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- 2006年
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2011年
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2006年
論文
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Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 25(9) 2023年8月2日AIMS: The relationship between local unipolar voltage (UV) in the pulmonary vein (PV)-ostia and left atrial wall thickness (LAWT) and the utility of these parameters as indices of outcome after atrial fibrillation (AF) ablation remain unclear. METHODS AND RESULTS: Two-hundred seventy-two AF patients who underwent AF ablation were enrolled. Unipolar voltage of PV-ostia was measured using a CARTO system, and LAWT was measured using computed tomography. The primary endpoint was atrial tachyarrhythmia (ATA) recurrence including AF. The ATA recurrence was documented in 74 patients (ATA-Rec group). The UV and LAWT of the bilateral superior PV roof to posterior and around the right-inferior PV in the ATA-Rec group were significantly greater than in patients without ATA recurrence (ATA-Free group) (P < 0.001). The UV had a strong positive correlation with LAWT (R2 = 0.446, P < 0.001). The UV 2.7 mV and the corresponding LAWT 1.6 mm were determined as the cut-off values for ATA recurrence (P < 0.001, respectively). Multisite LA high UV (HUV, ≥4 areas of >2.7 mV) or multisite LA wall thickening (≥5 areas of >1.6 mm), defined as LA hypertrophy (LAH), was related to higher ATA recurrence. Among 92 LAH patients, 66 had HUV (LAH-HUV) and the remaining 26 had low UV (LAH-LUV), characterized by history of non-paroxysmal AF and heart failure, reduced LV ejection fraction, or enlarged LA. In addition, LAH-LUV showed the worst ablation outcome, followed by LAH-HUV and No LAH (log-rank P < 0.001). CONCLUSION: Combining UV and LAWT enables us to stratify recurrence risk and suggest a tailored ablation strategy according to LA tissue properties.
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Journal of arrhythmia 36(5) 874-882 2020年10月BACKGROUND: To investigate the clinical implication of the temporal difference in atrial fibrillation (AF)-onset in acute decompensated heart failure (ADHF) and its impact on post-discharge prognosis. METHODS: 336 new-onset ADHF patients without any history of AF before admission were enrolled (201 males, 63 ± 16 year-old) and classified into two groups based on their history of AF: the Control group (No AF was detected during hospitalization, n = 278), and the In-hos-AF group (AF occurred during hospitalization, n = 58). Post discharge prognosis including rehospitalization due to worsening HF, cardiac death, all-cause death and cerebrovascular event were compared. RESULTS: Kaplan-Meier analysis demonstrated that the incidence of rehospitalization due to HF, cardiac death, all-cause death and cerebrovascular event in the In-hos-AF group was not significantly different from that in the Control group (P > 0.05 respectively). However, when AF recurred in the In-hos-AF group patients (n = 24, 41%) after discharge, the incidence of rehospitalization due to HF and cardiac deaths were higher than those without AF recurrence (P = 0.018 and P = 0.027 respectively). Cox proportional analysis revealed that AF developing after discharge was proven to be an independent risk factor for rehospitalization due to HF (HR 1.845, P = 0.043), cardiac death (HR 3.562, P = 0.013) and all-cause deaths (HR 2.138, P = 0.020). CONCLUSION: Clinical outcomes of new-onset in-hospital AF patients were as good as those without AF history until AF recurrence. However, AF recurrence led to worse prognosis. Therefore, treatment for new-onset in-hospital AF in ADHF patients might be postponed until AF recurrence.
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Circulation. Arrhythmia and electrophysiology 13(10) e008602 2020年10月BACKGROUND: The mechanism of esophageal thermal injury (ETI; esophageal mucosal injury and periesophageal nerve injury leading to gastric hypomotility) remains unknown when using a high-power short-duration (HP-SD) setting. This study sought to evaluate the characteristics of esophageal injuries in atrial fibrillation ablation using a HP-SD setting. METHODS: After exclusion of 5 patients with their esophagus at the right portion of left atrium and 21 patients with additional ablations such as box isolation and low voltage area ablation in left atrium posterior wall, 271 consecutive patients (62±10 years, 56 women) who underwent pulmonary vein isolation by radiofrequency catheter ablation were analyzed. In the 101 patients, a HP-SD setting at 45 to 50 W with an Ablation Index module was used (HP-SD group). In the remaining 170 patients before introduction of the HP-SD setting, a conventional power setting of 20 to 30 W with contact force monitoring was used (conventional group). We performed esophagogastroduodenoscopy after pulmonary vein isolation in all patients and investigated the incidence and characteristics of ETI. RESULTS: Although the incidence of ETI was significantly higher in the HP-SD group compared with the conventional group (37% versus 22%, P=0.011), the prevalence of esophageal lesions did not differ between the groups (7% versus 8%). Multivariate logistic regression analysis revealed that the use of the HP-SD setting (odds ratio, 6.09, P<0.001), and the parameters that suggest anatomic proximity surrounding the esophagus, were independent predictors of ETI. However, the majority of ETI in the HP-SD group was gastric hypomotility, and the thermal injury was limited to the shallow layer of the periesophageal wall using the HP-SD setting. CONCLUSIONS: Although the use of the HP-SD setting was a strong predictor of ETI, it could avoid deeper thermal injuries that reach the esophageal mucosal layer.
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Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc 25(4) e12749 2020年7月BACKGROUND: Cardiac amyloidosis (CA) is characterized by left ventricular hypertrophy (LVH) and autonomic nervous imbalance due to amyloid infiltration. However, autonomic dysfunction is often seen in heart failure (HF) with LVH from other etiologies. We aimed to characterize autonomic dysfunction in CA from other etiologies of LVH. METHODS: Fifty-five HF patients with LVH (35 males, mean age 65 ± 16 years) were enrolled. LVH was defined as left ventricular mass index measured by echocardiography >95 g/m2 in women and 115 g/m2 in men. The etiology was as follows: amyloid light chain (AL)-CA, n = 14; hypertrophic cardiomyopathy, n = 21; and aortic stenosis (AS), n = 20. With the patient in a clinically stable condition, heart rate variability (HRV) and heart rate turbulence (HRT), which reflect autonomic dysfunction, were measured using Holter monitoring and compared among the three groups. RESULTS: Brain natriuretic peptide levels, LVH severity, left ventricular ejection fraction, and tissue Doppler index E/e' did not differ among the three groups. However, severe abnormalities of HRV and HRT were obtained in AL-CA. In the ROC analysis to identify AL-CA in HF with LVH, the best cutoff value for standard deviation of all R-R intervals, standard deviation of the 5-min mean R-R intervals, turbulence onset, and turbulence slope were 68.5 ms (AUC: 0.865), 58.5 ms (AUC: 0.834), 0.25% (AUC: 0.813), and 1.00 ms/RR (AUC 0.736), respectively. CONCLUSION: Autonomic dysfunction is a hallmark of AL-CA, and its noninvasive assessment by Holter monitoring may be a useful tool for differential diagnosis of HF with LVH.
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Journal of Interventional Cardiac Electrophysiology 54(2) 101-108 2019年3月 査読有り
MISC
57-
日本循環器学会学術集会抄録集 85回 OJ46-3 2021年3月
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INTERNATIONAL HEART JOURNAL 56(6) 613-617 2015年11月Several studies have demonstrated that oral intake of n-3 polyunsaturated fatty acids, specifically eicosapentaenoic acid (EPA), prevents ventricular tachyarrhythmias (VT) with ischemic heart disease, but the underlying mechanisms still remain unclear. Thus, we examined the relation between the serum EPA/arachidonic acid (AA) ratio and electrophysiological properties in patients with ischemic heart disease. The study subjects consisted of 57 patients (46 males, mean age, 66 +/- 13 years) with ischemic heart disease. T-wave alternans (TWA) and heart rate variability were assessed by 24-hour Holier ECG, and left ventricular ejection fraction (LVEF) was determined by echocardiography. Fasting blood samples were collected, and the serum EPA/AA ratio was determined. Based on a median value of the serum EPA/AA ratio, all subjects were divided into two groups: serum EPA/AA ratio below 0.33 (Group-L, n = 28) or not (Group-H, n = 29). We compared these parameters between the two groups. LVEF was not different between the two groups. The maximum value of TWA was significantly higher in Group-L than in Group-H (69.5 +/- 22.8 mu V versus 48.7 +/- 12.0 mu V, P = 0.007). In addition, VT defined as above 3 beats was observed in 7 cases (25%) in Group-L, but there were no cases of VT in Group-H (P = 0.004). However, low-frequency (LF) component, high-frequency (HF) component, LF to BF ratio, and standard deviation of all R-R intervals were not different between the two groups. These results suggest that a low EPA/AA ratio may induce cardiac electrical instability, but not autonomic nervous imbalance, associated with VT in patients with ischemic heart disease.
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INTERNATIONAL HEART JOURNAL 56(6) 613-617 2015年11月Several studies have demonstrated that oral intake of n-3 polyunsaturated fatty acids, specifically eicosapentaenoic acid (EPA), prevents ventricular tachyarrhythmias (VT) with ischemic heart disease, but the underlying mechanisms still remain unclear. Thus, we examined the relation between the serum EPA/arachidonic acid (AA) ratio and electrophysiological properties in patients with ischemic heart disease. The study subjects consisted of 57 patients (46 males, mean age, 66 +/- 13 years) with ischemic heart disease. T-wave alternans (TWA) and heart rate variability were assessed by 24-hour Holier ECG, and left ventricular ejection fraction (LVEF) was determined by echocardiography. Fasting blood samples were collected, and the serum EPA/AA ratio was determined. Based on a median value of the serum EPA/AA ratio, all subjects were divided into two groups: serum EPA/AA ratio below 0.33 (Group-L, n = 28) or not (Group-H, n = 29). We compared these parameters between the two groups. LVEF was not different between the two groups. The maximum value of TWA was significantly higher in Group-L than in Group-H (69.5 +/- 22.8 mu V versus 48.7 +/- 12.0 mu V, P = 0.007). In addition, VT defined as above 3 beats was observed in 7 cases (25%) in Group-L, but there were no cases of VT in Group-H (P = 0.004). However, low-frequency (LF) component, high-frequency (HF) component, LF to BF ratio, and standard deviation of all R-R intervals were not different between the two groups. These results suggest that a low EPA/AA ratio may induce cardiac electrical instability, but not autonomic nervous imbalance, associated with VT in patients with ischemic heart disease.
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CLINICAL RESEARCH IN CARDIOLOGY 104(7) 544-554 2015年7月Ventricular arrhythmias (VAs) from the left ventricular outflow tract (LVOT) can originate from within or below the aortic sinus of valsalva (ASV). Mapping and ablation below the ASV is challenging and there are limited data predicting VA origins using electrocardiographic and electrophysiological features. Thirty-four patients (56.7 +/- A 15.2 years; 19 males) with symptomatic VAs were analyzed. VA origins were determined by successful ablation. Patients were classified into 2 groups (group 1, VAs within the ASV; group 2, VAs below the ASV). Local activation and QRS morphology were compared between these 2 groups. Twelve patients were classified as group 1 and 22 as group 2. Presystolic potentials (PPs) during VAs were present in 11 patients (91 %) in group 1 and 3 (13 %) in group 2. S-wave amplitude and duration in lead I were lower and shorter in group 1 vs. group 2, respectively. Q-wave aV(L)/aV(R) ratio (Q-aV(L)/aV(R)) was smaller in group 1 vs. group 2. No group 1 patients had Q-aV(L)/aV(R) > 1.45. PPs in the ASV was the strongest independent predictor for VAs originating within the ASV (OR: 30.003, P = 0.006). Deeper and longer S-waves in lead I and Q-aV(L)/aV(R) > 1.45 suggest VAs originating below the ASV. Local PPs strongly suggest an origin within the ASV. ECG characteristics combined with local PPs can be a practical guide for ablating LVOT-VAs.
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CLINICAL RESEARCH IN CARDIOLOGY 104(7) 544-554 2015年7月Ventricular arrhythmias (VAs) from the left ventricular outflow tract (LVOT) can originate from within or below the aortic sinus of valsalva (ASV). Mapping and ablation below the ASV is challenging and there are limited data predicting VA origins using electrocardiographic and electrophysiological features. Thirty-four patients (56.7 +/- A 15.2 years; 19 males) with symptomatic VAs were analyzed. VA origins were determined by successful ablation. Patients were classified into 2 groups (group 1, VAs within the ASV; group 2, VAs below the ASV). Local activation and QRS morphology were compared between these 2 groups. Twelve patients were classified as group 1 and 22 as group 2. Presystolic potentials (PPs) during VAs were present in 11 patients (91 %) in group 1 and 3 (13 %) in group 2. S-wave amplitude and duration in lead I were lower and shorter in group 1 vs. group 2, respectively. Q-wave aV(L)/aV(R) ratio (Q-aV(L)/aV(R)) was smaller in group 1 vs. group 2. No group 1 patients had Q-aV(L)/aV(R) > 1.45. PPs in the ASV was the strongest independent predictor for VAs originating within the ASV (OR: 30.003, P = 0.006). Deeper and longer S-waves in lead I and Q-aV(L)/aV(R) > 1.45 suggest VAs originating below the ASV. Local PPs strongly suggest an origin within the ASV. ECG characteristics combined with local PPs can be a practical guide for ablating LVOT-VAs.
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EUROPACE 17(3) 396-402 2015年3月Aims The multipolar irrigated radiofrequency (RF) ablation catheter (nMARQ (TM)) is a novel tool for pulmonary vein isolation (PVI). We investigated the incidence of thermal oesophageal injury (El) using the nMARQ (TM) for PVI. Methods and results In the initial six patients (Group 1), RF was delivered at the posterior wall with a maximum duration of 60 sand a maximum power (maxP) of 20W for unipolar ablation, and a maxP of 10W for the bipolar ablation. In the Latter 15 patients (Group 2), RF application was Limited at the posterior wall to a maximum duration of 30 sand a maxP of 15 Wfor unipolar ablation a max P of 10W for bipolar ablation. Oesophageal temperature monitoring was performed in all patients and ablation was terminated at a temperature rise >41 degrees C. Endoscopy was carried out within 2 days post-ablation. Pulmonary vein isolation was performed during sinus rhythm and was successfully achieved in 83 of 84 PVs except the septal inferior vein in one patient. Charring was seen in 3 of 21 (14.3%) patients without any evidence of embolism. Phrenic nerve patsy occurred in one patient. Endoscopy revealed severe El in 3 of 6 (50%) patients in Group 1 and in 1 of 15 patients (6.7%) in Group 2. Procedure times between Groups 1 and 2 were similar (228.3 + 60.2 min vs. 221.3 + 51.8 min; P = 0.79). Conclusion An unexpectedly high incidence of thermal El was noted following PVI using the nMARQ (TM) with the initial ablation protocol. However, the incidence of thermal El can be sigificantly reduced with limited power and RF application time at the posterior Left atrium.
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EUROPACE 17(3) 396-402 2015年3月Aims The multipolar irrigated radiofrequency (RF) ablation catheter (nMARQ (TM)) is a novel tool for pulmonary vein isolation (PVI). We investigated the incidence of thermal oesophageal injury (El) using the nMARQ (TM) for PVI. Methods and results In the initial six patients (Group 1), RF was delivered at the posterior wall with a maximum duration of 60 sand a maximum power (maxP) of 20W for unipolar ablation, and a maxP of 10W for the bipolar ablation. In the Latter 15 patients (Group 2), RF application was Limited at the posterior wall to a maximum duration of 30 sand a maxP of 15 Wfor unipolar ablation a max P of 10W for bipolar ablation. Oesophageal temperature monitoring was performed in all patients and ablation was terminated at a temperature rise >41 degrees C. Endoscopy was carried out within 2 days post-ablation. Pulmonary vein isolation was performed during sinus rhythm and was successfully achieved in 83 of 84 PVs except the septal inferior vein in one patient. Charring was seen in 3 of 21 (14.3%) patients without any evidence of embolism. Phrenic nerve patsy occurred in one patient. Endoscopy revealed severe El in 3 of 6 (50%) patients in Group 1 and in 1 of 15 patients (6.7%) in Group 2. Procedure times between Groups 1 and 2 were similar (228.3 + 60.2 min vs. 221.3 + 51.8 min; P = 0.79). Conclusion An unexpectedly high incidence of thermal El was noted following PVI using the nMARQ (TM) with the initial ablation protocol. However, the incidence of thermal El can be sigificantly reduced with limited power and RF application time at the posterior Left atrium.
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Journal of Cardiology Cases 10(5) 171-175 2014年11月1日We report a case with acute coronary syndrome due to in-stent plaque rupture that occurred 9 years after bare metal stent deployment. From the results of intravascular imaging and pathological findings, we diagnosed this case as acute coronary syndrome caused by in-stent plaque rupture. In-stent neoatherosclerosis is an important mechanism of very late stent thrombosis, and the intravascular imaging is helpful to identify this and to decide clinical judgment.< . Learning objective: In-stent neoatherosclerosis is an important mechanism of very late stent thrombosis, and the intravascular imaging is helpful to identify this and to decide clinical judgment> .
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Journal of Cardiology Cases 10(5) 171-175 2014年11月1日We report a case with acute coronary syndrome due to in-stent plaque rupture that occurred 9 years after bare metal stent deployment. From the results of intravascular imaging and pathological findings, we diagnosed this case as acute coronary syndrome caused by in-stent plaque rupture. In-stent neoatherosclerosis is an important mechanism of very late stent thrombosis, and the intravascular imaging is helpful to identify this and to decide clinical judgment.< . Learning objective: In-stent neoatherosclerosis is an important mechanism of very late stent thrombosis, and the intravascular imaging is helpful to identify this and to decide clinical judgment> .
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EUROPACE 16(9) 1387-1395 2014年9月Aims Clinical outcomes following radiofrequency ablation of ventricular tachycardias (VTs) depend on catheter tip-to-tissue contact force (CF). Left-ventricular (LV) mapping is performed via antegrade-transseptal or retrograde-transaortic approaches, and the applied CF may depend on the approach used. This study evaluated (i) the impact of antegrade-transseptal vs. retrograde- transaortic LV-mapping approaches on CF and catheter stability and (ii) the clinical value of the commonly used surrogate markers of catheter-myocardial contact-impedance, unipolar, and bipolar electrogram amplitudes. Methods and results An antegrade-transseptal and a retrograde-transaortic LV-mapping approach was performed in 10 patients undergoing VT ablation by using CF-sensing catheters. Operators were blinded to CF data and data were analysed according to 11 predefined LV segments. Three thousand three hundred and twenty-four mapping points (1577 antegrade, 1747 retrograde) were analysed, including 80 (2.4%) points with maximum CF > 100 g. Median antegrade and retrograde CF were 16.0 g (q1-q3; 8.4-26.2) and 15.3 g (9.8-23.4), respectively. Contact force was significantly higher antegradely in mid-anteroseptum, mid-lateral, and apical segments, and significantly higher retrogradely in basal-anteroseptum, basal-inferoseptum, basal-inferior, and basal-lateral segments. Contact force did correlate with impedance, unipolar, and bipolar electrogram amplitudes; however, there were large overlaps. Conclusions Antegrade vs. retrograde LV-mapping approaches result in different CF. A combined approach to the LV mapping may improve the overall LV mapping, potentially resulting in better clinical outcomes for the left VT catheter ablation. The previous surrogate markers used to assess CF docorrelate with in vivo CF; however, due to a larger over lap, their clinical value is limited.
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EUROPACE 16(9) 1387-1395 2014年9月Aims Clinical outcomes following radiofrequency ablation of ventricular tachycardias (VTs) depend on catheter tip-to-tissue contact force (CF). Left-ventricular (LV) mapping is performed via antegrade-transseptal or retrograde-transaortic approaches, and the applied CF may depend on the approach used. This study evaluated (i) the impact of antegrade-transseptal vs. retrograde- transaortic LV-mapping approaches on CF and catheter stability and (ii) the clinical value of the commonly used surrogate markers of catheter-myocardial contact-impedance, unipolar, and bipolar electrogram amplitudes. Methods and results An antegrade-transseptal and a retrograde-transaortic LV-mapping approach was performed in 10 patients undergoing VT ablation by using CF-sensing catheters. Operators were blinded to CF data and data were analysed according to 11 predefined LV segments. Three thousand three hundred and twenty-four mapping points (1577 antegrade, 1747 retrograde) were analysed, including 80 (2.4%) points with maximum CF > 100 g. Median antegrade and retrograde CF were 16.0 g (q1-q3; 8.4-26.2) and 15.3 g (9.8-23.4), respectively. Contact force was significantly higher antegradely in mid-anteroseptum, mid-lateral, and apical segments, and significantly higher retrogradely in basal-anteroseptum, basal-inferoseptum, basal-inferior, and basal-lateral segments. Contact force did correlate with impedance, unipolar, and bipolar electrogram amplitudes; however, there were large overlaps. Conclusions Antegrade vs. retrograde LV-mapping approaches result in different CF. A combined approach to the LV mapping may improve the overall LV mapping, potentially resulting in better clinical outcomes for the left VT catheter ablation. The previous surrogate markers used to assess CF docorrelate with in vivo CF; however, due to a larger over lap, their clinical value is limited.
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CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY 7(3) 445-455 2014年6月Background Ventricular arrhythmias (VAs) originating from the anterosuperior left ventricular outflow tract (LVOT) represent a challenging location for catheter ablation. This study investigates mapping and ablation of VA from anterosuperior LVOT via a transseptal approach. Methods and Results This study included 27 patients with symptomatic VA, of which 13 patients had previous failed ablations. LVOT endocardial 3-dimensional mapping via retrograde transaortic and antegrade transseptal approaches was performed. Previous ECG markers for procedure failure were analyzed. In all patients, earliest activation with low-amplitude potentials was identified at the anterosuperior LVOT 5.12.8 mm below the aortic cusp and preceded the QRS onset by 39.5 +/- 7.7 ms only via an antegrade transseptal approach using a reversed S curve. In all patients, pace mapping failed to demonstrate perfect QRS morphology match. The anatomic location was below the left coronary cusp in 16, below the left coronary cusp/right coronary cusp junction in 8, and below the right coronary cusp in 3 patients. Radiofrequency energy resulted in rapid disappearance of VAs in all patients. ECG analysis showed aVL/aVR Q-wave amplitude ratio >1.4 in 7, lead III/II R-wave amplitude ratio >1.1 in 10, and peak deflection index >0.6 in 11 patients. There were no complications or clinical VA recurrence during a mean follow-up of 8.4 +/- 2.5 months. Conclusions The anterosuperior LVOT can be reached via a transseptal approach with a reversed S curve of the ablation catheter. The rapid effect from radiofrequency energy indicates that the VA is most likely located under the endocardium. Also, previous ECG markers for procedure failure need further investigation.
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CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY 7(3) 445-455 2014年6月Background Ventricular arrhythmias (VAs) originating from the anterosuperior left ventricular outflow tract (LVOT) represent a challenging location for catheter ablation. This study investigates mapping and ablation of VA from anterosuperior LVOT via a transseptal approach. Methods and Results This study included 27 patients with symptomatic VA, of which 13 patients had previous failed ablations. LVOT endocardial 3-dimensional mapping via retrograde transaortic and antegrade transseptal approaches was performed. Previous ECG markers for procedure failure were analyzed. In all patients, earliest activation with low-amplitude potentials was identified at the anterosuperior LVOT 5.12.8 mm below the aortic cusp and preceded the QRS onset by 39.5 +/- 7.7 ms only via an antegrade transseptal approach using a reversed S curve. In all patients, pace mapping failed to demonstrate perfect QRS morphology match. The anatomic location was below the left coronary cusp in 16, below the left coronary cusp/right coronary cusp junction in 8, and below the right coronary cusp in 3 patients. Radiofrequency energy resulted in rapid disappearance of VAs in all patients. ECG analysis showed aVL/aVR Q-wave amplitude ratio >1.4 in 7, lead III/II R-wave amplitude ratio >1.1 in 10, and peak deflection index >0.6 in 11 patients. There were no complications or clinical VA recurrence during a mean follow-up of 8.4 +/- 2.5 months. Conclusions The anterosuperior LVOT can be reached via a transseptal approach with a reversed S curve of the ablation catheter. The rapid effect from radiofrequency energy indicates that the VA is most likely located under the endocardium. Also, previous ECG markers for procedure failure need further investigation.
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INTERNATIONAL HEART JOURNAL 55(3) 249-255 2014年5月In addition to contact force (CF), catheter stability is considered to be an important factor in creating radiofrequency lesions. To evaluate the catheter stability during pulmonary vein isolation (PVI) using CF-sensing catheter. PVI was performed in 32 patients using a CF-sensing catheter. Operators were blinded to CF. The application was arbitrarily defined as a "visually unstable" point if the catheter moved >= 4 mm Data were analyzed according to 6 predefined segments for the ipsilateral PVs. As a parameter of catheter stability, the standard deviation (SD) of CF and relative standard deviation (RSD = 100 x SD of CF/average CF) were introduced. A total of 932 RF applications with 426 visually unstable points (UP; 45.7%) and 506 stable points (SP; 54.3%) were analyzed. SD was significantly higher at UP (8.0g versus 5.7g, P < 0.001), and RSD was significantly higher at UP (43.7% versus 26.5%, P < 0.001). Higher RSD was associated with visual instability in all the segments of both PVs, however, higher SD of CF was not in all segments. At the antero-superior segment of the LPV, and the roof and postero-inferior segments of the RPV, the RSD values were over 50%, suggesting catheter instability. Catheter instability occurred in 45% of ablations during PVI and was predominantly located in the antero-superior segment of the LPV and postero-inferior segment of the RPV, which may result in incomplete lesion formation. RSD had significant correlation with visual catheter stability.
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JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY 25(5) 466-470 2014年5月The Incidence of Phrenic Nerve Injury Introduction The second-generation cryoballoon (CB; Arctic Front Advance, Medtronic Inc., Minneapolis, MN, USA) has demonstrated greater procedural efficacy compared to the original CB. Whether increased efficacy translates into a higher incidence of phrenic nerve (PN) injury needs further evaluation. Materials and Methods In patients with drug-refractory paroxysmal atrial fibrillation (AF) or short-standing persistent AF, pulmonary vein isolation (PVI) was performed using the 28 mm second-generation CB. During cryoenergy delivery along the septal PVs, continuous PN pacing was performed. The freeze cycle was aborted in case of weakening or loss of diaphragmatic contraction. Results A total of 115 patients (42 female, mean age 61 +/- 11 years, mean LA-diameter 43 +/- 6 mm) with a history of paroxysmal AF (93/115 patients [81%]) or short-standing persistent AF (22/115 patients [19%]) underwent CB-based PVI. A total 445 of 448 (99%) PVs were isolated successfully. PN palsy (PNP) occurred in 4 of 115 (3.5%) patients, while applying cryoenergy to the right superior PV. Despite prompt interruption of the freezing cycle, PN function failed to recover during the periprocedural phase. PN recovery was observed as late as 10 months postablation. Conclusions Using the second-generation 28 mm CB, PNP occurred in 4 of 115 (3.5%) patients. While 1 of 4 PNP recovered 10 months after ablation, long-term outcome in the remaining 3 patients is currently unknown due to the rather short follow-up period.
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INTERNATIONAL HEART JOURNAL 55(3) 249-255 2014年5月In addition to contact force (CF), catheter stability is considered to be an important factor in creating radiofrequency lesions. To evaluate the catheter stability during pulmonary vein isolation (PVI) using CF-sensing catheter. PVI was performed in 32 patients using a CF-sensing catheter. Operators were blinded to CF. The application was arbitrarily defined as a "visually unstable" point if the catheter moved >= 4 mm Data were analyzed according to 6 predefined segments for the ipsilateral PVs. As a parameter of catheter stability, the standard deviation (SD) of CF and relative standard deviation (RSD = 100 x SD of CF/average CF) were introduced. A total of 932 RF applications with 426 visually unstable points (UP; 45.7%) and 506 stable points (SP; 54.3%) were analyzed. SD was significantly higher at UP (8.0g versus 5.7g, P < 0.001), and RSD was significantly higher at UP (43.7% versus 26.5%, P < 0.001). Higher RSD was associated with visual instability in all the segments of both PVs, however, higher SD of CF was not in all segments. At the antero-superior segment of the LPV, and the roof and postero-inferior segments of the RPV, the RSD values were over 50%, suggesting catheter instability. Catheter instability occurred in 45% of ablations during PVI and was predominantly located in the antero-superior segment of the LPV and postero-inferior segment of the RPV, which may result in incomplete lesion formation. RSD had significant correlation with visual catheter stability.
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JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY 25(5) 466-470 2014年5月The Incidence of Phrenic Nerve Injury Introduction The second-generation cryoballoon (CB; Arctic Front Advance, Medtronic Inc., Minneapolis, MN, USA) has demonstrated greater procedural efficacy compared to the original CB. Whether increased efficacy translates into a higher incidence of phrenic nerve (PN) injury needs further evaluation. Materials and Methods In patients with drug-refractory paroxysmal atrial fibrillation (AF) or short-standing persistent AF, pulmonary vein isolation (PVI) was performed using the 28 mm second-generation CB. During cryoenergy delivery along the septal PVs, continuous PN pacing was performed. The freeze cycle was aborted in case of weakening or loss of diaphragmatic contraction. Results A total of 115 patients (42 female, mean age 61 +/- 11 years, mean LA-diameter 43 +/- 6 mm) with a history of paroxysmal AF (93/115 patients [81%]) or short-standing persistent AF (22/115 patients [19%]) underwent CB-based PVI. A total 445 of 448 (99%) PVs were isolated successfully. PN palsy (PNP) occurred in 4 of 115 (3.5%) patients, while applying cryoenergy to the right superior PV. Despite prompt interruption of the freezing cycle, PN function failed to recover during the periprocedural phase. PN recovery was observed as late as 10 months postablation. Conclusions Using the second-generation 28 mm CB, PNP occurred in 4 of 115 (3.5%) patients. While 1 of 4 PNP recovered 10 months after ablation, long-term outcome in the remaining 3 patients is currently unknown due to the rather short follow-up period.
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CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY 7(2) 288-292 2014年4月Background The use of second-generation cryoballoon for pulmonary vein isolation in patients with paroxysmal atrial fibrillation has demonstrated encouraging acute and mid-term results. Long-term outcome data are not yet available. Methods and Results Fifty patients (18 women; mean age, 6111 years; mean left atrial diameter, 43 +/- 5 mm) with paroxysmal (36 of 50 patients; 72%) or short-standing (<3-month duration) persistent atrial fibrillation (14 of 50 patients; 28%) underwent cryoballoon-based pulmonary vein isolation. Freeze cycle duration was 240 seconds. After successful pulmonary vein isolation, a bonus freeze was applied. Follow-up was based on outpatient clinic visits at 3, 6, and 12 months including Holter-ECGs and telephonic interviews. Recurrence was defined as a symptomatic or documented arrhythmia episode >30 seconds excluding a 3-month blanking period. A total of 192 pulmonary veins were identified, and 191 of 192 (99%) pulmonary veins were successfully isolated. Phrenic nerve palsy occurred in 1 of 50 (2%) patients. Follow-up was available for 49 of 50 (98%) patients with a mean follow-up duration of 440 +/- 39 days. Thirty-nine of 49 (80%) patients remained in stable sinus rhythm. Of 8 of 10 patients with arrhythmia recurrence, a second procedure using radiofrequency ablation demonstrated left atrial to pulmonary vein reconduction. Conclusions The use of second-generation 28-mm cryoballoon for pulmonary vein isolation results in an 80% 1-year success rate.
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CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY 7(2) 288-292 2014年4月Background The use of second-generation cryoballoon for pulmonary vein isolation in patients with paroxysmal atrial fibrillation has demonstrated encouraging acute and mid-term results. Long-term outcome data are not yet available. Methods and Results Fifty patients (18 women; mean age, 6111 years; mean left atrial diameter, 43 +/- 5 mm) with paroxysmal (36 of 50 patients; 72%) or short-standing (<3-month duration) persistent atrial fibrillation (14 of 50 patients; 28%) underwent cryoballoon-based pulmonary vein isolation. Freeze cycle duration was 240 seconds. After successful pulmonary vein isolation, a bonus freeze was applied. Follow-up was based on outpatient clinic visits at 3, 6, and 12 months including Holter-ECGs and telephonic interviews. Recurrence was defined as a symptomatic or documented arrhythmia episode >30 seconds excluding a 3-month blanking period. A total of 192 pulmonary veins were identified, and 191 of 192 (99%) pulmonary veins were successfully isolated. Phrenic nerve palsy occurred in 1 of 50 (2%) patients. Follow-up was available for 49 of 50 (98%) patients with a mean follow-up duration of 440 +/- 39 days. Thirty-nine of 49 (80%) patients remained in stable sinus rhythm. Of 8 of 10 patients with arrhythmia recurrence, a second procedure using radiofrequency ablation demonstrated left atrial to pulmonary vein reconduction. Conclusions The use of second-generation 28-mm cryoballoon for pulmonary vein isolation results in an 80% 1-year success rate.
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HEART RHYTHM 11(2) 330-335 2014年2月
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CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY 7(1) 46-54 2014年2月
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HEART RHYTHM 11(2) 330-335 2014年2月
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CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY 7(1) 46-54 2014年2月
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Journal of General Practice 2(4) 1000160 2014年
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Journal of General Practice 2(4) 1000160 2014年
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CIRCULATION JOURNAL 77(6) 1466-1473 2013年6月Background: It has been shown that sleep-disordered breathing (SDB) is associated with adverse prognosis in patients with chronic heart failure (CHF), but little is known about the relationship between SDB and life-threatening arrhythmias. Methods and Results: Fifty patients with CHF and SDB (33 male; mean age, 61 years) underwent Hotter electrocardiogram and portable sleep monitoring simultaneously. The circadian variation in positive T-wave alternans (TWA; >65 mu V) was determined during 6-h intervals (0-6, 6-12, 12-18, and 18-24h). In addition, power spectral analysis of heart rate variability (HRV) was evaluated across a 24-h period. The subjects were divided into 2 groups based on whether respiratory disturbance index was >= 20events/h (Group A, n=24) or not (Group B, n=26). The prevalence of positive TWA, parameters in HRV and the occurrence of ventricular tachycardia (>5 beats) were compared between the 2 groups. The prevalence of positive TWA in Group A was significantly higher than that in Group B in all 6-h intervals. Low-frequency and high-frequency powers of HRV were significantly lower in Group A than in Group B across a 24-h period. Importantly, the prevalence of ventricular tachycardia was significantly higher in Group A than in Group B (46% vs. 19%, P=0.04). Conclusions: SDB may induce cardiac electrical instability associated with life-threatening arrhythmias across a 24-h period in CHF.
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Circulation Journal 77(6) 1466-1473 2013年Background: It has been shown that sleep-disordered breathing (SDB) is associated with adverse prognosis in patients with chronic heart failure (CHF), but little is known about the relationship between SDB and life-threatening arrhythmias. Methods and Results: Fifty patients with CHF and SDB (33 male mean age, 61 years) underwent Holter electrocardiogram and portable sleep monitoring simultaneously. The circadian variation in positive T-wave alternans (TWA > 65 μV) was determined during 6-h intervals (0-6, 6-12, 12-18, and 18-24 h). In addition, power spectral analysis of heart rate variability (HRV) was evaluated across a 24-h period. The subjects were divided into 2 groups based on whether respiratory disturbance index was ≥20 events/h (Group A, n=24) or not (Group B, n=26). The prevalence of positive TWA, parameters in HRV and the occurrence of ventricular tachycardia (> 5 beats) were compared between the 2 groups. The prevalence of positive TWA in Group A was significantly higher than that in Group B in all 6-h intervals. Low-frequency and high-frequency powers of HRV were significantly lower in Group A than in Group B across a 24-h period. Importantly, the prevalence of ventricular tachycardia was significantly higher in Group A than in Group B (46% vs. 19%, P=0.04). Conclusions: SDB may induce cardiac electrical instability associated with life-threatening arrhythmias across a 24-h period in CHF.
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JOURNAL OF CARDIOLOGY 60(3-4) 222-227 2012年9月Background: Cheyne-Stokes respiration (CSR-CSA) is often observed in patients with chronic heart failure (CHF). Although cardiac resynchronization therapy (CRT) is effective for CHF patients with left ventricular dyssynchrony, it is still unclear whether adaptive servo ventilation (ASV) improves cardiac function and prognosis of CHF patients with CSR-CSA after CRT. Methods and results: Twenty two patients with CHF and CSR-CSA after CRT defibrillator (CRTD) implantation were enrolled in the present study and randomly assigned into two groups: 11 patients treated with ASV (ASV group) and 11 patients treated without ASV (non-ASV group). Measurement of plasma B-type natriuretic peptide (BNP) levels (before 3, and 6 months later) and echocardiography (before and 6 months) were performed in each group. Patients were followed up to register cardiac events (cardiac death and re-hospitalization) after discharge. In the ASV group, indices for apnea-hypopnea, central apnea, and oxyhemoglobin saturation were improved on ASV. BNP levels, cardiac systolic and diastolic function were improved with ASV treatment for 6 months. Importantly, the event-free rate was significantly higher in the ASV group than in the non-ASV group. Conclusions: ASV improves CSR-CSA, cardiac function, and prognosis in CHF patients with CRTD. Patients with CSR-CSA and post CRTD implantation would get benefits by treatment with ASV. (C) 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
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INTERNATIONAL HEART JOURNAL 53(5) 306-312 2012年9月The purpose of this study was to determine whether high sensitivity C-reactive protein (hsCRP) before cardiac re-synchronization therapy (CRT) implantation was able to predict the response to CRT and cardiac deaths in severe heart failure patients. The study population consisted of 65 heart failure patients (46 males, mean age 65.0 +/- 11.8 years, NYHA class III/IV) with CRT implantation. Levels of hsCRP and B-type natriuretic peptide (BNP) were measured before CRT implantation. Left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI), and left ventricular ejection fraction (LVEF) were assessed by echocardiography at the same time. At 6 months after device implantation follow-up, echocardiography was performed and reverse remodeling was defined as > 15% reduction in LVESV. Of the 61 patients (4 patients died within 6 months), 41 patients (67%) and 20 patients (33%) were classified as responders (group-R) and nonresponders (group-NR), respectively. Cardiac deaths occurred more frequently in group-NR than in group-R (29% versus 5%, P < 0.05). Hs-CRP level was significantly higher in group-NR than in group-R (P < 0.01). Multivariate logistic regression analysis showed an independent relationship between hsCRP and the incidence of nonresponders (odds ratio: 1.499, P = 0.011). Stepwise multivariate Cox proportional hazard analysis identified the hsCRP level as the strongest predictive factor for cardiac death (hazard ratio: 1.337, P = 0.001). Receiver operating characteristic (ROC) analysis revealed hsCRP levels of 3.0 mg/L as the cut-off value for cardiac mortality. The hsCRP level may provide a new insight into CRT implantation for severe heart failure by predicting responses to CRT and cardiac death. (Int Heart J 2012; 53: 306-312)
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International Heart Journal 53(5) 306-312 2012年The purpose of this study was to determine whether high sensitivity C-reactive protein (hsCRP) before cardiac resynchronization therapy (CRT) implantation was able to predict the response to CRT and cardiac deaths in severe heart failure patients. The study population consisted of 65 heart failure patients (46 males, mean age 65.0 ± 11.8 years, NYHA class III/IV) with CRT implantation. Levels of hsCRP and B-type natriuretic peptide (BNP) were measured before CRT implantation. Left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI), and left ventricular ejection fraction (LVEF) were assessed by echocardiography at the same time. At 6 months after device implantation follow-up, echocardiography was performed and reverse remodeling was defined as > 15% reduction in LVESV. Of the 61 patients (4 patients died within 6 months), 41 patients (67%) and 20 patients (33%) were classified as responders (group-R) and nonresponders (group-NR), respectively. Cardiac deaths occurred more frequently in group-NR than in group-R (29% versus 5%, P < 0.05). Hs-CRP level was significantly higher in group-NR than in group-R (P < 0.01). Multivariate logistic regression analysis showed an independent relationship between hsCRP and the incidence of nonresponders (odds ratio: 1.499, P = 0.011). Stepwise multivariate Cox proportional hazard analysis identified the hsCRP level as the strongest predictive factor for cardiac death (hazard ratio: 1.337, P = 0.001). Receiver operating characteristic (ROC) analysis revealed hsCRP levels of 3.0 mg/L as the cut-off value for cardiac mortality. The hsCRP level may provide a new insight into CRT implantation for severe heart failure by predicting responses to CRT and cardiac death.
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Fukushima Journal of Medical Science 58(2) 101-106 2012年Backgrounds. Elevated uric acid (UA) level is reported to be related to the development of left ventricular hypertrophy (LVH) which is associated with high incidence of ventricular tachycardia (VT) and sudden cardiac death. However, little is known about the association between serum UA levels and the occurrence of VT. Thus, we examined the relationship between serum UA levels and the appearance of VT in patients with LVH. Methods. The study subjects consisted of 167 patients (110 males, mean age 67.4 ± 12.7 years) with LVH detected by echocardiography. These patients were divided into two groups based on whether VT was presented (defined by more than 5 beats, n=27) or not (n=140) by 24-hour Holter ECG monitoring. Left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVDd), the E/A ratio and deceleration time of transmitral flow velocity were assessed by echocardiography in each group. In addition, blood urea nitrogen (BUN), creatinine, estimated glomerular filtration rate (eGFR), sodium, potassium, hemoglobin, total bilirubin and UA were compared in each group. Results. Echocardiographic findings did not show the difference between the two groups. However, BUN and UA levels in the VT group were significantly higher than those in the Non-VT group (p< 0.01). eGFR was significantly lower in the VT group than that in the Non-VT group (p< 0.01). A multivariate logistic regression analysis identified the UA level as an independent predictive factor for the occurrence of VT (odds ratio 1.61, 95% confidence interval 1.1-2.2, p< 0.01). Conclusions. These results suggest that serum UA level is a useful marker for predicting ventricular arrhythmias in patients with LVH.
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Journal of Cardiology 60(3) 222-227 2012年
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Fukushima Journal of Medical Science 58(2) 101-106 2012年
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JOURNAL OF CELLULAR PHYSIOLOGY 226(6) 1554-1563 2011年6月An advanced glycation end products (AGE)/a receptor for AGE (RAGE) axis plays a key role in diabetic vascular complications. Membrane type 1-matrix metalloproteinase (MT1-MMP) has been shown to function not only as a proteolytic enzyme but also as a signaling molecule. In this study, we investigated the role of MT1-MMP in the AGE/RAGE-triggered signaling pathways in cultured rabbit smooth muscle cells (SMCs) and the molecular interaction between RAGE and MT1-MMP in vitro and in vivo. In SMCs, AGE-activated Rac1 and p47(phox) within 1 min, NADPH oxidase activity and reactive oxygen species (ROS) generation within 5 min, and NF-kappa B phosphorylation within 15 min, thereby inducing redox-sensitive molecular expression. Silencing of RAGE by small-interfering RNA (siRNA) blocked the AGE-induced signaling pathways. AGE-induced geranylgeranyl transferase I (GGTase I) activity, Rac1.p47(phox) activation, NADPH oxidase activity, ROS generation, and molecular expression were also markedly attenuated by silencing of MT1-MMP. An inhibitor of GGTase I mimicked the effects of MT1-MMP-specific siRNA. Fluorescent immunohistochemistry revealed that MT1-MMP was partially co-localized with RAGE in SMCs, and RAGE was found to form a complex with MT1-MMP in both cultured SMCs and the aortae of diabetic rats by immunoprecipitation. Furthermore, MT1-MMP and RAGE formed a complex in the aortic atherosclerotic lesions of hyperlipidemic rabbits. We show that MT1-MMP plays a crucial role in RAGE-activated NADPH oxidase-dependent signaling pathways and forms a complex with RAGE in the vasculature, thus suggesting that MT1-MMP may be a novel therapeutic target for diabetic vascular complications. J. Cell. Physiol. 226: 1554-1563, 2011. (C) 2010 Wiley-Liss, Inc.
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JOURNAL OF CELLULAR PHYSIOLOGY 226(6) 1554-1563 2011年6月An advanced glycation end products (AGE)/a receptor for AGE (RAGE) axis plays a key role in diabetic vascular complications. Membrane type 1-matrix metalloproteinase (MT1-MMP) has been shown to function not only as a proteolytic enzyme but also as a signaling molecule. In this study, we investigated the role of MT1-MMP in the AGE/RAGE-triggered signaling pathways in cultured rabbit smooth muscle cells (SMCs) and the molecular interaction between RAGE and MT1-MMP in vitro and in vivo. In SMCs, AGE-activated Rac1 and p47(phox) within 1 min, NADPH oxidase activity and reactive oxygen species (ROS) generation within 5 min, and NF-kappa B phosphorylation within 15 min, thereby inducing redox-sensitive molecular expression. Silencing of RAGE by small-interfering RNA (siRNA) blocked the AGE-induced signaling pathways. AGE-induced geranylgeranyl transferase I (GGTase I) activity, Rac1.p47(phox) activation, NADPH oxidase activity, ROS generation, and molecular expression were also markedly attenuated by silencing of MT1-MMP. An inhibitor of GGTase I mimicked the effects of MT1-MMP-specific siRNA. Fluorescent immunohistochemistry revealed that MT1-MMP was partially co-localized with RAGE in SMCs, and RAGE was found to form a complex with MT1-MMP in both cultured SMCs and the aortae of diabetic rats by immunoprecipitation. Furthermore, MT1-MMP and RAGE formed a complex in the aortic atherosclerotic lesions of hyperlipidemic rabbits. We show that MT1-MMP plays a crucial role in RAGE-activated NADPH oxidase-dependent signaling pathways and forms a complex with RAGE in the vasculature, thus suggesting that MT1-MMP may be a novel therapeutic target for diabetic vascular complications. J. Cell. Physiol. 226: 1554-1563, 2011. (C) 2010 Wiley-Liss, Inc.
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心臓 43(6) 760-765 2011年早期再分極は広く健常者でもみられる心電図変化で, 人口の1～5％に認められる. 近年, 特発性心室細動患者の中に下壁誘導で早期再分極を認める患者群の存在が報告され, 注目を集めている. われわれは, 特発性心室細動蘇生後の12誘導心電図において, 下壁誘導でST上昇を呈した症例を経験した. 胸部X線では心拡大, 肺うっ血は認めず, 心臓超音波検査でも器質的心疾患を示唆する異常所見はなかった. 入院後の深夜3時に記録した心電図においてST上昇が顕在化した. 冠動脈造影では, 有意狭窄はみられなかったが, アセチルコリン負荷でST上昇が顕在化し, 右室早期三連刺激にて, 心室細動が誘発された. 一方, イソプロテレノール負荷下ではST上昇は基線に戻り, 心室細動は誘発されなかった. 以上より, 本症例の心室細動の発症ならびに早期再分極の増悪に迷走神経の緊張が関与している可能性が示唆された.
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CARDIOVASCULAR RESEARCH 88(3) 492-501 2010年12月Small GTPases RhoA and Rac1 play crucial roles in endothelial dysfunction and reactive oxygen species (ROS) generation. We reported evidence that in thrombin-stimulated endothelial cells, rapid geranylgeranylation is an essential process for full activation of unprocessed RhoA, which is blocked by statin. In this study, we examined the effects of intravenous administration of pravastatin on thrombin-triggered vascular responses in vivo, as well as on the lipid modification of unprocessed forms of RhoA and Rac1 and their activation induced by thrombin. Thrombin (50 U/kg) was intravenously injected with or without 0.3 mg/kg pravastatin into Wistar and spontaneously hypertensive rats. Coadministration of pravastatin prevented thrombin-induced impaired endothelium-dependent coronary vasodilation and down-regulated Akt/endothelial nitric oxide synthase (eNOS) phosphorylation within 1 h, as well as the down-regulation of eNOS protein expression within 4 h. In addition, thrombin increased Rac1/p47(phox)-dependent NAD(P)H oxidase activities of rat aortas within 1 h, resulting in ROS generation, which was prevented by the coadministration of pravastatin. Furthermore, the coadministration of pravastatin prevented thrombin-induced conversion of unprocessed RhoA and Rac1 into the geranylgeranylated forms as well as GTP-loading and membrane translocation within 1 h. Intravenous injection of pravastatin prevents impaired NO-dependent vasodilation and Rac1/NAD(P)H oxidase-mediated-ROS generation by blocking the down-regulation of Akt/eNOS pathways and the full activation of unprocessed RhoA and Rac1 in vivo.
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CARDIOVASCULAR RESEARCH 88(3) 492-501 2010年12月Small GTPases RhoA and Rac1 play crucial roles in endothelial dysfunction and reactive oxygen species (ROS) generation. We reported evidence that in thrombin-stimulated endothelial cells, rapid geranylgeranylation is an essential process for full activation of unprocessed RhoA, which is blocked by statin. In this study, we examined the effects of intravenous administration of pravastatin on thrombin-triggered vascular responses in vivo, as well as on the lipid modification of unprocessed forms of RhoA and Rac1 and their activation induced by thrombin. Thrombin (50 U/kg) was intravenously injected with or without 0.3 mg/kg pravastatin into Wistar and spontaneously hypertensive rats. Coadministration of pravastatin prevented thrombin-induced impaired endothelium-dependent coronary vasodilation and down-regulated Akt/endothelial nitric oxide synthase (eNOS) phosphorylation within 1 h, as well as the down-regulation of eNOS protein expression within 4 h. In addition, thrombin increased Rac1/p47(phox)-dependent NAD(P)H oxidase activities of rat aortas within 1 h, resulting in ROS generation, which was prevented by the coadministration of pravastatin. Furthermore, the coadministration of pravastatin prevented thrombin-induced conversion of unprocessed RhoA and Rac1 into the geranylgeranylated forms as well as GTP-loading and membrane translocation within 1 h. Intravenous injection of pravastatin prevents impaired NO-dependent vasodilation and Rac1/NAD(P)H oxidase-mediated-ROS generation by blocking the down-regulation of Akt/eNOS pathways and the full activation of unprocessed RhoA and Rac1 in vivo.
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JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 17(1) 54-63 2010年Aim: We investigated the role of endothelin-1 (ET-1) in coronary microvascular spasm in a porcine model. Methods: A flowmeter was implanted around the left anterior descending coronary artery (LAD), and epicardial coronary artery endothelial denudation (ED) was performed just distal to the flowmeter every 2 weeks (W) until 6 W in 10 pigs (ED group). Ten pigs were chronically treated with endothelia type A receptor (ETA) antagonist (TA-0201, 0.1 mg/kg/day, ED + ETA group), while neither ED nor administration of ETA antagonist was performed in 12 pigs (Control group). We assessed changes in LAD blood flow and the denuded site diameter induced by acetylcholine (ACh, 0.05 mu g/kg i.c.). Results: In the ED group, administration of ACh to LAD induced zero flow without LAD diameter reduction at 8 W In the ED + ETA group, the decrease in LAD blood flow response to ACh was suppressed. Chronic administration of TA-0201 suppressed ROS generation in the myocardium. Decreases of eNOS and intimal thickening were smaller in the TA-0201 administration group than the non-TA-0201 administration group. Conclusion: Chronic administration of ETA receptor antagonist is effective to prevent coronary microvascular spasm.
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JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 17(6) 590-600 2010年Aim: Advanced glycation end products (AGE) and a receptor for AGE (RAGE) play a key role in diabetic vascular complications. Matrix metalloproteinases (MMPs) and apoptosis contribute to plaque instability. The renin-angiotensin system (RAS) is crucial for NADPH oxidase-dependent redox signaling pathways in the vascular wall. We investigated the effects of RAS blockade on AGE-triggered signaling pathways and its downstream events, including MMP-9 and apoptosis. Methods: We used cultured rabbit aortic smooth muscle cells (SMCs), which were stimulated with AGE in the presence or absence of temocaprilat or olmesartan. Results: Angiotensin converting enzyme (ACE) mRNA levels were increased 4 to 6 hours after adding AGE. AGE induced Rac1 and p47(phox) membrane translocation, reactive oxygen species (ROS) generation and NF-kappa B phosphorylation within 15 minutes, and various molecular expressions after 18 hours, which were attenuated by RAS blockade by temocaprilat or olmesartan. AGE-induced RAGE expression, as well as other molecules, including membrane type 1-MMP (MT1-MMP), monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1), was NADPH oxidase signaling-dependent and blunted by temocaprilat and olmesartan. The parameters of plaque instability, including MMP-9 expression and activity, and apoptosis were up-regulated by AGE, which was markedly attenuated by temocaprilat or olmesartan. Using isolated human monocyte culture, AGE-induced ROS generation and molecular expression were also attenuated by RAS blockade. Conclusion: The present study shows that AGE-triggered NADPH oxidase signaling pathways, including MMP-9 and apoptosis, were attenuated by RAS blockade, which may be an attractive strategy for treating plaque instability in diabetic vascular complications.
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JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 17(1) 54-63 2010年Aim: We investigated the role of endothelin-1 (ET-1) in coronary microvascular spasm in a porcine model. Methods: A flowmeter was implanted around the left anterior descending coronary artery (LAD), and epicardial coronary artery endothelial denudation (ED) was performed just distal to the flowmeter every 2 weeks (W) until 6 W in 10 pigs (ED group). Ten pigs were chronically treated with endothelia type A receptor (ETA) antagonist (TA-0201, 0.1 mg/kg/day, ED + ETA group), while neither ED nor administration of ETA antagonist was performed in 12 pigs (Control group). We assessed changes in LAD blood flow and the denuded site diameter induced by acetylcholine (ACh, 0.05 mu g/kg i.c.). Results: In the ED group, administration of ACh to LAD induced zero flow without LAD diameter reduction at 8 W In the ED + ETA group, the decrease in LAD blood flow response to ACh was suppressed. Chronic administration of TA-0201 suppressed ROS generation in the myocardium. Decreases of eNOS and intimal thickening were smaller in the TA-0201 administration group than the non-TA-0201 administration group. Conclusion: Chronic administration of ETA receptor antagonist is effective to prevent coronary microvascular spasm.
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Journal of Atherosclerosis and Thrombosis 17(6) 590-600 2010年Aim: Advanced glycation end products (AGE) and a receptor for AGE (RAGE) play a key role in diabetic vascular complications. Matrix metalloproteinases (MMPs) and apoptosis contribute to plaque instability. The renin-angiotensin system (RAS) is crucial for NADPH oxidase-dependent redox signaling pathways in the vascular wall. We investigated the effects of RAS blockade on AGE-triggered signaling pathways and its downstream events, including MMP-9 and apoptosis. Methods: We used cultured rabbit aortic smooth muscle cells (SMCs), which were stimulated with AGE in the presence or absence of temocaprilat or olmesartan. Results: Angiotensin converting enzyme (ACE) mRNA levels were increased 4 to 6 hours after adding AGE. AGE induced Rac1 and p47phox membrane translocation, reactive oxygen species (ROS) generation and NF-κB phosphorylation within 15 minutes, and various molecular expressions after 18 hours, which were attenuated by RAS blockade by temocaprilat or olmesartan. AGE-induced RAGE expression, as well as other molecules, including membrane type 1-MMP (MT1-MMP), monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1), was NADPH oxidase signaling-dependent and blunted by temocaprilat and olmesartan. The parameters of plaque instability, including MMP-9 expression and activity, and apoptosis were up-regulated by AGE, which was markedly attenuated by temocaprilat or olmesartan. Using isolated human monocyte culture, AGE-induced ROS generation and molecular expression were also attenuated by RAS blockade. Conclusion: The present study shows that AGE-triggered NADPH oxidase signaling pathways, including MMP-9 and apoptosis, were attenuated by RAS blockade, which may be an attractive strategy for treating plaque instability in diabetic vascular complications.
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JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 16(6) 846-856 2009年12月Aim: The activation of RhoA and Rac1 is crucial for the pathogenesis of atherosclerosis. This study investigated the changes of unprocessed and mature forms of RhoA and Rac1 in the progression of atherosclerosis. Methods: Unprocessed and geranylgeranylated forms of RhoA and Rac1 in aortic atherosclerotic lesions were separated by the Triton X-114 partition method using Watanabe heritable hyperlipidemic (WHHLMI) rabbits prone to myocardial infarction. The activation of RhoA and Rac1 was determined by membrane translocation and pull-down assays. Results: The levels of unprocessed RhoA and Rac1 of the aortas were higher at 7 months than 3 months, accompanied by increased levels of total RhoA and Rac1. Membrane-bound RhoA and Rac1 levels of the aortas at 7 months were significantly increased compared with those at 3 months, consistent with the results of GTP-loading. Unprocessed and activated forms of RhoA and Rac1 had gradually decreas at 15 and 24 months compared to 7 months. Conclusions: We show evidence of marked increases in unprocessed RhoA and Rac1 with enhanced activities in the progression of atherosclerosis in WHHLMI rabbits. This is important for better understanding of the pathogenesis of hyperlipidemia-dependent atherosclerosis.
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JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 16(6) 846-856 2009年12月Aim: The activation of RhoA and Rac1 is crucial for the pathogenesis of atherosclerosis. This study investigated the changes of unprocessed and mature forms of RhoA and Rac1 in the progression of atherosclerosis. Methods: Unprocessed and geranylgeranylated forms of RhoA and Rac1 in aortic atherosclerotic lesions were separated by the Triton X-114 partition method using Watanabe heritable hyperlipidemic (WHHLMI) rabbits prone to myocardial infarction. The activation of RhoA and Rac1 was determined by membrane translocation and pull-down assays. Results: The levels of unprocessed RhoA and Rac1 of the aortas were higher at 7 months than 3 months, accompanied by increased levels of total RhoA and Rac1. Membrane-bound RhoA and Rac1 levels of the aortas at 7 months were significantly increased compared with those at 3 months, consistent with the results of GTP-loading. Unprocessed and activated forms of RhoA and Rac1 had gradually decreas at 15 and 24 months compared to 7 months. Conclusions: We show evidence of marked increases in unprocessed RhoA and Rac1 with enhanced activities in the progression of atherosclerosis in WHHLMI rabbits. This is important for better understanding of the pathogenesis of hyperlipidemia-dependent atherosclerosis.
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CARDIOVASCULAR RESEARCH 84(1) 127-136 2009年10月Aims RhoA and Rac1 activation plays a key role in endothelial dysfunction. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a major receptor for oxidized low-density lipoprotein (ox-LDL) in endothelial cells (ECs). Membrane type 1 matrix metalloproteinase (MT1-MMP) has been shown to be involved in atherogenesis. This study was conducted to investigate the role of the LOX-1-MT1-MMP axis in RhoA and Rac1 activation in response to ox-LDL in ECs. Methods and results Ox-LDL induced rapid RhoA and Rac1 activation as well as MT1-MMP activity in cultured human aortic ECs. Inhibition of LOX-1 prevented ox-LDL-dependent RhoA and Rac1 activation. Knockdown of MT1-MMP by small interfering RNA prevented ox-LDL-induced RhoA and Rac1 activation, indicating that MT1-MMP is upstream of RhoA and Rac1. Fluorescent immunostaining revealed the colocalization of LOX-1 and MT1-MMP, and the formation of a complex of LOX-1 with MT1-MMP was detected by immunoprecipitation. Blockade of LOX-1 or MT1-MMP prevented RhoA-dependent endothelial NO synthase protein downregulation and cell invasion, Rac1-mediated NADPH oxidase activity, and reactive oxygen species generation. Conclusion The present study provides evidence that the LOX-1-MT1-MMP axis plays a crucial role in RhoA and Rac1 activation signalling pathways in ox-LDL stimulation, suggesting that this axis may be a promising target for treating endothelial dysfunction.
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CARDIOVASCULAR RESEARCH 84(1) 127-136 2009年10月Aims RhoA and Rac1 activation plays a key role in endothelial dysfunction. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a major receptor for oxidized low-density lipoprotein (ox-LDL) in endothelial cells (ECs). Membrane type 1 matrix metalloproteinase (MT1-MMP) has been shown to be involved in atherogenesis. This study was conducted to investigate the role of the LOX-1-MT1-MMP axis in RhoA and Rac1 activation in response to ox-LDL in ECs. Methods and results Ox-LDL induced rapid RhoA and Rac1 activation as well as MT1-MMP activity in cultured human aortic ECs. Inhibition of LOX-1 prevented ox-LDL-dependent RhoA and Rac1 activation. Knockdown of MT1-MMP by small interfering RNA prevented ox-LDL-induced RhoA and Rac1 activation, indicating that MT1-MMP is upstream of RhoA and Rac1. Fluorescent immunostaining revealed the colocalization of LOX-1 and MT1-MMP, and the formation of a complex of LOX-1 with MT1-MMP was detected by immunoprecipitation. Blockade of LOX-1 or MT1-MMP prevented RhoA-dependent endothelial NO synthase protein downregulation and cell invasion, Rac1-mediated NADPH oxidase activity, and reactive oxygen species generation. Conclusion The present study provides evidence that the LOX-1-MT1-MMP axis plays a crucial role in RhoA and Rac1 activation signalling pathways in ox-LDL stimulation, suggesting that this axis may be a promising target for treating endothelial dysfunction.
講演・口頭発表等
150Works(作品等)
1共同研究・競争的資金等の研究課題
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日本学術振興会 科学研究費助成事業 2012年4月 - 2013年3月