Possible association of papillary muscle hypertrophy with the genesis of J-waves.

BACKGROUND: Although J-waves have been known to be associated with vulnerability to ventricular fibrillation, their electrophysiologic mechanism remains to be elucidated. The papillary muscles (PMs) of the left ventricle (LV) have been recognized as the target site of radiofrequency ablation for ventricular arrhythmias. However, the relationship between PM hypertrophy and J-waves has not been investigated. OBJECTIVE: To investigate the electrocardiographic characteristics, including the J-waves, in patients with solitary PM hypertrophy. METHODS: We studied 101 patients with PM hypertrophy without LV hypertrophy (PMH group) and 159 age- and sex-matched control subjects (control group). The parameters of the 12-lead electrocardiogram and the echocardiogram were compared between the two groups. RESULTS: Compared with the control group, the PMH group had significantly higher incidence (15% vs. 33%, p=0.001) and amplitude (0.17±0.06mV vs. 0.28±0.17mV, p<0.01) of J-waves; significantly longer QRS, QTc, and JTc intervals (p=0.0001, p<0.0001, and p<0.05, respectively); significantly greater Sokolow-Lyon index (p<0.001); and significantly greater LV wall thickness and LV mass index (p<0.0001 for each). Multivariate logistic regression analysis showed that only the PM hypertrophy was an independent predictor of the presence of J-waves. CONCLUSION: PM hypertrophy was related to the genesis of J-waves.

Hyperleptinemia Exacerbates High-Fat Diet-Mediated Atrial Fibrosis and Fibrillation.

BACKGROUND: Obesity including metabolic syndrome is an independent risk factor of atrial fibrillation (AF). Although hyperleptinemia is usually a characteristic of obese subjects, the relationship with atrial fibrosis and AF is unknown. We tested the hypothesis that high-fat diet (HFD)-induced hyperleptinemia exacerbates atrial fibrosis and AF. METHODS AND RESULTS: Eight-week-old male C57BL/6 (WT) and leptin-deficient ob/ob (Ob) mice were treated with a normal-fat diet (NFD) or 60% HFD. After 8 weeks, transesophageal burst pacing and electrophysiological study using isolated perfused hearts were performed and left atrial (LA) tissues were collected for histological analysis, hydroxyproline assay, and reverse transcription-polymerase chain reaction. HFD treatment increased body weight in both WT and Ob mice compared with NFD (both P < 0.01). In WT-HFD mice, hyperleptinemia was observed as expected. While transesophageal burst pacing invariably induced AF (8/8, 100%) in WT-HFD mice, AF was induced less frequently (1/8, 12.5%) in Ob-HFD mice (P < 0.01). In isolated perfused hearts, the interatrial conduction time was prolonged in WT-HFD mice, but not in Ob-HFD mice (P < 0.05). Masson's trichrome staining and the hydroxyproline assay revealed interstitial LA fibrosis in WT-HFD mice, which was not observed in Ob-HFD mice (P < 0.05). Upregulation of collagen1, collagen3, α-smooth muscle actin, tumor necrosis factor-α, and monocyte chemoattractant protein-1 mRNA levels was noted in WT-HFD mice LA, but attenuated in Ob-HFD mice LA. CONCLUSIONS: Our findings suggest that hyperleptinemia exacerbates HFD-mediated atrial fibrosis and AF. Inhibition of leptin signaling may become a novel therapeutic target to prevent obesity-related AF.

Mast Cells Play an Important Role in the Pathogenesis of Hyperglycemia-Induced Atrial Fibrillation.

BACKGROUND AND OBJECTIVES: Recently, it was reported that mast cells (MCs) could underlie the mechanisms of several cardiovascular diseases. However, the role of MCs in diabetes-induced atrial fibrillation (AF) has not been notably investigated. We tested the hypothesis that MC deficiency attenuates hyperglycemia-induced AF in mice. METHODS AND RESULTS: Mast cell-deficient W/W(v)  mice, and congenic +/+ littermates (WT) were divided into either the vehicle (VEH)-injection group or the streptozotocin (STZ)-injection group (MCKO-VEH, MCKO-STZ, WT-VEH, and WT-STZ groups). On day 28 of our studies, we observed that (1) STZ-induced hyperglycemia increased MC infiltration in the left atrium (LA) in WT mice (P < 0.01), (2) atrium isolated from the WT-STZ group showed inhomogeneous interstitial fibrosis, abundant infiltration of macrophages, and enhanced apoptosis compared to the WT-VEH group (P < 0.01, P < 0.01, P < 0.05, respectively). However, the changes observed in the WT-STZ group were significantly attenuated in the MCKO-STZ mice. In addition, we observed that (3) messenger RNA levels of tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-1ß, transforming growth factor-ß, and collagen-1 in the LA were increased in the WT-STZ group, but not in the MCKO-STZ group, (4) STZ-induced hyperglycemia increased AF induction and prolonged interatrial conduction time in the WT mice, which were not observed in the MCKO mice, and that (5) hyperglycemia-enhanced atrial production of reactive oxygen species (ROS) was equally observed in the WT and MCKO mice. CONCLUSIONS: Our results suggest that MCs contribute to the pathogenesis of hyperglycemia-induced AF via enhancement of inflammation and fibrosis.

Glucose Fluctuations Aggravate Cardiac Susceptibility to Ischemia/Reperfusion Injury by Modulating MicroRNAs Expression.

BACKGROUND: The influence of glucose fluctuations (GF) on cardiovascular complications of diabetes mellitus (DM) has been attracting much attention. In the present study, whether GF increase susceptibility to ischemia/reperfusion in the heart was investigated. METHODS AND RESULTS: Male rats were randomly assigned to either a control, DM, and DM with GF group. DM was induced by an injection of streptozotocin, and glucose fluctuation was induced by starvation and insulin injection. One sequential program comprised 2 hypoglycemic episodes during 4 days. The isolated hearts were subjected to 20-min ischemia/30-min reperfusion. The infarct size was larger in hearts with GF than those with sustained hyperglycemia. Activities of catalase and superoxide dismutase were decreased, and expressions of NADPH oxidase and thioredoxin-interacting protein were upregulated by GF accompanied by an increase of reactive oxygen species (ROS). Swollen mitochondria with destroyed cristae were observed in diabetic hearts; they were further devastated by GF. Microarray analysis revealed that the expressions of microRNA (miRNA)-200c and miRNA-141 were abundant in those hearts with GF. Overexpression of miRNA-200c and miRNA-141 decreased mitochondrial superoxide dismutase and catalase activities, and increased ROS levels. Meanwhile, knockdown of miRNA-200c and miRNA-141 significantly decreased ROS levels in cardiomyocytes exposed to GF. CONCLUSIONS: GF increased ROS generation and enhanced ischemia/reperfusion injury in the diabetic heart. Upregulated miRNA-200c and miRNA-141 may account for the increased ROS.

Endothelial Function Predicts New Hospitalization due to Heart Failure Following Cardiac Resynchronization Therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) has been established as a treatment for patients with chronic heart failure (HF). We tested the hypothesis that assessment of peripheral endothelial function is associated with the long-term outcome of CRT and its linkage to coronary flow reserve (CFR) was also investigated. METHODS: From 2010, a total of 34 consecutive patients implanted with CRT for the treatment of advanced HF were evaluated at baseline (immediately before CRT) and 6-8 months after CRT. Endothelial function was evaluated by measurement of reactive hyperemia peripheral arterial tonometry (RH-PAT). In 24 of 34 patients, CFR was determined by transthoracic echocardiography. RESULTS: Based on the receiver-operating characteristic curves, depressed RH-PAT index (RHI) was defined as ≤1.5. Accurate follow-up information during the mean of 343 ± 120 days was obtained in 20 preserved RHI group (mean age 66 ± 1.8 years) and 14 depressed RHI group (71 ± 2.2 years). Kaplan-Meier survival analysis demonstrated that depressed RHI group had higher prevalence of new hospitalization due to HF progression (log-rank 5.40). Cox proportional hazards regression analysis revealed that the baseline log brain natriuretic peptide (hazard ratio 5.95) and the baseline RHI value (hazard ratio 0.066) were independently associated with the incidence of new hospitalization due to HF progression. The baseline RHI values were positively correlated with the 6-8 months change of CFR (R = 0.434, P = 0.0343). CONCLUSIONS: Our results suggest that the baseline peripheral endothelial function could predict the long-term outcome of CRT. The results also suggest that improvement of coronary microcirculation might be associated with the better baseline endothelial function.

Cardiac autonomic dysfunction in patients with head-up tilt test-induced vasovagal syncope.

BACKGROUND: Vasovagal syncope (VVS) is the result of an autonomic reflex that has a final effect of reducing sympathetic drive and increasing vagal activity. However, whether syncopal symptoms are associated with pathological cardiac autonomic modulation is not fully known. We tested the hypothesis that cardiac autonomic function is impaired in patients with VVS. METHODS: Eighty-four consecutive patients (59 males; 48.8 ± 20.9 years) with recurrent unexplained syncope were enrolled. The head-up tilt test (HUTT) was positive in 38 patients and negative in 46 patients. Cardiac autonomic function was assessed by baroreflex sensitivity (BRS), heart rate variability, plasma concentrations of norepinephrine, and (123) I-metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: BRS indices were significantly lower in the HUTT-positive group than in the HUTT-negative group (6.1 ± 5.5 mm Hg/s vs 9.8 ± 7.6 mm Hg/s, P = 0.02). With regard to cardiac (123) I-MIBG scintigraphy, the mean heart-to-mediastinum ratio at the delayed phase tended to be lower in HUTT-positive than in HUTT-negative individuals, but this difference was not significant (2.75 ± 0.55 vs 3.02 ± 0.49, P = 0.08).The percent washout rate of (123) I-MIBG was significantly higher in the positive group compared with the negative group (40.7 ± 13.1% vs 31.5 ± 13.3%, P = 0.02). Multivariate logistic analysis revealed that the appearance of HUTT-induced VVS was predicted independently by a high percent washout rate of (123) I-MIBG (odds ratio, 0.954; 95% confidence interval, 0.903-0.998; P = 0.048). CONCLUSIONS: Our results suggest that pathological autonomic cardiac modulation may play a role in the appearance of syncope in VVS patients.

Combination therapy of cilostazol and bepridil suppresses recurrent ventricular fibrillation related to J-wave syndromes.

BACKGROUND: Brugada syndrome and idiopathic ventricular fibrillation (VF) associated with inferolateral early repolarization patterns are termed "J-wave syndromes." In such patients, an implantable cardioverter-defibrillator (ICD) is first-line therapy for prevention of sudden cardiac death. However, frequent ICD shocks due to recurrent VF remain serious problems. OBJECTIVE: The purpose of this study was to ascertain if combination therapy of cilostazol and bepridil could suppress recurrent VF. METHODS: We enrolled 7 patients with J-wave syndromes who experienced ICD shocks due to recurrent VF after ICD implantation. At first, cilostazol was instituted. In all subjects, palpitations due to sinus tachycardia caused by cilostazol were symptomatic. Addition of bepridil attenuated cilostazol-induced palpitations and maintained the suppressive effect of cilostazol against VF (87 ± 12 bpm to 66 ± 7 bpm, P < .01). RESULTS: Six patients remained free of VF. Three patients underwent replacement of the ICD generator 4-5 years after ICD placement. Cilostazol was discontinued 2 days before replacement because of its antiplatelet effects. In all 3 patients, temporary discontinuation of cilostazol led to the reappearance of J waves, culminating in VF and an appropriate ICD shock in 1 patient. J waves disappeared with reinstitution of cilostazol. CONCLUSION: These data suggest that combination therapy of cilostazol and bepridil may be effective and safe in suppressing VF recurrence in some cases of J-wave syndromes.

Plasma norepinephrine is an independent predictor of adverse cerebral and cardiovascular events in type 2 diabetic patients without structural heart disease.

BACKGROUND: Resting plasma norepinephrine (NE) level was reportedly related to high mortality in patients with heart failure. The current study investigated whether resting NE could predict long-term major adverse cerebral and cardiovascular events (MACCEs) in Japanese type 2 diabetic patients without heart disease. METHODS AND SUBJECTS: We evaluated resting NE in 95 patients with type 2 diabetes who did not have severe complications. Based on the ROC curves, high NE was defined as ≥333pg/ml. Accurate follow-up information during a mean of 3.6±1.9 years was obtained in 27 high NE patients (13 female, mean age 64±12 years) and 68 low NE patients (29 female, 60±12 years). ESSENTIAL RESULTS: The Kaplan-Meier curves revealed that MACCE-free ratio was significantly lower in the high NE patients than in the low NE patients (log-rank 10.3, p=0.0013). Cox proportional hazards regression analysis revealed that female gender (hazard ratio 7.75), low baroreflex sensitivity (hazard ratio 6.66), and high NE (hazard ratio 5.40) were independently associated with the incidence of MACCE. PRINCIPAL CONCLUSIONS: Our results suggest that resting NE is comparably useful to identify the high-risk patients for MACCE to baroreflex sensitivity in type 2 diabetic patients. The results also suggest that pathogenic sympathetic activation leading to MACCE may be identified by the assessment of resting NE, more easily and less expensively compared to cardiac iodine 123 metaiodobenzylguanidine scintigraphy in this population.

False tendons may be associated with the genesis of J-waves: prospective study in young healthy male.

BACKGROUND: Recent studies showed that J-waves are associated with vulnerability to ventricular fibrillation. Recently we reported the association between false tendons (FTs) and J-waves in a retrospective study. METHODS AND RESULTS: We prospectively studied 50 young healthy men (mean age 24.6±2.7 years). FTs were detected echocardiographically and classified based on their points of attachment as type 1 (longitudinal type), type 2 (diagonal type), and type 3 (transverse type). J-waves were defined as terminal QRS notching or slurring with ≥0.1 mV. The filtered QRS duration (fQRSd), RMS40, and LAS40 were measured on signal-averaged ECGs. FTs were detected in 37 of the 50 subjects (74%). The incidence of J-waves was significantly higher in subjects with type 1 or type 2 FTs than those with no- or type 3 FTs (61% vs. 26%, p<0.05). The leads with J-waves were closely associated with the location of the FT. While no late potential was recorded in any study subjects, fQRSd and LAS40 were significantly longer in subjects with type 1 or type 2 FTs (p<0.05). Univariate and multivariate logistic regression analysis revealed that only the existence of FTs (type 1 or 2) was an independent predictor of the presence of J-waves. CONCLUSIONS: Our results suggest that FTs were related to the genesis of J-waves with conduction delay.