Dongzhu Xu

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.

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.

Left Atrial Stiffness Relates to Left Ventricular Diastolic Dysfunction and Recurrence After Pulmonary Vein Isolation for Atrial Fibrillation

Left Atrial Stiffness and Atrial Fibrillation. Introduction: An increased left atrial (LA) stiffness reflects the structural remodeling and deterioration of the LA function. This study was designed to estimate LA stiffness by measuring a combination of the strain and LA pressure in patients undergoing pulmonary vein isolation (PVI) of atrial fibrillation (AF) and to evaluate the influence of the LA stiffness on the cardiac function, serum markers, and recurrence of AF after PVI.

Systematic Treatment Approach to Ventricular Tachycardia in Cardiac Sarcoidosis

Background—Fatal arrhythmia is commonly observed in cardiac sarcoidosis, but clinical effects of a systematic treatment approach are still uncertain. This study sought to describe both clinical and electrophysiological characteristics and outcomes of systematic treatment approach to ventricular tachycardia (VT) associated with cardiac sarcoidosis. Methods and Results—We enrolled 37 consecutive patients (11 men; age, 56±11 years) with a diagnosis of sustained VT associated with cardiac sarcoidosis. Clinical effects of a systematic treatment approach including medical therapy (both steroid and antiarrhythmic agents), in association with radiofrequency catheter ablation, were evaluated. All patients received antiarrhythmic agents, and 34 received steroid therapy. During a 39-month follow-up, 23 (62%) patients were free from any VT episodes with medical therapy. Multivariable Cox regression analyses revealed that the absence of gallium-67 myocardial uptake was an independent predictor for VT recurrence (hazard ratio, 7.51; 95% confidence interval, 1.65–34.26; P<0.01). Fourteen patients who experienced VT recurrences even while on drug therapy underwent radiofrequency catheter ablation. Electrophysiological study revealed that the mechanisms of VTs could be classified into 2 subgroups: Purkinje-related or scar-related VT. The QRS duration of VT was narrower in Purkinje-related than in scar-related VTs (157±23 versus 183±22 ms; P<0.05). After a 33-month follow-up subsequent to the radiofrequency catheter ablation, 6 of 14 patients experienced VT recurrence. The number of VTs sustained during electrophysiological study was higher in the patients with VT recurrence than in those without (3.7±1.4 versus 1.9±0.8; P<0.01). Conclusions—A systematic treatment approach to cardiac sarcoidosis with VT successfully suppressed VT recurrences in the majority of patients studied.

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.

Age-related increase in atrial fibrillation induced by transvenous catheter-based atrial burst pacing: an in vivo rat model of inducible atrial fibrillation.

AF Rat Model Induced by Transvenous Catheter Pacing. Introduction: Large animal models of atrial fibrillation (AF) are well established, but limited experimental reports exist on small animal models. We sought to develop an in vivo rat model of AF using a transvenous catheter and to evaluate the models underlying characteristics.

Anti-hypertensive effect of radiofrequency renal denervation in spontaneously hypertensive rats.

AIMS We aimed to investigate the anti-hypertensive effect of radiofrequency (RF) renal denervation (RDN) in an animal model of hypertension. MATERIALS AND METHODS RF energy was delivered to bilateral renal arteries through a 2 Fr catheter with opening abdomen in 8 spontaneously hypertensive rats (SHRs) and 8 Wistar-Kyoto rats (WKYs). Sham operation was performed in other 8 SHRs and 8 WKYs. Blood pressure (BP), heart rate (HR), and urinary norepinephrine excretion were followed up for 3 months. Plasma and renal tissue concentrations of norepinephrine and plasma renin activity were measured 3 months after the procedure. The RDN was confirmed by a decrease in renal tissue norepinephrine. KEY FINDINGS RF-RDN restrained a spontaneous rise in systolic BP (46 ± 12% increase from 158 ± 8 to 230 ± 14 mmHg vs. 21 ± 18% increase from 165 ± 9 to 197 ± 20 mmHg, p = 0.01) and diastolic BP (55 ± 27% increase from 117 ± 9 to 179 ± 23 mmHg vs. 28 ± 13% increase from 120 ± 7 to 154 ± 13 mmHg, p = 0.04) in SHRs; however, WKYs were not affected. Although there were no changes in HR and systemic norepinephrine, the renal tissue norepinephrine was decreased by RF-RDN in both SHR (302 ± 41 vs. 159 ± 44 ng/g kidney, p<0.01) and WKY (203 ± 33 vs. 145 ± 26 ng/g kidney, p = 0.01). Plasma renin activity was reduced by the RF-RDN only in SHR (35.3 ± 9.5 vs. 21.4 ± 8.6 ng/mL/h, p<0.01). SIGNIFICANCE RF-RDN demonstrated an anti-hypertensive effect with a reduction of renal tissue norepinephrine and plasma renin activity in SHR.

Phospholamban is concentrated in the nuclear envelope of cardiomyocytes and involved in perinuclear/nuclear calcium handling

AIMS Phospholamban (PLB) regulates the cardiac Ca2+-ATPase (SERCA2a) in sarcoplasmic reticulum (SR). However, the localization of PLB at subcellular sites outside the SR and possible contributions to Ca2+ cycling remain unknown. We examined the intracellular distribution of PLB and tested whether a pool of PLB exists in the nuclear envelope (NE) that might regulate perinuclear/nuclear Ca2+ (nCa2+) handling in cardiomyocytes (CMs). METHODS AND RESULTS Using confocal immunofluorescence microscopy and immunoblot analyses of CMs and CM nuclei, we discovered that PLB was highly concentrated in NE. Moreover, the ratio of PLB levels to SERCA levels was greater in NE than in SR. The increased levels of PLB in NE were a consistent finding using a range of antibodies, tissue samples, and species. To address a possible role in affecting Ca2+ handling, we used Fluo-4 based confocal Ca2+ imaging, with scan-lines across cytosol and nuclei, and evaluated the effects of PLB on cytosolic and nCa2+ uptake and release in mouse CMs. In intact CMs, isoproterenol increased amplitude and decreased the decay time of Ca2+ transients not only in cytosol but also in nuclear regions. In saponin-permeabilized mouse CMs ([Ca2+]i=400nM), we measured spontaneous Ca2+ waves after specific reversal of PLB activity by addition of the Fab fragment of an anti-PLB monoclonal antibody (100μg/ml). This highly selective immunological reagent enhanced Ca2+ uptake (faster decay times) and Ca2+ release (greater intensity) in both cytosol and across the nuclear regions. CONCLUSIONS Besides SR, PLB is concentrated in NE of CMs, and may be involved in modulation of nCa2+ dynamics.