ATP remodeling or congestive heart failure substrates.

Induction of Heat Shock Response Protects the Heart Against Atrial Fibrillation

There is evidence suggesting that heat shock proteins (HSPs) may protect against clinical atrial fibrillation (AF). We evaluated the effect of HSP induction in an in vitro atrial cell line (HL-1) model of tachycardia remodeling and in tachypaced isolated canine atrial cardiomyocytes. We also evaluated the effect of HSP induction on in vivo AF promotion by atrial tachycardia–induced remodeling in dogs. Tachypacing (3 Hz) significantly and progressively reduced Ca2+ transients and cell shortening of HL-1 myocytes over 4 hours. These reductions were prevented by HSP-inducing pretreatments: mild heat shock, geranylgeranylacetone (GGA), and transfection with human HSP27 or the phosphorylation-mimicking HSP27-DDD. However, treatment with HSP70 or the phosphorylation-deficient mutant HSP27-AAA failed to alter tachycardia-induced Ca2+ transient and cell-shortening reductions, and downregulation (short interfering RNA) of HSP27 prevented GGA-mediated protection. Tachypacing (3 Hz) for 24 hours in vitro significantly reduced L-type Ca2+ current and action potential duration in canine atrial cardiomyocytes; these effects were prevented when tachypacing was performed in cells exposed to GGA. In vivo treatment with GGA increased HSP expression and suppressed refractoriness abbreviation and AF promotion in dogs subjected to 1-week atrial tachycardia–induced remodeling. In conclusion, our findings indicate that (1) HSP induction protects against atrial tachycardia–induced remodeling, (2) the protective effect in HL-1 myocytes requires HSP27 induction and phosphorylation, and (3) the orally administered HSP inducer GGA protects against AF in a clinically relevant animal model. These findings advance our understanding of the biochemical determinants of AF and suggest the possibility that HSP induction may be an interesting novel approach to preventing clinical AF.

Atrial fibrillation: Basic mechanisms, remodeling and triggers

Atrial fibrillation (AF) is the most common and troublesome arrhythmia in clinical practice and is a significant contributor to cardiovascular morbidity and possibly mortality [1,2]. Although AF can clearly occur in patients without evident heart disease (so-called lone AF), organic heart diseases, such as congestive heart failure (CHF), mitral valve disease, and coronary artery disease, are major co-existing conditions that contribute to the occurrence and persistence of AF. The mechanisms by which these cardiac conditions favor the occurrence of AF are interesting and may help in designing more effective therapeutic approaches. Despite the fact that the pathophysiology of AF has been investigated extensively for almost a century, the underlying mechanisms remain incompletely understood [3]. Classical mechanisms of AF first described in the early 20th century [3] still form the framework for our understanding of its pathophysiology. However, numerous studies performed over the past 10 years have given us more detailed insights into the pathogenesis of clinically-relevant AF. This article reviews the contributions of some of this recent work to our understanding of electrophysiological, ionic and molecular mechanisms of AF and of its clinical pathophysiology and management.

Mechanisms of atrial fibrillation termination by rapidly unbinding Na+ channel blockers: insights from mathematical models and experimental correlates

Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is a problem of growing proportions. Recent studies have increased interest in fast-unbinding Na(+) channel blockers like vernakalant (RSD1235) and ranolazine for AF therapy, but the mechanism of efficacy is poorly understood. To study how fast-unbinding I(Na) blockers affect AF, we developed realistic mathematical models of state-dependent Na(+) channel block, using a lidocaine model as a prototype, and studied the effects on simulated cholinergic AF in two- and three-dimensional atrial substrates. We then compared the results with in vivo effects of lidocaine on vagotonic AF in dogs. Lidocaine action was modeled with the Hondeghem-Katzung modulated-receptor theory and maximum affinity for activated Na(+) channels. Lidocaine produced frequency-dependent Na(+) channel blocking and conduction slowing effects and terminated AF in both two- and three-dimensional models with concentration-dependent efficacy (maximum approximately 89% at 60 microM). AF termination was not related to increases in wavelength, which tended to decrease with the drug, but rather to decreased source Na(+) current in the face of large ACh-sensitive K(+) current-related sinks, leading to the destabilization of primary generator rotors and a great reduction in wavebreak, which caused primary rotor annihilations in the absence of secondary rotors to resume generator activity. Lidocaine also reduced the variability and maximum values of the dominant frequency distribution during AF. Qualitatively similar results were obtained in vivo for lidocaine effects on vagal AF in dogs, with an efficacy of 86% at 2 mg/kg iv, as well as with simulations using the guarded-receptor model of lidocaine action. These results provide new insights into the mechanisms by which rapidly unbinding class I antiarrhythmic agents, a class including several novel compounds of considerable promise, terminate AF.

Heat shock proteins as molecular targets for intervention in atrial fibrillation

Atrial fibrillation (AF) is the most common sustained clinical tachyarrhythmia. AF is a progressive condition as demonstrated by the finding that maintenance of normal rhythm and contractile function becomes more difficult the longer AF exists. AF causes cellular stress, which induces atrial remodelling, involving reduction in the expression of L-type Ca(2+) channels and structural changes (myolysis), finally resulting in contractile dysfunction. Heat shock proteins (HSPs) comprise a family of proteins involved in the protection against different forms of cellular stress. Their classical function is the prevention of toxic protein aggregation by binding to (partially) unfolded proteins. Recent investigations reveal that HSPs prevent atrial remodelling and attenuate the promotion of AF in both cellular and animal experimental models. Furthermore, studies in humans suggest a protective role for HSPs against progression from paroxysmal AF to chronic, persistent AF. Therefore, manipulation of the HSP system may offer novel therapeutic approaches for the prevention of atrial remodelling. Such approaches may contribute to the maintenance or restoration of tissue integrity and contractile function. Ultimately, this concept may offer an additional treatment strategy to delay progression towards chronic AF and/or improve the outcome of cardioversion.

Effects of a heat shock protein inducer on the atrial fibrillation substrate caused by acute atrial ischaemia

AIMS Heat shock proteins (HSPs) are a set of endogenous cytoprotective factors activated by various pathological conditions. This study addressed the effects of geranylgeranylacetone (GGA), an orally active HSP inducer, on the atrial fibrillation (AF) substrate associated with acute atrial ischaemia (AI). METHODS AND RESULTS Four groups of mongrel dogs were studied: (1) a group subjected to AI without GGA (AI-CTL, n = 13 dogs); (2) dogs that underwent AI after GGA pretreatment (120 mg/kg/day; AI-GGA, n = 12); (3) dogs receiving GGA pretreatment without AI (n = 5); (4) control dogs for tissue sampling (n = 5). Isolated right AI was produced by occluding a right atrial (RA) coronary-artery branch. AI reduced ischaemic-zone conduction velocity (CV, from 94 +/- 3 to 46 +/- 5 cm/s; P < 0.01) and increased maximum local phase delays (P95, from 1.6 +/- 0.1 to 4.6 +/- 0.6 ms/mm; P < 0.01), conduction heterogeneity index (CHI, from 0.7 +/- 0.1 to 2.9 +/- 0.5; P < 0.01), and the mean duration of burst pacing-induced AF (DAF, from 44 +/- 18 to 890 +/- 323 s; P < 0.01) in AI-CTL dogs. GGA pretreatment attenuated ischaemia-induced conduction abnormalities (CV, 77 +/- 8 cm/s; P95, 2.1 +/- 0.4 ms/mm; CHI, 1.1 +/- 0.2; all P < 0.01 vs. AI-CTL) and DAF (328 +/- 249 s; P < 0.01) in AI-GGA dogs. GGA treatment alone, without ischaemia, did not alter DAF or conduction indices. AI slightly prolonged atrial refractory period, an effect also prevented by GGA. GGA significantly increased HSP70 protein expression in RA tissues of ischaemic hearts. CONCLUSIONS GGA prevents ischaemia-induced atrial conduction abnormalities and suppresses ischaemia-related AF. These results suggest that HSP induction might be a useful new anti-AF intervention for patients with coronary artery disease.