Abstract: An open, randomized, four-phased crossover study using 4 mg of pitavastatin or 20 mg of atorvastatin was performed to compare their efficacy and safety, especially regarding plasma levels of coenzyme Q10 (CoQ10) in 19 Japanese patients with heterozygous familial hypercholesterolemia. Pitavastatin and atorvastatin caused significant and almost comparable reductions in serum levels of total cholesterol (-35.4 vs. -33.8%), low-density lipoprotein cholesterol (-42.8 vs. -40.7%), and triglyceride (-26.1 vs. -29.4%), and significantly increased serum levels of high-density lipoprotein cholesterol (12.1 vs. 11.4%). Under these conditions, plasma levels of CoQ10 were reduced by atorvastatin (-26.1%, P=0.0007) but not by pitavastatin (-7.7%, P=0.39), although no adverse events or abnormalities of liver and muscle enzyme were observed after either statin treatment. It remains to be seen whether the observed changes in CoQ10 levels are related to the long-term safety of this drug.

Abstract: Mutations in the betaMHC (beta-myosin heavy chain), a sarcomeric protein are responsible for hypertrophic and dilated cardiomyopathy. However, the mechanisms whereby distinct mutations in the betaMHC gene cause two kinds of cardiomyopathy are still unclear. In the present study we report a novel betaMHC mutation found in a patient with isolated LVNC [LV (left ventricular) non-compaction] and the phenotype of a mouse mutant model carrying the same mutation. To find the mutation responsible, we searched for genomic mutations in 99 unrelated probands with dilated cardiomyopathy and five probands with isolated LVNC, and identified a p.Met531Arg mutation in betaMHC in a 13-year-old girl with isolated LVNC. Next, we generated six lines of transgenic mice carrying a p.Met532Arg mutant alphaMHC gene, which was identical with the p.Met531Arg mutation in the human betaMHC. Among these, two lines with strong expression of the mutant alphaMHC gene were chosen for further studies. Although they did not exhibit the features characteristic of LVNC, approx. 50% and 70% of transgenic mice in each line displayed LVH (LV hypertrophy) by 2-3 months of age. Furthermore, LVD (LV dilation) developed in approx. 25% of transgenic mice by 18 months of age, demonstrating biphasic changes in LV wall thickness. The present study supports the idea that common mechanisms may be involved in LVH and LVD. The novel mouse model generated can provide important information for the understanding of the pathological processes and aetiology of cardiac dilation in humans.

Abstract: Although several cytokines and chemokines have been demonstrated to play pivotal roles in the pathophysiological conditions of atherosclerosis, few findings exist regarding the expression and function of cytokine-modulating molecules such as ephrin-Bs and their cognate receptors, EphBs, in human atherosclerosis. Therefore, in the present study, we screened novel genes modulating atherogenesis by cDNA array and quantitatively determined them by real-time RT (reverse transcription)-PCR in human carotid atherosclerotic plaques. Ephrin-B1 and EphB2, key regulators of embryogenesis, were significantly up-regulated in plaques compared with those in adjacent control tissues [ephrin-B1, 0.638+/-0.106 compared with 0.831+/-0.152, or 130% (P<0.05); EphB2, 1.296+/-0.281 compared with 2.233+/-0.506, or 172% (P<0.05)]. Immunohistological analysis demonstrated that both ephrin-B1 and EphB2 were expressed in macrophages and T-lymphocytes in plaques as well as in monocytes, T-lymphocytes and arterial endothelial cells isolated from healthy adults. Interestingly, the extracellular domains of ephrin-B1 and EphB2, the expression of which were both enhanced in stimulated THP-1 cells, significantly inhibited spontaneous (22.5 and 27.6% respectively; P<0.01) and MCP-1 (monocyte chemoattractant protein-1)-dependent (29.7 and 22.6% respectively; P<0.01) migration of monocytes. In conclusion, these results demonstrate that ephrin-B1 and EphB2 are overexpressed in atherosclerotic tissue and might locally regulate cell migration, possibly through modulating cytokine-related chemotaxic activity; however, the functional role of these molecules in atherogenesis should be investigated further.

Abstract: In the new world-wide criteria for metabolic syndrome (MetS) by the International Diabetes Federation (IDF) in 2006, the Japanese is the only ethnicity in which the recommended waist circumference (WC) cutoff value is higher in women (>or=90cm) than in men (>or=85cm), and its validity appears to be controversial. We investigated the optimal cutoff points for the diagnosis of central obesity in Japanese men and women, using the receiver operating characteristic (ROC) curve analysis for both of WC and visceral fat area (VFA) in 1870 middle-aged Japanese. VFA was superior to WC and Body mass index (BMI) for discriminating the subjects with two or more nonadipose components of MetS. The optimal cutoff points of VFA and WC were 132.6cm(2) and 89.8cm for men and 91.5cm(2) and 82.3cm for women. The stratifications of MetS components more than 1.0 in average occurred more steeply by the accumulation of VFA in women than in men. In conclusion, setting the cutoff points of WC and VFA lower values in women than in men for the definition of central obesity is needed to identify the subjects with MetS in Japanese, as in other Asian populations.

Abstract: Mikulicz's disease (MD) is gaining acceptance as an immunoglobulin G4 (IgG4)-related disease characterized by bilateral lacrimal and salivary gland swelling. The aetiology of MD and other IgG4-related diseases is still unclear. The present work was performed to study the clonality of infiltrating IgG4-positive plasma cells in lacrimal glands and circulating peripheral blood cells in patients with MD, and compare the clonal relationship between infiltrating and circulating IgG4 positive cells. Total cellular RNA was extracted from the lacrimal glands and peripheral blood in five MD patients. Reverse transcription polymerase chain reaction was performed with primers specific for activation-induced cytidine deaminase (AID) and for Ig VH and IgG4. Sequences of Ig VH were compared with the structure of Ig VH of the lacrimal glands and the peripheral blood cells. AID was expressed to varying degrees in lacrimal glands of all MD patients. Most IgG4-positive cells infiltrating lacrimal glands and in peripheral blood were polyclonal, although several clonally related pairs were detected. In one patient, two of the circulating IgG4 VH4-59 clones shared identical CDR3 sequences with the clones within the lacrimal glands. In conclusion, while most tissue-infiltrating and circulating IgG4-positive cells in MD are polyclonal, some clonally related IgG4 positive cells exist between lacrimal gland and peripheral blood, accounting for the clinical features of MD as an IgG4-related disease involving multiple organs.

Abstract: Background The impact of body mass index (BMI) on outcomes after primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) remains unclear. Methods and Results A total of 3,076 patients undergoing PCI for AMI within 48 h after symptom onset were studied. Patients were divided into 4 groups according to baseline BMI: lean (<20 kg/m(2)), normal weight (20.0-24.9 kg/m(2)), overweight (25.0-29.9 kg/m(2)) and obese (>/=30.0 kg/m(2)). Obese patients were younger and had a higher frequency of diabetes mellitus, hyperlipidemia, hypertension and smoking. Lean patients were older, usually women and had a lower frequency of the aforementioned risk factors. Killip class on admission, renal insufficiency, and final Thrombolysis In Myocardial Infarction (TIMI) flow grade did not differ among the 4 groups. In lean, normal weight, overweight and obese patients, in-hospital mortality was 9.2%, 4.4%, 2.5% and 1.8%, respectively (p<0.01). Multivariate analysis showed that compared with normal weight patients, odds ratios for in-hospital death in lean, overweight and obese patients were 1.92, 0.79 and 0.40, respectively (p=NS). Independent predictors were age, Killip class on admission, renal insufficiency and final TIMI flow grade. Conclusion BMI itself had no impact on in-hospital mortality in patients undergoing primary PCI for AMI. The phenomenon ;obesity paradox' may be explained by the fact that obese patients were younger at presentation. (Circ J 2008; 72: 521 - 525).

Abstract: A 79-year-old woman with systemic sclerosis was admitted to our hospital because of syncope. On admission, electrocardiogram showed progression of intraventricular conduction defect. Chest radiograph showed marked cardiomegaly. Echocardiogram revealed deterioration of left ventricular systolic function. We suspected progressive myocardial disease with Stokes-Adams attack. When we were preparing a temporary pacemaker, paroxysmal atrioventricular block with asystole for 15 seconds and convulsion occurred. Electrophysiological study showed His-ventricular block and sinus node dysfunction. A permanent pacemaker was implanted. In systemic sclerosis, progression of ventricular conduction defect may warrant prompt electrophysiological study and prophylactic pacemaker implantation.

Abstract: BACKGROUND: There is conflicting information about whether nitrate treatment aggravates long-term prognosis, so the present retrospective study was designed to determine the effects of long-term nitrate therapy on major adverse events after acute myocardial infarction (AMI) in the coronary interventional era. METHODS AND RESULTS: Using the Japanese Acute Coronary Syndrome Study database, 1,236 consecutive patients who were hospitalized within 48 h of onset of symptoms of AMI from January to December 2003 were evaluated. All-cause mortality, cardiac events and cardiovascular events were lower in patients treated with nitrates than in the untreated controls. However, these crude comparisons included several confounding factors on nitrate prescription. To minimize the effect of selection bias on outcomes, the technique of propensity score matching for clinical characteristics was used and distortion of effective nitrate treatment was excluded as much as possible. The results of propensity score matching showed that nitrate therapy had no impact on all-cause mortality, cardiac events and cardiovascular events at 30, 60 or 90 days, 6 months, 1 year, and 2 years follow-up. CONCLUSIONS: Long-term nitrate therapy after AMI neither improves nor aggravates prognosis. Prospective randomized clinical trials are warranted to determine the effects of long-term nitrate therapy for secondary prevention of AMI.

Abstract: The relationship between post-prandial plasma glucose (PPG) and post-challenge plasma glucose (PCG) within individuals was investigated in Japanese population. The oral glucose tolerance test (OGTT) and measurements of PPG 2h after ingestion of a standardized rice-based meal (PPG2h), were performed in 4471 middle-aged Japanese subjects (2774 men and 1697 women, 50.7+/-8.5 years). There was a loose correlation between PPG2h and PCG2h (r=0.327, p<0.001). The diabetes group (n=170) showed the highest PPG2h, followed by the IGT group (n=786) and the NGT group (n=3414) (p<0.05). At the cutoff point of 140 mg/dl (7.8 mmol/l) for PPG2h, specificities were 94.9% for IGT plus diabetes and 92.9% for diabetes, but sensitivities were as low as 23.2% for IGT plus diabetes and 44.7% for diabetes. The correlation of PPG2h with PCG2h was stronger in the obese group (BMI>or=25 kg/m2) than in the lean group (BMI<20 kg/m2). We conclude that the correlation between PPG2h and PCG2h was significant but not very tight. In evaluating PPG2h, if the cutoff point of 140 mg/dl (7.8 mmol/l) for PCG2h is extrapolated, the majority of subjects with dysglycemia could be overlooked.

Abstract:

Abstract: OBJECTIVE: The genetic background of familial combined hyperlipidemia (FCHL) has not been fully clarified. Because several nuclear receptors play pivotal roles in lipid metabolism, we tested the hypothesis that genetic variants of nuclear receptors contribute to FCHL. METHODS AND RESULTS: We screened all the coding regions of the PPARalpha, PPARgamma2, PPARdelta, FXR, LXRalpha, and RXRgamma genes in 180 hyperlipidemic patients including 60 FCHL probands. Clinical characteristics of the identified variants were evaluated in other 175 patients suspected of coronary disease. We identified PPARalpha Asp140Asn and Gly395Glu, PPARgamma2 Pro12Ala, RXRgamma Gly14Ser, and FXR -1g->t variants. Only RXRgamma Ser14 was more frequent in FCHL (15%, P<0.05) than in other primary hyperlipidemia (4%) and in controls (5%). Among patients suspected of coronary disease, we identified 9 RXRgamma Ser14 carriers, who showed increased triglycerides (1.62+/-0.82 versus 1.91+/-0.42 [mean+/-SD] mmol/L, P<0.05), decreased HDL-cholesterol (1.32+/-0.41 versus 1.04+/-0.26, P<0.05), and decreased post-heparin plasma lipoprotein lipase protein levels (222+/-85 versus 149+/-38 ng/mL, P<0.01). In vitro, RXRgamma Ser14 showed significantly stronger repression of the lipoprotein lipase promoter than RXRgamma Gly14. CONCLUSION: These findings suggest that RXRgamma contributes to the genetic background of FCHL.

Abstract: Differences in the diagnostic value of a variety of definitions of negative T waves for HCM (hypertrophic cardiomyopathy) have not yet been clarified, resulting in a number of definitions being applied in previous studies. The aim of the present study was to determine the most accurate diagnostic definition of negative T waves for HCM in genotyped populations. Electrocardiographic and echocardiographic findings were analysed in 161 genotyped subjects (97 carriers and 64 non-carriers). We applied three different criteria that have been used in previous studies: Criterion 1, negative T wave >10 mm in depth in any leads; Criterion 2, negative T wave >3 mm in depth in at least two leads; and Criterion 3, negative T wave >1 mm in depth in at least two leads. Of the three criteria, Criterion 3 had the highest sensitivity (43% compared with 5 and 26% in Criterion 1 and Criterion 2 respectively; P<0.0001) and retained a specificity of 95%, resulting in the highest accuracy. In comparison with abnormal Q waves, negative T waves for Criterion 3 had a lower sensitivity in detecting carriers without LVH (left ventricular hypertrophy) (12.9% for negative T waves compared with 22.6% for abnormal Q waves). On the other hand, in detecting carriers with LVH, the sensitivity of negative T waves increased in a stepwise direction with the increasing extent of LVH (P<0.001), whereas there was less association between the sensitivity of abnormal Q waves and the extent of LVH. In conclusion, Criterion 3 for negative T waves may be the most accurate definition of HCM based on genetic diagnoses. Negative T waves may show different diagnostic value according to the different criteria and phenotypes in genotyped populations with HCM.

Abstract: BACKGROUND: There have been few multicenter studies using intravascular ultrasound (IVUS) to assess the process of atherosclerosis in a Japanese population with hypercholesterolemia that is being treated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors for control of low-density lipoprotein-cholesterol. METHODS AND RESULTS: An open-label multicenter study is planned to evaluate with IVUS whether treatment with rosuvastatin for 76 weeks results in regression of coronary artery atheroma volume in patients who have coronary heart disease (CHD) and hypercholesterolemia. Sample size is 200 subjects with CHD who are to undergo percutaneous coronary intervention. The planned duration is between October 2005 and October 2008. CONCLUSIONS: The COSMOS study will be the first multicenter cardiovascular study in a Japanese population and may provide new evidence on the effects of rosuvastatin on the progression of coronary atherosclerotic lesions.

Abstract: The objective of this study was to establish a hepatic lipase (HL) assay method that can be applied to automatic clinical analyzers. Seventy-four hyperlipidemic subjects (men/women 45/29) were recruited. Lipase activity was assayed measuring the increase in absorbance at 546 nm due to quinonediimine dye production. Reaction mixture R-1 contained 50 mM Tris-HCl (pH 9.5), 0.5 mM glycerol-1,2-dioleate, 0.4% (unless otherwise noted) polyoxyethylene-nonylphenylether, 3 mM ATP, 3 mM MgCl(2), 1.5 mM CaCl(2), monoacylglycerol-specific lipase, glycerol kinase, glycerol-3-phosphate oxidase, 0.075% N,N-bis-(4-sulfobutyl)-3-methylaniline-2 Na, peroxidase, ascorbic acid oxidase. Reaction mixture R-2 contained 50 mM Tris-HCl (pH9.5), 0.15% 4-aminoantypirine. Automated assay for activity was performed with a Model 7080 Hitachi analyzer. In the lipase assay, 160 microl of R-1 was incubated at 37 degrees C with 3 microl of samples for 5 min, and 80 microl of R-2 was added. Within-run coefficient of variations was 0.9-1.0%. Calibration curve of lipase activity was linear (r = 0.999) between 0 and 320 U/l. Analytical recoveries of purified HL added to plasma were 96.6-99.8%. HL activity in postheparin plasma measured in this method had a closer correlation with HL mass by a sandwich ELISA (r = 0.888, P < 0.0001) than those in the conventional method using [(14)C-]triolein (r = 0.730, P < 0.0001). This assay method for HL activity can be applied to an automatic clinical analyzer.

Abstract: BACKGROUND: There have been no previous reports showing specifically the relation between lipoprotein lipase (LPL) and apolipoprotein (apo) B-48 or remnant metabolism. In this study, we have clarified the relationships of LPL mass in pre-heparin with serum apo B-48 measured by enzyme-linked immunosorbent assay, triglycerides (TG), and remnant-like particle triglycerides (RLP-TG). MATERIAL AND METHODS: Seventy-nine type 2 diabetic subjects [age, 55+/-13; body mass index (BMI), 25+/-5.0 kg/m2; fasting plasma glucose (FPG), 7.39+/-2.22 mmol/l, HbA1c, 6.5+/-1.3%, total cholesterol (TC), 5.36+/-1.09 mmol/l, TG, 2.32+/-2.53 mmol/l; HDL-C, 1.22+/-0.44 mmol/l; serum LPL mass, 45+/-22 ng/ml; apo B-48, 6.6+/-6.3 microg/ml] were recruited in this study. Fasting serum apo B-48 were measured by ELISA using anti-human apo B-48 monoclonal antibodies (MoAb) and LPL mass by ELISA using anti-bovine milk LPL MoAb. RLP-TG levels were measured using monoclonal antibodies to apo B-100 and apo A-1. RESULTS: There was no relationship of LPL mass to age, BMI, FPG, and HbA1c. Serum LPL mass was correlated inversely with TG (r=-0.529 p<0.0001) and positively with HDL-C (r=0.576, p<0.0001). Also, LPL mass showed inverse correlations with apo B-48 (r=-0.383 p<0.0001) and RLP-TG (r=-0.422 p<0.0001, n=51). Multiple regression analysis with TG, apo B-48, or RLP-TG as dependent variables, and age, gender, BMI, plasma glucose, and LPL mass as independent variables showed that LPL mass was associated independently with TG, apo B-48, or RLP-TG. CONCLUSION: The decrease in LPL protein mass could cause an increase in serum apo B-48 and RLP-TG levels, which is related to the retardation of remnant metabolism.

Abstract: AIM: The aim of this study was to investigate the effect of SNP45 of the adiponectin gene on body fat distribution and carotid atherosclerosis in Japanese obese subjects. METHODS: A total of 64 obese subjects were investigated. Genotypes of SNP45 were assayed by polymerase chain reaction-restriction fragment length polymorphism. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured using computed tomography. The progression of atherosclerosis was evaluated by plaque score (PS) of carotid artery using B-mode ultrasonography. RESULTS: Men carrying the G allele of SNP45 showed higher VFA (172.8+/-50.8 vs. 147.1+/-58.7, p=0.005), lower SFA (209.9+/-101.8 vs. 273.4+/-142.2, p=0.007), higher VFA/SFA (V/S) ratio (1.00+/-0.46 vs. 0.60+/-0.26, p <0.001) and higher PS (9.5+/-3.7 vs. 6.8+/-4.2, p=0.012) than those with TT genotype. Multivariate analysis showed that SNP45 was an independent determinant of V/S ratio and PS in men. In subgroup analysis, PS tended to be associated with V/S ratio only in the carrier of 45G allele. CONCLUSION: These results suggest that the G allele could be a risk factor of metabolic syndrome and the development of atherosclerosis in Japanese obese subjects.

Abstract: BACKGROUND: Studies from North America indicate that patients admitted during the weekend with acute myocardial infarction (AMI) have a worse outcome than weekday-admitted patients, probably reflecting a lower rate of invasive procedures. However, it is unclear whether the same is true in Japan, which has a different healthcare system. METHODS AND RESULTS: Using the Japanese Acute Coronary Syndrome Study (JACSS) database, this study included 4,805 consecutive patients who were admitted within 48 h of onset of AMI (3,526 [73.4%] patients with weekday onset [Monday through Friday] and 1,279 [26.6%] with weekend onset [Saturday and Sunday]). There were no significant differences between the 2 groups in patient background and clinical features. The proportions of patients who underwent emergency catheterization (88.4% vs 88.0%) and reperfusion therapy (81.5% vs 81.4%) were also similar. There were no differences between the 2 groups in the in-hospital, 30-day, and 1-year mortality rates. Even after various adjustments, there was no difference in the risk of death associated with weekend versus weekday onset of AMI. CONCLUSION: There were no obvious differences in outcome for Japanese AMI patients in the weekday- or weekend-onset group, suggesting the quality of the Japanese healthcare system is similar for the entire week.

Abstract: BACKGROUND: Aldosterone is an important pathogenetic factor, independent of the renin-angiotensin system in cardiovascular and renal disease. Aldosterone breakthrough during angiotensin-converting enzyme (ACE) inhibitor therapy was reported in hypertension, diabetes mellitus, and chronic renal disease. It is unclear whether the angiotensin II receptor blocker (ARB) causes aldosterone breakthrough in patients with hypertension and diabetes mellitus, and whether aldosterone breakthrough contributes to renal injury in these patients. METHODS: We prospectively studied 95 hypertensive patients with diabetes mellitus. Patients were treated with candesartan (8 mg/day, n = 47) or valsartan (80 mg/day, n = 48) for 15 months. Blood pressure (BP), urinary albumin excretion (UAE), biochemical markers, plasma aldosterone concentration (PAC), and plasma renin activity (PRA) were measured before and at 3, 6, 12, and 15 months of treatment. Nine patients who exhibited aldosterone breakthrough after treatment with ARB were placed on spironolactone (25 mg/day) for 3 months, and BP, UAE, and biochemical markers were measured after treatment. RESULTS: Although the overall PAC was significantly decreased (P < .05) in each group, it eventually increased in 21 (candesartan, 11 patients; valsartan, 10 patients) of 95 patients (22%; aldosterone breakthrough). Blood pressure, PRA, and biomedical markers did not differ between the two groups during treatment. Although UAE was significantly decreased in patients with or without aldosterone breakthrough at 6 months, it was increased again at 15 months of treatment in patients with aldosterone breakthrough. Treatment with spironolactone markedly reduced UAE in these patients. CONCLUSIONS: Aldosterone breakthrough was seen to be equal in hypertensive patients with diabetes mellitus treated with candesartan or valsartan. Aldosterone blockade therapy may be effective in preventing renal injury in hypertensive patients with aldosterone breakthrough.

Abstract: A 62-year-old woman was admitted to hospital because of nausea. A grade 5/6 continuous murmur was audible near the left sternal border at the second intercostal space. Chest X-ray showed cardiomegaly and bilateral pleural effusion. She was diagnosed as heart failure and a diuretic was prescribed. After remission of the heart failure, echocardiography showed shunt flow from the right coronary cusp to the right ventricle. Aortography revealed that an aneurysm of the right coronary sinus of Valsalva had ruptured into the right ventricle. Coronary angiography revealed a single coronary artery. Chest computed tomography revealed persistent left superior vena cava. Surgical repair was carried out and the patient made an uneventful recovery. In addition to these cardiovascular abnormalities, she had Wildervanck syndrome (Klippel-Feil syndrome, Duane syndrome and sensorineural hearing disturbance), blepharoptosis and short stature. This rare combination has not been reported previously.

Abstract: BACKGROUND: We previously reported that a high-sodium diet activates the local renin-angiotensin-aldosterone system (RAAS) in cardiovascular tissues of Dahl salt-sensitive hypertensive (DS) rats. Angiotensin-converting enzyme 2 (ACE2) is a novel regulator of blood pressure (BP) and cardiac function. The effect of blockade of aldosterone or angiotensin II (Ang II) on cardiac angiotensinogen and ACE2 in DS rats is unknown. METHODS: The BP, plasma renin activity (PRA), plasma aldosterone concentration (PAC), heart weight, endothelium-dependent relaxation (EDR), and messenger RNA (mRNA) levels of collagen III, angiotensinogen, ACE, and ACE2 in the heart were measured in DS rats and in Dahl salt-resistant (DR) rats fed high or low salt diets. The rats were treated orally with or without eplerenone (100 mg/kg/d), candesartan (10 mg/kg/d), or both drugs combined for 8 weeks. RESULTS: A high salt diet increased BP (140%), heart/body weight (132%), and collagen III mRNA levels (146%) and decreased PRA and PAC concomitant with increased expression of cardiac angiotensinogen mRNA and decreased mRNA levels of ACE2 in DS rats. Eplerenone or candesartan significantly decreased the systolic BP from 240 +/- 5 mm Hg to 164 +/- 4 mm Hg or to 172 +/- 10 mm Hg, respectively (P < .05). Eplerenone or candesartan partially improved heart/body weight and cardiac fibrosis, improved EDR and decreased cardiac ACE and angiotensinogen mRNA levels in DS rats. Candesartan increased ACE2 mRNA levels in the heart. Combination therapy normalized BP and further improved cardiac hypertrophy, fibrosis, and EDR. CONCLUSIONS: In DS rats, blockade of aldosterone or Ang II protects cardiac hypertrophy and fibrosis by inactivation of the local RAAS in the heart.

Abstract: Objectives To investigate left ventricular (LV) function reserve in hypertrophic cardiomyopathy (HCM) patients with and without cardiac troponin gene mutations before transition to the dilated phase. Methods LV ejection fraction (EF) was continuously evaluated in 52 patients with non-obstructive HCM during supine ergometer exercise using radionuclide ventricular function monitoring with a cadmium telluride detector (VEST). On the basis of genetic analysis, patients were divided into 2 groups: 10 with cardiac troponin gene mutations (group A) and 42 without these gene mutations (group B). Results Exercise duration, peak exercise load, and heart rate during exercise did not differ between the 2 groups. The differences from baseline to peak exercise of the LV end-diastolic volume decreased similarly in the 2 groups. In contrast, the difference of the LV end-systolic volume in group A increased significantly compared with group B (p = 0.0031). Consequently, the difference of LVEF in group A decreased significantly in contrast with group B (p = 0.0025). Additionally, the changes in LVEF and stroke volume decreased significantly more in group A than in group B (p = 0.0017 and 0.0042, respectively). Conclusions These results suggest that HCM patients with cardiac troponin gene mutations may display exercise-induced LV systolic dysfunction more frequently than HCM patients without this abnormality.

Abstract:

Abstract: Systemic capillary leak syndrome is characterized by recurrent hypovolemic shock attributable to increased systemic capillary leakage. A 26-year-old woman was admitted because of recurrent episodes of hypovolemic shock. Hemoconcentration, hypoalbuminemia, and monoclonal gammopathy were observed. We diagnosed systemic capillary leak syndrome. Three years later, she again had an attack of systemic capillary leak syndrome complicated with pretibial compartment syndrome. This case emphasizes the importance of muscle compartment pressure monitoring during volume resuscitation in patients with systemic capillary leak syndrome.

Abstract: Hypertension contributes to the occurrence and progression of cardiovascular diseases. The angiotensin II type 1 receptor blocker telmisartan is reported to activate the peroxisome proliferator-activated receptor gamma and improve insulin sensitivity. We investigated the effects of telmisartan treatment on visceral fat, serum adiponectin and vascular inflammation markers in Japanese hypertensive patients. This was an open-label, non-controlled study. Twenty-eight essential hypertensive patients (22 men and 6 women; age 60.6+/-1.9 years; body mass index [BMI] 25.5+/-0.6 kg/m(2)) participated. Fat area was assessed with computerized tomography. All the subjects were started on telmisartan 40 mg/day, which was increased to 80 mg/day to achieve the blood pressure target of less than 130/80 mmHg. We assessed the visceral and subcutaneous fat areas, serum adiponectin levels, and vascular inflammation markers at baseline and 24 weeks of telmisartan treatment. There were significant reductions in visceral fat area (from 103.1+/-7.9 to 93.3+/-8.4 cm(2), p<0.01) and pulse wave velocity (from 1,706+/-52 to 1,587+/-51 cm/s, p<0.01) at 24 weeks. In contrast, significant increases in serum high-density lipoprotein cholesterol (from 5.06+/-0.15 to 5.32+/-0.13 mmol/L, p<0.05) and adiponectin levels (from 8.27+/-0.76 to 9.13+/-0.81 microg/mL, p<0.05) were observed. Also, there were reductions in the interleukin-6 level (from 2.26+/-0.27 to 1.60+/-0.14 pg/mL, p<0.01). We also conducted these investigations in male subjects alone and similar findings were obtained for all of these parameters. In conclusion, telmisartan treatment was associated with an improvement of vascular inflammation, reductions in visceral fat and increases in serum adiponectin.

Abstract: BACKGROUND: Limited information exists regarding the impact of gender on in-hospital outcome after primary stenting for acute myocardial infarction (AMI). METHODS AND RESULTS: A total of 2,981 patients (790 women and 2,191 men) participated in the study who were admitted within 24 h after symptom onset and underwent emergency primary stenting for AMI. Compared with men, women were significantly older; had higher incidences of hypertension, diabetes mellitus, hyperlipidemia, Killip class > or =2, and cardiogenic shock; had a higher blood glucose level and a lower serum creatinine level on admission. Other baseline characteristics, including the incidences of ST-segment elevation AMI, anterior infarction, 3-vessel disease, initial or final Thrombolysis in Myocardial Infarction (TIMI) flow grade did not significantly differ between the sexes. The in-hospital mortality rate was significantly higher in women than in men (9.4% vs 5.2%, p<0.001). On multivariate analysis, age, Killip class, blood glucose level, serum creatinine level, and final TIMI grade were independent predictors of in-hospital death, but female gender was not (odds ratio 1.01, p=0.69). CONCLUSIONS: Our findings suggest that in patients undergoing primary stenting for AMI, women have higher in-hospital mortality than men, but female gender itself is not independently associated with increased in-hospital mortality after adjustment for baseline differences.

Abstract: This study measured flow-mediated dilation (FMD) of the brachial artery 3 times a day (6:30 a.m., 11:30 a.m., and 9 p.m.) in 7 normal subjects and 14 patients with idiopathic dilated cardiomyopathy (7 in New York Heart Association [NYHA] functional class I or II and 7 in NYHA functional class III or IV). FMD in normal subjects and patients in NYHA class I or II showed a circadian variation, being lowest in the morning and highest at night. Compared with them, FMD in patients in NYHA class III or IV was lower and almost constant during the day, showing loss of significant circadian variation in endothelial function in patients with congestive heart failure.

Abstract: BACKGROUND: Progressive aortic dilatation has prognostic significance in the Marfan syndrome. METHODS: To identify which patients were at high risk of rapid progression, we echocardiographically studied 43 patients (age 22 +/- 14 years) with the mean follow-up period of 5.2 +/- 3.2 years. Aortic diameters, left ventricular (LV) size, fractional shortening, and the severity of aortic and mitral regurgitation were assessed. Transmitral peak early and atrial flow velocities, their ratio and the deceleration time of peak early velocity were also obtained. RESULTS: Mean annual increases of aortic diameters were 0.4 +/- 0.3 mm at the annulus, 1.5 +/- 1.3 mm at the sinuses of Valsalva, 0.7 +/- 0.6 mm at the supraaortic ridge and 0.4 +/- 0.4 mm at the proximal ascending aorta. Patients were divided into 2 groups according to the aortic growth rate at the sinuses of Valsalva level: rapid (R, >3% per year, 15 patients) or slow (S, < or =3% per year, 28 patients) progression groups. Measured variables did not show significant differences between the 2 groups except older age, higher blood pressure and more severe aortic regurgitation in group R. Multiple regression analysis identified prolonged deceleration time as the most important variable predicting aortic complications. Aortic dissection occurred more frequently in group R (7 patients, 47%) than in group S (0%, P < 0.001). CONCLUSIONS: Marfan patients at older age, with higher blood pressure, and with significant aortic regurgitation were at high risk of progression of aortic dilatation, with the most remarkable increase at the sinuses of Valsalva. Prolonged deceleration time may relate to an increased risk for aortic complications.

Abstract: Admission white blood cell (WBC) count and plasma glucose (PG) have been associated with adverse outcomes after acute myocardial infarction (AMI). This study investigated the joint effect of WBC count and PG on predicting in-hospital outcomes in patients with AMI. WBC count and PG were measured at the time of hospital admission in 3,665 patients with AMI. Patients were stratified into tertiles (low, medium, and high) based on WBC count and PG. Patients with a high WBC count had a 2.0-fold increase in in-hospital mortality compared with those with a low WBC count. Patients with a high PG level had a 2.7-fold increase in mortality compared with those with a low PG level. When a combination of different strata for each variable was analyzed, a stepwise increase in mortality was seen. There was a considerable number of patients with a high WBC count and low PG level or with a low WBC count and high PG level. These patients had an intermediate risk, whereas those with a high WBC count and high PG level had the highest risk, i.e., 4.8-fold increase in mortality, compared with those with a low WBC count and low PG level. Multivariate analysis was performed to assess the predictor for in-hospital mortality using WBC count and PG level as continuous variables and showed that WBC count and PG level were independently associated with in-hospital mortality. These findings suggested that a simple combination of WBC count and PG level might provide further information for predicting outcomes in patients with AMI.

Abstract: OBJECTIVE: To clarify the effects of walking with a pedometer on metabolic parameters, including adiponectin (APN). METHODS: We recruited 44 male Japanese volunteers (age, 37 +/- 9 yrs; body mass index (BMI), 24.2 +/- 2.9 kg/m2; fasting plasma glucose (FPG), 96 +/- 11 mg/dL; total cholesterol (TC) 190 +/- 26 mg/dL; triglycerides (TG) 119 +/- 80 mg/dL; HDL-C56 +/- 14 mg/dL). Subjects were instructed to walk with a pedometer and record the number of steps they walked every day for 50 days. Serum adiponectin (APN) levels were measured by enzyme immunoassay. Treatment effects were examined by Wilcoxon's rank test. RESULTS: The average number of steps was 8211 +/- 2084 per day. There were significant reductions in BMI, sBP, TG and TNF-alpha levels after 50 days, but no changes in adiponectin levels. We then divided the subjects into 2 groups according to the steps walked per day, namely, more than 8000 steps (MT group, n = 22) and less than 8000 steps (LT group, n = 22) and found that the reduction in TG and BP was observed only in the MT group. CONCLUSIONS: Walking with a pedometer is effective for improving metabolic parameters, such as TG and blood pressure, but is not sufficient to increase adiponectin levels in Japanese men.

Abstract: CETP (cholesteryl ester transfer protein) and HL (hepatic lipase) play a role in the metabolism of plasma lipoproteins, but the effects of CETP and LIPC (gene encoding HL) genotypes on coronary atherosclerosis may be dependent on LDL (low-density lipoprotein)-receptor activity. Recently, the -1337 C>T polymorphism in the CETP gene has been reported in REGRESS (Regression Growth Evaluation Statin Study) to be a major determinant of promoter activity and plasma CETP concentration. In the present study, we have investigated the effects of the CETP promoter -1337 C>T and LIPC promoter -514 C>T polymorphisms on serum lipid profiles and risk of coronary atherosclerosis in 206 patients (154 males) with heterozygous FH (familial hypercholesterolaemia). To evaluate coronary atherosclerosis, we used CSI (coronary stenosis index) calculated from coronary angiograms. The CETP -1337 T allele was less frequent in subjects with a CSI > or =14 (mean value) in the group with coronary artery disease (P=0.04, as determined by chi(2) test). ANOVA revealed that HDL-C (high-density lipoprotein-cholesterol) and triacylglycerol (triglyceride) levels were not significantly higher in the presence of the CETP promoter -1337 T allele. Combined with LIPC promoter polymorphisms, HDL-C levels were highest and CSI were lowest with CETP -1337 CT+TT and LIPC -514 CC genotypes, but a significant interaction was not shown. A multiple logistic regression analysis revealed that, in patients with coronary atherosclerosis, the CETP- 1337 CC genotype was a significant genetic risk factor in FH (odds ratio=2.022; P=0.0256). These results indicate that the CETP promoter -1337C>T polymorphism is associated with the progression of coronary atherosclerosis in Japanese patients with FH, independent of HDL-C and triacylglycerol levels.

Abstract: BACKGROUND: The balance between degradation and synthesis of extracellular matrix determines its content in atherosclerotic tissue. To examine the role of expression balance of matrix metalloproteinases (MMPs) to their inhibitors, tissue inhibitors of metalloproteinases (TIMPs) and tissue factor pathway inhibitor-2 (TFPI-2) in the development and disruption of atherosclerotic plaque, these gene expressions in human carotid plaque were quantitatively determined by real-time reverse transcription (RT)-polymerase chain reaction (PCR) method. METHODS: Total RNA for cDNA synthesis was extracted from tissues in 24 patients with carotid endarterectomy. The amounts of cDNAs for MMP-1, -2, -3 and -9, TFPI-2 and TIMP-1, -2 and -3 were determined by real-time RT-PCR method, and normalized with glutaraldehyde 3-dehydrogenase. RESULTS: In plaques, the expression MMP-1 (1.53+/-0.25, mean+/-S.E.M.), MMP-3 (1.99+/-0.59) and MMP-9 (2.00+/-0.51) was augmented compared to those in the adjacent control regions (0.60+/-0.16, 0.46+/-0.18 and 0.58+/-0.21, respectively, p<0.05). The expression of TFPI-2 was lower in plaques (0.32+/-0.08) than in controls (0.94+/-0.23, p<0.01). Although the expression of TIMP-1 was higher in plaques (1.28+/-0.23) than in controls (0.81+/-0.10, p<0.05), the indices of MMP-1/TIMP-1, MMP-3/TIMP-3 and MMP-9/TIMP-1 were still significantly higher in plaques. Interestingly, MMP-9 and the resulting MMP-9/TIMP-1 balance in plaques with disruption were significantly higher (3.36+/-1.52 and 1.66+/-0.12, n=11) than those in non-disrupted plaques (1.11+/-0.52 and 0.76+/-0.12, n=13, p<0.05). CONCLUSION: With the decreased expression of TFPI-2, upregulation of MMPs in atherosclerotic plaque was disproportional to that of TIMPs, suggesting that imbalanced degradation and synthesis of extracellular matrix persists in advanced lesions, particularly in plaques with disruption.

Abstract: We retrospectively evaluated the frequency and identified the factors associated with the development of aortic stenosis (AS) in 96 patients with heterozygous familial hypercholesterolemia (FH). The frequency of AS was 31% (4/13) and that of critical stenosis was 15% (2/13) in older patients over the age of 70 years. All 4 patients with AS were female aged more than 70 years who were diagnosed with FH when aged more than 60 years. There were no significant differences in conventional coronary risk factors; however, the age at cardiac catheterization, age at diagnosis of FH and the cholesterol-years score (CYS) with AS were significantly higher than those without AS (p=0.006, p=0.017, p=0.021, respectively). In multiple regression analysis, CYS was a significant independent predictor for the development of AS (p=0.037) in 13 older patients over the age of 70 years. These results suggest that physicians should be aware that AS needs attention in older patients with heterozygous FH, especially women who have been diagnosed late in life and those who have been inadequately treated.

Abstract: BACKGROUND: Many trials have shown that 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce the incidence of cardiovascular events and mortality. One method of decreasing the incidence of cardiovascular events could be to reduce the progression of coronary atherosclerosis, and a recent study found that atorvastatin can cause coronary plaque to regress. To generalize this finding, using conventional HMG-CoA reductase inhibitors at many Japanese centers, randomized trials of pitavastatin and atorvastatin will be conducted with patients with acute coronary syndrome (ACS). METHODS AND RESULTS: Patients with ACS who have undergone successful percutaneous coronary intervention under intravascular ultrasound guidance will be studied. They will be randomly allocated to pitavastatin or atorvastatin groups and followed up for 8-12 months. The primary endpoint will be the percent change in coronary plaque volume, and secondary endpoints will include absolute changes in coronary plaque volume, serum lipid levels and inflammatory markers. The safety profile will also be evaluated. CONCLUSIONS: This study will examine the ability of HMG-CoA reductase inhibitors to regress coronary plaque in Japanese patients with ACS and the findings should help to improve the prognosis of such patients and clarify the involved mechanisms.

Abstract: BACKGROUND: The effects of glucose abnormalities on outcomes after percutaneous coronary intervention (PCI) remain unclear. We examined the association between glucose abnormalities and in-hospital outcome in patients undergoing PCI for acute myocardial infarction (AMI). METHODS AND RESULTS: A total of 849 patients with AMI who were admitted within 12 h after symptom onset and underwent emergency PCI were classified according to the presence or absence of admission hyperglycemia, defined as a blood glucose level on admission of >11 mmol/L and whether they had a history of diabetes mellitus: group 1 (n = 504), non-diabetic patients without admission hyperglycemia; group 2 (n = 111), diabetic patients without admission hyperglycemia; group 3 (n = 87), non-diabetic patients with admission hyperglycemia; and group 4 (n = 147), diabetic patients with admission hyperglycemia. Among groups 1, 2, 3 and 4, in-hospital mortality was 2.6, 2.7, 11.5 and 8.8%, respectively (p < 0.01). Multivariate analysis showed that compared with group 1 patients, the odds ratio (95%confidence interval) for in-hospital mortality among those in groups 2, 3, and 4 were 0.80 (0.24-2.60, p = 0.708), 2.29 (1.10-5.49, p = 0.039), and 2.14 (1.14-4.69, p = 0.048), respectively. CONCLUSIONS: In-patients undergoing PCI for AMI, admission hyperglycemia, irrespective of the presence or absence of diabetes, is associated with increased in-hospital mortality, whereas diabetes without admission hyperglycemia is not.

Abstract: BACKGROUND: Preinfarction angina improves survival after acute myocardial infarction (AMI) in nonelderly but not elderly patients in the thrombolytic era. However, it remains unclear whether preinfarction angina has a beneficial effect on clinical outcome in elderly patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: The study group comprised 484 anterior AMI patients who were admitted within 24 h of onset and underwent emergency PCI. Patients were divided into 2 groups: those aged < 70 years (nonelderly patients, n = 290) and those aged > or = 70 years (elderly patients, n = 194). Angina within 24 h before AMI was present in 42% of nonelderly patients and in 37% of elderly patients. In nonelderly patients, preinfarction angina was associated with a lower in-hospital mortality rate (1% vs 7%, p = 0.02). Similarly, in elderly patients, preinfarction angina was associated with a lower in-hospital mortality rate (6% vs 16%, p = 0.03). Multivariate analysis showed that the absence of preinfarction angina was an independent predictor of in-hospital mortality in both nonelderly (odds ratio 4.20; 95% confidence interval (CI) 1.20-10.6; p = 0.04) and elderly patients (odds ratio 3.04; 95%CI 1.06-18.1; p = 0.04). CONCLUSIONS: Angina within the 24 h before AMI is associated with better in-hospital outcomes in elderly and nonelderly patients.

Abstract: BACKGROUND: Previous studies have shown that adrenomedullin (AM) inhibits vascular endothelial cell apoptosis and induces angiogenesis. We investigated whether AM enhances bone marrow cell-induced angiogenesis. METHODS AND RESULTS: Immediately after hindlimb ischemia was created, rats were randomized to receive AM infusion plus bone marrow-derived mononuclear cell (MNC) transplantation (AM+MNC group), AM infusion alone (AM group), MNC transplantation alone (MNC group), or vehicle infusion (control group). The laser Doppler perfusion index was significantly higher in the AM and MNC groups than in the control group (0.74+/-0.11 and 0.69+/-0.07 versus 0.59+/-0.07, respectively, P<0.01), which suggests the angiogenic potency of AM and MNC. Importantly, improvement in blood perfusion was marked in the AM+MNC group (0.84+/-0.08). Capillary density was highest in the AM+MNC group, followed by the AM and MNC groups. In vitro, AM inhibited MNC apoptosis, promoted MNC adhesiveness to a human umbilical vein endothelial cell monolayer, and increased the number of MNC-derived endothelial progenitor cells. In vivo, AM administration not only enhanced the differentiation of MNC into endothelial cells but also produced mature vessels that included smooth muscle cells. CONCLUSIONS: A combination of AM infusion and MNC transplantation caused significantly greater improvement in hindlimb ischemia than MNC transplantation alone. This effect may be mediated in part by the angiogenic potency of AM itself and the beneficial effects of AM on the survival, adhesion, and differentiation of transplanted MNCs.

Abstract: Forty-three patients with cardiac sarcoidosis were studied echocardiographically before and after (mean follow-up 88 months) steroid therapy to determine the effectiveness of corticosteroids to prevent left ventricular (LV) remodeling and improve LV contractility. In patients with initial LV ejection fractions (LVEFs) >or=55%, long-term steroid therapy showed preventive effects for LV remodeling and LV function. Patients with LVEF <54% showed significant reductions of LV volumes and LVEF improvement. However, in patients with LVEFs <30%, steroid therapy resulted in neither LV volume reductions nor improved LVEFs. In the early or middle stage of the disease, steroid therapy may be protective or therapeutic in preventing LV remodeling and preserving LV function. However, it may not be as effective in the late stage.

Abstract: A cardiac tumor was the first manifestation of acquired immunodeficiency syndrome (AIDS) in a female patient in a state of severe immunodeficiency caused by human immunodeficiency virus (HIV) infection. The extensive cardiac and extracardiac involvement shown by various imaging modalities, including echocardiography and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), suggested that she was in the critical stage of non-Hodgkin's lymphoma (NHL). AIDS was treated by highly active-antiretroviral therapy and the NHL was treated by a combination of rituximab-cyclophosphamide-vincristine-doxorubicine-predonisolone. After 6 cycles of chemotherapy, she was in complete remission. Her cardiac tumor dramatically reduced in size and FDG-PET showed no positive uptake on whole body imaging. Generally, an AIDS-related cardiac tumor tends to be diagnosed at the late stage of the disease because of its nonspecific clinical findings, resulting in an extremely poor prognosis. In the present case, the cardiac tumor was detected by echocardiography and treated with appropriate chemotherapy. Early diagnosis and prompt treatment may improve a patient's prognosis.

Abstract: OBJECTIVE: Little has been reported on the relationship between left main coronary artery atherosclerosis and carotid ultrasonographic results. We evaluated the association between carotid and coronary atherosclerosis assessed by coronary intravascular ultrasonography (IVUS) in 45 patients. METHODS: We counted the number of plaques with intima-media thickness (IMT) greater than or equal to 1.1 mm and calculated a plaque score by summing all plaque thicknesses. With the use of IVUS, the percent plaque area was calculated at the proximal, middle, and distal sites of the left main coronary artery. The maximum percent plaque area and mean percent plaque area of the 3 sites were also calculated. Relationships among the degree of left main coronary artery atherosclerosis and carotid atherosclerosis and vascular risk factors were evaluated. RESULTS: The mean percent plaque area and maximum percent plaque area were increased in men and in patients with hypertension compared with women and those without hypertension (P < .1). Both the average of the maximum common carotid IMT and plaque number were correlated with both the mean percent plaque area and maximum percent plaque area (P < .05). Men, the presence of hypertension, and the average of the maximum common carotid IMT were correlated with both the mean percent plaque area and maximum percent plaque area by multiple linear regression analysis (P < .05). CONCLUSIONS: The average of the maximum common carotid IMT was significantly correlated with left main coronary artery atherosclerosis evaluated by IVUS.

Abstract: PURPOSE: This study was undertaken to assess the association between acute hyperglycemia and inhospital outcome after acute myocardial infarction (AMI) in the percutaneous coronary intervention (PCI) era. We also assessed outcome of patients with a history of diabetes mellitus in the PCI era. METHODS: Between January 2001 and December 2001, 1253 patients were admitted to the hospitals within 48 hours after the onset of AMI. Plasma glucose was measured at hospital admission. Acute hyperglycemia was defined as plasma glucose of > 11 mmol/L (198 mg/dL), regardless of the diabetic status. Primary PCI was performed in 898 (72%) patients. RESULTS: The inhospital mortality rate was significantly higher in patients with acute hyperglycemia than in patients without (16% vs 6%, P < .001). However, there was no significant difference in mortality between diabetic and nondiabetic patients (8% vs 9%, P = .54). Acute hyperglycemia was associated with a higher inhospital mortality rate both in nondiabetic patients (24% vs 6%, P < .001) and in diabetic patients (10% vs 5%, P = .039). Acute hyperglycemia was associated with a higher incidence of no reflow during PCI (21% vs 12%, P < .001), but diabetes was not (14% vs 15%, P = .71). CONCLUSION: Acute hyperglycemia, but not diabetes, was a predictor for inhospital mortality after AMI in the PCI era. No reflow occurred more frequently during PCI in patients with acute hyperglycemia, suggesting that microvascular dysfunction might have contributed to adverse outcome of these patients.

Abstract: BACKGROUND: Although cytokines are known to be pivotal in the development of atherosclerotic diseases, few data exist regarding their expressions in the established stages such as aneurysmal or occlusive lesions. Therefore, in the present study the gene expression levels of cytokine-related substances in abdominal aortic aneurysm (AAA) and carotid artery stenosis (CAS) were determined using cDNA macroarray and real-time reverse transcriptase polymerase chain reaction (RT-PCR) methods. METHODS AND RESULTS: Tissue samples were obtained from 31 patients with AAA and 24 with CAS. The array-specific [33P]-labeled cDNA probe mixture synthesized from 2.5 microg total RNA with gene-specific primers was hybridized with nylon membranes containing 375 cDNA clones. Densitometric analysis confirmed differences in expression (>5-fold) for 97 of the cytokine-related gene products between AAA and adjacent control tissue. Among these, simultaneous upregulation was found in the expression of interleukin (IL)-8 (9-fold) and its receptor, CXCR-2 (11-fold). Thus, the expressions of IL-8 and CXCR-2 were further quantified by real-time RT-PCR. The expression of both the genes was significantly upregulated in both AAA and CAS compared with control regions as followed: IL-8=0.53+/-0.16 vs 0.11+/-0.04 (p<0.01); CXCR-2=2.04+/-0.75 vs 0.29+/-0.10 (p<0.01) in AAA, and IL-8=1.35 +/-0.25 vs 0.60+/-0.16; CXCR-2=2.00 +/-0.51 vs 0.58+/-0.21 (p<0.05) in CAS. Under these conditions, the gene expressions of monocyte chemotactic protein-1 and its receptor, CCR-2, were not significantly different in the control and diseased regions of both AAA and CAS. CONCLUSIONS: Sustained upregulation of IL-8 and CXCR-2 was observed in both AAA and CAS, suggesting the inflammatory process is still active in established dilated and occlusive atherosclerotic diseases. Whether upregulation of this system could be protective or not protective for disease development requires further study.

Abstract: Serum uric acid (UA) levels reflect circulating xanthine oxidase activity and oxidative stress production. Hyperuricemia has been identified in patients who have congestive heart failure and is a marker of poor prognosis in such patients. We investigated the relation between serum UA levels and Killip's classification suggestive of the severity of heart failure and whether hyperuricemia influences mortality of patients who have acute myocardial infarction (AMI). Using the Japanese Acute Coronary Syndrome Study database, we evaluated 1,124 consecutive patients who were hospitalized within 48 hours of onset of symptoms of AMI from January to December 2002. There was a close relation between serum UA concentration and Killip's classification. Patients who developed short-term adverse events had high UA concentrations. Serum UA levels, Killip's class, age, and peak creatine phosphokinase level were significant predictors of long-term mortality. The hazard ratio for patients in the highest quartile of UA was 3.7 compared with those in the lowest quartile for death after AMI after adjustment for independent factors that were related to mortality. The combination of the best UA cutoff (447 micromol/L) for predicting survival based on receiver-operating characteristics analysis and Killip's class significantly predicted the prognosis of acute and long-term AMI-related complications. In conclusion, our results suggest that hyperuricemia after AMI is associated with the development of heart failure. Serum UA level is a suitable marker for predicting AMI-related future adverse events, and the combination of Killip's class and serum UA level after AMI is a good predictor of mortality in patients who have AMI.

Abstract: Cystic tumor of the atrioventricular nodal region is a rare cardiac primary tumor that can cause heart blockage and sudden death. Antemortem diagnosis and successful excision of the atrioventricular nodal region are extremely rare. A 45-year-old woman who presented with palpitations is reported. Electrocardiography revealed first-degree atrioventricular block. Echocardiography, computed tomography, and magnetic resonance imaging scans revealed a cystic mass attached to the interatrial septum. Complete surgical excision of the mass was achieved, although placement of a permanent pacemaker was required for complete heart blockage. Histopathological examination revealed the mass to be a cystic tumor of the atrioventricular nodal region. A 5-year follow-up has revealed no sign of recurrence.

Abstract: BACKGROUND: Although the elevation of circulating plasma matrix metalloproteinase (MMP)-9 levels in patients with acute myocardial infarction (AMI) has been documented, the origin of MMP-9 remains unclear. METHODS AND RESULTS: Plasma MMP-9 levels in both the peripheral circulation and coronary arteries were measured in patients with AMI (n=23) and with stable angina pectoris (SAP, n=10) during percutaneous coronary intervention (PCI) with a distal protection device. Blood samples were collected from the femoral artery (FA) and the coronary artery before (Initial) and after (Second) dilation of the culprit lesion. Coronary sinus blood samples were obtained immediately after PCI (n=7). Coronary artery plaque fragments were aspirated in patients with AMI (n=20) and compared with those from patients with SAP who underwent directional atherectomy (n=10). MMP-9 levels in Initial and Second were significantly higher in patients with AMI than in patients with SAP (p<0.01). In AMI patients MMP-9 levels were significantly higher in Initial than in the FA (p<0.05), and were further increased in Second (p<0.0001), whereas those in the coronary sinus were similar to the FA. Immunohistochemistry revealed augmented MMP-9 expression in the coronary artery plaque fragments from AMI patients. CONCLUSIONS: MMP-9 is mainly released into the coronary circulation from the coronary artery plaque in patients with AMI.

Abstract: BACKGROUND: Pluripotent mesenchymal stem cells (MSCs) differentiate into a variety of cells, including cardiomyocytes and vascular endothelial cells. However, little information is available about the therapeutic potency of MSC transplantation in cases of dilated cardiomyopathy (DCM), an important cause of heart failure. METHODS AND RESULTS: We investigated whether transplanted MSCs induce myogenesis and angiogenesis and improve cardiac function in a rat model of DCM. MSCs were isolated from bone marrow aspirates of isogenic adult rats and expanded ex vivo. Cultured MSCs secreted large amounts of the angiogenic, antiapoptotic, and mitogenic factors vascular endothelial growth factor, hepatocyte growth factor, adrenomedullin, and insulin-like growth factor-1. Five weeks after immunization, MSCs or vehicle was injected into the myocardium. Some engrafted MSCs were positive for the cardiac markers desmin, cardiac troponin T, and connexin-43, whereas others formed vascular structures and were positive for von Willebrand factor or smooth muscle actin. Compared with vehicle injection, MSC transplantation significantly increased capillary density and decreased the collagen volume fraction in the myocardium, resulting in decreased left ventricular end-diastolic pressure (11+/-1 versus 16+/-1 mm Hg, P<0.05) and increased left ventricular maximum dP/dt (6767+/-323 versus 5138+/-280 mm Hg/s, P<0.05). CONCLUSIONS: MSC transplantation improved cardiac function in a rat model of DCM, possibly through induction of myogenesis and angiogenesis, as well as by inhibition of myocardial fibrosis. The beneficial effects of MSCs might be mediated not only by their differentiation into cardiomyocytes and vascular cells but also by their ability to supply large amounts of angiogenic, antiapoptotic, and mitogenic factors.

Abstract: BACKGROUND: In the era before the use of coronary reperfusion therapy, an elevated white blood cell (WBC) count was associated with a higher risk of adverse events following acute myocardial infarction (AMI). However, the relationship between WBC count and prognosis after AMI has not been investigated since coronary intervention was introduced. AIM: To evaluate whether a high WBC count within 48 hours of the onset of AMI predicts future adverse events in patients undergoing percutaneous coronary intervention (PCI). METHOD: We evaluated 1,016 patients who underwent PCI in the acute phase of MI using the Japanese Acute Coronary Syndrome Study (JACSS) database. RESULTS. WBC count was significantly associated with smoking, sudden onset AMI, and the no-reflow phenomenon during PCI, as were age, peak creatine kinase level, and Killip class. An elevated WBC count was significantly associated with higher risk of in-hospital mortality. Patients in the highest quartile of WBC count were about three times more likely to have a poor prognosis after AMI compared to those in the lowest quartile. CONCLUSIONS: The WBC count is of great significance for stratifying patient risk and can be used as a universal marker for predicting future adverse events following any treatment for AMI.

Abstract: We found a five-basepair insertion/deletion polymorphism in intron 3 of TNNT2, one of the genes responsible for hypertrophic cardiomyopathy. These five bases may be part of an intronic polypyrimidine tract sequence that may affect splicing. The purpose of the study was to examine the association of the polymorphism with cardiac hypertrophy. The study population consisted of 151 subjects with prominent concentric left ventricular hypertrophy, and 987 healthy subjects recruited from medical checkups (control population). The deletion/deletion genotype tended to be associated with a larger left ventricular mass/height ratio in the HCM population ( p<0.0001). Multiple regression analyses indicated that the left ventricular mass/height ratio was determined ( p<0.0001, R=0.738) by the TNNT2 genotype. Moreover, the frequency of the deletion allele was significantly higher in the hypertrophy population than in the control population ( p<0.0001). In vitro expression study revealed the deletion allele significantly affected the mRNA expression pattern by skipping exon 4 during splicing. In conclusion, TNNT2 deletion allele could be associated with a predisposition to prominent left ventricular hypertrophy.

Abstract: OBJECTIVE: To clarify the mechanism of improvement in exercise capacity after the maze procedure. DESIGN: Retrospective study. SETTING: Tertiary referral centre. PATIENTS: 26 patients (mean (SD) age 57 (9) years) with atrial fibrillation (AF) and mitral valve disease were studied with echocardiography and cardiopulmonary exercise testing before and after the maze procedure combined with mitral valve surgery. Of these, eight had persistent AF and 18 had restored sinus rhythm (SR) by the surgery. Six patients (mean (SD) age 59 (12) years) with AF undergoing mitral valve surgery without the maze procedure who had cardiopulmonary exercise testing before and after the surgery formed the control group. MAIN OUTCOME MEASURES: Echocardiographic parameters of atrial function were measured from transmitral flow recordings. Peak oxygen uptake (VO2) and the slope of the relation between VO2 and workload (ratio of DeltaVO2 to Delta work) were determined as indices of exercise capacity. RESULTS: The degree of improvements in peak VO2 and the ratio of DeltaVO2 to Delta work after the mitral valve surgery was comparable between the maze and control group. It was also comparable between patients with and those without successfully restored SR after the maze procedure. The degree of the increase in peak VO2 correlated with the change in left atrial diameter (r = -0.40, p = 0.047) but atrial contraction did not correlate with the increase. CONCLUSIONS: Improvement in exercise capacity may not be caused by restored SR and atrial contraction but may at least partly relate to the reduction of left atrial size and improvement of haemodynamic variables by the surgery.

Abstract: Ghrelin, a novel growth hormone-releasing peptide, has been shown to cause a positive energy balance by reducing fat use and stimulating food intake. This study investigated whether plasma ghrelin is associated with clinical parameters in patients with chronic obstructive pulmonary disease. Plasma ghrelin was measured in 50 patients and 13 control subjects, together with anabolic and catabolic factors. Patients were divided into two groups based on body mass index: underweight patients (n = 26) or normal weight patients (n = 24). Plasma ghrelin was significantly higher in underweight patients than in normal weight patients and healthy control subjects. Circulating tumor necrosis factor-alpha, interleukin-6, and norepinephrine were significantly higher in underweight patients than in normal weight patients. Plasma ghrelin correlated negatively with body mass index and correlated positively with catabolic factors such as tumor necrosis factor-alpha and norepinephrine. In addition, plasma ghrelin correlated positively with percent predicted residual volume and residual volume-to-total lung capacity ratio. In conclusion, plasma ghrelin was elevated in underweight patients with chronic obstructive pulmonary disease, and the level was associated with a cachectic state and abnormality of pulmonary function.

Abstract: Mesenchymal stem cells (MSCs) are pluripotent cells that differentiate into a variety of cells, including cardiomyocytes and endothelial cells. However, little information is available regarding the therapeutic potency of systemically delivered MSCs for myocardial infarction. Accordingly, we investigated whether intravenously transplanted MSCs induce angiogenesis and myogenesis and improve cardiac function in rats with acute myocardial infarction. MSCs were isolated from bone marrow aspirates of isogenic adult rats and expanded ex vivo. At 3 h after coronary ligation, 5 x 10(6) MSCs (MSC group, n=12) or vehicle (control group, n=12) was intravenously administered to Lewis rats. Transplanted MSCs were preferentially attracted to the infarcted, but not the noninfarcted, myocardium. The engrafted MSCs were positive for cardiac markers: desmin, cardiac troponin T, and connexin43. On the other hand, some of the transplanted MSCs were positive for von Willebrand factor and formed vascular structures. Capillary density was markedly increased after MSC transplantation. Cardiac infarct size was significantly smaller in the MSC than in the control group (24 +/- 2 vs. 33 +/- 2%, P <0.05). MSC transplantation decreased left ventricular end-diastolic pressure and increased left ventricular maximum dP/dt (both P <0.05 vs. control). These results suggest that intravenous administration of MSCs improves cardiac function after acute myocardial infarction through enhancement of angiogenesis and myogenesis in the ischemic myocardium.

Abstract: BACKGROUND: The relative expression levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), key regulators in remodeling of extracellular matrix, are considered to play a pivotal role in the development of abdominal aortic aneurysm (AAA). However, few data exist regarding quantitative assessment of their expression in clinical settings. METHODS: In 22 patients with AAA who underwent graft replacement, tissue samples of the AAA and non-dilated aorta were obtained. Using a real-time RT-PCR method that enabled quantitative measurement of mRNA levels in small tissue samples, we determined gene expression levels of MMPs and TIMPs relative to that of glutaraldehyde 3-phosphate dehydrogenase in each sample. RESULTS: The expression levels of the MMP-1 and -3 genes were significantly augmented in AAA compared with non-dilated regions (4.48 +/- 2.01 versus 0.26 +/- 0.12, P < 0.01 and 1.89 +/- 1.00 versus 5.01 +/- 0.97, P < 0.05, respectively). Although genes for TIMP-1, -2 and -3 tended to be upregulated in AAA, relative expression levels of MMP-1 to TIMP-1, MMP-1 to TIMP-2, MMP-1 to TIMP-3, and MMP-3 to TIMP-2 were still higher in AAA than in non-dilated regions (1.12 +/- 0.63 versus 0.10 +/- 0.03, 4.13 +/- 1.12 versus 0.43 +/- 0.11, 1.61 +/- 0.59 versus 0.14 +/- 0.03, and 7.81 +/- 1.60 versus 2.56 +/- 0.76, respectively, P < 0.05). CONCLUSION: These results demonstrate that the present real-time RT-PCR method is reliable for the determination of mRNA levels in small samples of vascular tissue and that disproportional expression of both MMP-1 and MMP-3 relative to TIMPs relates pathologically to the evolution of AAA.

Abstract: BACKGROUND: Data mining is a technique for discovering useful information hidden in a database, which has recently been used by the chemical, financial, pharmaceutical, and insurance industries. It may enable us to detect the interesting and hidden data on useful drugs especially in the field of cardiovascular disease. METHODS AND RESULTS: We evaluated the current treatments for chronic heart failure (CHF) in our institute using a decision tree method of data mining and compared the results with those of large-scale clinical trials. We enrolled 1,100 patients with CHF (NYHA classes II-IV and EF < 40%) who were hospitalized at the National Cardiovascular Center during the past 31 months. Drugs prescribed at discharge were extracted from the clinical database. Both echocardiograms and plasma BNP level at 6-12 months after discharge were determined prospectively. It was found that beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin II receptor antagonists independently improve both the plasma BNP level and %fractional shortening (FS), while oral inotropic agents increased the plasma BNP level and decreased %FS. These findings agree with evidence accumulated from several large-scale trials. Interestingly, statins, histamine receptor blockers, and alpha-glucosidase inhibitors also attenuated the severity of CHF, suggesting the possibility of new treatment of CHF. CONCLUSION: Clinical data mining using Japanese CHF patients yielded almost identical data to the results of large-scale trials, and also suggested novel and unexpected candidates for CHF therapy. Further validation of the data mining approved in the cardiovascular field is warranted.

Abstract: C-type natriuretic peptide (CNP) has been shown to act as a local regulator of vascular tone and remodeling. We investigated whether CNP ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Rats received a continuous infusion of CNP or placebo. Significant pulmonary hypertension developed 3 weeks after MCT. However, infusion of CNP significantly attenuated the development of pulmonary hypertension and vascular remodeling. Neither systemic arterial pressure nor heart rate was altered. Interestingly, CNP enhanced Ki-67 expression, a marker for cell proliferation, in pulmonary endothelial cells and augmented lung tissue content of endothelial nitric oxide synthase. CNP significantly suppressed apoptosis of pulmonary endothelial cells, decreased the number of monocytes/macrophages, and inhibited expression of plasminogen activator inhibitor type 1, a marker for fibrinolysis impairment, in the lung. In addition, CNP significantly increased the survival rate in MCT rats. Finally, infusion of CNP after the establishment of pulmonary hypertension also had beneficial effects on hemodynamics and survival. In conclusion, infusion of CNP ameliorated MCT-induced pulmonary hypertension and improved survival. These beneficial effects may be mediated by regeneration of pulmonary endothelium, inhibition of endothelial cell apoptosis, and prevention of monocyte/macrophage infiltration and fibrinolysis impairment.

Abstract: A73-year-old man with a history of bronchial asthma and atrial fibrillation was admitted to our hospital because of dyspnea and back pain. Blood analysis revealed a marked increase in total blood cell and eosinophil counts. The creatine kinase and creatine kinase-MB increased slightly. The ECG demonstrated significant ST-segment depression that mimicked acute posterior myocardial infarction. Emergent coronary angiography showed no stenotic lesions. The histological findings in endomyocardial biopsy showed thickened endocardium associated with significant eosinophilic infiltration, which was compatible with Löffler's endocarditis. After the administration of prednisolone, the patient's general condition, eosinophilia, ECG abnormalities, and histological findings were improved dramatically. The endomyocardial biopsy in the acute phase was helpful for diagnosis and therapeutic decision-making.

Abstract: A 64-year-old woman with hypertension presented with a left atrial giant mass during the treatment of congestive heart failure. She was admitted to our hospital for intensive treatment. Transesophageal echocardiography demonstrated a cauliflower-like, large (3 x 2 cm), mobile echogenic mass attached to the left atrial wall. There were no signs of systemic embolism. Anticoagulant therapy was started. Repeated echocardiography showed the mass was reduced gradually and had diminished on the 10th day. She remained asymptomatic during the anticoagulant therapy. The diagnosis was thrombus based on the response to treatment. Surgical removal should be considered for such a large thrombus, but the present case of giant thrombus was successfully treated by anticoagulants without systemic complication.

Abstract: Complicating mitral regurgitation (MR) apparently enhances left ventricular ejection fraction, thereby leading to the underestimation of myocardial damage by routine echocardiography. We sought to assess the significance of myocardial velocity gradient (MVG) derived from Doppler tissue imaging as an indicator of the severity of myocardial damage in the presence or absence of MR. Peak systolic and diastolic MVG was obtained from 39 participants: 12 healthy participants, 10 patients with dilated cardiomyopathy complicating moderate to severe MR [MR (+) group], and 17 patients with dilated cardiomyopathy without significant MR [MR (-) group]. MVG was compared with standard echocardiographic and Doppler transmitral flow velocity indices. Plasma brain natriuretic peptide levels were measured in all patients. Left ventricular dimension and fractional shortening was similar between MR (+) and MR (-) groups. Plasma brain natriuretic peptide levels were significantly increased in MR (+) group (440 +/- 417 pg/mL) as compared with MR (-) group (122 +/- 107 pg/mL, P <.05). Peak systolic MVG was significantly attenuated in dilated cardiomyopathy group with or without MR [MR (+) group = 1.3 +/- 0.5 seconds(-1), MR (-) group = 2.1 +/- 0.5 seconds(-1), where normal = 4.0 +/- 0.9 seconds(-1), P <.01, respectively]. Peak systolic MVG was further attenuated in MR (+) group than in MR (-) group (P <.01). Plasma brain natriuretic peptide levels were negatively correlated with peak systolic MVG (r = -0.66, P <.0005). Peak diastolic MVG was attenuated in MR (+) and also in MR (-) groups [MR (+) group = -4.5 +/- 2.0 seconds(-1), MR (-) group = -4.4 +/- 1.1 seconds(-1), where normal = -8.7 +/- 2.4 seconds(-1), P <.01, respectively], whereas transmitral flow indices failed to distinguish MR (+) group from normal as a result of pseudonormalization. MVG may reflect the severity of myocardial damage regardless of the presence or absence of complicating MR.

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Abstract: We describe a patient with acute myocardial infarction who showed ruptured plaque distant from the maximally stenotic lesion. In a 54-year-old male patient with acute antero-lateral myocardial infarction, coronary angiography showed a resolution of occlusive lesion with residual stenotic lesion in the middle portion of the left anterior descending artery (LAD) following t-PA administration. One month later, coronary angiography again disclosed significant stenosis of the middle LAD. Intravascular ultrasound revealed ruptured plaque that was located proximal to the maximally stenotic site which is generally considered as the culprit lesion. In this case, transient vessel occlusion occurred at the maximally stenotic site probably associated with plaque rupture distant from this lesion.

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Abstract: Although left ventricular wall motion has been usually assessed with four-point scale (1 = normal; 2 = hypokinesis; 3 = akinesis; 4 = dyskinesis) based on the visual assessment, this method is only qualitative and subjective. Recently, a new echocardiographic system that enables calculation of myocardial strain rate based on tissue Doppler information has been developed. We investigated whether myocardial strain rate could quantify regional myocardial contraction in 17 patients with and without wall motion abnormalities including 6 patients undergoing dobutamine stress echocardiography. Left ventricular short-axis wall motion was assessed with standard two-dimensional echocardiography at basal, mid-ventricular, and apical levels. The same levels were imaged with tissue Doppler method to determine regional myocardial strain rate. Sixty-four segments were judged normokinesis, 53 segments hypokinesis, and 18 segments akinesis at rest; 16 segments were judged normokinesis and 6 segments hypokinesis at stress. No segments characterized dyskinesis. Strain rates of normokinetic, hypokinetic, and akinetic wall segments at rest were significantly different each other (-2.0 +/- 0.6 for normokinesis,-0.6 +/- 0.5 for hypokinesis,P < 0.0001 vs. normokinesis, and-0.008 +/- 0.3 for akinesis, P < 0.0001 vs. normokinesis and hypokinesis). Further, strain rates well reflected the change in wall motion induced by dobutamine challenge: strain rates in the 15 segments revealing augmented wall motion changed from -2.0 +/- 0.7 to -4.7 +/- 1.7 (1/sec) (P < 0.0001) and those in the 7 segments revealing deteriorated or unchanged wall motion changed from -2.1 +/- 1.0 to -1.7 +/- 0.8 (1/sec) (P < 0.05). In conclusion, strain rate agreed well with assessed wall motion. Strain rate imaging may be a new powerful tool to quantify regional wall contraction.

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Abstract: In the present study, the intravascular ultrasound (IVUS) morphologic appearance of coronary atherosclerotic plaque associated with focal spasm was prospectively studied in 45 patients with or without focal coronary spasm provoked by ergonovine or acetylcholine. The percent plaque area and plaque arc were determined from the IVUS images at the sites of spasm. Calcified lesion was defined as the presence of high-intensity echo with acoustic shadowing. Twenty-three patients had focal coronary spasm defined as angiographic narrowing >75% and IVUS demonstrated atherosclerotic plaque in these 23 sites. In the 22 patients without focal spasm, IVUS demonstrated 18 atherosclerotic lesions in 17 patients and the remaining 5 patients did not have significant lesions. There was no difference in the percent plaque area and plaque arc between plaque lesions with (47+/-10%, 298+/-71 degrees ) and without (39+/-15%, 249+/-83 degrees ) coronary spasm. Interestingly, calcified lesion was less frequently present at the sites with than at those without spasm (p<0.05). These results indicate that the presence of plaque without calcification is likely to be related to the occurrence of focal vasospasm, although the severity and distribution of the disease did not differ between each patient group.

Abstract: The high frame-rate tissue-velocity imaging method may be superior to the conventional M-mode method in accurately localizing accessory pathways without consuming large amounts of time.

Abstract: A 44-year-old woman with restrictive cardiomyopathy showed right-sided dominant heart failure after conversion to sinus rhythm from paroxysmal atrial fibrillation (AF). During cardiac catheterization, the hemodynamics were compared before and after cardioversion; that is, with AF and with sinus rhythm. The hemodynamic parameters worsened after conversion to sinus rhythm, with a significant decrease in heart rate, but improved with atrial pacing. Pacemaker implantation was performed to avoid bradycardia while keeping the sinus rhythm with amiodarone. As a result, the patient has been free from symptoms of heart failure for almost 1 year and her serum brain natriuretic peptide level also improved remarkably.

Abstract: Although patients with medically treated vasospastic angina have a good outcome, few data exist regarding the role of underlying lesion severity associated with or without hyperlipidemia in the prognosis. Therefore, the aim of the present study was to assess the relationship between the long-term outcome of vasospastic angina and the factors influencing its prognosis. A total of 256 patients (219 men, 37 women; mean age, 54.1+/-9.2) who had coronary spasm with or without underlying lesions and were being treated with calcium channel antagonists were enrolled and followed for 13.6+/-3.7 years. Cardiac events consisted of cardiac death and ischemic events, which included acute myocardial infarction and unstable angina. Cox analysis selected coronary artery stenosis (CAS, >/=50%) and risk factors such as age, hypertension, diabetes mellitus, low-density lipoprotein-cholesterol (LDL-C), sex and smoking. There were 19 cases of cardiac death (7.4%) and 58 of ischemic events (22.7%) during the follow-up period. The presence of significant CAS was an independent predictor of event-free survival (hazard ratio (HR) =2.84, 95% confidence interval (CI) =1.79-4.52, p<0.0001). In 193 patients without significant CAS, there were 10 cases of cardiac death (5.2%, p<0.05) and 34 of ischemic events (17.6%, p<0.01). In that group, high LDL-C was the independent predictor of event-free survival (HR = 3.89, 95% CI = 1.20-12.6, p=0.02). Kaplan-Meier survival analysis revealed significantly lower event-free survival in patients with than in those without lesions (p<0.0001 by log-rank test). These results demonstrate that the most important factor for long-term prognosis of vasospastic angina treated with calcium channel antagonists is significant CAS. High LDL-C, which might alter the underlying coronary endothelial function and/or accelerate atherosclerotic lesions, could also contribute to the occurrence of cardiac events, particularly in patients without significant CAS.

Abstract: OBJECTIVES: Left ventricular dysfunction is known in patients with mitral stenosis, but the incidence and cause remain unclear. The incidence and the factors related to left ventricular dysfunction were investigated in strictly selected patients with isolated mitral stenosis. METHODS: This study investigated 33 patients (5 males, 28 females) with isolated mitral stenosis aged 56 +/- 9 years. Left atrial dimension, left ventricular diastolic and systolic dimensions, mitral valve area, and mean transmitral pressure gradient were measured by echocardiography. Left ventricular ejection fraction was measured by Simpson's method. Patients were divided into two groups according to the ejection fraction (< 50%, > or = 50%). RESULTS: Seven patients (21%) had decreased left ventricular contraction and 26(79%) had normal contraction. The incidence of patients with atrial fibrillation in the low ejection fraction group was significantly higher than in the normal ejection fraction group(86% vs 31%, p < 0.01). There were no significant differences in the severity of mitral stenosis or other echocardiographic indices between the two groups. CONCLUSIONS: Low ejection fraction was present in 21% of patients with mitral stenosis. Since atrial fibrillation was more common in patients with low ejection fraction than those with normal ejection fraction, the rhythm disturbance may be related to the decreased left ventricular contraction.

Abstract: We studied the effect of preinfarction angina on in-hospital outcomes after percutaneous coronary intervention for anterior and nonanterior acute myocardial infarction. Beneficial effects of preinfarction angina on infarct size and in-hospital outcome are evident in patients with anterior infarction, but not in those with nonanterior infarction.

Abstract: BACKGROUND: Patients with bicuspid aortic valve (BAV) have been frequently complicated with ascending aortic dilation possibly because of hemodynamic burdens by aortic stenosis (AS) or regurgitation (AR) or congenital fragility of the aortic wall. METHODS AND RESULTS: To clarify if the aortic dilation could be prevented by aortic valve replacement (AVR) in BAV patients, we studied 13 BAV (8 AR dominant, 5 AS dominant) and 14 tricuspid aortic valve (TAV) patients (7 AR, 7 AS) by echocardiography before and after AVR (9.7+/-4.8 years). We also studied 18 BAV (11 AR, 7 AS) without AVR. Diameters of the sinuses of Valsalva, sinotubular junction and the proximal aorta were measured. The annual dilation rate was calculated by dividing changes of diameters during the follow-up period by the body surface area and the observation interval. We found that aortic dilation in BAV patients tended to be faster than that in TAV patients, although a significant difference was found only at the proximal aorta (0.18+/-0.08 versus -0.08+/-0.08 mm/(m2/year), P=0.03). BAV patients with and without AVR showed similar progressive dilation. AR dominant group showed tendency of more progressive dilation than AS dominant group in BAV, although it did not reach statistical significance. TAV patients did not show further aortic dilation after AVR. CONCLUSIONS: AVR could not prevent progressive aortic dilation in BAV. Since the aorta did not dilate in TAV, progressive aortic dilation in BAV seems mainly due to the fragility of the aortic wall rather than hemodynamic factors.

Abstract: A 62-year-old woman was referred because of an abnormal mediastinal shadow that had first been noted 4 years ago on the left cardiac border on plain chest roentgenogram and which had gradually increased in size since. A huge saccular aneurysm in coronary-pulmonary fistula into which both the left and right coronary arteries drained was revealed by computed tomography and coronary angiography. The patient underwent aneurysmal resection and ligation of the fistulas. Histological study of the aneurysmal wall did not reveal atherosclerotic change but instead cystic medial necrosis, although there was no other clinical manifestation associated with this.

Abstract: The tolerability and effectiveness of amiodarone in patients with advanced heart failure (HF) who are intolerant of beta-blockers was investigated in 22 patients (13 with and 9 without 180+/-26 mg/day of amiodarone). Heart rate (HR), blood pressure (BP), left ventricular diastolic dimension and fractional shortening (FS) using echocardiography, plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and norepinephrine concentrations were determined at baseline and after 1 and 3 months of therapy. Although 9 patients tolerated amiodarone without any signs of HF, it was exacerbated in 4 patients. In 10 patients taking amiodarone who could be followed medically for 3 months, HR decreased after 1 month and remained unchanged until after 3 months (81+/-12 vs 65+/-7 vs 65+/-7beats/min), accompanied by decreased concentration of BNP (688+/-485 vs 392+/-203 vs 261+/-192pg/ml). FS increased significantly only after 3 months (0.12+/-0.05 vs 0.14+/-0.05 vs 0.16+/-0.04). Amiodarone may be used in patients with advanced HF who are intolerant of beta-blockers.

Abstract: BACKGROUND: Although right ventricular (RV) contractility is important in determining functional capacity, few quantification methods are clinically available. RV dP/dt(max) can be assessed by Doppler echocardiography by using tricuspid regurgitation (TR) but is not routinely used because of its dependency on a Doppler incident angle and preload. Doppler-derived dP/dt/P(max) is relatively insensitive to preload and theoretically independent of the incident angle. We investigated the clinical feasibility of this index as an RV contractility index. METHODS: We computed RV dP/dt(max) and dP/dt/P(max) from the TR-derived RV pressure in 68 patients with dominant RV failure (13 in New York Heart Association [NYHA] class I, 33 in class II, 17 in class III, and 5 in class IV). Peak oxygen consumption (peak VO(2)) was measured in 20 patients during a maximal bicycle ergometer test. RESULTS: dP/dt(max) did not significantly correlate with NYHA class. In contrast, dP/dt/P(max) decreased monotonically with the functional class (r = -0.49, P <.0001), and correlated with peak VO(2) (r = 0.66, P <.002). CONCLUSION: TR-derived dP/dt/P(max), not dP/dt(max), is a clinically useful index of RV contractility, allowing researchers to account for the functional capacity.

Abstract: To predict left ventricular (LV) reverse remodeling after surgical repair of aortic regurgitation, we examined 30 patients with aortic regurgitation accompanying LV dilatation by myocardial tissue characterization with integrated backscatter method. Before and after operation, the magnitude of cyclic variation of integrated backscatter (CVIB) was obtained from anterior septum and posterior wall, and averaged value was calculated in each patient. Before operation, LV end-diastolic dimension, fractional shortening, and LV end-diastolic pressure were not significantly different between the patients with (group GR) and without (group PR) decreased LV end-diastolic dimension after operation. Under these conditions, CVIB, which was 9.6 +/- 1.0 dB from healthy volunteers, was significantly greater in group GR, 5.7 +/- 1.4 dB, than that in group PR, 3.8 +/- 0.8 dB (P =.0003). The patients with CVIB >/= 4 before operation were expected to have reverse remodeling after operation with a sensitivity of 79%, a specificity of 82%. These data indicate that preoperative CVIB from the left ventricle provides pivotal information for predicting reverse remodeling after operation for aortic regurgitation in addition to the conventional echocardiographic parameters.

Abstract: The present study sought to determine whether myocardial fatty acid metabolism as assessed with iodine-123-labeled 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) scintigraphy is impaired in patients with aortic valve disease (AVD) and whether the degree of the metabolic abnormality reflects the severity of AVD. BMIPP scintigraphy was performed in 12 patients with aortic stenosis (AS), 14 patients with aortic regurgitation (AR), and 9 healthy volunteers, and from that the heart-mediastinum uptake ratio (H/M ratio) corrected by the left ventricular (LV) mass (U/Mass ratio) and the myocardial washout rate (WR) were obtained. The H/M ratio tended to be higher in patients than in healthy volunteers (3.3 +/- 0.7 for AS, 3.5 +/- 0.5 for AR, 3.0 +/- 0.3 for healthy volunteers), and the WR was significantly higher in patients than in healthy volunteers (42.8 +/- 9.1% for AS, 35.7 +/- 6.5% for AR, 19.6 +/- 9.1% for healthy volunteers, p<0.01). In the AS patients, the U/Mass ratio showed significant negative correlations (r=-0.79 to -0.90, all p<0.01) and the WR showed significant positive correlations (r=0.61 to 0.82, all p<0.01) with transaortic pressure gradient, LV wall thickness, and LV mass. Similarly, in AR patients these BMIPP parameters showed proportional changes to the LV volumes and LV mass (r=-0.79 to -0.83, all p<0.01 for U/Mass ratio, r=0.55 to 0.70, p<0.05 to <0.01 for WR). In the 9 patients who underwent aortic valve replacement, the BMIPP parameters tended to normalize with increasing U/Mass ratio (0.90 +/- 0.41 x 10(-2)/g to 1.34 +/- 0.59 x 10(-2)/g, p<0.05) and decreasing WR (41.9 +/- 8.8% to 35.4 +/- 9.2%, p<0.01) after surgery. Myocardial fatty acid metabolism as assessed with BMIPP scintigraphy was impaired in patients with aortic valve disease and the U/Mass ratio and WR reflect the severity. These parameters may be useful for the noninvasive assessment of the myocardial metabolic abnormalities caused by hemodynamic overload.

Abstract: Although previous studies have demonstrated that even quantitative coronary angiography (QCA) can not provide accurate disease morphology, there has not been a systematic comparison of disease morphology determined by QCA and intravascular ultrasound (IVUS), particularly in Japanese patients. Therefore, the present study prospectively examined patients in a multicenter cooperative study. A total of 491 coronary sites from 562 patients (446 men, 116 women; mean age, 64+/-11 years) who underwent coronary interventions were enrolled. The target lesions (>50% diameter stenosis) were evaluated pre-operatively by both QCA and IVUS operating at 30-40 MHz and the percent area stenosis, eccentricity index (EI) and lesion length were determined. The minimal (min) and maximal (max) distances from the center of the stenotic lesion to the outline of the vessel wall were measured, and the EI was calculated by the formula: [(max - min)/max]. By QCA, lesion length was determined by measuring the distance between the proximal and distal shoulders of the lesion. When the lesions were observed by IVUS with a motorized pull-back system, the length was calculated by multiplying the time for observation of the disease and 0.5 or 1 mm/s. Although the severity of the stenosis determined by QCA (86+/-10%, mean +/- SD) did not differ from that by IVUS (83+/-13%), there was no correlation between them (r=0.32, y=0.25x+65) and the correlation did not improve when lesions with remodeling, enlargement (n=176) or shrinkage (n=79) were omitted from the calculation. The EIs by QCA and IVUS were 0.51+/-0.26 and 0.52+/-0.22, respectively (NS), and there was no correlation between them (r=0.30, y=0.36x+33). However, when the lesions with remodeling were excluded, the correlation greatly improved (r=0.80, y=0.84x+10.6, p<0.05). Lesion length determined by QCA (12.4+/-6.1 mm) was significantly shorter than that by IVUS (16.3+/-8.9 mm, p<0.01). These results demonstrate that coronary angiography significantly misinterprets disease morphology in terms of severity, eccentricity and length, in part because of vessel remodeling that can be accurately determined only by IVUS.

Abstract: OBJECTIVES: We sought to assess the effects of low density lipoprotein (LDL)-apheresis (LDL-A) for regression of coronary plaque in familial hypercholesterolemia (FH), we set up a one-year follow-up multicenter trial using coronary angiography and intravascular ultrasound (IVUS). BACKGROUND: It is still unclear whether aggressive lipid-lowering therapy by LDL-A leads to the regression of coronary plaque in patients with FH. METHODS: Eighteen patients with FH were assigned to one of two groups: medication + LDL-A (LDL-A group, n = 11) and medication only (medication group, n = 7). Total cholesterol, triglycerides, high density lipoprotein cholesterol and LDL cholesterol were measured in all subjects at the outset of treatment (baseline) and every three months thereafter. Coronary angiography and IVUS were performed at the outset and after the one-year follow-up period to measure minimal lumen diameter (MLD) by coronary angiogram and plaque area (PA) by IVUS. RESULTS: The LDL-A group showed 28.4% reduction in total cholesterol (from 275 +/- 27 mg/dl to 197 +/- 19 mg/dl) and 34.3% reduction in LDL cholesterol (from 213 +/- 25 mg/dl to 140 +/- 27 mg/dl) after one-year follow-up, while the medication group showed no changes in cholesterol levels. There were significant interactions between both treatments in total cholesterol (p = 0.0001), LDL cholesterol (p = 0.0001), MLD (p = 0.008) and PA (p = 0.017) using two-way repeated-measures analysis of variance by the SAS system (SAS Institute Inc., Cary, North Carolina). Significant differences were seen in net change in MLD (p = 0.004) and PA (p = 0.008) during the one-year follow-up period between both groups. CONCLUSIONS: These results suggest that aggressive lipid-lowering therapy using the combination of LDL-A and lipid-lowering drugs may induce regression of coronary atherosclerotic plaque in FH patients.

Abstract: BACKGROUND: Compensatory remodeling occurs to maintain lumen area in human coronary vessels. However, few data exist regarding the relationship between vessel remodeling and plaque distribution. Therefore, we studied coronary sites with or without remodeling by intravascular ultrasound and correlated with disease distribution. METHODS AND RESULTS: A total of 90 coronary sites with significant stenosis (>50%) from 80 patients were examined before interventions. For identifying the vessel remodeling, external elastic membrane (EEM) area was measured at the stenotic sites and the adjacent proximal and distal sites. The reference EEM area was calculated by averaging proximal and distal EEM areas, and percent enlargement of the EEM area was calculated by the formula: [(stenosis EEM area-reference EEM area)/reference EEM area]x100. Plaque area was determined by reducing the lumen from EEM areas. The maximal (max) and minimal (min) distances from the center of the lumen to the EEM were also measured, and the disease eccentricity index was calculated by the formula: [(max-min)/max]. The lesion was defined as eccentric if the index was >0.5 and as concentric if <or=0.5. There were 39 eccentric and 51 concentric lesions. The enlargement remodeling was observed at 32 lesions with the enlargement of EEM area of 28.0+/-16.0% (5.5 to 71.3%). Enlargement was more frequently observed in the eccentric than in concentric lesions (P<0.05). However, within 32 stenoses, which showed enlargement, there was no difference in enlargement between eccentric (n=19, 25.6+/-21.0%) and concentric lesions (n=13, 21.5+/-12.0%). Also, there was no statistical correlation between the increase in plaque area and % enlargement of EEM area irrespective of plaque morphology. CONCLUSIONS: These data demonstrate that in advanced coronary disease compensatory enlargement occurs more frequently at the eccentric than concentric coronary lesions. However, the EEM area was limited to expand regardless of the disease morphology.

Abstract: The purpose of this study was to clarify whether or not a change in the clinical characteristics of cardiac myxoma has occurred during the past 2 decades. The clinical records of 57 patients (22 men, 35 women; age, 52+/-14 years) with myxoma that had been surgically treated between May 1978 and July 1997 at the National Cardiovascular Center in Japan were reviewed. All myxomas were discovered by transthoracic echocardiography. They were divided into an early group (n=30) treated in the first decade (1978-1987) and a late group (n=27) treated in the second decade (1988-1997). The incidence of myxoma, patient characteristics, preoperative symptoms and echocardiographic features did not differ between the 2 groups. In contrast, the maximal dimensions of myxoma in the early group were significantly larger than those in the late group (6.3 +/-2.7 cm vs 4.3+/-1.3 cm, p=0.012). The weight of myxoma in the early group tended to be heavier than that in the late group (76+/-80 g vs 25+/-18 g, p=0.054). The incidence of patients with asymptomatic myxoma also tended to increase in the late group (7% vs 26%, p=0.07). Although there was no difference in the incidence of myxoma, smaller and asymptomatic myxomas were more frequent during the last decade, probably as a result of the development of cardiac imaging, particularly echocardiography.

Abstract: We report a rare case of bicuspid aortic stenosis complicated by an ascending aortic aneurysm and aortic dissection of DeBakey type IIIb. A 35-year-old woman was admitted to our hospital to examine her systolic murmur identified at birth. Severe aortic stenosis, dilatation of the ascending aorta, and the narrow color flow signal in the descending aorta were detected by transthoracic echocardiography. Initially, coarctation of the descending aorta was suspected, but aortic dissection, DeBakey type IIIb, was revealed by transesophageal echocardiography. Transesophageal echocardiography is indicated when only insufficient information is available on valve and aortic morphology in patients with bicuspid aortic valve.

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Abstract: To elucidate the validity and reproducibility of the use of intravenous echo-contrast agent in the evaluation of left ventricular (LV) performance, we measured LV volume and ejection fraction (EF) in 42 patients with triggered harmonic contrast imaging (THCI), compared with continuous harmonic imaging without contrast agent (CHI) and with cineventriculography (CVG). In 10 of 42 patients, THCI improved LV border delineation which could not be obtained even with CHI. LV end-diastolic, end-systolic volumes and EF by both CHI and THCI correlated well with those by CVG. Although LV volumes are underestimated, THCI lessened the mean differences to about in half, compared with CHI. The observer variabilities obtained using THCI were smaller than those by CHI. These results indicate the validity of LV enhancement and the measurement of EF using THCI. We suggest that this method noninvasively provides more accurate LV systolic function with the acceptable reproducibility.

Abstract: The efficacy of treating dilated cardiomyopathy with metoprolol was compared with that of carvedilol. Metoprolol was administered to 29 patients, and carvedilol to 62. Patients who could not be dosed with up to 40 mg daily of metoprolol or 20 mg daily of carvedilol were defined as intolerant. As well as the tolerability of these beta-blockers, the effects on left ventricular end-diastolic dimension (LVDd), fractional shortening (FS), plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations, the delayed heart and mediastinum (H/M) ratio determined from metaiodobenzylguanidine imaging were compared. Drug intolerance occurred in 24% of patients in the metoprolol group and 19% in the carvedilol group. Among the drug-tolerant patients, LVDd, FS and plasma BNP concentration improved in both groups and to the same degree. Only 25% of drug-tolerant patients in the metoprolol group had a delayed H/M ratio below 1.9 compared with 57% in the carvedilol group. Both metoprolol and carvedilol, when tolerated, improve cardiac function and neurohumoral factors to the same degree. However, carvedilol is preferable to metoprolol for patients with a low delayed H/M ratio.

Abstract: BACKGROUND: Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, that may also cause a positive energy balance by stimulating food intake and inducing adiposity. We sought to investigate the pathophysiology of ghrelin in the cachexia associated with chronic heart failure (CHF). METHODS AND RESULTS: Plasma ghrelin was measured in 74 patients with CHF and 12 control subjects, together with potentially important anabolic and catabolic factors, such as GH and tumor necrosis factor (TNF-alpha). Patients with CHF were divided into two groups, those with cachexia (n=28) and those without cachexia (n=46). Plasma ghrelin did not significantly differ between all CHF patients and controls (181+/-10 versus 140+/-14 fmol/mL, P=NS). However, plasma ghrelin was significantly higher in CHF patients with cachexia than in those without cachexia (237+/-18 versus 147+/-10 fmol/mL, P<0.001). Circulating GH, TNF-alpha, norepinephrine, and angiotensin II were also significantly higher in CHF patients with cachexia than in those without cachexia. Interestingly, plasma ghrelin correlated positively with GH (r=0.28, P<0.05) and TNF-alpha (r=0.31, P<0.05) and negatively with body mass index (r=-0.35, P<0.01). CONCLUSIONS: Plasma ghrelin was elevated in cachectic patients with CHF, associated with increases in GH and TNF-alpha and a decrease in body mass index. Considering ghrelin-induced positive energy effects, increased ghrelin may represent a compensatory mechanism under catabolic-anabolic imbalance in cachectic patients with CHF.

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