Clinical outcomes and predictors of delayed echocardiographic response to cardiac resynchronization therapy.

INTRODUCTION: The clinical outcomes and mechanisms of delayed responses to cardiac resynchronization therapy (CRT) remain unclear. We aimed to investigate the differences in outcomes and gain insight into the mechanisms of early and delayed responses to CRT. METHODS: This retrospective study included 110 patients who underwent CRT implantation. Positive response to CRT was defined as ≥15% reduction of left ventricular (LV) end-systolic volume on echocardiography at 1 year (early phase) and 3 years (delayed phase) after implantation. The latest mechanical activation site (LMAS) of the LV was identified using two-dimensional speckle-tracking radial strain analysis. RESULTS: Seventy-eight (71%) patients exhibited an early response 1 year after CRT implantation. Of 32 non-responders in the early phase, 12 (38%) demonstrated a delayed response, and 20 (62%) were classified as non-responders after 3 years. During the follow-up time of 10.3 ± 0.5 years, the delayed and early responders had a similar prognosis of mortality and heart failure (HF) hospitalization. In contrast, non-responders had a worse prognosis. Multivariate analysis revealed that a longer duration (months) between initial HF hospitalization and CRT (odds ratio [OR]: 1.126; 95% confidence interval [CI]: 1.036-1.222; p = .005), non-exact concordance of LV lead location with LMAS (OR: 32.744; 95% CI: 1.101-973.518; p = .044), and pre-QRS duration (OR: 0.901; 95% CI: 0.827-0.981; p = .016) were independent predictors of delayed response to CRT compared with early response. CONCLUSION: The prognoses were similar regardless of the response time after CRT. A longer history of HF, suboptimal LV lead position, and shorter pre-QRS duration were related to delayed response than early response.

Comparison of novel intrinsic versus conventional antitachycardia pacing for ventricular tachycardia among implantable cardioverter-defibrillator recipients.

INTRODUCTION: Intrinsic antitachycardia pacing (iATP) is a novel automated antitachycardia pacing (ATP) that provides individual treatment to terminate ventricular tachycardia (VT). However, the clinical efficacy of iATP in comparison with conventional ATP is unknown. We aim to compare the termination rate of VT between iATP and conventional ATP in patients with implantable cardioverter-defibrillators using a unique setting of different sequential orders of both ATP algorisms. METHODS: Patients with the iATP algorithm were assigned to iATP-first and conventional ATP-first groups sequentially. In the iATP-first group, a maximum of seven iATP sequences were delivered, followed by conventional burst and ramp pacing. In contrast, in the conventional ATP-first group, two bursts and ramp pacing were initially programmed, followed by iATP sequences. We compared the success rates of VT termination in the first and secondary programmed ATP zones between the two groups. RESULTS: Fifty-eight and 56 patients were enrolled in the iATP-first and conventional ATP-first groups, and 67 and 44 VTs were analyzed in each group, respectively. At the first single ATP therapy, success rates were 64% and 70% in the iATP and conventional groups, respectively. At the end of the first iATP treatment zone, the success rate increased from 64% to 85%. Moreover, secondary iATP therapy following the failure of conventional ATPs increased the success rate from 80% to 93%. There was a significant benefit of alternative iATP for VT termination compared to secondary conventional ATP (100% vs. 33%, p = .028). CONCLUSIONS: iATP may be beneficial as a secondary therapy after failure of conventional ATP to terminate VT.

A Novel Liver Fibrosis Marker FIB-5 Index Predicted Response to Cardiac Resynchronization Therapy and Prognostic Outcomes in Patients With Heart Failure.

BACKGROUND: The fibrosis-5 (FIB-5) index is a noninvasive marker for assessing the progression of liver fibrosis and predictor in patients with heart failure (HF). This study investigated the association between the FIB-5 index and response to cardiac resynchronization therapy (CRT) and evaluated its predictive value for prognosis. METHODS: In total, 203 patients who underwent CRT/CRT-defibrillator (CRT-D) implantation were retrospectively included. The FIB-5 index was calculated using blood samples obtained before and after CRT/CRT-D. Response to CRT was defined as a relative reduction in left ventricular end-systolic volume of ≥15% 6 months after CRT/CRT-D. We compared the prognosis after CRT/CRT-D between the groups according to the FIB-5 index. RESULTS: One hundred and twenty-three patients (61%) responded to CRT. The responder group demonstrated a significantly higher FIB-5 index than the nonresponder group (-2.76 ± 3.85 vs. -4.67 ± 3.29, p < 0.001). Receiver-operating characteristic analysis demonstrated that the area under the curve of the FIB-5 index was 0.660 with a cutoff value of -4.00 for responders. In multivariate analysis, FIB-5 index ≥ -4.00 was an independent predictor for CRT response (odds ratio: 3.665, p = 0.003), in addition to QRS duration ≥ 150 ms and echocardiographic dysynchrony. The FIB-5 index increased significantly after 6 months in the responder group but not in the nonresponder group. The FIB-5 index ≥ -4.00 group showed a significantly better prognosis for cardiac death, HF hospitalization, and composite endpoint than the FIB-5 index < -4.00 group. CONCLUSION: The FIB-5 index in addition to classical predictors may be a useful marker for predicting response to CRT.

A novel practical algorithm using machine learning to differentiate outflow tract ventricular arrhythmia origins.

INTRODUCTION: Diagnosis of outflow tract ventricular arrhythmia (OTVA) localization by an electrocardiographic complex is key to successful catheter ablation for OTVA. However, diagnosing the origin of OTVA with a precordial transition in lead V3 (V3TZ) is challenging. This study aimed to create the best practical electrocardiogram algorithm to differentiate the left ventricular outflow tract (LVOT) from the right ventricular outflow tract (RVOT) of OTVA origin with V3TZ using machine learning. METHODS: Of 498 consecutive patients undergoing catheter ablation for OTVA, we included 104 patients who underwent ablation for OTVA with V3TZ and identified the origin of LVOT (n = 62) and RVOT (n = 42) from the results. We analyzed the standard 12-lead electrocardiogram preoperatively and measured 128 elements in each case. The study population was randomly divided into training group (70%) and testing group (30%), and decision tree analysis was performed using the measured elements as features. The performance of the algorithm created in the training group was verified in the testing group. RESULTS: Four measurements were identified as important features: the aVF/II R-wave ratio, the V2S/V3R index, the QRS amplitude in lead V3, and the R-wave deflection slope in lead V3. Among them, the aVF/II R-wave ratio and the V2S/V3R index had a particularly strong influence on the algorithm. The performance of this algorithm was extremely high, with an accuracy of 94.4%, precision of 91.5%, recall of 100%, and an F1-score of 0.96. CONCLUSIONS: The novel algorithm created using machine learning is useful in diagnosing the origin of OTVA with V3TZ.

A rare case of delayed complete lead dislodgement after deep septal pacing: A hidden risk of the specific procedure.

Deep septal ventricular pacing is a recently developed physiological pacing modality with good efficacy; however, it has a potential risk of unusual complications. Here, we report a patient with pacing failure and spontaneous, complete lead dislodgement after >2 years of deep septal pacing, possibly caused by systemic bacterial infection and specific lead behavior in the septal myocardium. This case report may implicate a hidden risk of unusual complications in deep septal pacing.

Mechanisms of torsades de pointes: an update.

Torsades de Pointes (TdP) refers to a polymorphic ventricular tachycardia (VT) with undulating QRS axis that occurs in long QT syndrome (LQTS), although the term has been used to describe polymorphic ventricular tachyarrhythmias in which QT intervals are not prolonged, such as short-coupled variant of TdP currently known as short-coupled ventricular fibrillation (VF) and Brugada syndrome. Extensive works on LQTS-related TdP over more than 50 years since it was first recognized by Dessertennes who coined the French term meaning "twisting of the points", have led to current understanding of the electrophysiological mechanism that TdP is initiated by triggered activity due to early afterdepolarization (EAD) and maintained by reentry within a substrate of inhomogeneous repolarization. While a recently emerging notion that steep voltage gradients rather than EADs are crucial to generate premature ventricular contractions provides additions to the initiation mode, the research to elucidate the maintenance mechanism hasn't made much progress. The reentrant activity that produces the specific form of VT is not well characterized. We have conducted optical mapping in a rabbit model of electrical storm by electrical remodeling (QT prolongation) due to chronic complete atrioventricular block and demonstrated that a tissue-island with prolonged refractoriness due to enhanced late Na+ current (INa-L) contributes to the generation of drifting rotors in a unique manner, which may explain the ECG characteristic of TdP. Moreover, we have proposed that the neural Na+ channel NaV1.8-mediated INa-L may be a new player to form the substrate for TdP. Here we discuss TdP mechanisms by comparing the findings in electrical storm rabbits with recently published studies by others in simulation models and human and animal models of LQTS.

Electrical storm: recent pathophysiological insights and therapeutic consequences.

The implantable cardioverter-defibrillator significantly improves survival in patients with malignant ventricular arrhythmias but does not target the underlying pathological substrate responsible for arrhythmic events. A significant proportion of defibrillator recipients experience multiple ventricular tachycardia/fibrillation episodes over a short period of time, termed electrical storm (ES). The current therapeutic strategy for ES is complex and unsatisfactory because simultaneous administration of several medications and additional invasive procedures are often required to control ES. Moreover, this treatment does not favorably influence the long-term outcome. Clearly, improved ES therapies are necessary and desirable, but a lack of understanding of the pathophysiological mechanisms underlying ES has hindered the development of more effective, rationally based therapeutic approaches. This paper reviews emerging experimental and clinical findings that provide insights into the pathophysiology of ES and discusses mechanism-based innovative therapeutic strategies.

Cystatin C as a predictor of mortality and cardiovascular morbidity after cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) has been reported to improve symptoms and cardiac performance in patients with severe heart failure (HF), but CRT recipients with advanced HF do not always experience improved mortality rates. Cystatin C has recently been involved in HF, but the association of serum cystatin C level with adverse events and long-term prognosis after CRT is unknown. This study investigated whether cystatin C level can predict mortality and cardiovascular events after CRT. METHODS AND RESULTS: A total of 117 consecutive patients receiving a CRT device for the treatment of advanced HF were assessed according to cystatin C level and long-term outcome after implantation of the device. Over a median follow-up of 3.2 years, 34 patients (29.1%) died and 59 patients (50.4%) developed cardiovascular events. Kaplan-Meier survival analysis indicated that elevated cystatin C level was significantly associated with higher all-cause mortality and prevalence of cardiovascular events, including hospitalization for progressive HF. After multivariate Cox regression analysis, serum cystatin C level and QRS duration, but not conventional echocardiographic parameters, were found to independently predict all-cause death or cardiovascular events. Of importance, only cystatin C level was an independent predictor of all-cause mortality after CRT. CONCLUSIONS: Cystatin C level independently predicts cardiac mortality or morbidity in patients receiving CRT. The assessment of cystatin C level could provide valuable information about long-term prognosis after CRT.

Different time course effect of autonomic nervous modulation after cryoballoon and hotballoon catheter ablations for paroxysmal atrial fibrillation.

BACKGROUND: Few studies have reported on the quantitative evaluation of autonomic nerve modification after balloon ablation. Therefore, this study aimed to evaluate the effects of cryoballoon and hotballoon ablations on the autonomic nervous system (ANS) and their relationship with prognosis. METHODS: We included 234 patients who underwent cryoballoon ablation (n = 190) or hotballoon ablation (n = 44) for paroxysmal atrial fibrillation. Heart rate variability (HRV) analysis was performed on all patients using a 3-min electrocardiogram at baseline, 1, 3, 6, and 12 months after ablation. HRV parameters and prognoses were compared between the two balloon systems. RESULTS: Ln low-frequency (LF), Ln high-frequency (HF), standard deviation of the R-R intervals (SDNN), and RR intervals significantly decreased after 1 month in both groups, but the changes were more pronounced in the cryoballoon group than in the hotballoon group. In contrast, HRV indices in the hotballoon ablation group decreased gradually and reached their lowest point 3-to-6 months after the procedure, which was later than in the cryoballoon ablation group. The recurrence rate did not differ between the two groups. HRV parameters changed similarly in the cryoballoon group, regardless of recurrence. However, patients with recurrence had significantly higher SDNN and Ln LF at 12 months than those without recurrence in the hotballoon group (41.2 ± 39.3 ms vs. 18.5 ± 12.6 ms, p = 0.006, and 2.2 ± 0.7 ms2 vs. 1.5 ± 0.7 ms2, p = 0.003, respectively). CONCLUSIONS: The time course of HRV changes differed between cryoballoon and hotballoon ablations. Hence, the two balloon systems may have distinct effects on the ANS and its role in prognosis.

Ca(2+)-related signaling and protein phosphorylation abnormalities play central roles in a new experimental model of electrical storm.

BACKGROUND: Electrical storm (ES), characterized by recurrent ventricular tachycardia/fibrillation, typically occurs in implantable cardioverter-defibrillator patients and adversely affects prognosis. However, the underlying molecular basis is poorly understood. In the present study, we report a new experimental model featuring repetitive episodes of implantable cardioverter-defibrillator firing for recurrent ventricular fibrillation (VF), in which we assessed involvement of Ca(2+)-related protein alterations in ES. METHODS AND RESULTS: We studied 37 rabbits with complete atrioventricular block for ≈80 days, all with implantable cardioverter-defibrillator implantation. All rabbits showed long-QT and VF episodes. Fifty-three percent of rabbits developed ES (≥3 VF episodes per 24-hour period; 103±23 VF episodes per rabbit). Expression/phosphorylation of Ca(2+)-handling proteins was assessed in left ventricular tissues from rabbits with the following: ES; VF episodes but not ES (non-ES); and controls. Left ventricular end-diastolic diameter increased comparably in ES and non-ES rabbits, but contractile dysfunction was significantly greater in ES than in non-ES rabbits. ES rabbits showed striking hyperphosphorylation of Ca(2+)/calmodulin-dependent protein kinase II, prominent phospholamban dephosphorylation, and increased protein phosphatase 1 and 2A expression versus control and non-ES rabbits. Ryanodine receptors were similarly hyperphosphorylated at Ser2815 in ES and non-ES rabbits, but ryanodine receptor Ser2809 and L-type Ca(2+) channel α-subunit hyperphosphorylation were significantly greater in ES versus non-ES rabbits. To examine direct effects of repeated VF/defibrillation, VF was induced 10 times in control rabbits. Repeated VF tissues showed autophosphorylated Ca(2+)/calmodulin-dependent protein kinase II upregulation and phospholamban dephosphorylation like those of ES rabbit hearts. Continuous infusion of a calmodulin antagonist (W-7) to ES rabbits reduced Ca(2+)/calmodulin-dependent protein kinase II hyperphosphorylation, suppressed ventricular tachycardia/fibrillation, and rescued left ventricular dysfunction. CONCLUSIONS: ES causes Ca(2+)/calmodulin-dependent protein kinase II activation and phospholamban dephosphorylation, which can explain the vicious cycle of arrhythmia promotion and mechanical dysfunction that characterizes ES.

Recent Insights Into Mechanisms and Clinical Approaches to Electrical Storm.

Electrical storm, characterized by repetitive ventricular tachycardia/ventricular fibrillation over a short period, is becoming more common with widespread use of implantable cardioverter defibrillator (ICD) therapy. Electrical storm, sometimes called "arrhythmic storm" or "ventricular tachycardia storm," is usually a medical emergency requiring hospitalization and expert management, and significantly affects short- and long-term outcomes. This syndrome typically occurs in patients with underlying structural heart disease (ischemic or nonischemic cardiomyopathy) or inherited channelopathies. Triggers for electrical storm should be sought but are often unidentifiable. Initial management is dictated by the hemodynamic status, whereas subsequent management typically involves ICD interrogation and reprogramming to reduce recurrent shocks, identification and management of triggers like electrolyte abnormalities, myocardial ischemia, or decompensated heart failure, and antiarrhythmic drug therapy or catheter ablation. Sympathetic nervous system activation is central to the initiation and maintenance of arrhythmic storm, so autonomic modulation is a cornerstone of management. Sympathetic inhibition can be achieved with medications (particularly ß-adrenoreceptor blockers), deep sedation, or cardiac sympathetic denervation. More definitive management targets the underlying ventricular arrhythmia substrate to terminate and prevent recurrent arrhythmia. Arrhythmia targeting can be achieved with antiarrhythmic medications, catheter ablation, or more novel therapies, such as stereotactic radiation therapy, that target the arrhythmic substrate. Mechanistic studies point to adrenergic activation and other direct consequences of ICD shocks in promoting further arrhythmogenesis and hypocontractility. In this report, we review the pathophysiologic mechanisms, clinical features, prognosis, and therapeutic options for electrical storm. We also outline a clinical approach to this challenging and complex condition, along with its mechanistic basis.

Rotors anchored by refractory islands drive torsades de pointes in an experimental model of electrical storm.

BACKGROUND: Electrical storm (ES) is a life-threatening emergency in patients at high risk of ventricular tachycardia/ventricular fibrillation (VF), but the pathophysiology and molecular basis are poorly understood. OBJECTIVE: The purpose of this study was to explore the electrophysiological substrate for experimental ES. METHODS: A model was created by inducing chronic complete atrioventricular block in defibrillator-implanted rabbits, which recapitulates QT prolongation, torsades des pointes (TdP), and VF episodes. RESULTS: Optical mapping revealed island-like regions with action potential duration (APD) prolongation in the left ventricle, leading to increased spatial APD dispersion, in rabbits with ES (defined as ≥3 VF episodes/24 h). The maximum APD and its dispersion correlated with the total number of VF episodes in vivo. TdP was initiated by an ectopic beat that failed to enter the island and formed a reentrant wave and perpetuated by rotors whose centers swirled in the periphery of the island. Epinephrine exacerbated the island by prolonging APD and enhancing APD dispersion, which was less evident after late Na+ current blockade with 10 µM ranolazine. Nonsustained ventricular tachycardia in a non-ES rabbit heart with homogeneous APD prolongation resulted from multiple foci with an electrocardiographic morphology different from TdP driven by drifting rotors in ES rabbit hearts. The neuronal Na+-channel subunit NaV1.8 was upregulated in ES rabbit left ventricular tissues and expressed within the myocardium corresponding to the island location in optically mapped ES rabbit hearts. The NaV1.8 blocker A-803467 (10 mg/kg, intravenously) attenuated QT prolongation and suppressed epinephrine-evoked TdP. CONCLUSION: A tissue island with enhanced refractoriness contributes to the generation of drifting rotors that underlies ES in this model. NaV1.8-mediated late Na+ current merits further investigation as a contributor to the substrate for ES.

Eicosapentaenoic acid prevents atrial fibrillation associated with heart failure in a rabbit model.

Atrial fibrillation (AF) is associated with morbidity and mortality of heart failure. Eicosapentaenoic acid (EPA), which is contained in fish oil, was shown to reduce the risk of cardiovascular diseases. We investigated the effects of EPA on AF associated with heart failure in a rabbit model. Rabbits were subjected to ventricular tachypacing (VTP) for 4 wk with or without EPA treatment. Continuous VTP induced heart failure status in these rabbits. The duration of AF (DAF) induced by burst pacing was analyzed by electrophysiological studies. VTP resulted in increased DAF following burst pacing. EPA treatment attenuated increased DAF. Atrial fibrosis increased in response to VTP, accompanied by extracellular signal-regulated kinase (ERK) phosphorylation and transforming growth factor-ß1 (TGF-ß1) expression in the atrium. Treatment with EPA attenuated atrial fibrosis, ERK phosphorylation, and TGF-ß1 expression in response to VTP. EPA treatment increased adiponectin as an anti-inflammatory adipokine and decreased tumor necrosis factor-α as a proinflammatory adipokine in the atrium and epicardial adipose tissues. EPA attenuated VTP-induced AF promotion and atrial remodeling, which was accompanied by modulating the profiles of adipokine production from epicardial adipose tissue. EPA may be useful for prevention and treatment of AF associated with heart failure.

Rate-dependent shortening of action potential duration increases ventricular vulnerability in failing rabbit heart.

Congestive heart failure (CHF) predisposes to ventricular fibrillation (VF) in association with electrical remodeling of the ventricle. However, much remains unknown about the rate-dependent electrophysiological properties in a failing heart. Action potential properties in the left ventricular subepicardial muscles during dynamic pacing were examined with optical mapping in pacing-induced CHF (n=18) and control (n=17) rabbit hearts perfused in vitro. Action potential durations (APDs) in CHF were significantly longer than those observed for controls at basic cycle lengths (BCLs)>1,000 ms but significantly shorter at BCLs<400 ms. Spatial APD dispersions were significantly increased in CHF versus control (by 17-81%), and conduction velocity was significantly decreased in CHF (by 6-20%). In both groups, high-frequency stimulation (BCLs<150 ms) always caused spatial APD alternans; spatially concordant alternans and spatially discordant alternans (SDA) were induced at 60% and 40% in control, respectively, whereas 18% and 82% in CHF. SDA in CHF caused wavebreaks followed by reentrant excitations, giving rise to VF. Incidence of ventricular tachycardia/VFs elicited by high-frequency dynamic pacing (BCLs<150 ms) was significantly higher in CHF versus control (93% vs. 20%). In CHF, left ventricular subepicardial muscles show significant APD shortenings at short BCLs favoring reentry formations following wavebreaks in association with SDA. High-frequency excitation itself may increase the vulnerability to VF in CHF.

Electrical storm and calcium signaling: a review.

Electrical storm (ES), characterized by recurrent ventricular tachycardia/fibrillation, is a serious condition, adversely affecting prognosis in patients with implantable cardioverter/defibrillators. Electrical storm patients often die of progressive heart failure, but the underlying molecular basis is poorly understood. We have recently created an animal model of ES that features repetitive implantable cardioverter/defibrillator firing for recurrent ventricular fibrillation and found that ES events cause striking activation of Ca(2+)/calmodulin-dependent protein kinase II and prominent alteration of Ca(2+)-handling protein phosphorylation, possibly explaining mechanical dysfunction and arrhythmia promotion that characterize ES. Here, the pathophysiology and potential therapeutic strategies for ES, based on experimental and clinical studies by us and others, are described.

Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long QT syndrome.

AIMS: Impaired repolarization in cardiac myocytes can lead to long QT syndrome (LQTS), with delayed repolarization and increased susceptibility to Torsades de Pointes (TdP) arrhythmias. Current pharmacological treatment of LQTS is often inadequate. This study sought to evaluate the antiarrhythmic effect of a novel compound (NS1643) that activates the rapid delayed-rectifier K+ current, I(Kr), in two rabbit models of acquired LQTS. METHODS AND RESULTS: We used two clinically relevant in vivo rabbit models of TdP in which we infused NS1643 or vehicle: (i) three-week atrioventricular block with ventricular bradypacing; (ii) dofetilide-induced I(Kr) inhibition in methoxamine-sensitized rabbits. In addition, we studied effects on ionic currents in cardiomyocytes with I(Kr) suppressed by bradycardia remodelling or dofetilide exposure. Bradypaced rabbits developed QT interval prolongation, spontaneous ventricular ectopy, and TdP. Infusion of NS1643 completely suppressed arrhythmic activity and shortened the QT interval; vehicle had no effect. NS1643 also suppressed ventricular tachyarrhythmias caused by infusion of dofetilide to methoxamine-sensitized rabbits, and reversed dofetilide-induced QT prolongation. NS1643 increased I(Kr) in cardiomyocytes isolated from normal and bradycardia-remodelled rabbits by approximately 75% and 50%, respectively (P < 0.001 for each). Similarly, NS1643 restored I(Kr) suppressed by 5 nmol/L dofetilide (tail current 0.28 +/- 0.03 pA/pF pre-dofetilide, 0.20 +/- 0.01 pA/pF in the presence of dofetilide, 0.27 +/- 0.02 pA/pF after adding NS1643 to dofetilide-containing solution, P < 0.01). CONCLUSION: Pharmacological activation of I(Kr) reverses acquired LQTS and TdP caused by bradycardic remodelling and I(Kr)-blocking drugs. I(Kr)-activating drug therapy could be a potentially interesting treatment approach for LQTS.

Pioglitazone, a peroxisome proliferator-activated receptor-gamma activator, attenuates atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure.

BACKGROUND: The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activator pioglitazone antagonizes angiotensin II actions and possesses anti-inflammatory and antioxidant properties in vitro. There is evidence that pioglitazone improves ventricular remodeling in some experimental models. OBJECTIVE: The purpose of this study was to assess the effects of pioglitazone on arrhythmogenic atrial structural remodeling versus the effects of the angiotensin II type 1 receptor blocker candesartan in a rabbit model of congestive heart failure. METHODS: Rabbits subjected to ventricular tachypacing at 380 to 400 bpm for 4 weeks in the absence and presence of treatment with pioglitazone, candesartan, and combined pioglitazone and candesartan were assessed by electrophysiologic study, atrial fibrosis measurements, and cytokine expression analyses. RESULTS: Atrial fibrillation (AF) lasting longer than 2 seconds was induced in no nonpaced controls but in all ventricular tachypacing-only rabbits (mean duration of AF: 8.0 +/- 1.4 seconds). Pioglitazone reduced the duration of AF (3.5 +/- 0.2 seconds, P <.05) and attenuated atrial structural remodeling, with significant reductions in interatrial activation time (50 +/- 2 ms vs 41 +/- 2 ms, P <.05) and atrial fibrosis (16.8% +/- 0.8% vs 10.9% +/- 0.7%, P <.05; control 1.6% +/- 0.2%), effects comparable to those of candesartan (duration of AF: 3.0 +/- 0.2 seconds; activation time 44 +/- 2 ms; fibrosis: 9.4% +/- 0.6%). Both pioglitazone and candesartan reduced transforming growth factor-beta1, tumor necrosis factor-alpha, and activated extracellular signal-regulated kinase expression similarly, but neither affected p38-kinase or c-Jun N-terminal kinase activation. The effects of combined pioglitazone and candesartan therapy were not significantly different from the effects of pioglitazone or candesartan alone. CONCLUSION: Pioglitazone can attenuate congestive heart failure-induced atrial structural remodeling and AF promotion, with effects similar to those of candesartan. PPAR-gamma may be a potential therapeutic target for human AF.