Satoru Sakagami

Blood Lipid Mediator Sphingosine 1-Phosphate Potently Stimulates Platelet-derived Growth Factor-A and -B Chain Expression through S1P1-Gi-Ras-MAPK-dependent Induction of Krüppel-like Factor 5

Platelet-derived growth factors (PDGFs), potent mitogens and chemoattractants for mesenchymal cell types, play essential roles in development of several organs including blood vessels, kidney, and lung, and are also implicated in the pathogenesis of atherosclerosis and malignancies. Blood lipid mediator sphingosine 1-phosphate (S1P) regulates migration, proliferation, and apoptosis in a variety of cell types through multiple G protein-coupled receptors of the Edg family, and is necessary for vascular formation at the developmental stage. We found in the present study that S1P induced severalfold increases in the mRNA and protein levels of PDGF-A and -B chains in vascular smooth muscle cells and neointimal cells. S1P stimulation of PDGF mRNA and protein expression was abolished by the small interfering RNA duplexes targeting S1P1/Edg1 receptor subtype. S1P stimulated the small GTPase Ras in a Gi-dependent manner, and activated ERK and p38 MAPK in Gi- and Ras-dependent manners. Pertussis toxin pretreatment, adenovirus-mediated Asn17Ras expression, the MEK inhibitor PD98059, or the p38 MAPK inhibitor SB203580 markedly suppressed PDGF mRNA and protein up-regulation, indicating the involvement of Gi-Ras-ERK/p38 MAPK in S1P stimulation of PDGF expression. S1P stimulated expression of the transcription factor KLF5 in manners dependent on Gi, Ras, and ERK/p38 MAPK. Down-regulation of KLF5 by small interfering RNA duplexes abolished S1P-induced PDGF-A and -B chain expression. On the other hand, overexpression of KLF5 stimulated basal and S1P-induced PDGF expression. Either S1P stimulation or KLF5 overexpression increased the PDGF-B promoter activity in a cis-element-dependent manner. These results reveal the S1P1-triggered, Gi-Ras-ERK/p38 MAPK-KLF5-dependent, stimulatory regulation of PDGF gene transcription in vascular smooth muscle cells.

Spectral analysis of heart rate, arterial pressure, and muscle sympathetic nerve activity in normal humans

We investigated the frequency components of fluctuations in heart rate, arterial pressure, respiration, and muscle sympathetic nerve activity (MSNA) in 11 healthy women using an autoregressive model and examined the relation among variables using Akaikes relative power contribution analysis with multivariate autoregressive model fitting. Power spectral analysis of MSNA revealed two peaks, with low-frequency (LF) and high-frequency (HF) components. The LF component of MSNA was a major determinant of the LF component of arterial pressure and R-R interval variability (0.70 +/- 0.07 and 0.18 +/- 0.05, respectively). The effect of the LF component of MSNA on arterial pressure showed no change in response to propranolol but was diminished (0.35 +/- 0.08) by phentolamine (P < 0.02). The effect of the LF component of MSNA on R-R interval was not altered by pharmacological sympathetic nerve blockade. The HF component of MSNA did not influence other variables but was influenced by R-R interval, arterial pressure, and respiration. These findings indicate that the LF component of MSNA reflects autonomic oscillations, whereas the HF component is passive and influenced by other cardiovascular variables.

Influences of bilateral endoscopic transthoracic sympathicotomy on cardiac autonomic nervous activity

OBJECTIVES Endoscopic transthoracic sympathicotomy (ETS) is a minimal invasive procedure of thoracic sympathetic blockage. The purpose of this study was to evaluate cardiac autonomic nervous activity after ETS in order to confirm the reliability and safety of ETS. METHODS A series of electrophysiological studies were performed before and 1 week after bilateral 2nd and 3rd thoracic sympathicotomy in 13 patients with primary palmar hyperhydrosis. Palmar perspiration was measured under sympathetic stress, and body surface mapping was recorded in a supine position. In the head-up tilt test of 0, 30, 60 and 90 degrees, corrected QT interval (QTc) and T wave amplitude (Twa) were assessed. The power spectral analysis of heart rate variability was processed to attain power values of the low-frequency (0.04-0.15 Hz), the high-frequency (0.15-0.40 Hz) and the low/high frequency ratio. RESULTS In all patients, the perspiration response on the palm to sympathetic stimulation was completely inhibited after ETS. Isointegral mapping revealed that ETS altered electroactivity on the heart. In the head-up tilt study, R-R intervals significantly increased after the surgery in the head-up tilt positions (P < 0.05), although there was no significant difference in the supine position. There is no significant difference in QTc and Twa before and after the surgery, both in the supine and the head-up tilt positions. There was no significant difference in the LF or HF before and after surgery, either in the supine position or the head-up tilt positions. In the LF/HF, there was no significant difference before and after surgery in the supine position. However, the LF/HF in the head-up tilt positions was significantly decreased after surgery (P < 0.05). Sympathetic suppression of ETS was recognized more obviously under the steeper head-up tilt positions. CONCLUSIONS The influences on the cardiac autonomic nerve system of the ETS of upper thoracic sympathetic nerve were seen to be of a lesser degree at rest. However, the response to sympathetic stimulation was suppressed after the surgery.

Optimal Force-Time Integral for Pulmonary Vein Isolation According to Anatomical Wall Thickness Under the Ablation Line.

Background Low contact force and force–time integral (FTI) during catheter ablation are associated with ineffective lesion formation, whereas excessively high contact force and FTI may increase the risk of complications. We sought to evaluate the optimal FTI for pulmonary vein (PV) isolation based on atrial wall thickness under the ablation line. Methods and Results Contact force parameters and FTI during anatomical ipsilateral PV isolation for atrial fibrillation and atrial wall thickness were assessed retrospectively in 59 consecutive patients for their first PV isolation procedure. The PV antrum was divided into 8 segments, and the wall thickness of each segment under the ablation line was determined using multidetector computed tomography. The FTI for each ablation point was divided by the wall thickness of the PV antrum segment where each point was located to obtain FTI/wall thickness. In total, 5335 radiofrequency applications were delivered, and 85 gaps in PV isolation ablation lines and 15 dormant conductions induced by adenosine were detected. The gaps or dormant conductions were significantly associated with low contact force, radiofrequency duration, FTI, and FTI/wall thickness. Among them, FTI/wall thickness had the best prediction value for gaps or dormant conductions by receiver operating characteristic curve analysis. FTI/wall thickness of <76.4 gram‐seconds per millimeter (gs/mm) predicted gaps or dormant conductions with sensitivity (88.0%) and specificity (83.6%), and FTI/wall thickness of <101.1 gs/mm was highly predictive (sensitivity 97.0%; specificity 69.6%). Conclusions FTI/wall thickness is a strong predictor of gap and dormant conduction formation in PV isolation. An FTI/wall thickness ≈100 gs/mm could be a suitable target for effective ablation.

Detection of the Earliest Ventricular Contraction Site in Patients with Wolff-Parkinson-White Syndrome Using Two-Dimensional Guided M-Mode Tissue Doppler Echocardiography

Objective: The purpose of this study was to examine the feasibility of M-mode tissue Doppler imaging for localizing the accessory pathway in patients with Wolff-Parkinson-White (WPW) syndrome. Methods: Two-dimensional guided tissue Doppler M-mode was recorded at the mitral and tricuspid annular levels in 13 WPW patients. Time intervals were measured from the onset of the δ wave or the R wave to the beginning of the ventricular systolic motion. The earliest contraction site was defined as the site demonstrating the shortest time interval, and compared with the earliest activated site determined by body surface mapping and the successful ablation site. Results: In 6 patients with a left-sided pathway, tissue Doppler localization was identical to the ablation site. In 3 with a left-sided pathway and 3 with a right-sided pathway, localization was judged as an adjacent region of the ablation site. In 1 patient with a right lateral pathway, the pathway location was misdiagnosed. The tissue Doppler diagnosis for the left-sided pathways correlated well with the ablation site, in contrast to the right-sided pathways (p = 0.05). Prediction of the accessory pathway localization by tissue Doppler M-mode was equivalent to localization based on body surface mapping. Conclusions: In WPW syndrome, tissue Doppler M-mode can detect the earliest contraction sites and seems helpful in localizing the left-sided accessory pathways, but is of limited use for right-sided pathways.

Ultrasonic analysis of anthracycline-induced myocardial damage using cyclic variation of integrated backscatter ☆

To test the feasibility of integrated backscatter (IB) for detecting anthracycline cardiotoxicity, we performed conventional echocardiography and IB analysis. For interindividual comparison, 32 patients with non-Hodgkins lymphoma and 14 control subjects were selected. Of the patients, 10 had been treated with doxorubicin doses of </=200 mg/m(2) (low dose), 15 with </=400 mg/m(2) (moderate dose), and 7 with >400 mg/m(2) (high dose). In intraindividual comparison, 8 patients were examined before doxorubicin therapy and at a dose of 100 mg/m(2) and 8 were examined before and at a 300-mg/m(2) dose. Cyclic variation of IB (CV-IB) was obtained at the left ventricular posterior wall, using a modified, commercially available system in M-mode format. In interindividual comparison, CV-IB in high- and moderate-dose groups was smaller. In intraindividual comparison, CV-IB decreased after treatment with 300 mg/m(2) of doxorubicin. CV-IB was affected in some patients treated with a moderate dose of doxorubicin. IB analysis may be helpful for detecting early anthracycline cardiotoxicity.

Two-dimensional guided M-mode color tissue Doppler echocardiography in artificial preexcitation models.

The purpose of this study was to analyze the left ventricular contraction patterns in artificial preexcitation models by using 2-dimensional guided M-mode color tissue Doppler echocardiography. Three types of preexcitation models were produced in 12 patients by right atrio-mitral annular sequential pacing, carried out at the left ventricular lateral, posterior, and posteroseptal walls. Tissue Doppler M-mode was recorded at anteroseptal, posterior, lateral, and posteroseptal sites in the parasternal short-axis view. The time interval from the onset of the QRS complex during sinus rhythm or from the annular pacing spike during fusion beats to the beginning of systolic motion was measured. During sinus rhythm, the time interval at the anteroseptal wall was shortest. During fusion beats, the time intervals at the mitral annular pacing sites were shortest. In preexcitation models, tissue Doppler M-mode could clearly distinguish the difference of left ventricular contraction patterns and detect the earliest contraction site of the left ventricle.

Potential association of bystander-patient relationship with bystander response and patient survival in daytime out-of-hospital cardiac arrest.

AIM To investigate whether the bystander-patient relationship affects bystander response to out-of-hospital cardiac arrest (OHCA) and patient outcomes depending on the time of day. METHODS This population-based observational study in Japan involving 139,265 bystander-witnessed OHCAs (90,426 family members, 10,479 friends/colleagues, and 38,360 others) without prehospital physician involvement was conducted from 2005 to 2009. Factors associated with better bystander response [early emergency call and bystander cardiopulmonary resuscitation (BCPR)] and 1-month neurologically favourable survival were assessed. RESULTS The rates of dispatcher-assisted CPR during daytime (7:00-18:59) and nighttime (19:00-6:59) were highest in family members (45.6% and 46.1%, respectively, for family members; 28.7% and 29.2%, respectively, for friends/colleagues; and 28.1% and 25.3%, respectively, for others). However, the BCPR rates were lowest in family members (35.5% and 37.8%, respectively, for family members; 43.7% and 37.8%, respectively, for friends/colleagues; and 59.3% and 50.0%, respectively, for others). Large delays (≥ 5 min) in placing emergency calls and initiating BCPR were most frequent in family members. The overall survival rate was lowest (2.7%) for family members and highest (9.1%) for friends/colleagues during daytime. Logistic regression analysis revealed that the effect of bystander relationship on survival was significant only during daytime [adjusted odds ratios (95% CI) for survival from daytime OHCAs with family as reference were 1.51 (1.36-1.68) for friends/colleagues and 1.23 (1.13-1.34) for others]. CONCLUSIONS Family members are least likely to perform BCPR and OHCAs witnessed by family members are least likely to survive during daytime. Different strategies are required for family-witnessed OHCAs.

Percutaneous transluminal mitral valvuloplasty improves cardiopulmonary baroreflex sensitivity in patients with mitral stenosis

Patients with heart failure frequently have increased sympathetic tone, which could result in part from impairment of the inhibitory influence of cardiopulmonary baroreflexes. Percutaneous transluminal mitral valvuloplasty (PTMV) provides a unique model for evaluating functional changes in cardiopulmonary baroreflexes without open-heart surgical manipulation. We examined the effects of PTMV on cardiopulmonary baroreflexes and sympathetic nerve activity in 10 patients with mitral stenosis. We measured muscle sympathetic nerve activity using microneurography. Cardiopulmonary baroreflex provocation was performed by applying a lower body negative pressure of -10 mm Hg, and its sensitivity was determined by dividing the percent change in muscle sympathetic nerve activity by the change in central venous pressure. Response to isometric exercise was assessed by handgrip at 30% of maximal voluntary contraction for 3 min. PTMV significantly increased mitral valve area and cardiac index and decreased mean left atrial pressure. PTMV significantly decreased burst rate from 25.1+/-2.5 to 15.6+/-2.6 bursts/min (p < 0.01) and burst incidence from 37.1+/-3.7 to 23.6+/-3.3 bursts/100 heart beats (p < 0.01). After PTMV, cardiopulmonary baroreflex sensitivities measured using burst rate and burst incidence were -39.9+/-4.9%/mm Hg and -38.7+/-6.2%/mm Hg, respectively, which were significantly steeper than those before PTMV (-9.2+/-1.1%/mm Hg and -8.4+/-1.1%/mm Hg; p < 0.01). There were significant correlations between muscle sympathetic nerve activity at rest and cardiopulmonary baroreflex sensitivity. PTMV did not affect muscle sympathetic responses to handgrip exercise. These results suggest that patients with mitral stenosis have baseline sympathetic nerve activation, which could result in part from impaired cardiopulmonary baroreflexes.

Advantage of CPR-first over call-first actions for out-of-hospital cardiac arrests in nonelderly patients and of noncardiac aetiology

AIM To assess the benefit of immediate call or cardiopulmonary resuscitation (CPR) for survival from out-of-hospital cardiac arrests (OHCAs). METHODS Of 952,288 OHCAs in 2005-2012, 41,734 were bystander-witnessed cases without prehospital involvement of physicians but with bystander CPR (BCPR) on bystanders own initiative. From those OHCAs, we finally extracted the following three call/BCPR groups: immediate Call+CPR (N=10,195, emergency call/BCPR initiated at 0 or 1 min after witness, absolute call-BCPR time interval=0 or 1 min), immediate Call-First (N=1820, emergency call placed at 0 or 1 min after witness, call-to-BCPR interval=2-4 min), immediate CPR-First (N=5446, BCPR initiated at 0 or 1 min after witness, BCPR-to-call interval=2-4 min). One-month neurologically favourable survivals were compared among the groups. Critical comparisons between Call-First and CPR-First groups were made considering arrest aetiology, age, and bystander-patient relationship after confirming the interactions among variables. RESULTS The overall survival rates in immediate Call+CPR, Call-First, and CPR-First groups were 11.5, 12.4, and 11.5%, respectively without significant differences (p=0.543). Subgroup analyses by multivariate logistic regression following univariate analysis disclosed that CPR-first group is more likely to survive in subgroups of noncardiac aetiology (adjusted odds ratio; 95% confidence interval, 2.01; 1.39-2.98) and of nonelderly OHCAs (1.38; 1.09-1.76). CONCLUSIONS Immediate CPR-first action followed by an emergency call without a large delay may be recommended when a bystander with sufficient skills to perform CPR witnesses OHCAs in nonelderly people and of noncardiac aetiology.