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Background: Lead V1 on electrocardiography (ECG) can detect the dominant frequency (DF) of atrial fibrillation (AF) in the right atrium (RA). Paroxysmal AF is characterized by a frequency gradient from the left atrium (LA) to the right atrium (RA). We examined the ability of magnetocardiography (MCG) to detect regional DFs in both the atria. Methods: Study subjects comprised 18 consecutive patients referred for catheter ablation of persistent AF. An MCG system with 64 magnetic sensors was used to perform MCG in the frontal, lateral, and back planes prior to the ablation procedure in each patient. DFMCG and organization index (OIMCG) were calculated using fast Fourier transformation. Intracardiac electrograms (ICEs) in both the atria and the coronary sinus (CS) were mapped at 17 sites. Regional DFsICE were also determined. Results: Mean LA DFICE was higher than mean RA DFICE (6.4070.66 versus 6.1670.80 Hz, P¼0.03). DFMCG in the channel having the highest OIMCG was 6.6170.88 Hz in the frontal plane, 6.5270.64 Hz in the lateral plane, and 6.4270.62 Hz in the back plane (P¼0.3). In each plane, DFMCG correlated with DFICE at the RA appendage (R¼0.95, Po0.0001), the LA appendage (R¼0.91, Po0.0001), and the CS (R¼0.93, Po0.0001). DFECG in V5 modestly correlated with DFICE at the LA appendage (R¼0.82, Po0.0001). Conclusions: MCG could more precisely detect the DFs in the LA and the CS than ECG. However, the usefulness of pre-procedural detection of the AF frequency gradient for ablation therapy needs to be evaluated in future prospective studies.

BackgroundRivaroxaban is an oral anticoagulant that effectively prevents thromboembolic complications using fixed doses without requiring laboratory monitoring. In this study, we aimed to examine the coagulation status in patients with non-valvular atrial fibrillation (NVAF) treated with rivaroxaban compared with warfarin.Methods and resultsThe study group consisted of 85 consecutive Japanese patients with NVAF who received rivaroxaban (n=33) or warfarin (n=52) from June 2013 to February 2014. We compared the coagulation status between the rivaroxaban and warfarin treatments. The prothrombin time (PT) values did not significantly differ between the two groups. However, the prothrombin fragment 1+2 (F1+2) level, a marker of thrombin generation, was significantly higher in the rivaroxaban group than the warfarin group (202±88pmol/l vs. 114±79pmol/l, p

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

Causative arrhythmias of sudden cardiac arrest (SCA) are changing in this age of improved coronary care.The purpose of this study was to examine the frequency of terminal arrhythmias and the electrical events prior to SCA.We analyzed 24-hour Holter recordings of 132 patients enrolled from 41 institutions who either died (n = 88) or had an aborted death (n = 44). The Holter recordings were obtained for diagnosing and evaluating diseases and arrhythmias in those without any episodes suggestive of SCA.In 97 patients (73%), SCA was associated with ventricular tachyarrhythmias and in 35 (27%) with bradyarrhythmias. The bradyarrhythmia-related SCA patients were older than those with a tachyarrhythmia-related SCA (70 ± 13 years vs. 58 ± 19 years, P.001). The most common arrhythmia for a tachyarrhythmia-related SCA was ventricular tachycardia degenerating to ventricular fibrillation (45%). The bradyarrhythmia-related SCA was caused by asystole (74%) or AV block (26%). Spontaneous conversion was observed in 37 patients (38%) with ventricular tachyarrhythmias. Of those, 62% of the patients experienced symptoms including syncope, chest pain, or convulsion. Multivariate logistic analysis revealed that independent predictors of mortality for tachyarrhythmia-related SCAs were advanced age (odds ratio 1.04, 95% confidence interval 1.02-1.08) and ST elevation within the hour before SCA (odds ratio 3.54, 95% confidence interval 1.07-13.5). In contrast, the presence of preceding torsades de pointes was associated with spontaneous conversion (odds ratio 0.20, 95% confidence interval 0.05-0.66).The most frequent cause of SCA remains ventricular tachyarrhythmias. Advanced age and ST elevation before SCA are risk factors for mortality in tachyarrhythmia-related SCAs.

Background: Magnetocardiography (MCG) is a new technique for visualizing a current distribution in the myocardium. In recent years, current distribution parameters (CDPs) have been developed based on the distribution. The CDPs reflect spatial-time current abnormalities in patients with coronary heart disease (CHD). However, the criteria and scoring method of the abnormalities using CDPs are still controversial. Method: We measured MCG signals for 101 normal controls and 56 CHD patients (single-, double-, and triple-vessel diseases) using a MCG system. The CDPs (maximum current vector [MCV], total current vector [TCV], current integral map, and current rotation) during ventricular repolarization were analyzed. To evaluate the CDPs that are effective in distinguishing between normal controls and CHD patients, the areas under the receiver operating characteristic curve (Az) are calculated. Furthermore, the total scores (“0” to “4”) of four CDPs with high Az values are also calculated. Results: MCV and TCV angles at the T-wave peak had the highest Az value. Furthermore, TCV angular differences between the ST-T segment also had high Az values. Using the four CDPs, the averaged total score for patients with triple-vessel disease was the highest (“2.67”) compared to the other groups (normal controls: 0.53). Furthermore, based on the assumption that subjects with a total score over “1” were suspected of having CHD, sensitivity and specificity were 85.7% and 74.3%, respectively. Conclusion: We concluded that the score and criteria using MCV and TCV during repolarization in CHD patients can reflect lesion areas and time changes of electrical activation dispersion due to ischemia.

The prevalence and characteristics of sleep-disordered breathing (SDB) in patients with ventricular arrhythmias, such as premature ventricular complexes and ventricular tachycardia, are unknown. Therefore, this study was conducted to evaluate the prevalence of SDB in patients with severe ventricular arrhythmias and normal left ventricular (LV) function. Thirty-five patients (63% men, mean age 57.4 +/- 13.8 years) underwent a sleep study. All patients had ventricular tachycardia or frequent premature ventricular complexes (or=300/hour) and had been referred to the cardiology department for medication, catheter ablation therapy, or the implantation of a cardioverter-defibrillator. Patients with heart failure with LV ejection fractions50% were excluded; in the remaining patients, the mean LV ejection fraction was 63.9 +/- 8.0%. Twenty-one patients (60%) had SDB with apnea-hypopnea indexesor=5/hour, and the average apnea-hypopnea index was 22.7 +/- 17.9/hour. Twelve patients (34%) had moderate to severe SDB, with an average apnea-hypopnea index of 33.6 +/- 16.6/hour. Central dominant sleep apnea was evident in 3 patients with SDB. The average age and body mass index were significantly higher in patients with SDB than in those without SDB (age 62.0 +/- 12.8 vs 50.6 +/- 12.7 years, body mass index 26.3 +/- 4.0 vs 21.2 +/- 2.0 kg/m2). In conclusion, this study found a high prevalence of SDB in patients with ventricular arrhythmias and normal LV function.

In routine substrate mapping of the left ventricle, an abnormal area is defined as having an amplitude1.5 mV. However, that is usually too large for catheter ablation in post-infarction ventricular tachycardia (VT) and the use of strict voltage criteria may produce better outcomes.Twenty patients with post-infarction VT underwent substrate mapping using an electroanatomic mapping system. Strict voltage criteria were defined as: non-arrhythmogenic area,0.6 mV; low-voltage area (LVA),0.1 toor=0.6 mV; scar,or=0.1 mV. Radiofrequency applications targeted the LVA only, which was 48+/-26 cm(2), 55% smaller than that of the generally targeted area with an amplitudeor=1.5 mV. The prevalence of delayed electrograms (durationor=150 ms) was significantly higher in the LVAs than in the border areas with an amplitude of0.6 toor=1.5 mV (33.2% vs 3.7%, p0.001). With the exception of 2 instances of peri-mitral VT, all VT isthmuses resided within the LVA. During follow-up of 24+/-13 months, 16 patients (80%) have been free of any VT episodes.Catheter ablation targeting LVAs with an amplitudeor=0.6 mV appears to be useful for efficient and effective treatment of post-infarction VT.

Background Magnetocardiography (MCG) is sensitive to minute cardiac electric abnormalities, but its clinical utility in diagnosing ischemic heart disease (IHD) has not been established. The present study examined the usefulness of an integral MCG value of ventricular repolarization in patients with IHD. Methods and Results MCG was performed at rest in 14 patients with coronary stenosis >75% confirmed by coronary angiography (IHD group) using a 64-channel system, and then the sum of the 64-channel integral values of the QRS or JT intervals (QRSi and JTi, respectively) was calculated. The JTi/QRSi value indicated the total power of currents in JT compared with those in QRS. These measurements were repeated within 2 weeks after coronary revascularization. The Control group comprised 30 healthy volunteers. The baseline value of JTi/QRSi was significantly smaller in the IHD than in the Control group, but after revascularization it increased and did not significantly differ from the Control group. No significant difference in ST deviation was identified by electrocardiography (ECG) before and after coronary revascularization. Analysis of the Control group revealed that JTi/QRSi was not affected by age. Conclusions The JTi/QRSi of the MCG is more sensitive to coronary stenosis than ECG, and this parameter improves soon after coronary revascularization. (Circ J 2007; 71: 1586 - 1592)

Introduction: Amiodarone infusion has been recommended for life-threatening ventricular arrhythmias. However its effectiveness in Japanese patients has not yet been determined. Methods: This was an uncontrolled, open-label trial involving patients with hemodynamically unstable ventricular tachycardia (VT) or ventricular fibrillation (VF). Intravenous amiodarone was delivered as a 125 mg bolus followed by infusion of 50 mg/h for 6 hours, then 25 mg/h for 42 hours. The primary endpoint for efficacy was the proportion of patients free from hemodynamically unstable VT/VF at 48-hour. Secondary endpoints included: event frequency; proportion of patients event-free, treatment outcome, and safety. Results: Forty-seven patients were enrolled. Forty-one patients were evaluated for efficacy and safety parameters were assessed for all 47 patients. The proportion of patients free from hemodynamically unstable VT/VF was 53.9%; the proportion of patients free from hemodynamically unstable VT/VF relapse or whose treatment was discontinued was 48.8%. Eight patients died; all deaths were judged, by the investigator, as being unrelated to amiodarone. No cases of torsades de pointes were reported. Mild abnormal thyroid function was noted in one patient. No cases of interstitial lung disease or pulmonary fibrosis were observed. Conclusion: Amiodarone infusion provides a useful tool in preventing acute relapse of lifethreatening ventricular arrhythmias in Japanese patients.

Background: The objective of this study is to use magnetocardiography to determine the existence of a small abnormal current during ventricular depolarization in patients with Brugada syndrome. To understand this small difference in abnormal current during ventricular depolarization, we compared abnormal currents of patients with cases of complete right-bundle-branch block (CRBBB). Methods and Results: We developed a whole-heart electrical bull's eye map (WHEBEM) that uses magnetocardiograms (MCGs) to visualize the current distribution in a circular map. MCGs of Brugada syndrome patients (n = 16), CRBBB patients (n = 10), and controls (n = 12) at rest were recorded. In the WHEBEMs of Brugada syndrome patients, the magnitude of the S-wave current in the upper-right direction of the anterior side is larger than that of the controls. In addition, the R-wave current direction is similar to that of the controls, and the R-wave vector is distributed over a larger area than that of the controls. On the other hand, the CRBBB patients have a distribution of R-wave currents over a larger area in the left anteromedian region and the left posteromedian region. Moreover, in all CRBBB patients, S-wave currents with a large magnitude have the same direction distributed over a small area. Conclusions: The WHEBEM findings suggest that there is an abnormal current in the direction to the upper right (in the S-wave) in the anterosuperior region of Brugada syndrome patients. We thus conclude that a WHEBEM has the potential to detect characteristics of heart disease.

Background Carotid arterial ultrasound examination may be helpful for screening populations at high risk for acute coronary syndrome (ACS), so the present study was designed to identify the carotid arterial characteristics of patients with ACS. Methods and Results Carotid ultrasound examinations were performed in 172 patients with ACS, 166 patients with stable coronary artery disease (CAD), and 96 control subjects. Common carotid arterial structures were assessed by the intima - media thickness (IMT), interadventitial diameter (IAD), lumen diameter (LD), the IMT to LD ratio (IMT/LD), and the plaque burden based on the plaque score. Plaque morphology was assessed by the echogenecity based on the gray-scale median (GSM). IMT, IAD, IMT/LD, and plaque score did not differ between the ACS and stable CAD groups. The GSM in the ACS group was lower (47.5±25.3, p

Wall motion abnormality in the apical legion of the left ventricle (LV) with stagnant flow alone is not sufficient to identify patients at high risk for LV thrombus formation among those with first anterior acute myocardial infarction (AMI). The aim of this study was to identify the determinants of LV thrombus formation using contrast echocardiography.In 75 patients with first anterior AMI, standard and contrast echocardiography was performed to detect LV thrombus. Although LV thrombus was found in 10 patients (13%) using standard echocardiography, it was found in 15 patients (20%) using contrast echocardiography. Apical stagnant flow was observed in 14 patients (93%) with LV thrombus. In addition, patients with LV thrombus had a higher peak C-reactive protein (CRP) concentration (18.2+/-4.3 vs 7.9+/-5.5 mg/dl, p0.0001). In multivariate analysis, only peak CRP concentration was identified as an independent predictor of LV thrombus (p=0.02, odds ratio: 1.400, confidence interval: 1.040-1.884). The receiver-operating characteristics (ROC) analysis revealed the best cutoff value of a peak CRP concentration10.7 mg/dl to identify patients with LV thrombus (sensivity 0.93, specificity 0.75, area under ROC curve 0.91).The peak CRP concentration is a useful marker of patients with first anterior AMI who are at high risk for LV thrombus.

Doxorubicin (DOX) is widely used to treat patients suffering from cancer, but the usage for patients is limited because of the dose-dependent cardiotoxicity. We hypothesized that DOX induces apoptosis through caspase activation in cardiomyocytes, and we examined this hypothesis using both rat primary cultured cardiomyocytes and rat hearts from an animal model. Cardiomyocytes were treated with DOX for 24 h. The activity of caspase-3 was significantly increased by DOX treatment. In rats with DOX injected intravenously once a week for 5 weeks, left ventricular fractional shortening evaluated by echocardiography was significantly decreased at age 14 weeks, 2 weeks after the end of DOX-administration. At 16 weeks of age, endothelin-1 mRNA and atrial natriuretic peptide mRNA were also significantly increased, likewise, and TUNEL positive cells were significantly increased in the ventricles of DOX-treated rats. The activity of caspase-3 in the ventricles was also significantly increased compared to that of untreated rats at 16 weeks. However, the activity of caspase-8 and the expression level of Fas-ligand mRNA were comparable with those of the untreated rats. In conclusion, DOX induces apoptosis through the activation of caspase-3, suggesting that apoptosis has an important role in the progression of cardiomyopathy due to DOX. Keywords:: doxorubicin, apoptosis, cardiomyopathy, caspase, mitochondria

The clinical program of intravenous coronary angiography (IVCAG) using synchrotron radiation is moving on at the ESRF and at the KEK. Since the X-ray optics and types of detectors are different depending on the needs of technology, the ESRF adopts dual-energy digital subtraction system and the KEK does single-energy two-dimensional dynamic imaging system. A contrast agent is injected intravenously and the image sequence is started. The former technique enhances the image contrast of the coronary arteries in spite of intravenous injection of a contrast agent; whereas, the latter technique produces excellent temporal resolution for imaging of moving objects such as the coronary arteries and the left ventricle. So, the obtained image, the radiation dose, the examination time, and other details are different between the two facilities. Both systems sufficiently visualize the right coronary artery disease, even after coronary angioplasty or coronary artery bypass grafting. Also, the two-dimensional dynamic IVCAG permits the visualization of the left coronary arteries. The coronary morphology obtained by the IVCAG, was almost completely coincident with the results of selective CAG. Accordingly, the IVCAG is clinically validated and useful for the screening and the follow-up of coronary artery disease. However, as some portions of the left circumflex coronary artery are overlapped by the left ventricle, more contrivance is required and its imaging should be improved in future.

Background In patients with chronic heart failure, an inadequate increase in muscle blood flow resulting from impaired vasodilation plays a key role in their exercise intolerance. However, no non-invasive methods to assess muscle vasodilation during dynamic exercise were available. We investigated whether the changes in tissue hemoglobin and myoglobin content (total-Hb + Mb) determined by non-invasive measurement using near-infrared spectroscopy (NIRS) reflect vessel conductance of working muscle during exercise. Methods and Results Sixteen patients (10 patients with normal cardiac systolic function, 6 with cardiac dysfunction) performed incremental bicycle exercise testing. Total-Hb + Mb from the right vastus lateralis muscle was monitored using NIRS. Leg blood flow (LBF) in the right femoral vein was measured using a thermodilution technique every 30-60 s. Leg vessel conductance was calculated as LBF/mean arterial pressure at each time of the measurement. In all cases except 1, the levels of total-Hb + Mb showed significant correlation with the leg vessel conductance (r=0.792 to 0.980). Intra-subject reproducibility of the NIRS measurement was also confirmed in 6 patients. Conclusions Total-Hb + Mb from NIRS reflected muscle vasodilation during sub-maximal dynamic exercise in patients with and without cardiac dysfunction, indicating that NIRS provides a valuable method to assess the working muscle vasodilation. (Circ J 2005; 69: 802 - 814)

Eye disorder accompanied with chronic retinal microvascular obstruction, such as diabetic retinopathy, exists in many diseases. However, it is difficult to produce this model experimentally in the animal eye. Endothelin-1 eyedrops were prepared in order to examine whether the eyedrops affect the rat retina and whether we can produce an obstruction model. Endothelin-1 eyedrops diluted by artificial tears in seven stages from 4 x 10(-5) M to 4 x 10(-11) M were arranged. We administered this solution three times a day in the left eye of male Sprague-Dawley rats. Artificial tears alone were applied to the right eye as a control vehicle. After 2 weeks, rats were sacrificed under anesthesia and the retinal tissues were isolated. As an index to the action of endothelin- 1 eyedrops to the retina, the expressions of endothelin-A (ETA) and endothelin-B (ETB) receptors in the retina were compared in both eyes. Frozen sections of the retina were immunostained to reveal the distribution of the ETA and ETB receptors. We also examined ETA and ETB mRNA expression by quantitative real-time polymerase chain reaction. As a result, the expressions of ETA and ETB receptors are reduced with both immunostaining and the mRNA levels in the left eye, in which endothelin-1 eyedrops were applied at 4 x 10(-5) M. It is suggested that endothelin-1 eyedrops affected the retina and the possibility of producing the experimental model of chronic microvascular obstruction in the rat retina.

The effects of the novel, selective endothelin-A (ET A ) receptor antagonist YM598 on both-side heart failure were investigated. Right-side heart failure secondary to pulmonary hypertension was produced by a single subcutaneous injection of 60 mg/kg monocrotaline, and post-ischemic congestive left-side heart failure (CHF) produced by surgical left coronary artery ligation. In right-side heart failure rats, oral YM598 (0.1 and 1 mg/kg for 4 weeks), but not bosentan (30 mg/kg), significantly inhibited the progression of pulmonary hypertension and the development of right ventricular hypertrophy. YM598 also improved hypoxemia and morphological pulmonary lesions in these rats. In CHF rats, moreover, long-term oral administration of YM598 (1 mg/kg/day for approximately 30 weeks) significantly ameliorated their poor survival rate (P < 0.05). In the measurement of cardio-hemodynamic parameters, YM598 improved the contractile/diastolic capacity of the left ventricle and the preload in the right ventricle to the levels seen in sham-operated rats. YM598 also markedly inhibited both ventricular hypertrophy and pulmonary congestion, as well as lowering high plasma brain natriuretic peptide levels in CHF rats. These findings suggest that YM598 may have a clinical benefit with regards to ameliorating the cardiopulmonary changes of right-side heart failure, and the cardiac dysfunction and mortality/morbidity of CHF.

Aims We analysed the cardiac magnetic fields on the body surface to visualize electrical currents noninvasively during reentrant arrhythmias. Methods and results Seven patients with counterclockwise atrial flutter (AFL) were studied during 17 episodes of AFL using 64-channel magnetocardiograms (MCGs) and electrophysiological study. Eight of the episodes were paroxysmal AFL, in which MCGs were recorded from the time of spontaneous onset to the time of termination. We constructed iso-magnetic field maps of the tangential components and produced MCG animations. With respect to AFL initiation, an atrial premature complex induced AFL. Prior to the initiation of AFL, atrial fibrillation (AF) transiently occurred. The cardiac magnetic fields revealed a single peak during sinus rhythm or with premature complexes but a disorganized pattern during AF. When AF transformed to AFL, the magnetic fields changed from a disorganized pattern to a single peak at first and then evolved to a circular pattern. During persistent AFL, the magnetic source moved in a counterclockwise circuit. Conclusion MCG animation can be used to visualize the sequence in which a premature complex transforms sinus rhythm to AFL via AF. Our findings indicate that MCGs can be used to identify noninvasively the mechanisms responsible for atrial tachyarrhythmias.

A 14-year-old boy with coarctation of the aorta who showed repeat ventricular fibrillation during anesthesia, and ultimately sudden cardiac death in school, is presented. Electrocardiography showed J waves in the left precordial leads, which became prominent after an episode of ventricular fibrillation. While some of the clinical features and electrophysiological findings were similar to those seen in Brugada syndrome, others were inconsistent. J waves in the left precordial leads should be recognized as a possible waveform change inducing ventricular fibrillation predominantly at rest.

Background and Aims: Animal models of heart failure (HF) are useful to clarify the mechanism and to develop therapeutic interventions. To produce an easy ischemic HF model, we induced myocardial infarction (MI) in pigs by placing a tube in the coronary artery. Methods: Twelve pigs underwent echocardiography and were randomly allocated to the myocardial infarction group (MI group) and the control group. In the MI pigs, a 4.2 F nylon tube was placed via the carotid artery in the left circumflex coronary (LCx) artery to induce MI. Three months thereafter, thoracotomy was performed in the both groups and left ventricular (LV) pressure–volume relation was evaluated. Results: Body weight, LV dimension and function did not differ in the baseline state between the two groups. Three months after the tube placement, LV diameter was larger (47±3 vs. 42±2 mm) and its fractional shortening was lower in the MI group than the control group. In addition, aortic flow was decreased, LV ejection fraction was decreased (25±5 vs. 52±6%) and LV diastolic pressure was elevated (14±3 vs. 8±2 mmHg) in the MI group compared with the control group. The extent of MI was 26±5% of the LV in the MI pigs. Conclusion: The method of placing a tube in the coronary artery does not need thoracotomy or an additional procedure and enables the production of an ischemic HF model of pigs.

The long-term effects of amlodipine, a calcium channel blocker, were examined in patients with moderate to severe hypertension. Eighteen never-treated patients with moderate to severe essential hypertension (49 +/- 8 years) were studied. In all patients, forearm blood flow (FBF) was measured by plethysmography before and 6 months after amlodipine treatment. Endothelium-nondependent and endothelium-dependent vasodilations were assessed by intrabrachial infusion of sodium nitroprusside (SNP) and acetylcholine (ACh), respectively. FBF modification by vitamin C, an oxygen radical scavenger, was also assessed under ACh infusion. The results were compared with those of 13 normal subjects. Blood pressure was significantly lowered (from 176 +/- 17/97 +/- 13 to 144 +/- 12/82 +/- 10 mm Hg) after treatment (P < 0.01). Forearm vascular resistance was increased in the hypertensive patients before treatment; however, it was normalized after treatment during SNP infusion and was improved during ACh infusion. Since vitamin C improved FBF under ACh infusion both before and after the amlodipine treatment, it is suggested that the production of free radicals was not canceled by amlodipine. The analysis of heart rate variability showed that amlodipine does not activate sympathetic nerve function. Therefore, amlodipine is effective in lowering blood pressure associated with the improvement of vascular function, and is suggested to be an effective antihypertensive agent for patients with moderate to severe hypertension.

Background— Two subtypes of endothelin (ET) receptors, ET A and ET B , are distributed in vascular smooth muscle cells to cause contraction and proliferation. Vascular endothelial cells express only ET B receptors, which cause NO release. Although ET A receptor blockade is reported to be effective in ameliorating vascular remodeling, there is no report on the long-term effect of ET B receptor blockade on vascular remodeling after injury. Methods and Results— ET B receptor–knockout (KO) mice, which were genetically rescued from lethal intestinal aganglionosis, and wild-type (WT) mice underwent complete ligation of the right common carotid artery, ie, a blood flow cessation model of vascular remodeling. Fourteen days after ligation, the intimal area, the ratio of intimal to medial areas, and the stenotic ratio in the ligated artery of KO mice were significantly increased compared with those of WT mice. The expression level of ET-1 mRNA in the ligated artery of KO mice was increased similarly to that of WT mice, whereas tissue NO x levels in lesions of KO mice were significantly lower than those of WT mice. Long-term treatment with the ET A receptor antagonist TA-0201 (0.5 mg · kg −1 · d −1 ) significantly ameliorated vascular stenosis in both groups. Long-term treatment with the ET B receptor antagonist A-192621 (30 mg · kg −1 · d −1 ) worsened vascular remodeling in WT mice. Conclusions— We demonstrated that inhibition of the ET B receptor system is harmful for vascular remodeling after injury, the mechanism of which is partly attributed to decreased NO release, in KO mice. These results suggest that the overall effect of vascular ET B receptors is antiproliferative in the injured artery.

Heart rate is largely affected by the autonomic nervous system. However, little is known about the anatomic pathway of autonomic nerve fibers innervating the sinus node. The present study: (1) evaluates the effects of cavotricuspid isthmus ablation for common atrial flutter (AFL) on autonomic nervous function by using heart rate variability analysis, and (2) investigates the distribution of autonomic nerve pathways innervating the sinus node. Twelve patients with paroxysmal common atrial flutter who maintained sinus rhythm both before and after radiofrequency ablation were selected for the study. Holter ambulatory recordings were performed before and after (2.3 +/- 1.0 days) radiofrequency ablation of cavotricuspid isthmus. Heart rate and time domain (SDANN, rMSSD, pNN50) and frequency domain (low frequency (LF), high frequency (HF), LF/HF) analysis of heart rate variability were compared before and after ablation. Mean heart rate did not change significantly after ablation (59 +/- 6 vs 61 +/- 9 beats/min); parasympathetic indices of heart rate variability (SDANN, rMSSD, pNN50, HF) did not change significantly (110 +/- 37 vs 117 +/- 20 ms; 32 +/- 21 vs 28 +/- 9 ms; 4.8 +/- 0.9 vs 4.7 +/- 0.71n(ms2)); and sympathetic indices of heart rate variability (LF/HF) did not change significantly (1.1 +/- 0.2 vs 1.2 +/- 0.1). Cavotricuspid isthmus ablation for atrial flutter did not significantly change heart rate and heart rate variability because parasympathetic and sympathetic fibers innervating the sinus node are scarce in this region.

Electrocardiographic recognition of the P' wave during tachycardia is very useful in the diagnosis of supraventricular tachycardias. In slow/fast (S/F) atrioventricular nodal reentrant tachycardia (AVNRT), no discrete P' waves are observed on ECG and pseudo r' deflection in lead V1 (pseudo r') is commonly recognized. However, the atrial components that contribute to the genesis of pseudo r' in lead V1 have not been described and this study aimed to clarify them by analysis of the whole activation sequence of the right atrium using Basket catheter isochronal mapping. The study group comprised 48 patients with AVNRT. Pseudo r' was defined as an upward deflection in the terminal portion of the QRS complex during tachycardia that was not recognized during sinus rhythm and it occurred in 45 patients (94%). During S/F AVNRT, the retrograde atrial activation was earliest on His bundle electrogram, followed by the coronary sinus ostium, distal coronary sinus and high right atrium. Only the high lateral aspect of the right atrium was activated after the end of the QRS complex. The interval between the onset of QRS in multiple surface ECG leads and the atrial activities on high right atrium was similar to the V-r' interval in lead V1 (111+/-20ms, 117+/-11 ms) and correlated with the V-r' interval (r=0.56). Pseudo r' deflection in lead V1 is a highly sensitive indicator of S/F AVNRT, and appears to result from the activation of the superolateral aspect of the right atrium.

Plasma norepinephrine (NE) level can be a guide to mortality in patients with heart failure. This study aimed to evaluate the significance of plasma NE level compared with plasma natriuretic peptides (atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)) levels in patients with atrial fibrillation (AF).Included in this study were 137 consecutive patients referred for catheter ablation of lone AF (paroxysmal in 90 and persistent in 47 patients). Blood samples for measurements of ANP, BNP and NE were drawn in the supine position before the procedure.ANP, BNP and NE levels were greater in patients with persistent AF than in patients with paroxysmal AF (median (25th-75th centile)=28 (18-49) vs 69 (36-106), p0.0001; 28 (15-50) vs 94 (39-156), p0.0001; and 315 (223-502) vs 382 (299-517) pg/mL, p=0.04, respectively). NE level correlated weakly with ANP and BNP levels (r=0.28 and r=0.23, respectively, p0.01 for both). BNP and NE levels differed between patients with and without recurrence of AF (55 (26-135) vs 35 (18-64), p=0.005 and 431 (323-560) vs 302 (225-436) pg/mL, p0.001, respectively). Of note, only NE level was significantly greater in patients with symptomatic sick sinus syndrome (SSS) (n=21) than in those without SSS (560 (466-632) vs 321 (242-437) pg/mL, p0.0001). Logistic regression analysis showed NE level to be the only independent discriminator for SSS (OR 1.006, 95% CI 1.002 to 1.010, p=0.001).An increase in plasma NE level was observed in patients with AF and SSS. Although this implies a pathophysiological link between clinical manifestation of SSS and the autonomic nervous dysfunction, further studies are needed to clarify the mechanisms for this novel finding.

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

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

The development of pulmonary hypertension (PH) causes right-sided heart failure. We investigated whether chronic treatment with the endothelin-A- (ETA) receptor antagonist BMS-193884 in rats with monocrotaline- (MCT) induced PH improves right-sided heart failure. Administration of BMS-193884 (100mg/kg) was commenced on the day before treatment with MCT. At 19 days, hemodynamics were measured under anesthesia and hearts were removed. The right ventricular systolic pressure (RVSP), an indicator for pulmonary hypertension, was remarkably elevated in the PH group compared with the normal control group. BMS-193884 effectively prevented this elevation. The central venous pressure, an indicator for right-sided heart failure, was markedly increased in the PH group. This increase was reduced to the normal level by BMS-193884. In the failing right ventricle of the PH group, the expression of atrial natriuretic peptide (ANP) mRNA, which is a molecular marker for the failing heart, was markedly increased. BMS-193884 greatly prevented this increase. The present study suggests that ET-1 contributes to the right-sided heart failure caused by PH and that an ETA-receptor antagonist is a beneficial drug which improves both hemodynamics and cardiac gene expression in the failing right ventricle.

It has been reported that at the end stage, apoptosis is involved in the progression of heart failure. It is suggested that cardiac energy metabolism is impaired during the progression of heart failure. Although the mechanism of induction of apoptosis in the failing heart varies according to the model of heart failure, it is not known whether an impairment of energy metabolism in cardiomyocytes is a primary cause of apoptosis. In this study, we applied mitochondrial inhibitors, such as rotenone, cobalt chloride and antimycin A, which inhibit mitochondrial function at different sites of the mitochondrial respiratory chain, to cardiomyocytes. All these reagents markedly decreased 3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay (MTT) reduction activity, an indicator of mitochondrial function, of cardiomyocytes and greatly increased glucose consumption, suggesting that cardiac energy metabolism is switched from beta-oxidation of fatty acid to glycolysis. It was shown that after 48-72 h of treatment with each reagent, apoptosis was shown to occur by DNA laddering and increase in caspase activity. Interestingly, each reagent with a different action site greatly activated caspase-3, but not caspase-8 activity, suggesting that mitochondria are involved in induction of apoptosis. On the other hand, within 24 h of the treatment, when apoptosis of cardiomyocytes was not observed, the treated cardiomyocytes showed a marked increase in preproendothelin-1 and atrial natriuretic peptide (ANP) gene expressions. In conclusion, the present study suggests that mitochondrial dysfunction with impaired energy metabolism elevates gene expression of cardiac ET-1, an aggravating factor in heart failure, and then finally induces apoptosis in cardiomyocytes. The finding of marked increases in expression of molecular markers (ET-1 mRNA and ANP mRNA) in the failing heart, followed by apoptosis in the treated cardiomyocytes suggests that the inhibition of mitochondrial function of cultured cardiomyocytes provides a possible new in vitro model of heart failure.

We investigated whether impairment of myocardial energy metabolism attenuates cardiac function and increases cardiac endothelin-1 (ET-1) gene expression in rats. Three weeks after commencing administration of cobalt chloride (CoCl 2 ), an inhibitor of mitochondrial function, the peak positive first derivative of left ventricular (LV) pressure, an indicator of myocardial contractility, was significantly decreased in the CoCl 2 -treated rats. LV end-diastolic pressure and right ventricular systolic pressure were increased in the CoCl 2 -treated rats. Echocardiography showed that fractional shortening was significantly decreased in the CoCl 2 -treated rats. Myocardial expressions of acyl-CoA synthase mRNA, an enzyme involved in fatty acid utilization, was markedly decreased in the CoCl 2 -treated rats. Under such conditions, myocardial expression of preproendothelin-1 mRNA and atrial natriuretic peptide (ANP) mRNA, molecular markers of heart failure, was markedly increased in the CoCl 2 rats. In conclusion, the data suggest that impairment of myocardial energy metabolism causes hemodynamic abnormality and increases molecular markers of heart failure (ET- 1, ANP mRNA). These data suggest that myocardial energy metabolism is one of the factors involved in the upregulation of ET-I 1 gene expression in the failing heart.

The pharmacological characterization of endothelin-1 (ET-1) in the pulmonary circulation in pulmonary hypertension (PH) is not known precisely. We investigated the effect of intravenous injection of ET-1 (1000 pmol/kg) on right ventricular systolic pressure (RVSP) (which is equal to systolic pulmonary arterial pressure) in rats with monocrotaline-induced PH. ET-1 decreased RVSP in PH rats; however, ET-1 did not alter RVSP in control rats, suggesting that ET-1 causes dilatation of the pulmonary artery in PH rats. Under pretreatment with the endothelin-A- (ET(A)) receptor antagonist BMS 193884, ET-1 decreased RVSP in PH rats more than in control rats, suggesting that pulmonary vasodilator action of ET-I mediated via the ET(B)-receptor pathway is augmented in PH rats. Under pretreatment with the ET(A/B)-receptor antagonist SB 209670, the effect of ET-1 in lowering pulmonary arterial pressure was abolished in both groups of rats. These results suggest that the hypotensive effect of ET-1 on pulmonary circulation mediated via the ET(B)-receptor pathway is enhanced in PH rats compared with control normal rats. It is considered that the blockade of only the ET(A)-receptor pathway is preferable to the blockade of both the ET(A)- and ET(B)-receptor pathways in the treatment of PH.

Endothelin (ET)-1 has a positive inotropic effect and induces hypertrophy in cardiomyocytes. We previously reported that the peptide level of ET-1 is increased in the failing heart of rats with chronic heart failure (CHF) and that treatment with an ETA-receptor antagonist greatly improves survival in rats with CHF. However, precise analysis for alteration of the myocardial ET system in the failing heart is not known. In this study, we used rats with CHF due to chronic myocardial infarction. Sham-operated rats served as a control. The results showed that the level of preproendothelin (preproET)-1 mRNA and the peptide level of ET-1 were markedly increased in the heart of rats with CHF, whereas the expression of endothelin-converting enzyme (ECE)-1 mRNA in the heart did not differ between CHF and control rats. The intensity of ET-1 staining (ET-1-like immunoreactivity) in cardiomyocytes was markedly stronger in rats with CHF than in control rats, and the fibrotic tissues of the infarcted area were not stained. The mRNA and protein levels of both ETAand ETBreceptors in the heart were significantly higher in rats with CHF than in control rats. The present study suggests that the increase in ET-1 peptide level in the heart of the rats with CHF originated from upregulation of preproET-1 mRNA, which was not attendant with the alteration of ECE-1 mRNA expression, and that both the ETA- and ETB-receptor systems are greatly accelerated in the failing heart.

A 72-year-old male patient with dilated cardiomyopathy was treated with oral flecainide (100 mg/day) for persistent atrial fibrillation (AF) that could not be converted to sinus rhythm by electrical cardioversion. Initiation of flecainide treatment provided sinus rhythm without prolongation of QRS and QTc, bradycardia and first-degree atrioventricular block at a serum flecainide level of 438 ng/mL. Then, he received cardiac resynchronization therapy (CRT). Dose reduction to 50 mg/day because of stabilization of heart rate after CRT produced AF at a serum flecainide level of 270 ng/mL. Electrical cardioversion did not restore the AF to a sinus or pacing rhythm. Dose escalation of flecainide (to 100 mg/day) restored the pacing rhythm at a serum flecainide level of 401 ng/mL. This case suggests that in the Japanese population, serum flecainide level should be maintained at >300 ng/mL to control AF even after effective CRT.

Exercise hypotension has been documented in patients with hypertrophic cardiomyopathy (HCM). Some investigators reported that this is due to an inadequate increase of systemic vascular resistance during or after exercise. The aim of this study was to investigate the pathogenesis of limb vascular response abnormalities in patients with idiopathic HCM. Thirteen patients with HCM and 9 healthy controls were administered an endothelium-dependent dilator (acetylcholine), a direct smooth muscle dilator (nitroglycerin), an alpha-adrenergic stimulator (phenylephrine), and a beta-adrenergic stimulator (isoproterenol) by intra-arterial infusion. Peripheral vascular resistance was assessed by forearm plethysmography at rest and during each infusion to obtain the percentage change in vascular resistance. Isoproterenol, acetylcholine and nitroglycerin produced dose-related vasodilatation with no significant differences between HCM patients and healthy controls. The percentage increase in vascular resistance was significantly less in HCM patients than in healthy controls after phenylephrine infusions of 0.5μg/min (155±38% vs 195±47%, mean ± SD, p

The objective of this study was to investigate the effects of inhaled nitric oxide (NO) on chronic pulmonary hypertension (PH). Thirty patients with valvular heart diseases (n=8, group A), chronic lung diseases (n=16, group B), primary PH or PH due to collagen disease (n=6, group C) were studied. NO was delivered for 20 min at concentration of 5, 10, and 20 ppm in spontaneous respiration. After inhalation, percentages of systolic pulmonary artery pressure (%SPAP) levels in group A were significantly decreased compared with those for pre-inhalation by 12%, 14%, and 14% at 5, 10 and 20 ppm, respectively (p

We have previously reported that production of endothelin (ET)- I is markedly increased in failing hearts of rats with chronic heart failure (CHF). It was also reported that the production of angiotensin II (Ang II) is increased in the failing heart. In this study we investigated both converting enzymes of the ET-1 system and the angiotensin system. We used left coronary artery-ligated rats as a model of CHF. The peptide level of ET- I in the left ventricle (LV) was markedly higher in CHF rats than in control rats. In the LV, expression of preproET-1 mRNA was also markedly higher in CHF rats than in controls. The expression of endothelin-converting enzyme (ECE)-1 mRNA in the rats with CHF was similar to that in controls. Therefore. we believed that the increase in ET-1 production in the failing heart originated from an increase in preproET-I production rather than increase in ECE. The expression of angiotensin-converting enzyme (ACE) mRNA in failing hearts of CHF rats was significantly higher than that of the sham-operated rats. The expression of angiotensinogen mRNA in failing hearts of these CHF rats was slightly higher than that of the sham-operated rats. This study suggests that there is a difference in the role of peptide synthesis between the ECE system and the ACE system in rats with CHF.

Background and hypothesis: Patients with dilated cardiomyopathy (DCM) with left ventricular hypertrophy (LVH) have been found to have a better prognosis than patients without LVH. However, the pathophysiologic mechanism for that has not been investigated. We sought to clarify the pathophysiologic significance of LVH in DCM. Methods: We performed isoproterenol infusion echocar-diography (0.02 mg/kg/min) in 17 patients with DCM, and measured plasma epinephrine and norepinephrine levels at rest and at the end of ergometer exercise in 14 of the 17 patients. Patients were classified into groups according to the presence (9 patients) (LVH+) or absence (8 patients) (LVH-) of LVH. Left ventricular hypertrophy was defined as an inter-ventricular thickness or posterior wall thickness ≥13 mm. Results: Although there was no significant difference between groups in fractional shortening at rest during isoproterenol infusion, fractional shortening was significantly higher in the LVH (+) group than in the LVH (-) group (29 ± 9 vs. 17 ± 8%;p

Objectives.We sought to assess whether isoproterenol stress echocardiography could detect in advance in which patients hypertrophic cardiomyopathy would progress to a phase resembling dilated cardiomyopathy.Background.In a few patients, hypertrophic cardiomyopathy has been reported to progress to a phase characterized by systolic dysfunction and left ventricular dilation, resembling dilated cardiomyopathy.Methods.Echocardiograms were recorded before and immediately after intravenous infusion of isoproterenol (0.02 μg/kg body weight per min) for 5 min in 18 patients with typical hypertrophic cardiomyopathy (i.e., hypertrophied, hyperdynamic and nondilated) to determine the difference in fractional shortening. The patients were categorized into those with a good response (difference in fractional shortening >7%, 14 patients) and those with a poor response (difference ≤ 7%, 4 patients). Changes in left ventricular end-diastolic diameter and fractional shortening were evaluated by using serial echocardiography over an average follow-up period of 5.4 years.Results.In the good response group, neither end-diastolic diameter nor fractional shortening changed significantly during the follow-up period. In the poor response group, end-diastolic diameter significantly increased from a mean ± SD of 41 ± 5 to 53 ± 5 mm (p < 0.05), and fractional shortening significantly decreased from 40 ± 12% to 29 ± 10% (p < 0.05). All patients in the poor response group showed a substantial decrease (≥ 5%) in fractional shortening and an increase (≥5 mm) in end-diastolic diameter. One patient developed congestive heart failure due to systolic dysfunction during the observation period.Conclusions.The present study confirmed that impaired responses to isoproterenol infusion are related to future deterioration of left ventricular performance in patients with typical hypertrophic cardiomyopathy.

To investigate the regulation of endothelin-l (ET-1) production, cardiac catheterization was performed in young patients with congenital heart disease (27 ± 5 months old, mean ± SEM), and plasma levels of ET-1 in the inferior vena cava were measured by a sandwich-enzyme immunoassay. Plasma ET-1 levels of age-matched healthy controls were 1.55 ± 0.07 pg/ml (n = 6). In patients with atrial septal defect [without pulmonary hypertension (PH)] who had volume but not pressure overload to the pulmonary circulation (PC), plasma ET-1 levels were significantly lower than in controls. In patients with PH due to ventricular septal defect (VSD) who had both volume and pressure overload to PC, the levels were significantly higher than in controls. In patients with PH and severe pulmonary congestion due to pulmonary venous stenosis (PVS), plasma ET-1 levels were significantly higher than in those with VSD, suggesting that ET-1 production is also augmented by pulmonary congestion. The present findings suggest that ET-1 production is increased by pressure overload to PC but decreased by volume overload to PC.

Sixteen patients with dilated cardiomyopathy were studied to define the abnormality of the beta-adrenergic pathway non-invasively, using echocardiographic left ventricular responses to isoproterenol (ISP; 0.02 microgram/kg/min) and dibutyryl cyclic AMP (DBcAMP; 0.1 mg/kg/min) infusion. The increase in fractional shortening induced by ISP (delta FS-ISP) was 9 +/- 6% and that by DBcAMP (delta FS-DBcAMP) was 7 +/- 3%. The patients could be divided into three groups according to their left ventricular response to each agent: Group A; normal response to ISP (delta FS-ISPor = 11%), Group B-1; poor response to ISP but better response to DBcAMP (delta FS-ISP11%, delta FS-DBcAMPor = 7%; damage to beta-receptors), and Group B-2; poor response to ISP and DBcAMP (delta FS-ISP11%, delta FS-DBcAMP7%; damage including post receptor levels). Seven patients were in Group A, four in Group B-1, and five in Group B-2. DCM patients had a diversity of left ventricular responses to ISP and DBcAMP, according to the site of damage in the beta-adrenergic pathway.

The aim of this study was to evaluate the volume doubling time (VDT) of lung cancer detected in our annual chest radiograph screening program and to compare it with those previously reported for computed tomography (CT) screening. In total, 209 patients who had a measurable tumor shadow and a history of participating in our chest radiograph mass screening program between 2006 and 2009 were included in this study. Indirect roentgenograms for patients with lung cancer were converted into digital images, and the section showing the tumor was enlarged on the monitor to a size of 0.01 mm. The mean VDT for all the patients was 158 days. Only 3.8% of the patients had a VDT of more than 400 days. In 140 patients with adenocarcinoma, the mean VDT was 177 days, and 5.0% of these patients had a VDT of more than 400 days. In the 44 patients with squamous cell carcinoma, the mean VDT was 133 days, and only 2.3% of these patients had a VDT of more than 400 days. These results were different from those previously reported for CT screening. In several reports on CT screening, more than 20% of the lung cancers had VDTs of more than 400 days. Since it is common knowledge that there are ‘indolent’ lung cancers with a VDT of more than 400 days, screening by annual chest radiography with rare overdiagnosis may need to be reconsidered.

Wall stress has been used as one of the parameters of myocardial mechanics. The present review focuses on recently developed data on ventricular wall stress, especially in relation to other newly developed areas in cardiology. In hypertensive hearts, there is a broad continuous spectrum in the structural and functional changes: those with low wall stress (inappropriate hypertrophy), those with normal wall stress (appropriate hypertrophy) and those with high wall stress (inadequate hypertrophy). Among them, the responses to neurohumoral stimuli are various, and their clinical features and courses also varied. These differences in wall stress among the different categories of hypertensive hearts may be caused by the variable influences of non-mechanical factors, such as molecular, metabolic and neurohumoral ones. Wall stress is an essential determinant of myocardial oxygen consumption, and is also an important determinant of the myocardial contractile state and diastolic function. In contrast to excitation-contraction coupling, contraction-excitation feedback has been studied, suggesting the importance of wall stress regulating electrical phenomena. The interrelationship between mechanical factors (including wall stress) and non-mechanical factors (including molecular, metabolic, neurohumoral and genetic ones) has been investigated intensively. In conclusion, wall stress (or force on the myocardial cell) may be a keystone in cardiology, relating to each of the cardiac phenomena. If wall stress deviates from the normal range, even with compensatory mechanisms, severe cardiac events occur. The compensatory mechanisms for wall stress may act as a risk factor on the heart, especially when the wall stress remains outside the normal range.

Thrombosis is a rare complication in patients with aplastic anemia because of the presence of coincidental thrombocytopenia. We have recently treated two cases, a 61-year-old male and a 59-year-old female, with acute myocardial infarction associated with aplastic anemia. Although their platelet counts were lower than normal in spite of treatment with anabolic steroids for aplastic anemia, the coronary angiographic findings strongly suggested coronary thrombosis in both cases. Anabolic steroids, which have been commonly used for the treatment of aplastic anemia, are a possible risk factor for coronary thrombosis because they have an accelerating effect on thrombus formation. We report two very rare but clinically important cases.

Peripartum cardiomyopathy is a rare cardiac disorder characterized by the development of heart failure in the last month of pregnancy or up to 5 months postpartum in women without other determinable causes of cardiac failure. Intracardiac thrombi have been found at autopsy in some patients with this condition and have been demonstrated in the left or right ventricles on 2-dimensional echocardiography. A 23-year-old woman presented with peripartum cardiomyopathy and biventricular thrombi on echocardiography. The thrombi were spherical, pedunculate, shaggy and irregular in configuration, and freely mobile, suggesting that they were fresh. She was treated with conventional heart failure therapy and anticoagulants. Four days later, the apical thrombi within both ventricles had disappeared and there was no evidence of embolism on physical examination. The hypercoagulable state of the peripartum period and the severe biventricular dysfunction most likely led to the formation of biventricular thrombi.

A 59-year-old woman with partial atrial standstill was studied using magnetocardiograms (MCGs), which revealed through QRS-T subtraction and time-frequency analysis that there was a high-frequency (6 Hz) magnetic source at the low atrial septum. MCGs are useful for noninvasively evaluating the clinical course of patients with atrial fibrillation. (Circ J 2002; 66: 1178 - 1180)

Endothelin-1 (ET-1) is known to have potent contractile and proliferative effects on vascular smooth muscle cells and is known to induce myocardial cell hypertrophy. We studied the pathophysiological role of endogenous ET-1 in rats with monocrotaline-induced pulmonary hypertension. Four-week-old rats were given a single subcutaneous injection of 60 mg/kg monocrotaline (MCT rats) or saline (control rats) and were killed after 6, 10, 14, 18, and 25 days. In the MCT rats, right ventricular systolic pressure progressively increased and right ventricular hypertrophy developed in a parallel fashion. The venous plasma ET-1 concentration also progressively increased, and this increase preceded the development of pulmonary hypertension. The isolated pulmonary artery exhibited a significantly weaker response to ET-1 in the MCT rats on day 25 but not on days 6 and 14. In the MCT rats, the expression of prepro ET-1 mRNA as measured by Northern blot analysis significantly increased in the heart on days 18 and 25, whereas it gradually decreased in the lungs. The peptide level of ET-1 in the lungs also significantly decreased in the pulmonary hypertensive stage. The expression of prepro ET-1 mRNA had increased by day 6 only in the kidneys. Continuous infusion of BQ-123, a selective ETA receptor antagonist, by an osmotic minipump (14.3 mg per day per rat for 18 days) significantly inhibited the progression of both pulmonary hypertension (right ventricular systolic pressure, 77.8 +/- 4.2 [mean +/- SEM] mm Hg [n = 10] versus 52.3 +/- 2.4 mm Hg [n = 7]; P < .01) and right ventricular hypertrophy (right ventricle/[left ventricle +/- septum], 0.56 +/- 0.03 [n = 10] versus 0.41 +/- 0.02 [n = 7]; P < .01). Histological examination revealed that BQ-123 also effectively prevented pulmonary arterial medial thickening. The inhibition of right ventricular hypertrophy by BQ-123 may be partly ascribed to the blockade of excessive stimulation of the heart by ET-1, in addition to the prevention of pulmonary hypertension. The present findings suggest that endogenous ET-1 contributes to the progression of cardiopulmonary alterations in rats with MCT-induced pulmonary hypertension.