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Biomedical subjects

H Mabuchi

Publications and source records attributed to H Mabuchi.

At least 55 records · Page 3Linked to original sources
PubMed2000

Clinical features of hypertrophic cardiomyopathy caused by a Lys183 deletion mutation in the cardiac troponin I gene.

BACKGROUND: Mutations that cause hypertrophic cardiomyopathy (HCM) have been identified in 9 genes that code proteins in the sarcomere. Previous reports have demonstrated that cardiac troponin I (cTnI) gene mutations may account for familial HCM; however, the clinical characteristics and prognosis of patients with HCM caused by cTnI gene mutations are not known. METHODS AND RESULTS: We analyzed cTnI gene mutations in 130 unrelated probands with HCM and their families to clarify the genotype-phenotype correlations. We identified 25 individuals in 7 families with a Lys183 deletion (Lys183 del) mutation in exon 7 of the cTnI gene. The disease penetrance in subjects aged >20 years was 88% by echocardiography and 96% by ECG. Sudden death occurred in 7 individuals of 4 families at any age. Overall, 7 (43.8%) of 16 individuals aged >40 years had left ventricular systolic dysfunction, and 3 (18.8%) displayed dilated cardiomyopathy-like features. Of affected individuals, 4 of 5 individuals aged >40 years followed by echocardiography showed septal thinning and decreased fractional shortening during >5 years of follow-up. CONCLUSIONS: The Lys183 del mutation in the cTnI gene in patients with HCM is associated with variable clinical features and outcomes. HCM caused by the Lys183 del mutation has a significant disease penetrance. This mutation is associated with sudden death at any age and dilated cardiomyopathy-like features in those aged >40 years. However, it remains unclear whether screening of families with HCM for this mutation will be useful in patient management and counseling.

Adolescent↗
PubMed2000

Effects of NK-104, a new hydroxymethylglutaryl-coenzyme reductase inhibitor, on low-density lipoprotein cholesterol in heterozygous familial hypercholesterolemia. Hokuriku NK-104 Study Group.

The clinical efficacy of NK-104, a novel and totally synthetic hydroxymethylglutaryl-coenzyme A reductase inhibitor, was assessed in 30 patients (men/women = 15/15, mean age 51 years) with heterozygous familial hypercholesterolemia. After a placebo phase of >4 weeks, NK-104 was given at an initial dose of 2 mg/day for 8 weeks, which was increased to 4 mg/day for a further 8 weeks. As a result of 2 mg/day of NK-104 treatment, mean +/- SD of total and low-density lipoprotein cholesterol levels decreased significantly (p<0.0001) from baseline, namely from 8.80+/-1.38 to 6.11+/-1.09 mmol/L (-31%) and from 6.81+/-1.52 to 4.09+/-1.03 mmol/L (-40%), respectively. They decreased further (p<0.0001) as a result of 4-mg/day administration, to 5.52+/-0.81 mmol/L (-37%) and 3.55+/-0.85 mmol/L (-48%), respectively. Changes in high-density lipoprotein cholesterol levels failed to reach statistical significance. Serum triglyceride levels decreased significantly (p<0.0001) from baseline as a result of 4 mg/day of NK-104, from 1.99+/-1.72 to 1.35+/-0.90 mmol/L (-23%). Serum apolipoprotein B, CII, CIII, and E levels significantly decreased: mean changes from baseline at the end of the study were -41% (p<0.0001), -27% (p<0.0001), -19% (p = 0.002), and -37% (p<0.0001), respectively. On the other hand, apolipoprotein AI and All levels significantly increased as a result of the treatment: + 10% (p = 0.002) and +6% (p = 0.008), respectively. There were no adverse events observed in either clinical or laboratory findings that could be attributed to the treatment. These results suggest that the potency of NK-104 appears to be dose-dependent, and that NK-104 is safe and well tolerated in the treatment of patients with heterozygous familial hypercholesterolemia, and thus also provides a new therapeutic choice for subjects requiring lipid-modifying therapy.

Female↗
PubMed2000

Mutational analysis of ATP7B and genotype-phenotype correlation in Japanese with Wilson's disease.

The gene ATP7B responsible for Wilson's disease (WD) produces a protein which is predicted to be a copper-binding P-type ATPase, homologous to the Menkes disease gene (ATP7A). Various mutations of ATP7B have been identified. This study aimed to detect disease-causing mutations, to clarify their frequency and distribution, to determine whether genotype correlates with phenotype, and to determine the rate of abnormal findings in heterozygotes for the WD gene. We analyzed 41 unrelated Japanese WD families, including 47 patients. Twenty-one mutations, including nine novel ones, were identified. 2871delC (15.9%), 1708-5T-->G (11. 0%), and Arg778Leu (13.4%) were the most common mutations. 2871delC was detected mainly in eastern Japan and 1708-5T-->G in western Japan. The homozygotes for the 1708-5T-->G, 2871delC, or Arg778Leu mutations did not show a correlation with their phenotypes. Ceruloplasmin and copper levels were abnormally low in 28.6% and 35. 0% of heterozygotes, respectively. When patients and their families are screened for WD, a high rate of abnormal laboratory data in heterozygotes must be taken into account.

Adenosine Triphosphatases↗
PubMed2000

Cardiac sympathetic activity in the asymmetrically hypertrophied septum in patients with hypertension or hypertrophic cardiomyopathy.

BACKGROUND: In patients with essential hypertension (HT), proportional (symmetric) left ventricular hypertrophy (LVH) is common. In contrast, hypertrophic cardiomyopathy (HCM) is characterized by disproportional LVH and, in particular, asymmetric septal hypertrophy (ASH); however, some hypertensive patients also develop ASH. It has not been determined whether such cases represent a distinct type of hypertensive LVH or HCM combined with hypertension. HYPOTHESIS: The study was undertaken to evaluate sympathetic activity in the interventricular septum in patients with HT and ASH or in patients with HCM. METHODS: The patients were evaluated by I-123 meta-iodobenzylguanidine (MIBG) and thallium-201 (201Tl) single-photon emission computed tomography (SPECT), respectively. They were divided into three groups: patients with essential HT and symmetric septal hypertrophy (Group A), patients with HT and ASH (Group B), and patients with HCM and ASH (Group C). RESULTS: Compared with the lateral wall, early uptake of MIBG in the septum was significantly higher in Group B than in Group A, but not significantly different between Groups A and C. Compared with the lateral wall, early uptake of 201Tl in the septum did not differ among the three groups. No significant difference in the MIBG clearance in the lateral wall was seen among the three groups. By contrast, MIBG clearances in the septum and apex were significantly greater in Group C than in Groups A and B. There was an inverse correlation between systolic thickening and MIBG clearance in the septum. CONCLUSION: These findings suggest that sympathetic activity in the septum differs between patients with HT and ASH and patients with HCM.

3-Iodobenzylguanidine↗
PubMed2000

A new variant deletion of a copper-transporting P-type ATPase gene found in patients with Wilson's disease presenting with fulminant hepatic failure.

A candidate gene (ATP7B) for Wilson's disease, an autosomal recessive disorder of copper transport, has recently been identified. We examined the ATP7B gene in two Japanese sisters with Wilson's disease presenting with fulminant hepatic failure but who did not exhibit Kayser-Fleischer rings or abnormal neurological findings. Genomic DNA was isolated from the whole blood of the patients and their family. Entire exons of ATP7B, and their associated splice junctions, were amplified by polymerase chain reaction. The sequencing of all exons was performed by a non-radioactive sequencing method. The sequencing of exon 12 of ATP7B revealed a 9-bp deletion. The mutation deleted 922Gly, 923Tyr, and 924Phe, and three residues conserved in the Menkes gene, ATP7A, located in the fifth transmembrane region. Of the 14 family members tested, 7 were normal and 7 were heterozygous for the deletion. Mean serum copper and cerulopasmin levels were significantly lower in the family members who were heterozygous for the deletion than in the normal family members, and two heterozygous family members showed abnormally low ceruloplasmin levels; however, there were no differences in mean aspartate aminotransferase or alanine aminotransferase levels between the two groups.

Adenosine Triphosphatases↗
PubMed2000

Left ventricular systolic dysfunction during exercise and dobutamine stress in patients with hypertrophic cardiomyopathy.

OBJECTIVES: We sought to characterize stress-induced left ventricular systolic dysfunction in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: Myocardial ischemia and diastolic dysfunction occur in patients with HCM. We hypothesized that, in the setting of transient myocardial ischemia, left ventricular systolic dysfunction occurs during exercise and dobutamine stress. METHODS: We studied 39 patients with HCM but without obstructive symptoms at rest or coronary artery disease. A continuous ventricular function monitor equipped with cadmium telluride detectors (VEST) was used to evaluate left ventricular function during supine bicycle ergometer exercise. Dobutamine stress echocardiography (DSE) was also performed. The left ventricular ejection fraction (LVEF) and regional wall motion were determined from echocardiographic images. RESULTS: Changes in the LVEF correlated between exercise and dobutamine stress (r = 0.643, p < 0.0001). The LVEF decreased more than 5% at peak exercise in 17 of patients (group II), while the other patients had normal responses (group I). New regional wall motion abnormalities during dobutamine infusion were detected in 18 of 110 (16.4%) segments in group I and 42 of 85 (49.4%) segments in group II. Decreased or unchanged regional wall motion occurred more frequently in hypertrophied segments than in nonhypertrophied segments (p < 0.0001). There were significant inverse correlations between the LVEF responses during both stresses and the number of abnormal segments noted during dobutamine stress in all patients (VEST: p < 0.005; DSE: p < 0.0005). Signs of left ventricular obstruction were observed in 11 of 39 patients during DSE. However, there was no significant correlation between the LVEF response and the dobutamine-induced left ventricular pressure gradient. CONCLUSIONS: Exercise-induced systolic dysfunction occurred in 50% of patients with HCM. In these patients, regional wall motion abnormalities were present in hypertrophied segments.

Adult↗
PubMed2000

Effect of bilirubin UDP glucuronosyltransferase 1 gene TATA box genotypes on serum bilirubin concentrations in chronic liver injuries.

TATA box abnormality in the promoter region of the bilirubin UDP glucuronosyltransferase 1 gene has been reported to cause Gilbert's syndrome in white subjects. It has also been reported that the majority of Japanese patients with Gilbert's syndrome are heterozygous for Gly71Arg in the coding region of this gene. On the other hand, some patients with chronic hepatitis often show signs of unexpected hyperbilirubinemia. The aims of this study were to determine which of the genetic variations, TATA box genotype or codon 71 genotype, is most closely related to serum bilirubin concentrations, and whether the TATA box genotype has an effect on serum bilirubin concentrations in patients with hepatitis C-associated chronic liver diseases. In a sample of 300 individuals selected from among the general Japanese population, mean concentrations of total serum bilirubin differed significantly among TATA box genotypes, but not among codon 71 genotypes. Concentration of total serum bilirubin was significantly correlated with TATA box genotypes. In 211 patients with hepatitis C-associated chronic liver diseases, mean concentrations of total serum bilirubin also differed significantly among TATA box genotypes. In patients with chronic hepatitis C, concentration of total serum bilirubin was significantly correlated with TATA box genotypes. In summary, TATA box genotypes, but not codon 71 genotypes, are closely related to serum bilirubin concentrations. TATA box genotypes should therefore be considered when evaluating hepatic function by serum bilirubin concentrations in cases of hepatitis C-associated chronic liver diseases.

Adult↗
PubMed2000

Exercise-induced ST-segment depression and systolic dysfunction in patients with nonobstructive hypertrophic cardiomyopathy.

BACKGROUND: ST-segment depression is common in patients with hypertrophic cardiomyopathy (HCM). However, it is not clear whether exercise-induced ST-segment depression in patients with HCM and patent coronary arteries is associated with changes in left ventricular function. METHODS: Left ventricular function was continuously evaluated in 53 patients with nonobstructive HCM during supine ergometer exercise with a radionuclide ventricular function monitor equipped with a cadmium telluride detector. On the basis of the ST-segment changes during exercise, the patients were divided into 2 groups: group N had no ST-segment depression, and group D had >/=0.1 mV ST-segment depression. RESULTS: Exercise duration, blood pressure, heart rate, and rate-pressure product during exercise did not differ between the 2 groups. End-diastolic volume at rest and at peak exercise did not differ between groups D and N. In contrast, the end-systolic volume in group N decreased during exercise, whereas in group D it increased. As a result, the left ventricular ejection fraction in group D decreased from 70% +/- 7% to 59% +/- 15% (P <.0001), whereas ejection fraction in group N increased from 65% +/- 8% to 71% +/- 11% (P =.0002). There was a strong correlation between exercise-induced ST-segment depression and changes in ejection fraction from rest to peak exercise (P <.0001). CONCLUSIONS: These results suggest that the exercise-induced ST-segment depression seen in patients with nonobstructive HCM is associated with systolic dysfunction during exercise.

Adolescent↗
PubMed2000

Effects of chronic neutral endopeptidase inhibition in rats with cyclosporine-induced hypertension.

OBJECTIVE: Cyclosporine (CysA), a potent immunosuppressant, is associated with hypertension and nephrotoxicity. Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides and endothelin-1 (ET-1). We conducted the present study to determine whether or not the NEP inhibitor, ecadotril, prevents cyclosporine-induced hypertension and to clarify the mechanisms responsible for the hypotensive effects of ecadotril. DESIGN AND METHODS: We studied the chronic effects of ecadotril (30 mg/kg per day) on blood pressure; the production of ET-1 and C-type natriuretic peptide (CNP); endothelial nitric oxide synthase (eNOS) activity; and the expression of messenger RNA (mRNA), for each substance in blood vessels of CysA-induced hypertensive rats. RESULTS: CysA (25 mg/kg per day) given for 4 weeks increased the blood pressure from 116 +/- 14 mmHg to 159 +/- 15 mmHg, in rats. This increase was blunted by the co-administration of ecadotril (blood pressure: 134 +/- 14 mmHg). CysA increased plasma NEP activity. CysA increased the production of ET-1 and the expression of ET-1 mRNA without affecting CNP synthesis and endothelin converting enzyme (ECE)-1 mRNA expression. CysA decreased the eNOS activity and eNOS mRNA levels. Addition of the NEP inhibitor decreased the synthesis of ET-1 and ET-1 mRNA levels and increased the eNOS activity and the eNOS mRNA levels. Vascular CNP synthesis and ECE-1 mRNA expression in rats treated with ecadotril did not differ from those in rats treated with CysA and ecadotril. CONCLUSION: These results indicate that chronic NEP inhibition may prevent the CysA-induced hypertension by decreasing local ET-1 synthesis and partly increasing vascular nitric oxide production.

Animals↗
PubMed2000

Cholesteryl ester transfer protein and atherosclerosis.

Plasma cholesteryl ester transfer protein facilitates the transfer of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins. Its significance in atherosclerosis has been debated in studies of human population genetics and transgenic mice. The current review will focus on human plasma cholesteryl ester transfer protein research, including TaqIB, 1405V, and D442G polymorphisms. Plasma cholesteryl ester transfer protein has a dual effect on atherosclerosis, depending on the metabolic background. In hypercholesterolaemia or combined hyperlipidaemia, plasma cholesteryl ester transfer protein may be pro-atherogenic and could be a therapeutic target.

Alleles↗
PubMed2000

Mutation analysis of the PTEN / MMAC1 gene in Japanese patients with Cowden disease.

Cowden disease (CD), also known as multiple hamartoma syndrome, is an autosomal dominant cancer syndrome associated with high risk of breast and thyroid cancer. Recently, germline mutations in PTEN / MMAC1, which has nine exons encoding a dual specificity phosphatase with homology to tensin and auxilin, have been identified on chromosome 10q23 in some 40 to 80% of CD patients. Our polymerase chain reaction amplification and sequence analysis of all coding regions identified five different mutations including four novel germline mutations among 5 of 12 unrelated Japanese CD patients. The novel findings included a missense mutation (G --> T) at nucleotide 1004 in exon 8 resulting in an arginine-to-leucine change at codon 335 (R335L), two novel splice-site mutations (209 + 1delGT and 209 + 1delGTAA) in intron 3, and insertion of G at nucleotide 632 in exon 6 (632insG). We also detected a nonsense mutation (C --> T) at nucleotide 697 producing R233X in exon 7, which has been reported previously. From reported phenotypic data concerning CD patients from five different families who had the R233X mutation, it may be suggested that R233X mutation correlates with macrocephaly. Although previous reports have implicated exon 5 as a "hot spot," we found no mutation in exon 5.

Adult↗
PubMed2000

Cardiac dysfunction and long-term prognosis in patients with nonobstructive hypertrophic cardiomyopathy and abnormal (123)I-15- (p-Iodophenyl)-3(R,S)-methylpentadecanoic acid myocardial scintigraphy.

To evaluate the relationship between myocardial scintigraphic abnormalities based on (123)I-radioiodinated 15-(p-iodophenyl)-3(R, S)-methylpentadecanoic acid (BMIPP) uptake and cardiac function and the relationship between these abnormalities and long-term prognosis in patients with hypertrophic cardiomyopathy (HCM), 27 patients with nonobstructive HCM underwent BMIPP myocardial scintigraphic study, echocardiography, and exercise radionuclide study. Based on the extent of BMIPP scintigraphic defects, the patients were divided into two groups: Group A (n = 19) patients had no or small defects, and group B (n = 8) patients had moderate to large defects. Cardiac events were recorded over an average period of 64 months. The left ventricular end-diastolic and end-systolic dimensions were significantly greater in group B than in group A. The fractional shortening in group B was less than in group A (p = 0.0002). The BMIPP score and fractional shortening at rest correlated significantly (p < 0.05). The BMIPP score and the change in ejection fraction between rest and peak exercise correlated significantly (p < 0.05). While only 1 cardiac event occurred in the 19 patients in group A during a mean follow-up period of 64 months, 6 cardiac events occurred in the 8 patients in group B. The 84-month event-free survival rate was 94.4% in group A and 14.6% in group B (p < 0.01). These results suggest that patients with HCM and moderate to large defects as assessed by BMIPP myocardial scintigraphy have decreased cardiac function and a poor prognosis.

Adult↗
PubMed2000

Cardiac aldosterone production in genetically hypertensive rats.

Aldosterone is synthesized in extra-adrenal tissues, both blood vessels and brain. We undertook the present study to determine whether the rat heart produces aldosterone and to investigate the effects of adrenalectomy, ACE inhibition, and angiotensin II on aldosterone synthesis in the heart. To clarify the pathophysiological role of cardiac aldosterone in the hypertensive heart, we compared the synthesis of aldosterone in the hearts of stroke-prone spontaneously hypertensive rats (SHRSP) with that in Wistar-Kyoto rats. The effects of the aldosterone antagonist spironolactone on myocardial hypertrophy in adrenalectomized SHRSP were also studied. Isolated rat hearts were perfused for 2 hours, and the perfusate was analyzed with HPLC and mass spectrometry. The activity of aldosterone synthase was estimated on the basis of the conversion of [(14)C]deoxycorticosterone to [(14)C]aldosterone. The levels of aldosterone synthase gene (CYP11B2) mRNA were determined with competitive polymerase chain reaction. Aldosterone production, the activity of aldosterone synthase, and the expression of CYP11B2 mRNA were increased in hearts from adrenalectomized rats and rats treated with angiotensin II. ACE inhibitors decreased cardiac aldosterone synthesis. Cardiac aldosterone, aldosterone synthase activity, and CYP11B2 mRNA levels in hearts from 2- and 4-week-old SHRSP were significantly greater than those of age-matched Wistar-Kyoto rats. Spironolactone prevented cardiac hypertrophy in adrenalectomized SHRSP. These results suggest that the rat heart produces aldosterone and that endogenous cardiac aldosterone may affect cardiac function and hypertrophy in hypertension in rats.

Adrenalectomy↗
PubMed2000

Sodium-induced cardiac aldosterone synthesis causes cardiac hypertrophy.

High sodium intake causes cardiac hypertrophy independently of increases in blood pressure. Aldosterone is synthesized in extraadrenal tissues such as blood vessels, brain, and heart. Effects of 8 weeks of high sodium intake on cardiac aldosterone synthesis, as well as cardiac structure, mass, and aldosterone production, levels of mRNA coding for aldosterone synthase (CYP11B2) and the angiotensin II AT1 receptor, were studied in normotensive Wistar-Kyoto (WKY) rats. Isolated rat hearts were perfused for 2 hr, and the perfusate was analyzed by high-performance liquid chromatography and mass spectrometry. Aldosterone synthase activity was estimated from the conversion of [14C]deoxycorticosterone to [14C]aldosterone. Levels of mRNA for CYP11B2 and AT1 receptor were determined by competitive polymerase chain reactions. A high sodium intake for 8 weeks produced left ventricular hypertrophy without elevation of blood pressure. Plasma aldosterone concentrations and plasma renin concentrations were decreased by high sodium intake. Aldosterone production, activity of aldosterone synthase, and expression of mRNA for CYP11B2 and AT1 receptor were increased in hearts of rats with high sodium intake. These results suggest that high sodium intake increases cardiac aldosterone synthesis, which may contribute to cardiac hypertrophy independently of the circulating renin-angiotensin-aldosterone system.

Aldosterone↗
PubMed2000

Microvascular ischemia in patients with myotonic dystrophy.

Two women with myotonic dystrophy underwent dipyridamole thallium-201 (201Tl) myocardial perfusion imaging, after which one patient developed flat T waves in lead I and aV(L), and inverted T waves in leads V(2-6). The other patient developed a nonspecific intraventricular block that progressed to complete left bundle branch block and was associated with chest discomfort. Reversible scintigraphic defects were observed in both women. Although there was evidence that suggested myocardial ischemia on the ECG changes and 201Tl scintigraphic findings, coronary angiography demonstrated no significant stenoses in either patient. These findings suggest that microvascular dysfunction may lead to myocardial ischemia and conduction disturbances in patients with myotonic dystrophy.

Electrocardiography↗
PubMed2000

Diagnostic usefulness of the post-exercise systolic blood pressure response for the detection of coronary artery disease in patients with diabetes mellitus.

Patients with diabetes mellitus (DM) often have a positive result on exercise testing despite a normal coronary arteriogram, which indicates that exercise-induced ST depression is not always an accurate indicator of the presence of coronary artery disease (CAD) in such patients. The present study evaluated the usefulness of the post-exercise systolic blood pressure (SBP) response for the detection of CAD in 47 consecutive patients with DM. Significant stenotic lesions were detected by angiography in 25 patients; 18 of these had true positive (TP) exercise testing results, and 7 had false negative (FN) results. No significant stenotic lesions were detected in the remaining 22 patients and of these 10 had true negative (TN) exercise testing results, and 12 had false positive (FP) results. The SBP ratio (SBP after 3 min of recovery divided by the SBP at peak exercise) was significantly higher in patients with coronary stenoses than in those without. Analysis of the relative cumulative frequency revealed that a SBP ratio greater than 0.87 was associated with significant stenoses. The sensitivity, specificity, and accuracy of ST change combined with a SBP ratio greater than 0.87 for detecting stenoses in patients with DM were 68%, 82%, and 74%, respectively. These results suggest that calculating the SBP ratio, in combination with monitoring for ST depression, improves the accuracy of treadmill exercise testing for the detection of CAD in patients with DM.

Adult↗