Nobuyuki Murakoshi

PPAR-γ Activator Pioglitazone Prevents Age-Related Atrial Fibrillation Susceptibility by Improving Antioxidant Capacity and Reducing Apoptosis in a Rat Model

PPAR‐γ Activator as Upstream Therapy for Atrial Fibrillation in Rat. Introduction: The in vivo role of peroxisome proliferator‐activated receptor (PPAR)‐γ, an essential transcriptional mediator of lipid and glucose metabolism, in atrial fibrillation (AF) remains to be fully elucidated. We investigated the effects of pioglitazone, a PPAR‐γ activator, in an in vivo AF rat model.

Novel molecular mechanism of increased myocardial endothelin-1 expression in the failing heart involving the transcriptional factor hypoxia-inducible factor-1α induced for impaired myocardial energy metabolism

Background—Hypoxia-inducible factor (HIF)-1&agr; is an important transcriptional factor that activates the gene expression of glycolytic enzymes, which are activated as compensation for impaired &bgr;-oxidation of fatty acid in the failing heart. We reported that cardiac endothelin (ET)-1 expression is markedly increased in heart failure. The mechanism, however, is unknown. Because we found an HIF-1&agr; binding site in the 5′-promoter region of the ET-1 gene, we hypothesized that HIF-1&agr; is involved in this mechanism. Methods and Results—In rat cardiomyocytes, luciferase assay and electrophoretic mobility shift assay showed that HIF-1&agr; transcriptionally activates ET-1 gene expression by direct interaction with the predicted DNA binding site in the 5′-promoter region. HIF-1&agr; mRNA and ET-1 mRNA in the failing heart increased during the aggravation of heart failure in vivo in animal models, ie, rats with myocardial infarction and hamsters with cardiomyopathy. In cultured cardiomyocytes treated with a mitochondrial inhibitor, HIF-1&agr; mRNA and ET-1 mRNA were markedly increased with activated glycolysis, and antisense oligonucleotide for HIF-1&agr; largely inhibited the increased gene expression of ET-1. Conclusions—The present study revealed a novel molecular mechanism of upregulation of myocardial ET-1 in heart failure, indicating that induction of HIF-1&agr; to stimulate glycolysis as an adaptation in heart failure against impaired energy metabolism alternatively causes an elevation of cardiac ET-1 gene expression as a maladaptation.

Left Ventricular Strain and Transmural Distribution of Structural Remodeling in Hypertensive Heart Disease

Left ventricular (LV) systolic wall strain is a new candidate for prognostic indicator of hypertensive heart failure. It remains unclear how underlying transmural structural remodeling corresponds to LV wall systolic deformation as hypertensive hypertrophy progresses. We fed 68 Dahl salt–sensitive rats a high-salt (hypertensive group) or low-salt diet (control group) from 6 weeks old. At 10, 14, and 18 weeks, pressure–volume relation, transmural distribution of LV fibrosis, and myocyte hypertrophy were evaluated. LV global longitudinal and circumferential strain was measured with speckle tracking echocardiography. Emax was preserved throughout the study period, whereas &tgr; and end-diastolic pressure–volume relation progressively deteriorated from 14 weeks (diastolic dysfunction stage). Lung weight increased significantly at 18 weeks (decompensated stage). Histological percentage area fibrosis and collagen type I/III, myocyte hypertrophy, and &agr;-myosin heavy chain isoform increased in the subendocardial layer at 14 weeks and progressed into the midlayer at 18 weeks. Longitudinal strain progressively deteriorated in the hypertensive group versus control group at 14 weeks (hypertensive group: −17±3%, control: −27±4%; P<0.001), and circumferential strain decreased at 18 weeks (hypertensive group: −17±2%, control: −27±3%; P=0.002). After adjustment for systolic wall stress, subendocardial percentage area fibrosis was selected as the independent determinant of longitudinal strain. This study showed that LV wall strain alternations were accompanied by fibrosis and myocyte hypertrophy from subendocardium to epicardium, and longitudinal strain related significantly to subendocardial layer fibrosis. Longitudinal strain could be a surrogate of subendocardial fibrotic changes and may be useful for risk stratification of hypertensive heart failure.

Concomitant chronic kidney disease increases the recurrence of atrial fibrillation after catheter ablation of atrial fibrillation: A mid-term follow-up

BACKGROUND Chronic kidney disease (CKD) is often associated with atrial fibrillation (AF). However, its impact on the results of radiofrequency catheter ablation for AF has not been fully examined. OBJECTIVE The purpose of this study was to clarify the relationship between CKD and postcatheter ablation AF recurrence. METHODS The study included 221 patients with AF who underwent successful catheter ablation. The prevalence and characteristics of AF recurrences were determined. CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m(2). RESULTS After mean follow-up of 31.9 ± 7.6 months, 87 (39%) patients had AF recurrences. Multivariate Cox regression analysis revealed that CKD (hazard ratio [HR] 2.089, 95% confidence interval [CI] 1.292-3.378, P <.01) and left atrial volume (HR 1.009, 95% CI 1.002-1.017, P <.05) were independent predictors of AF recurrences. Among the 221 patients, 54 (24.4%) had CKD. Patients with CKD had a higher incidence of AF recurrences (57.4%) compared to the non-CKD patients (33.5%, P <.01). Compared with patients without CKD, patients with CKD were older (64 ± 11 years vs 58 ± 10 years, P <.001) and had a higher prevalence of hypertension (72% vs 53%, P <.05), larger left atrial volume (74.7 ± 29.4 mL vs 62.0 ± 26.0 mL, P <.01), and higher plasma B-type natriuretic peptide levels (129.6 ± 209.3 pg/mL vs 68.8 ± 91.0 pg/mL, P <.01). CONCLUSION The presence of CKD increased the risk of AF recurrences after catheter ablation. Multifactorial physiologic factors due to CKD may account for the higher prevalence of recurrent AF in patients with CKD than in those without.

Impact of coronary plaque composition on cardiac troponin elevation after percutaneous coronary intervention in stable angina pectoris: a computed tomography analysis.

OBJECTIVES The authors used multidetector computed tomography (MDCT) to study the relation between culprit plaque characteristics and cardiac troponin T (cTnT) elevation after percutaneous coronary intervention (PCI). BACKGROUND Percutaneous coronary intervention is often complicated by post-procedural myocardial necrosis manifested by elevated cardiac biomarkers. METHODS Stable angina patients (n = 107) with normal pre-PCI cTnT levels underwent 64-slice MDCT before PCI to evaluate plaque characteristics of culprit lesions. Patients were divided into 2 groups according to presence (group I, n = 36) or absence (group II, n = 71) of post-PCI cTnT elevation ≥3 times the upper limit of normal (0.010 ng/ml) at 24 h after PCI. RESULTS Computed tomography attenuation values were significantly lower in group I than in group II (43.0 [26.5 to 75.7] HU vs. 94.0 [65.0 to 109.0] HU, p < 0.001). Remodeling index was significantly greater in group I than in group II (1.20 ± 0.18 vs. 1.04 ± 0.15, p < 0.001). Spotty calcification was observed significantly more frequently in group I than in group II (50% vs. 11%, p < 0.001). Multivariate analysis showed presence of positive remodeling (remodeling index >1.05; odds ratio: 4.54; 95% confidence interval: 1.36 to 15.9; p = 0.014) and spotty calcification (odds ratio: 4.27; 95% confidence interval: 1.30 to 14.8; p = 0.016) were statistically significant independent predictors for cTnT elevation. For prediction of cTnT elevation, the presence of all 3 variables (CT attenuation value <55 HU; remodeling index >1.05, and spotty calcification) showed a high positive predictive value of 94%, and their absence showed a high negative predictive value of 90%. CONCLUSIONS MDCT may be useful in detecting which lesions are at high risk for myocardial necrosis after PCI.

Successful catheter ablation of bidirectional ventricular premature contractions triggering ventricular fibrillation in catecholaminergic polymorphic ventricular tachycardia with RyR2 mutation.

The subject of this report is a 38-year-old woman who often experienced syncope since childhood. Syncope occurred >10 times a year and was associated with convulsion during exercise and emotionally exciting situations. The patients 13-year-old daughter had also experienced frequent episodes of syncope and developed ventricular fibrillation (VF) during treadmill exercise testing that was successfully defibrillated with electric shock. Witnessing this situation, the patient also lost consciousness, with documented VF that was converted to sinus rhythm by cardiopulmonary resuscitation without electric defibrillation. Both the patient and her daughter were admitted to our hospital. We performed echocardiography, coronary angiography, and cardiac CT, the results of which revealed no structural heart disease. Resting 12-lead ECG did not indicate any abnormalities, including long-QT syndrome or Brugada syndrome. A signal-averaged ECG revealed no late potentials. Treadmill exercise testing easily induced bigeminal ventricular premature contractions (VPCs) with a right bundle branch block configuration and inferior axis (Figure 1A), and the exercise was terminated because of intolerable symptoms. Catecholamine stress test was started with administration of continuous intravenous infusion of epinephrine in a stepwise manner from 0.025 μg/kg per minute.1 During epinephrine infusion at a rate of 0.1 μg/kg per minute, multifocal VPCs (VPC #1, right bundle branch block configuration and superior axis; VPC #2, right bundle branch block configuration and inferior axis [the same VPC configuration as that induced during the treadmill exercise testing]; and VPC #3, left bundle branch block configuration and inferior axis) appeared, and VPC #1 following VPC #2 subsequently induced VF (Figure 1B). Figure 1. A , Twelve-lead ECG recording during treadmill exercise testing. Bigeminal ventricular premature contractions (VPCs) appeared during the second stage of the Bruce protocol. VPC morphology …

Prevalence and characteristics of asymptomatic excessive transmural injury after radiofrequency catheter ablation of atrial fibrillation.

BACKGROUND Even with a low energy setting, radiofrequency energy applications on the left atrial (LA) posterior wall may cause excessive transmural injury (ETI) during catheter ablation of atrial fibrillation (AF). OBJECTIVE The purpose of this study was to clarify the prevalence and characteristics of ETI. METHODS This study included 104 patients with AF who underwent extensive encircling pulmonary vein isolation (EEPVI) followed by an endoscopic examination (≤48 hours after EEPVI). EEPVI was performed under conscious sedation, and the ablation settings at the LA posterior wall were a maximum energy of 20 to 25 W and duration of ≤30 seconds. The ETI was defined as any injury that resulted from EEPVI, including esophageal damage or periesophageal nerve injury. RESULTS ETIs were found in 10 (9.6%) patients and were all asymptomatic; esophageal damage in 4 patients and periesophageal nerve injury in the remaining 6. All patients with ETI were below normal weight (body mass index [BMI] < 24.9 kg/m(2)), and consisted of 17% of those below normal weight. The procedural parameters such as the type of energy source, total duration of energy applications to the LA posterior wall, additional LA linear ablation, and biochemical markers were not related to the ETI. In the logistic multiadjusted model, the BMI (per 1 kg/m(2)) was the only independent predictor of ETI (odds ratio = 0.76; 95% confidence interval = 0.59 to 0.97, P < .05). CONCLUSION Asymptomatic ETIs were not rare even with a low energy setting in patients below normal weight. Tailored energy settings based on the patients BMI may be required when performing EEPVI.

Anemia and reduced kidney function as risk factors for new onset of atrial fibrillation (from the Ibaraki prefectural health study).

Chronic kidney disease (CKD) is a potential independent risk factor for atrial fibrillation (AF). It remains unclear whether anemia is synergistically associated with increased risk of AF onset in subjects with CKD. We evaluated the association of kidney function, hemoglobin (Hb), and their combination with new-onset AF in a population-based cohort study. We conducted a 15-year prospective cohort study of 132,250 Japanese subjects aged 40 to 79 years who participated in annual health checkups from 1993. Kaplan-Meier survival analysis was used to compare freedom from new-onset AF between groups classified by estimated glomerular filtration rate grade, Hb grade, and their combination. Cox proportional hazard model analysis was used to estimate hazard ratios (HRs) for new-onset AF. During a 13.8-year mean follow-up period, 1,232 (0.93%) subjects with new-onset AF were identified. Lower estimated glomerular filtration rate and lower Hb grades were significantly associated with a higher incidence of new-onset AF. Multivariate HRs and 95% confidence intervals (CIs) of new-onset AF were 1.38 (1.21 to 1.56) for mild CKD group, 2.56 (2.09 to 3.13) for CKD group, and 1.50 (1.24 to 1.83) for anemia group. Borderline Hb level was not significantly associated with increased risk for new-onset AF (HR 1.07, CI 0.91 to 1.25, p = 0.4284). In the model with interaction term between CKD and anemia, the risk was significantly higher (p = 0.0343 for the interaction) than that predicted by each factor independently. In conclusion, decreased kidney function and lower Hb level are associated with increased risk for new-onset AF, especially when both are present.

Effect of eplerenone on maintenance of sinus rhythm after catheter ablation in patients with long-standing persistent atrial fibrillation.

Several studies have demonstrated a relation between the rennin-angiotensin-aldosterone system and atrial fibrillation (AF), but there are no reports on the effect of eplerenone, a selective aldosterone blocker, on the prevention of AF recurrence after radiofrequency catheter ablation (RFCA). The aim of this study was to evaluate the effects of eplerenone on clinical outcomes after RFCA in patients with long-standing persistent AF. A total of 161 consecutive patients with long-standing persistent AF (sustained AF duration 1 to 20 years, mean 3.4 ± 3.8) who underwent RFCA were investigated. Eplerenone was used in 55 patients and not used in the remaining 106 patients. Other conventional pharmacologic agents, including angiotensin-converting enzyme inhibitors or angiotensin type 1 receptor blockers, were used equally in the 2 groups. After 24 months of follow-up, 47% of the patients were free from AF recurrence. The rate of freedom from AF recurrence was significantly greater in the eplerenone group (60%) than in the noneplerenone group (40%) (p = 0.011). By univariate analysis, the duration of sustained AF (p <0.001), left atrial diameter (p = 0.010), left atrial volume index (p = 0.017), and early AF recurrence (p <0.001) were significantly associated with AF recurrence, and the use of eplerenone was associated with maintenance of sinus rhythm after RFCA (p = 0.022). Multivariate Cox regression analysis showed that longer duration of sustained AF (>3 years) (p <0.001) and early AF recurrence (p <0.001) were significantly associated with AF recurrence, and only eplerenone therapy significantly improved maintenance of sinus rhythm (p = 0.017). In conclusion, eplerenone significantly improved maintenance of sinus rhythm after RFCA in patients with long-standing persistent AF.

Prognostic impact of supraventricular premature complexes in community-based health checkups: The Ibaraki Prefectural Health Study

AIMS The long-term prognosis of subjects with supraventricular premature complexes (SVPCs) remains unclear in the general population. The aim of this study was to examine the prognostic significance of SVPCs in community-based health checkups. METHODS AND RESULTS We assessed 63 197 individuals (mean age, 58.8 ± 9.9 years; 67.6% women) who participated in annual community-based health checkups in 1993 and were followed until 2008. The primary endpoint was stroke death, cardiovascular death (CVD), or all-cause death during a 14-year mean follow-up, and the secondary endpoint was first atrial fibrillation (AF) event in subjects without self-reported heart diseases or AF at baseline. Compared with subjects without SVPCs, the multivariate-adjusted hazard ratios (HRs) [95% confidence interval (CI)] of stroke death, CVD, and all-cause death in subjects with SVPCs were 1.24 (0.98-1.56) for men and 1.63 (1.30-2.05) for women, 1.22 (1.04-1.44) for men and 1.48 (1.25-1.74) for women, and 1.08 (0.99-1.18) for men and 1.21 (1.09-1.34) for women, respectively. Atrial fibrillation occurred in 386 subjects during the follow-up (1.05/1000 person-years). The presence of SVPCs at baseline was the significant predictor of AF onset [HRs (95% CI): 4.87 (3.61-6.57) for men and 3.87 (2.69-5.57) for women]. Propensity score matched analyses also revealed the presence of SVPCs was significantly associated with increased risks of AF incidence and CVD even after adjusting the potential confounders. CONCLUSION The presence of SVPCs in 12-lead electrocardiograms was a strong predictor of AF development, and associated with increased risk of CVD in general population.