Osamu Wakisaka

Pioglitazone attenuates inflammatory atrial fibrosis and vulnerability to atrial fibrillation induced by pressure overload in rats

BACKGROUND Inflammatory processes are involved in the pathogenesis of atrial fibrillation (AF). OBJECTIVE The purpose of this study was to test the hypothesis that atrial fibrosis and enhanced vulnerability to AF evoked by pressure overload can be attenuated by pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, via suppression of inflammatory profibrotic signals. METHODS Male Sprague-Dawley rats were subjected to abdominal aortic constriction (AAC). Pioglitazone 3 mg/kg/day or vehicle was orally administered for 4 weeks. RESULTS Western blot analysis revealed that AAC enhanced expression of monocyte chemoattractant protein (MCP)-1, transforming growth factor-β1 and α-smooth muscle actin in the left atrium (LA), which was suppressed by pioglitazone. Messenger RNA expression of collagen type 1 and atrial natriuretic peptide in the LA was increased by AAC, which was suppressed by pioglitazone. Gelatin zymography demonstrated that activity of matrix metalloproteinase-9 was increased by AAC, which was suppressed by pioglitazone. Pioglitazone attenuated AAC-induced LA fibrosis. In isolated-perfused heart experiments, AAC did not alter the refractory period of the LA or the right atrium (RA), but it did prolong the interatrial conduction time. Programmed extrastimuli from the RA induced AF in all of the AAC-treated rats (8/8 [100%]). This was suppressed by pioglitazone (2/8 [25%], P <.05) with normalization to interatrial conduction time. CONCLUSION The results of this study suggest that inflammatory profibrotic mechanisms are involved in this pressure-overloaded AF model. The results also suggest that pioglitazone is effective at attenuating atrial fibrosis, possibly via suppression of MCP-1-mediated inflammatory profibrotic processes.

Electrocardiographic characteristics of patients with false tendon: Possible association of false tendon with J waves

BACKGROUND The false tendons (FTs) are fibromuscular bands that transverse the left ventricular cavity and often contain conduction tissue, suggesting that FTs may contribute to the occurrence of ventricular arrhythmias. The presence of J waves is associated with vulnerability to ventricular arrhythmias; however, the mechanisms underlying the manifestation of J waves remain to be elucidated. OBJECTIVE To investigate the electrocardiographic characteristics, including the presence of J waves, in patients with FTs. METHODS We studied 44 patients with distinct FTs detected by echocardiography (FT group) and 88 age- and sex-matched healthy subjects without FTs (control group). The PQ, QRS, JT, QT, corrected JT, and corrected QT intervals were automatically measured on surface 12-lead electrocardiograms, and the presence or absence of J waves was also determined. J waves were defined as terminal QRS notching or slurring. FTs were classified according to their points of attachment as type 1 (longitudinal, 52%), type 2 (diagonal, 25%), type 3 (transverse, 16%), and type 4 (weblike, 7%). RESULTS QRS and corrected QT intervals were significantly longer in the FT group than in the control group (P <.005 and P <.05, respectively). The incidence of J waves was significantly higher in the FT group (64%) than in the control group (19%) (P <.0001). J waves were more prevalent in type 1 (78%) and type 2 (73%) than in type 3 (14%) and 4 FTs (33%) (P <0.05) and in patients with thick FTs (≥ 2 mm) than with thinner FTs (<2 mm) (71% vs 33%; P <.05). The J-wave location differed according to the FT type. CONCLUSIONS Our results suggest that FTs may carry a certain role to the genesis of J waves.

Induction of heat shock proteins prevents the arrhythmogenic substrate for atrial fibrillation

Atrial fibrillation (AF) is the commonest arrhythmia. Studies have shown that atrial tachypacing (artificial persistent AF) causes electrical remodelling. This is characterised by the shortening of the atrial effective refractory period (ERP), in which reduction in L-type Ca2+ channel current plays an essential part. Atrial fibrosis, a feature of structural remodelling, is induced by continuous infusion of angiotensin II, and has been associated with conduction delay in atria, which promotes AF. Acute atrial ischaemia, frequently observed during development of acute coronary syndrome, has been associated with atrial conduction heterogeneity, which also promotes AF. Induction of heat shock proteins (Hsp72 and Hsp27) by hyperthermia and/or geranylgeranylacetone has demonstrated to protect the heart against such atrial remodelling. The potent protective role of Hsp72 and Hsp27 against clinical AF in patients who underwent open heart surgery has been shown. Taken together, interventions that induce heat shock responses (including induction of Hsp72 and Hsp27) may prevent newly developed AF and delay the progression of paroxysmal AF to persistent AF.

Candesartan restored cardiac Hsp72 expression and tolerance against reperfusion injury in hereditary insulin-resistant rats

AIMS We tested the hypothesis that candesartan, an angiotensin II (AII) type 1 receptor antagonist, would restore the depressed phosphatidylinositol 3 (PI3) kinase-dependent Akt phosphorylation, an essential signal to induce heat-shock protein 72 (Hsp72) in response to hyperthermia, in Otsuka Long-Evans Tokushima fatty (OLETF) rats. METHODS AND RESULTS At 14 weeks of age, male OLETF rats and Long-Evans Tokushima Otsuka (LETO) rats were treated with candesartan (0.25 mg/kg/day) for 2 weeks. Thereafter, hyperthermia (43°C for 20 min) was applied. We observed the following: (i) Candesartan did not improve insulin sensitivity in OLETF rats. (ii) Candesartan restored depressed PI3 kinase-dependent Akt phosphorylation and Hsp72 expression in OLETF rat hearts. (iii) Cardiac ventricular tissue contents of AII were greater in OLETF rats, which were suppressed by candesartan. (iv) Cardiac levels of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphorylation were greater in OLETF rats, which were suppressed by candesartan. In cultured cardiomyocytes, application of AII induced PTEN phosphorylation, which was suppressed by candesartan. (v) In high-fat diet insulin-resistant rats, similar results were observed with respect to Hsp72 expression, Akt phosphorylation and PTEN phosphorylation. (vi) In isolated, perfused heart experiments, reperfusion-induced cardiac functional recovery was suppressed in OLETF rat hearts, which was improved by candesartan. CONCLUSION Our results suggest that the depression of PI3 kinase-dependent Akt activation in response to hyperthermia in OLETF rats can be restored by candesartan. Substantial activation of the renin-angiotensin system, represented by increased myocardial AII content and subsequent PTEN phosphorylation, may underlie the pathogenesis which is ameliorated by candesartan.

Telmisartan effectively improves insulin sensitivity in hypertensive patients with insulin resistance

SUMMARY OBJECTIVE The angiotensin II receptor blocker (ARB) telmisartan has been shown to activate peroxisome proliferator-activated receptor γ and increase adiponectin protein content in adipocytes. We tested the hypothesis that telmisartan can increase the serum level of adiponectin and improve insulin resistance. METHODS The study participants were 25 consecutive hypertensive patients (8 females, 17 males; 65 ± 10 years). Insulin resistance was defined as a patient showing ≥2.5 in the homeostasis model assessment (HOMA) index. We divided subjects into non-insulin resistance (n = 10) and insulin resistance groups (n = 15) based on the HOMA index. Telmisartan was administered (40 mg/day) was administered for 24 weeks. RESULTS In the insulin resistance group, telmisartan treatment resulted in a significant decrease in the HOMA index and serum level of C-reactive protein, and it increased the serum level of adiponectin (P < 0.05, respectively). Such improvements were not observed in the non-insulin resistance group. Stepwise multiple regression analysis showed that the increase in the serum level of adiponectin was independently associated with reduction in the HOMA index. CONCLUSIONS Our findings suggest that telmisartan improves insulin resistance that parallels an increase in the serum level of adiponectin in hypertensive patients with insulin resistance. It may therefore have advantages in treating such populations.

New therapeutic target for the non-electrophysiological signaling in atrial fibrosis and fibrillation such as inflammation

We have experimentally established appropriate models of atrial fibrillation (AF) with atrial interstitial fibrosis. Two approaches were adopted. Firstly, left atrial fibrosis was induced by continuous infusion of angiotensin II (AII). In an electrophysiological study using isolated perfused heart, AF was easily induced following AII treatment. Repeated whole‐body hyperthermia led to the induction of heat‐shock protein 72, which resulted in attenuation of AII‐induced left atrial fibrosis and suppression of AF inducibility. Secondly, atrial fibrosis was induced by pressure overload by abdominal aortic constriction (AAC). AAC enhanced left atrial expression of monocyte chemoattractant protein‐1 and activity of matrix metalloproteinase‐9. Treatment with pioglitazone, a peroxisome proliferator‐activated receptor‐γ agonist, resulted in attenuation of pressure overload‐induced left atrial fibrosis and suppression of AF inducibility. In the same AAC model, the effects of candesartan on gap junction remodeling were investigated. Connexin 43 (Cx43) of the left atria was firmly located in the intercalated disks in control rats. A progressive redistribution of Cx43 from the intercalated disk to the lateral surface (lateralization) was observed in AAC rats. Candesartan prevented left Cx43 lateralization. Thus, heat‐shock proteins, pioglitazone, and candesartan could be novel therapeutic approaches to prevent atrial fibrosis and AF.

Effectiveness of Left Ventricular Only Pacing for Heart Failure Patients with Sinus Rhythm and Intrinsic Atrioventricular Conduction

Introduction: We compared the effectiveness of left ventricular (LV) only pacing with standard biventricular (BiV) pacing by a novel electrogram-based algorithm for atrioventricular (AV) optimization (SMART-AV®, Boston scientific, Minnesota). Methods: 20 patients with NYHA class ≥2 heart failure, LV ejection fraction (LVEF) ≤35% and QRS duration ≥120 ms were implanted with Cognis® (Boston scientific, Minnesota) for CRT and divided into two groups as follows: LV group (13 patients) with LV only pacing and BiV group (7 patients) with standard BiV pacing by SMART-AV® algorithm. LV volumes and systolic function were assessed with echocardiography at baseline and 6 months. A reduction in LV end systolic volume (LVESV) ≥15% was defined as responder. Results: There were no significant differences in baseline characteristics between LV group and BiV group. Although LVESV was significantly decreased in both groups 6 months after pacing, LVEF was improved only in LV group. Responder was higher in LV group than BiV group but there was no statistical significance (76.9% vs 41.9%, P=0.15). There were also no significant differences in reduction of LVESV and change in LVEF. Conclusion: Left ventricular only pacing for patients with intrinsic AV conduction by SMART-AV® algorithm is effective as well as standard BiV pacing.

The Single Center Experience of Pacing Device Implantation in Patients with Complex Congenital Heart Disease

Aim: Transvenous cardiovascular implantable electronic devices (CIEDs) implantation in patients with complex congenital heart disease (CCHD) is challenging because of their complex anatomy. We report our experience of CIEDs implantation in CCHD patients. Methods: CCHD patients underwent the CIEDs implantation, were analyzed retrospectively. Results: We implanted CIEDs (pacemaker n=19, ICD n=5, CRT-D n=2) in consecutive 26 CCHD patients (mean 25 y.o.) from 1994 to 2011. The underlying heart diseases were tricuspid atresia (n=2) and single RV (n=1) both after Fontan operation, single LV (n=1) underwent the septation, truncus arteiosus communis underwent Rastelli (n=1), transposition of great ateries (TGA) (n=9) and corrected TGA (n=12; SLL n=9, IDD n=3). Twelve patients with TGA and corrected TGA underwent atrial switch (n=6) or double switch (n=6) operation. The pacing leads were successfully positioned with favorable sensing and pacing threshold in all patients, transvenously, without major complications. In 2 patients with cTGA, we successfully positioned the leads at the LV apex and in the coronary vein for the resynchronization of anatomical RV. The lead revision was required during the follow-up period, due to the lead dislodgement (n=2) and the lead fracture (n=2). Conclusion: Transvenous implantation of CIEDs was safely performed and feasible even in patients with CCHD and sometimes with atrio-ventricular discordance.