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Osteoarthritis (OA) is a progressive degenerative disease of the joints caused in part by a change in the phenotype of resident chondrocytes within affected joints. This altered phenotype, often termed proinflammatory or procatabolic, features enhanced production of endoproteinases and matrix metallo-proteinases (MMPs) as well as secretion of endogenous inflammatory mediators. Degradation and reduced retention of the proteoglycan aggrecan is an early event in OA. Enhanced turnover of hyaluronan (HA) is closely associated with changes in aggrecan. Here, to determine whether experimentally increased HA production promotes aggrecan retention and generates a positive feedback response, we overexpressed HA synthase-2 (HAS2) in chondrocytes via an inducible adenovirus construct (HA synthase-2 viral overexpression; HAS2-OE). HAS2-OE incrementally increased high-molecular-mass HA >100-fold within the cell-associated and growth medium pools. More importantly, our results indicated that the HAS2-OE expression system inhibits MMP3, MMP13, and other markers of the procatabolic phenotype (such as TNF-stimulated gene 6 protein (TSG6)) and also enhances aggrecan retention. These markers were inhibited in OA-associated chondrocytes and in chondrocytes activated by interleukin-1β (IL1β), but also chondrocytes activated by lipopolysaccharide (LPS), tumor necrosis factor α (TNFα), or HA oligosaccharides. However, the enhanced extracellular HA resulting from HAS2-OE did not reduce the procatabolic phenotype of neighboring nontransduced chondrocytes as we had expected. Rather, HA-mediated inhibition of the phenotype occurred only in transduced cells. In addition, high HA biosynthesis rates, especially in transduced procatabolic chondrocytes, resulted in marked changes in chondrocyte dependence on glycolysis versus oxidative phosphorylation for their metabolic energy needs.

Objective Plasma cancer antigen (CA)-125 is a tumour marker recently shown to be associated with systolic heart failure and new-onset atrial fibrillation (AF) after myocardial infarction. However, no reports have described the relationship between CA-125 and new-onset AF in healthy postmenopausal women. The aim of the present study was to evaluate the relationship between CA-125 and new-onset AF in postmenopausal women. Methods Between 2005 and 2015, 2086 women, including 1012 postmenopausal women, visited our hospital for annual health check-ups. We excluded patients with systolic dysfunction, chronic inflammatory disease, chronic obstructive pulmonary disease, histories of AF or neoplastic diseases. A total of 746 postmenopausal women underwent thorough physical examinations, including those for biomarkers such as brain natriuretic peptide, high-sensitivity C-reactive protein (hs-CRP) and CA-125. Results During the 10-year observation period, AF was documented in 31 participants (4.2%). The mean age of participants developing AF (75±6 years) was higher than that of those without AF (68±8 years). Participants developing AF showed significantly higher CA-125 (11.4±6.3 U/mL) and hs-CRP (0.10±0.11 mg/dL) levels than did those without AF (7.7±3.2 U/mL, p

Depletion of the cartilage proteoglycan aggrecan is one of the earliest events that occurs in association with osteoarthritis. This loss is often accompanied by a coordinate loss in another glycosaminoglycan, hyaluronan. Chondrocytes experimentally depleted of cell-associated hyaluronan respond by switching to a pro-catabolic metabolism that includes enhanced production of endogenous inflammatory mediators and increased synthesis of matrix metalloproteinases. Hyaluronan turnover is also increased. Together, such a response provides for possible establishment of a self-perpetuating spiral of events that maintains or prolongs the pro-catabolic state. Chondrocytes or cartilage can also be activated by treatment with pro-inflammatory cytokines and mediators such as IL-1β, TNFα, LPS, fibronectin fragments, and hyaluronan oligosaccharides. To determine the mechanism of chondrocyte activation due to hyaluronan loss, a depletion method was required that did not include degrading the hyaluronan. In recent years, several laboratories have used the coumarin derivative, 4-methylumbelliferone, as a potent inhibitor of hyaluronan biosynthesis, due in part to its ability to sequester intracellular UDP-glucuronic acid and inhibition of hyaluronan synthase transcription. However, contrary to our expectation, although 4-methylumbelliferone was indeed an inhibitor of hyaluronan biosynthesis, this depletion did not give rise to an activation of chondrocytes or cartilage. Rather, 4-methylumbelliferone directly and selectively blocked gene products associated with the pro-catabolic metabolic state of chondrocytes and did so through a mechanism preceding and independent of hyaluronan inhibition. These data suggest that 4-methylumbelliferone has additional useful applications to block pro-inflammatory cell activation events but complicates how it is used for defining functions related to hyaluronan.

Background In the present study it was examined whether transthoracic Doppler echocardiography (TTDE) would be useful for noninvasive diagnosis of coronary spastic angina (CSA) by assessing coronary arterial tone in the morning. Methods and Results The study population comprised 21 CSA patients and 27 control subjects. All diagnoses were angiographically confirmed by provocation test using acetylcholine. Coronary flow velocity reserve (CFVR) was measured at the distal left anterior descending artery with a frequency of 5.0 MHz ultrasound at baseline and after sublingual administration of nitroglycerin (NTG). Coronary arterial tone was assessed by obtaining the change of CFVR induced by NTG administration (CFVRNTG/Pre). Basal CFVR tended to be lower in CSA patients (2.13±0.63, 2.71±0.67, respectively, p=0.05). CFVR after NTG was significantly higher in CSA patients (3.91±1.10, 3.07±0.74, p=0.003). The CFVRNTG/Pre was significantly higher in CSA patients than in the control subjects (1.90±0.49, 1.15±0.22, p

The efficacy of long-term drug therapy for patients with hypertrophic obstructive cardiomyopathy (HOCM) remains unclear. This study was performed to characterize the echocardiographic findings of patients responsive to drug therapy.Left ventricular outflow tract (LVOT) gradient and morphologic characteristics of the septum, posterior wall, and mitral valve were measured echocardiographically in 35 Japanese patients. The mean follow-up time was 41+/-22 months.Long-term drug therapy was effective in 14 patients and ineffective in 21 patients. Five of the refractory patients required mitral valve replacement to become free of symptoms. Only 5 of 21 patients whose LVOT gradient was 100 mm Hg were responsive to drug therapy, whereas 9 of 14 patients whose LVOT gradient was100 mm Hg were responsive to drug therapy. Seven of eight patients with an asymmetric septal hypertrophy (ASH) ratio==1.3 and LVOT gradient100 mm Hg were responsive to drug therapy. Only 3 of 16 patients with an ASH ratio1.3 were responsive to drug therapy. There was no correlation between the efficacy of drug therapy and the morphology of the mitral valve or the width of the LVOT.Our results demonstrate that drug therapy effectively reduces the LVOT gradient in patients with asymmetric septal hypertrophy and a less severe LVOT gradient.

Background and aim of the study: Treatment for hypertrophic obstructive cardiomyopathy (HOCM) has been reported; however, there has been no report on the characteristics of medication-responsive and -refractory hypertrophic obstructive cardiomyopathy (HOCM). Using the classification of systolic anterior movement (SAM) which has been previously reported, we tried to identify the characteristics and use them to treat HOCM appropriately. Methods: The clinical, echocardiographic, catheterization, and surgical data of 29 hospitalized patients with HOCM during 1980 to 1999 were analyzed retrospectively. We classified SAM in all patients by echocardiography. Ninteen patients improved with medical treatment (medical group), and 10 patients underwent surgical treatment because of ineffectiveness of medication (surgical group). We studied the relation between types of SAM and medical/surgical groups, and examined the relation between types of SAM and the surgical methods. Results: Type I SAM was significantly more frequent in the medical group, while type II SAM was more frequent in the surgical group (p = 0.047). Patients in the surgical group underwent mitral valve replacement (MVR), myectomy, or a combination of MVR and myectomy. Left ventricular outflow gradient (LVOG) of over 100 mmHg was recognized in almost all patients with type II SAM. Conclusions: It was suggested that patients with medication-responsive HOCM tended to have type I SAM and those with refractory HOCM tended to have type II SAM. We consider that in type I SAM, if the position of the papillary muscles changed with medication or myectomy, shift of the chordae and type I SAM were reduced or disappeared. However, in type II SAM, even if the position of the papillary muscles changed, SAM did not disappear because lifting of the mitral leaflets remained. It is therefore suggested that patients with type II SAM should undergo at least MVR.

A patient with infective endocarditis (IE) due to methicillin-resistant staphylococcus aureus (MRSA) was found to have conversion of the hypoechoic region of the posterior mitral valve ring apparatus into a clearly delineated echolucent space by repeating transthoracic echocardiography at an interval of 1 week. Color Doppler showed features of blood entry into this space. Abscess formation in IE due to MRSA may be quick and repeated echocardiography may help detect the complications of IE. Semiurgent mitral valve plasty was performed for the associated prolapse of the posterior mitral leaflet using a hand-made, rolled, twisted autologous pericardial ring.

The Japanese Circulation Society appointed a committee to develop guidelines for the prevention, diagnosis and management of infective endocarditis in Japan. In making such guidelines, the committee required information on the current clinical characteristics of infective endocarditis and therefore performed a nationwide questionnaire survey of cases from 2000 and 2001. In total, data were received for 848 cases from 277 of the 817 hospitals surveyed. Mean age was 55+/-18 years and most patients were aged in their 50 s or 60 s; 53.9% of the patients had infective endocarditis of unknown origin (without any prior predisposing conditions or procedures) and the second most common etiology was post dental procedures. The most common microorganism was Gram-positive cocci (345 streptococci and 221 staphylococci) and methicillin resistant Staphylococcus aureus (MRSA) was found in 7.3%. Although more than 90% of cases with Streptococcus viridans were sensitive to penicillin G, 6.6% were resistant. All MRSAs were sensitive to vancomycin. The information obtained from the survey assisted in the making of the guidelines, which should become an indispensable tool for all clinicians.

Aims HMG-CoA reductase inhibitors (statins) have been demonstrated to have in vitro vascular effects. The aim of this study was to determine whether statins actually have in vivo vascular effects independent of their cholesterol-lowering effect.

Aim: Abdominal aortic aneurysm (AAA) is a common vascular degenerative disease. AAA wall contains inflammatory cells that produce matrix metalloproteinases (MMPs) that probably contribute to elastolysis and remodeling of the aneurysm. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been shown to reduce the expression of various molecules (including MMPs) independently of their cholesterol-lowering effect. The aims of this study are to investigate whether statins could modulate the biology of AAA wall and have a potential therapeutic value against AAAs. Methods: We performed immunohistochemical analysis, evaluated MMP-9 production in the aortic wall from patients with infrarenal AAA (n = 10) and control patients with aortoiliac occlusive disease (n = 8), and examined the effect of cerivastatin on MMP-9 production in the AAA wall with organ culture. Results: Neutrophils and macrophages were the cellular sources of MMP-9 in the AAA wall. The tissue concentrations of both total and active MMP-9 were significantly higher in tissues from AAA walls than in control aortic walls. Cerivastatin (0.001 to 0.1 μmol/L) significantly reduced the tissue levels of both total and active MMP-9 in a concentration-dependent manner (P < .001), and the production of tissue inhibitor of MMP-1 was unaffected. Cerivastatin neither reduced the number of infiltrating neutrophils and macrophages nor enhanced apoptosis of those cells, as evaluated with terminal transferase-mediated deoxyurisine triphosphate nick end labeling. Conclusion: These results suggest that cerivastatin can directly modulate the biology of the AAA wall and suppress MMP-9 production in the AAA wall by inhibiting the activation of neutrophils and macrophages, indicating that statin therapy could be useful for the prevention or treatment of AAA. (J Vasc Surg 2002;36:158-63.)

Wave intensity (WI) is a new hemodynamic index, which is defined as (dP/dt)(dU/dt) at any site of the circulation, where dP/dt and dU/dt are the time derivatives of blood pressure and velocity, respectively. Arterial WI in normal subjects has two positive sharp peaks. The first peak occurs during early systole when a forward-traveling compression wave is generated by the left ventricle. The magnitude of this peak increases markedly with an increase in cardiac contractility. The second peak, which occurs towards the end of systole, is caused by generation of a forward-traveling expansion wave by the ability of the left ventricle to actively stop aortic blood flow. The interval between the R wave of the ECG and the first peak of WI (R-1st peak interval) and the interval between the first and second peaks (1st-2nd interval) are approximately equal to the preejection period and left ventricular ejection time, respectively. Using a combined Doppler and echo-tracking system, we obtained carotid arterial WI noninvasively. We examined the characteristics of WI in 11 patients with mitral regurgitation (MR) before and after surgery, and 24 normal volunteers. In the MR group before surgery, the second peak was decreased and the (1st-2nd interval)/(R-R interval) ratio was reduced, compared with the normal group (140 +/- 130 vs 750 +/- 290mmHg m/s3. P0.0083; 20.7% +/- 3.4% vs 26.7% +/- 2.8%, P0.083). There were no significant differences in the first peak between the normal group and the MR group before and after surgery. The second peak in the MR group was increased significantly (P0.016 vs before surgery) to 1,150 +/- 830mmHg m/s3 in the early period after surgery (stage I), and to 1,090 +/- 580mmHgm/s3 in the late period after surgery (stage II). These values did not differ significantly from that of the normal group. At stage I, the (R-1st peak interval)/ (R-R interval) ratio was increased from 13.4% +/- 2.7% to 20.6% +/- 5.6% (P0.016 vs before surgery). At stage II, this ratio decreased to 16.2% +/- 2.8% (P0.016 vs stage I). but was still significantly higher than that before surgery. The (1st-2nd interval)/(R-R interval) ratio increased significantly after surgery (P0.016 vs before surgery) to values (27.0% +/- 4.5% at stage I and 28.9% +/- 2.6% at stage II) which did not differ significantly from that of the normal group. The recovery of the second peak after surgery suggests that the left ventricle had recovered the ability to actively stop aortic blood flow. Wave intensity is useful for analyzing changes in the working condition of the heart.

methods: A total of 1055 adults (mean age 63±13, 58.8% men) without diabetes mellitus, systolic dysfunction or other heart disease underwent a thorough physical examination including tissue Doppler echocardiography. We designated peak early mitral annular velocity (e’) of less than 5.0 to indicate abnormal LV myocardial relaxation (LVMR). We performed single and multiple logistic regression analyses of e’ and cardiovascular risk factors, including MetS factors and indicators of major organ dysfunction and evaluated results with regard to three age groups: young (≤ 49 yrs), middle-aged (50-69 yrs) and elderly (≥ 70 yrs) for both men and women.

Accessory mitral valve (AMV) is a rare cause of left ventricular outflow tract (LVOT) obstruction and is extremely rare in adults. We report a case of an older adult with an AMV that caused severe LVOT obstruction. A parachute-like piece of tissue (the AMV) protruding into the LVOT during systole was first detected in a 45-year-old woman by echocardiography. Because the pressure gradient and dyspnea gradually progressed, she finally underwent a successful operation for removal when she was 48 years old.

We studied the echocardiographic findings and clinical features of left ventricular pseudoaneurysm after mitral valve replacement. From December 1979 to March 1991, 1050 patients underwent mitral valve replacement at our institute, and eight patients (0.8%) had left ventricular pseudoaneurysm. In all eight patients, left ventricular pseudoaneurysm developed after the second mitral valve replacement. The incidence of left ventricular pseudoaneurysm among 253 patients who had had previous mitral valve surgery was 3.1%. Seven of the eight patients were still alive and were followed up from 5 to 136 months (mean, 57 months) after the development of left ventricular pseudoaneurysm; these patients had no complications. One patient died as a result of low cardiac output after mitral valve replacement in spite of repair of the left ventricular pseudoaneurysm. This patient had a long and wide myocardial laceration near the left ventricular pseudoaneurysm. In the other seven patients, transthoracic echocardiography demonstrated a large extraventricular cavity along the posterobasal left ventricle. In five of these patients, a turbulent flow in the neck of the left ventricular pseudoaneurysm was recorded both in systole and diastole by pulsed and color Doppler echocardiography. Transesophageal echocardiography clearly showed the narrow neck of the left ventricular pseudoaneurysm and an abnormal flow between the left ventricle and the left ventricular pseudoaneurysm. Generally, when left ventricular pseudoaneurysm develops after mitral valve replacement, surgical repair is the first choice of therapy. Our study demonstrated, however, that the development of left ventricular pseudoaneurysm was not always associated with a poor prognosis without surgical intervention.(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous intravenous infusion of prostacyclin (epoprostenol) as a treatment for primary pulmonary hypertension (PPH) definitely improves the patient's quality of life, but few accurate parameters have been found to evaluate the efficacy of the treatment. We observed a patient with severe PPH whose plasma brain natriuretic peptide (BNP) level changed significantly as her condition and symptoms changed. Plasma BNP may be considered as one of the parameters for assessing the efficacy of prostacyclin treatment.

In this paper, we described a case of thrombosed Hall-Kaster valve who suffered from recurrent coronary thromboemboli.The patient was a 39 year-old man who received an operation of aortic valve replacement (Hall-Kaster valve) and mitral valve replacement (St. Jude Medical valve) for his rheumatic heart disease 10 years ago (Fig. 1). Since then he had been chronically anticoagulated using warfarin and remained symptom free. He suffered from acute myocardial infarction on January, 1989 and unstable angina on April, 1989. Coronary angiogram at the time of those two episodes revealed thrombi in left coronary artery system (middle portion of left anterior descending artery, left main trunk) (Fig. 4, 5, respectively). Although we suspected of thrombosed prosthetic valve, the diagnosis could not be made by auscultation, echocardiogram including Doppler technique, cardiac catheterization and angiogram before the operation. Patient's blood sample revealed high level of D-dimer at the time when the coronary artery thrombi disappeared on angiogram. It was speculated that thrombus derived from elsewhere (Table). On November 21, 1989 he suffered from acute left-sided heart failure due to thrombosed valve with chest pain. Although emergency re-operation of valve replacement was carried out, he died during the operation. The inspection at the time of the operation revealed thrombosed Hall-Kaster prosthetic valve (Fig. 6).

Background Previous studies indicate that individuals with metabolic syndrome (MetS) might be at risk for left ventricular (LV) diastolic dysfunction. However, little is known about which metabolic factors contribute to the development of LV dysfunction in individuals who are not obese or overweight and who do not have diabetes mellitus and/or cardiovascular disease. Methods Participants without diabetes mellitus, systolic dysfunction, or other heart diseases underwent a thorough physical examination, including tissue Doppler echocardiography. A peak early mitral annular velocity (e′) of

Background As coronary flow velocity (CFV) is inversely related to the luminal size that exists for the myocardial bed, the elevated arterial tone can be assessed as the higher flow velocity in the epicardial artery. We examined the usefulness of transthoracic Doppler echocardiography (TTDE) for the assessment of coronary arterial tone. Methods and Results A total of 32 patients underwent TTDE and angiography. The luminal diameter (LD) in the left anterior descending artery (LAD) was measured by using quantitative coronary angiography before and after nitroglycerin (NTG) administration. The ratio of post NTG LD to the control (LDNTG/Pre) was assessed as a standard parameter of coronary arterial tone. We also measured CFV and CFV reserve (CFVR) at the LAD by TTDE. We evaluated the change of CFV (CFVNTG/Pre) and CFVR (CFVRNTG/Pre) following NTG administration. The LD increased from 1.98±0.46 to 2.51±0.34 mm (p

HMG-CoA reductase inhibitors (statins) have been shown to improve the endothelial function by lowering lipids. Recent studies also suggest a direct impact of statins on the vascular wall. We assessed the rapid effect of cerivastatin on the coronary flow velocity reserve (CFVR) using transthoracic Doppler echocardiography (TTDE). The coronary flow velocity from the distal left anterior descending artery was measured in 16 healthy subjects (all male, age 24–38 years) using a 5-MHz transducer, on the day before, just before, and 3 h after administering 0.3 mg of cerivastatin. Hyperemia was achieved by the intravenous administration of adenosine, and the CFVR was calculated as the radio of the mean diastolic hyperemic coronary flow velocity to the basal flow velocity. The serum lipid profile and high-sensitivity C-reactive protein (hsCRP) were measured. The CFVR following the single administration of cerivastatin increased from 2.93 ± 0.58 to 3.91 ± 0.86, P = 0.003, and was significantly higher than the CFVR measured at the same time on the previous day (3.91 ± 0.86 vs 3.37 ± 0.48, P = 0.009). Neither the serum lipid profile nor hsCRP exhibited a remarkable change after cerivastatin administration. We concluded that a single-dose administration of cerivastatin, an HMG-CoA reductase inhibitor, improves the coronary flow velocity reserve without modifying the serum lipid profile.

We explore the association between the site of attachment of nonfamilial left atrial myxoma and it’s recurrence. Forty-three (11 male and 32 female; mean age, 55.9±13.6 years) of 49 consecutive patients with nonfamilial left atrial myxoma who had been evaluated with preoperative echocardiography, X were available for postoperative follow-up with transthoracic echocardiography, transesophageal echocardiography, or both, for an average period of 85.2±54.2 months (range, 6.5 to 215.5 months). We compared preoperative clinical and echocardiographic features of recurrent and nonrecurrent myxomas. Three (7%) of the 43 cases of atrial myxoma recurred at the same site after 24.1±7.6 months. Involvement of the mitral valve annulus or mitral valve leaflet (3 vs 0,p

A subepicardial aneurysm became evident in a male patient after anticoagulant therapy. On admission, it appeared to be an old anterior infarction accompanied by a mural thrombus. After warfarin administration, the thrombus disappeared and an echo-free space emerged outside the apical myocardial wall. The echo-free space communicated with the left ventricular cavity through the apical myocardial wall. Emergency surgery was undertaken and the patient survived. The aneurysm was covered with epicardium and there was an endomyocardial rupture of the muscle in the apical wall, which was the entrance of the aneurysm. This case suggests that cautious follow-up with echocardiography is necessary when anticoagulant therapy is selected for thrombi following myocardial infarction.

Objective and importance Patent foramen ovale (PFO) has been suggested as a potential source of paradoxical embolism. A higher prevalence of PFO in ischemic stroke of unexplained cause has been recognized. Brain abscesses are commonly associated with a contiguous focus of infection, hematogenous spread from a distant focus, or cranial trauma. However, no predisposing factors, including a distant focus with unknown cause, are identified in approximately 15 to 30% of reported cases. Clinical presentation We encountered two patients with brain abscess presumably caused by dental infections. Both patients displayed PFO, through which right-to-left atrial contrast shunting was revealed by transesophageal echocardiography. Although the radiological location of the abscesses suggested hematogenous spread as a cause, the patients had no arteriovenous shunting other than the PFO, despite exhaustive investigations for a potential infectious route. The patients displayed no definite focal orofacial inflammatory signs during the postoperative course despite diagnosis of pyorrhea alveolaris or periodontitis. Intervention In Patient 1, the abscess was aspirated stereotactically, and in Patient 2, the abscess disappeared radiologically after high-dose antibiotic treatment. Conclusion The mechanism of brain abscess formation putatively related to PFO should be different from that related to common dental sepsis. Analysis of these cases suggested that infectious embolism from a latent or even identifiable focus through the PFO may be an underrecognized cause of brain abscess, in contrast to simple seeding of the brain via transit of the infecting bacteria through the valveless emissary veins.

Background Cystic medial degeneration (CMD) is a histological abnormality that is common in the aortic diseases associated with Marfan’s syndrome (MFS). Although little known about the mechanism underlying CMD, several recent reports have demonstrated that vascular smooth muscle cell (VSMC) apoptosis could play a substantial role in CMD. On the other hand, angiotensin II (Ang II) has been reported to play an important role in the regulation of VSMC growth and apoptosis via the Ang II type 1 receptor (AT1R) and type 2 receptor (AT2R). Methods and Results To elucidate the role of Ang II signaling via the Ang II receptors in CMD, we investigated AT1R and AT2R mRNA expression and tissue concentration of Ang II in MFS aortas (n=10) and control aortas (n=12). Furthermore, we examined the effects of an ACE inhibitor, an AT1R blocker, and an AT2R blocker on serum deprivation-induced VSMC apoptosis by organ culture system. AT1R expression was significantly decreased ( P P P P Conclusions Accelerated ACE-dependent Ang II formation and signaling via upregulated AT2R play a pivotal role in VSMC apoptosis in CMD, and the ACE inhibitor could have clinical value in the prevention and treatment of CMD.