Yasuya Inden

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.

Smoking Cessation Rapidly Increases Circulating Progenitor Cells in Peripheral Blood in Chronic Smokers

Objective—Circulating endothelial progenitor cells (EPCs) contribute to postnatal angiogenesis. The number of circulating EPCs has an inverse correlation with coronary risk scores. However, the effect of smoking on the number of circulating EPCs is not well-known. Methods and Results—We examined the effects of chronic smoking and of smoking cessation on EPC levels. Circulating EPCs were quantified by flow cytometry as CD45lowCD34+CD133+ (progenitor cells [PCs]) or CD45lowCD34+CD133+VEGFR2+ (EPCs) in 14 nonsmokers and in 15 smokers. All smokers quit smoking. Eight quit smoking with nicotine patch and 7 without nicotine patch. PC/EPC levels were inversely correlated with the number of cigarettes smoked. Circulating PCs/EPCs increased rapidly after cessation (P < 0.0001) and decreased again after resumption of smoking to the level similar to that before cessation (P = 0.0031). The magnitude of increase in EPCs was greater in light smokers than in heavy smokers. Conclusions—The number of circulating PCs/EPCs was reduced in chronic smokers. Smoking cessation led to a rapid restoration of PC/EPC levels. The recovery of EPC levels was greater in light smokers than in heavy smokers. The decreased number of circulating EPCs would make smokers susceptible to cardiovascular disease, and even short-time cessation of smoking may be an effective means to reduce cardiovascular risk.

Sinoatrial Node Dysfunction and Early Unexpected Death of Mice With a Defect of klotho Gene Expression

Background—Homozygous mutant mice with a defect of klotho gene expression (kl/kl) show multiple age-related disorders and premature death from unknown causes. Methods and Results—The kl/kl mice subjected to 20-hour restraint stress showed a high rate (20/30) of sudden death, which was associated with sinoatrial node dysfunction (conduction block or arrest). Heart rate and plasma norepinephrine of kl/kl mice, unlike those of wild-type (WT) mice, failed to increase during the stress. Intrinsic heart rate after pharmacological blockade of autonomic nerves in kl/kl mice was significantly lower than that in WT mice (380±33 versus 470±44 bpm; n=7). The sinus node recovery time after an overdrive pacing (600 bpm, 30 seconds) in kl/kl mice was significantly longer than in WT mice (392±37 versus 233±24 ms; n=6). In isolated sinoatrial node preparations, the positive chronotropic effect of isoproterenol was significantly less, whereas the negative chronotropic effect of acetylcholine was significantly greater in kl/kl than in WT mice. There was no degenerative structural change in the sinoatrial node of kl/kl mice. The precise localization of klotho was analyzed in newly prepared klotho-null mice with a reporter gene system (kl−geo). Homozygous kl− geo mice showed characteristic age-associated phenotypes that were almost identical to those of kl/kl mice. In the kl− geo mice, klotho expression was recognized exclusively in the sinoatrial node region in the heart in addition to parathyroid, kidney, and choroid plexus. Conclusions—In the heart, klotho is expressed solely at the sinoatrial node. klotho gene expression is essential for the sinoatrial node to function as a dependable pacemaker under conditions of stress.

Idiopathic ventricular arrhythmias originating from the aortic root prevalence, electrocardiographic and electrophysiologic characteristics, and results of radiofrequency catheter ablation.

OBJECTIVES This study investigated the prevalence and electrocardiographic and electrophysiologic characteristics of aortic root ventricular arrhythmias (VAs). BACKGROUND Idiopathic VAs originating from the ostium of the left ventricle may be ablated at the base of the aortic cusps. METHODS We studied 265 patients with idiopathic VAs with an inferior QRS-axis morphology. RESULTS The successful ablation site was within (or below) the aortic cusps in 44 patients (16.6%). The site of the origin was the left coronary cusp (LCC) in 24 (54.5%), the right coronary cusp (RCC) in 14 (31.8%), the noncoronary cusp (NCC) in 1 (2.3%), and at the junction between the LCC and RCC (L-RCC) in 5 (11.4%) cases. The maximum amplitude of the R-wave in the inferior leads was significantly greater with an LCC than with an RCC origin (p < 0.05). The ratio of the R-wave amplitude in leads II and III was significantly greater with an LCC than with an RCC origin (p < 0.01) and was significantly smaller in the NCC than in the other sites (p < 0.0001). The ventricular deflection in the His bundle electrogram was significantly later relative to the surface QRS with an LCC or L-RCC origin than with an RCC or NCC origin (p < 0.0001). The ratio of the atrial-to-ventricular deflection amplitude was significantly greater in the NCC than in the other sites (p < 0.0001). No other factors predicted the site of origin. CONCLUSIONS Idiopathic VAs are more common in the LCC than in the RCC and rarely arise from the NCC. The electrocardiogram is useful for differentiating the site of origin.

Idiopathic Ventricular Arrhythmias Originating From the Left Ventricular Summit Anatomic Concepts Relevant to Ablation

Background—The summit of the left ventricle (LV) is the most superior portion of the epicardial LV bounded by an arc from the left anterior descending coronary artery, superior to the first septal perforating branch to the left circumflex coronary artery. Ventricular arrhythmias (VAs) originating from this region may present challenges for catheter ablation. Methods and Results—We studied 27 consecutive patients with VAs originating from the LV summit. The great cardiac vein (GCV) divides this region between an inferior area accessible to ablation and a superior, inaccessible area. Successful ablation was achieved within the GCV in 14 patients and on the epicardial surface in 4. Ventricular prepotentials were recorded at the successful ablation site in 80% of these patients. In 5 patients, ablation was abandoned because of inaccessibility of the catheter to the myocardium or high impedance with radiofrequency application within the GCV. In the remaining 4 patients, epicardial mapping suggested VA origins in a region of low voltage that was located superior to the GCV (inaccessible area), and ablation was abandoned because of close proximity to the coronary arteries or high impedance. A right bundle-branch block, transition zone, R-wave amplitude ratio in leads III to II, Q-wave amplitude ratio in leads aVL to aVR, and S waves in lead V6 accurately predicted the site of origin. Conclusions—LV summit VAs may be ablated within the GCV or inferior to the GCV on the epicardial surface, though sites superior to the GCV are usually inaccessible to ablation.

Increased Expression of Plasminogen Activator Inhibitor-1 in Cardiomyocytes Contributes to Cardiac Fibrosis after Myocardial Infarction

Plasminogen activator inhibitor-1 (PAI-1) plays a critical role in tissue fibrosis by inactivating matrix metalloproteinases, which might effect on the progression of left ventricular dysfunction. However, little has been known about the expression of PAI-1 during cardiac remodeling. We used a mouse model of myocardial infarction (MI) by coronary ligation, in which the progression of left ventricular remodeling was confirmed by echocardiography. Histological examination showed that interstitial and perivascular fibrosis progressed in the post-MI (PMI) heart at 4 weeks after the procedure. We observed the dramatic induction of cardiac PAI-1 mRNA and PAI-1 antigen in plasma in the PMI mice, as compared with the sham-operated (sham) mice. In situ hybridization analysis demonstrated that strong signals for PAI-1 mRNA were localized to cardiomyocytes in the border of infarct area and around fibrous lesions, and to perivascular mononuclear cells, which seemed to be mast cells, only in hearts of the PMI mice. Importantly, less development of cardiac fibrosis after MI was observed in mice deficient in PAI-1 as compared to wild-type mice. The mRNA expression of cytokines, transforming growth factor-beta, and tumor necrosis factor-alpha, was also increased in hearts of the PMI mice, but not in the sham mice. These observations suggest that cardiomyocytes and mast cells contribute to the increased PAI-1 expression, resulting in the development of interstitial and perivascular fibrosis in the PMI heart, and that the regional induction of cytokines may be involved in this process.

Electrocardiographic and Electrophysiological Characteristics in Idiopathic Ventricular Arrhythmias Originating From the Papillary Muscles in the Left Ventricle Relevance for Catheter Ablation

Background—Idiopathic ventricular arrhythmias (VAs) can originate from the left ventricular papillary muscles (PAMs). This study investigated the electrophysiological characteristics of these VAs and their relevance for the results of catheter ablation. Methods and Results—We studied 19 patients who underwent successful catheter ablation of idiopathic VAs originating from the anterior (n=7) and posterior PAMs (n=12). Although an excellent pace map was obtained at the first ablation site in 17 patients, radiofrequency ablation at that site failed to eliminate the VAs, and radiofrequency lesions in a relatively wide area around that site were required to completely eliminate the VAs in all patients. Radiofrequency current with an irrigated or nonirrigated 8-mm-tip ablation catheter was required to achieve a lasting ablation of the PAM VA origins. During 42% of the PAM VAs, a sharp ventricular prepotential was recorded at the successful ablation site. In 9 (47%) patients, PAM VAs exhibited multiple QRS morphologies, with subtle, but distinguishable differences occurring spontaneously and after the ablation. In 7 (78%) of those patients, radiofrequency lesions on both sides of the PAMs where pacing could reproduce an excellent match to the 2 different QRS morphologies of the VAs were required to completely eliminate the VAs. Conclusions—Radiofrequency catheter ablation of idiopathic PAM VAs is challenging probably because the VA origin is located relatively deep beneath the endocardium of the PAMs. PAM VAs often exhibit multiple QRS morphologies, which may be caused by a single origin with preferential conduction resulting from the complex structure of the PAMs.

Ionic Mechanisms of Acquired QT Prolongation and Torsades de Pointes in Rabbits With Chronic Complete Atrioventricular Block

Background—The ionic basis of acquired QT prolongation and torsade de pointes (TdP) unrelated to drugs is not fully understood. Methods and Results—We created a rabbit model with chronic complete atrioventricular block (AVB) (n=34), which showed prominent QT prolongation (by 120%), high incidence of spontaneous TdP (71%), and cardiac hypertrophy. Patch-clamp experiments were performed in left ventricular myocytes from 9 rabbits (8 with TdP, 1 without TdP) at ≈21 days of AVB and from 8 sham-operated controls with sinus rhythm. Action potential duration was prolonged in AVB myocytes compared with control (+61% at 0.5 Hz, +21% at 3 Hz). Both rapidly and slowly activating components of the delayed rectifier K+ current (IKr and IKs) in AVB myocytes were significantly smaller than in control by 50% and 55%, respectively. There was no significant difference in Ca2+-independent transient outward current (Ito1). L-type Ca2+ current (ICa,L) in control and AVB myocytes was similar in peak amplitude, but the half voltage for activation was shifted to the negative direction (5.9 mV) in AVB myocytes. Voltage dependence of ICa,L inactivation was not different in control and AVB myocytes. The inward rectifier K+ current (IK1) significantly increased in AVB myocytes compared with control. Conclusions—In the rabbit, chronic AVB leads to prominent QT prolongation and high incidence of spontaneous TdP. Downregulation of both IKr and IKs in association with altered ICa,L activation kinetics may underlie the arrhythmogenic ventricular remodeling.

Idiopathic Ventricular Arrhythmias Originating from the Papillary Muscles in the Left Ventricle: Prevalence, Electrocardiographic and Electrophysiological Characteristics, and Results of the Radiofrequency Catheter Ablation

Idiopathic VAs Originating from the LV Papillary Muscles. Introduction: Idiopathic ventricular arrhythmias (VAs) can originate from the left ventricular (LV) papillary muscles (PAMs). This study investigated the prevalence, electrocardiographic and electrophysiological characteristics, and results of catheter ablation of these VAs, and compared them with other LV VAs.

Reactive oxidative metabolites are associated with atrial conduction disturbance in patients with atrial fibrillation

BACKGROUND Oxidative stress is associated with atrial fibrillation (AF). However, little is known about the relationship between serum markers of oxidation and electrical activity in patients with AF. OBJECTIVE The purpose of this study was to investigate the possible association between serum markers of reactive oxidative metabolism and atrial remodeling in paroxysmal and persistent AF. METHODS Derivatives of reactive oxidative metabolites (DROM), an index of oxidative stress, were measured in 306 consecutive patients with AF (225 paroxysmal, 81 persistent) undergoing radiofrequency (RF) catheter ablation. Filtered P-wave duration by P-wave signal-averaged ECG and levels of high-sensitivity C-reactive protein (CRP) as an inflammatory marker also were measured. RESULTS Patients were followed up for 1.2 +/- 0.8 years. DROM levels in patients with persistent AF were significantly higher than in patients with paroxysmal AF (341.6 +/- 85.5 Carratelli [Carr] units vs 305.0 +/- 77.7 Carr units, P <.001). DROM levels showed a tighter, positive correlation with filtered P-wave duration in persistent AF patients (r = 0.56, P <.001) than in all AF patients (r = 0.13, P <.05). DROM levels also showed a weaker but significant correlation with high-sensitivity CRP in patients with AF. Kaplan-Meier analysis revealed that the highest quartile of basal DROM levels exhibited a significantly higher AF recurrence rate after RF catheter ablation in patients with paroxysmal AF (P <.01). CONCLUSION Serum markers of oxidative stress reflect atrial conduction disturbance and predict AF recurrence after RF catheter ablation in paroxysmal AF patients. DROM could serve as a biomarker for predicting risk of AF recurrence after RF catheter ablation.