Rapid-sequence phosphorus-31 magnetic resonance spectroscopy of the human heart using a 1.5-T clinical system.

PURPOSE: To compare a 'standard' slow phosphorus-31 magnetic resonance spectroscopy (31P-MRS) sequence with two faster sequences in phantoms and healthy volunteers using a 1.5-T clinical system. MATERIAL AND METHODS: Complete 3D localization was performed using a 2D phosphorus chemical-shift imaging sequence in combination with 30-mm axial slice-selective excitation. Two 31P-MRS rapid sequences (RS8-4: 8 x 8 phase-encoding, with an average of 4 acquisitions, and RS16-1: 16 x 16 phase-encoding, 1 acquisition) were compared with the standard sequence (StdP: 16 x 16 phase-encoding, with an average of 8 acquisitions) in phantom and healthy volunteers. RESULTS: Acquisition time for the 31P-MRS procedure with StdP, RS8-4, and RS16-1 in the healthy volunteer studies ranged from 30 to 45, 3 to 5, and 3 to 5 minutes, respectively. Metabolite measurements of healthy volunteers obtained from 31P-MRS using RS8-4 correlated with values obtained using StdP (PCr r2=0.63, P<0.001; ATP r=0.41, P<0.01 and PCr/ATP ratio r2=0.25, P<0.05). There was no correlation between StdP and RS16-1 for either ATP or the PCr/ATP ratio (r2=0.03, P=0.60, and r2=0.11, p=0.26, respectively). Reproducibility (intensity of phosphorus signal) with RS16-1 was worse than that of RS8-4 or StdP. CONCLUSION: 31P-MRS using RS8-4 may be a valid diagnostic tool for patients with cardiac diseases.

Effects of coffee consumption on oxidative susceptibility of low-density lipoproteins and serum lipid levels in humans.

Since little is known about how coffee intake affects low-density lipoprotein (LDL) oxidative susceptibility and serum lipid levels, we conducted an in vivo study in 11 healthy male students of Wakayama Medical University aged between 20 and 31 years fed an average Japanese diet. On days 1-7 of the study, the subjects drank mineral water. On day 7, the subjects began drinking coffee, 24 g total per day, for one week. This was followed by a one week "washout period" during which mineral water was consumed. Fasting peripheral venous blood samples were taken at the end of each one-week period. LDL oxidation lag time was approximately 8% greater (p < 0.01) after the coffee drinking period than the other periods. Serum levels of total cholesterol and LDL-cholesterol (LDL-C) and malondialdehyde (MDA) as thiobarbituric acid reactive substances (TBARS) were significantly decreased after the coffee drinking period. Finally, regular coffee ingestion may favorably affect cardiovascular risk status by modestly reducing LDL oxidation susceptibility and decreasing LDL-cholesterol and MDA levels.

Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias.

INTRODUCTION: Congenital long QT syndrome (LQTS) is a genetically heterogeneous arrhythmogenic disorder caused by mutations in at least five different genes encoding cardiac ion channels. It was suggested recently that common polymorphisms of LQTS-associated genes might modify arrhythmia susceptibility in potential gene carriers. METHODS AND RESULTS: We examined the known LQTS genes in 95 patients with definitive or suspected LQTS. Exon-specific polymerase chain reaction single-strand conformation polymorphism and direct sequence analyses identified six patients who carried only a single nucleotide polymorphism in KCNQ1 that is found in approximately 11% of the Japanese population. This 1727G>A substitution that changes the sense of its coding sequence from glycine to serine at position 643 (G643S) was mostly associated with a milder phenotype, often precipitated by hypokalemia and bradyarrhythmias. When heterologously examined by voltage-clamp experiments, the in vitro cellular phenotype caused by the single nucleotide polymorphism revealed that G643S-KCNQ1 forms functional homomultimeric channels, producing a significantly smaller current than that of the wild-type (WT) channels. Coexpression of WT-KCNQ1 and G643S-KCNQ1 with KCNE1 resulted in approximately 30% reduction in the slow delayed rectifier K+ current I(Ks) without much alteration in the kinetic properties except its deactivation process, suggesting that the G643S substitution had a weaker dominant-negative effect on the heteromultimeric channel complexes. CONCLUSION: We demonstrate that a common polymorphism in the KCNQ1 potassium channel could be a molecular basis for mild I(Ks) dysfunction that, in the presence of appropriate precipitating factors, might predispose potential gene carriers to life-threatening arrhythmias in a specific population.

Angiotensin II type 1 receptor blockade abolishes specific K(ATP)channel gene expression in rats with myocardial ischemia.

The cardiac ATP-sensitive potassium (K(ATP)) channel is potentially composed of an inward rectifier potassium channel (Kir6.1 and/or Kir6.2) subunit and the cardiac type of sulfonylurea receptor (SUR2A). We reported that cardiac Kir6.1 mRNA and protein are specifically upregulated in the non-ischemic as well as the ischemic regions in rats with myocardial ischemia, suggesting that humoral and/or hemodynamic factors are responsible for this regulation. In the present study, pretreatment with TCV-116, an angiotensin (Ang) II type 1 receptor antagonist, completely inhibited the upregulation of Kir6.1 mRNA and protein expression in both regions of rat hearts subjected to 60 min of coronary artery occlusion followed by 24 h of reperfusion; whereas pretreatment with lisinopril, an Ang converting enzyme (ACE) inhibitor, partly inhibited this upregulation. Except for rats pretreated with TCV-116, Kir6.1 mRNA levels were positively correlated with those for brain natriuretic peptide (BNP), a molecular indicator of regional wall stress, in both the non-ischemic and the ischemic regions. Plasma Ang II levels were not elevated in rats with control myocardial ischemia compared with sham rats. Thus, the stress-related induction of cardiac Kir6.1 mRNA and protein expression under myocardial ischemia is inhibited by pretreatment with an AT1 antagonist, but also in part by an ACE inhibitor, suggesting that activation of local renin-angiotensin system may play a role.

Dietary coenzyme Q(10) supplement renders swine hearts resistant to ischemia-reperfusion injury.

To examine whether nutritional supplementation of coenzyme Q(10) (CoQ(10)) can reduce myocardial ischemia-reperfusion injury, a group of swine was fed a regular diet supplemented with CoQ(10) (5 mg x kg(-1) x day(-1)) for 30 days. Another group of pigs that were fed a regular diet supplemented with placebo served as a control. After 30 days, isolated in situ pig hearts were prepared and hearts were perfused with a cardiopulmonary pump system. Each heart was subjected to 15 min of regional ischemia by snaring of the left anterior descending coronary artery, followed by 60 min of hypothermic cardioplegic global ischemia and 120 min of reperfusion. After the experiments were completed, myocardial infarct size was measured by triphenyltrazolium chloride staining methods. Postischemic left ventricular contractile function was better recovered in the CoQ(10) group than in the control group of pigs. CoQ(10)-fed pigs revealed less myocardial infarction and less creatine kinase release from the coronary effluent compared with control pigs. The experimental group also demonstrated a smaller amount of malonaldehyde in the coronary effluent and a higher content of the endogenous antioxidants ascorbate and thiol. Significant induction of the expression of ubiquitin mRNA was also found in the hearts of the CoQ(10)-fed group. The results of this study demonstrate that nutritional supplementation of CoQ(10) renders the hearts resistant to ischemia-reperfusion injury, probably by reducing the oxidative stress.

Fate of fibrin sealant in pericardial space.

BACKGROUND: Although fibrin sealant (Beriplast, Aventis Behring, Marburg, Germany) has been widely used as a supplementary measure for hemostasis during cardiac surgery in Europe and is becoming popular in the United States, the pharmocokinetics of fibrin sealant applied in pericardial space has not been elucidated. METHODS: A small incision was made on the epicardial surface of the left ventricle of a rat, and the incision was sutured. Total 0.2 ml of fibrin sealant containing iodine 125 (125I)-labeled fibrinogen, aprotinin, blood coagulation factor XIII and thrombin was applied to the area around the suture line. RESULTS: Distributions of 125I-labeled fibrinogen in the heart on postoperative days 1, 3, 7, and 14 were 48.2% +/- 1.8%, 20.7% +/- 2.2%, 0.15% +/- 0.02%, and 0.01% +/- 0.02%, respectively. The radioactivity was negligible in the blood, liver, spleen, and kidney except for the thyroid in which the radioactivity increased to 7.9% +/- 0.7% and 4.3% +/- 0.4%, respectively, on postoperative days 7 and 14. Iodine 125-labeled fibrinogen concentrations of the heart and other organs showed a similar change in the time course of distribution. Dense and thick fibrin network, observed on postoperative day 1, had dissipated and was thinner with collagen formation by postoperative day 7. CONCLUSIONS: Fibrin sealant applied to the pericardial cavity regresses rapidly and plays an important role in wound healing.

Vitamin E treatment of experimental glomerular disease in rats.

BACKGROUND: Kidney mesangial cells (MCs) and vascular smooth muscle cells (VSMCs) are closely related in terms of origin, microscopic anatomy, histochemistry, and contractility. This relationship suggests a similarity between kidney glomerular sclerosis and atherosclerosis. Vitamin E appears beneficial in the prevention and treatment of coronary heart disease and it also inhibits the proliferation of VSMCs in vitro. Thus, we investigated the effect of vitamin E on glomerular sclerosis and MC-proliferative glomerulonephritis (GN) in two rat models of glomerular disease. METHODS: A remnant kidney rat model accelerated with hyperlipidemia was used to examine progressive glomerular sclerosis leading to chronic renal failure. A rat model of MC-proliferative GN was induced by the intravenous administration of absorbed rabbit anti-rat thymocyte serum (ATS). RESULTS: In the remnant kidney rat model, dietary supplementation with vitamin E (500 IU dl-alpha-tocopheryl acetate/kg) and cholesterol (2%) significantly inhibited glomerular sclerosis and macrophage infiltration in glomeruli relative to controls receiving basal and cholesterol-supplemented diets. In the ATS-induced GN model, glomerular cell proliferation (principally MCs) was lower in rats fed diets supplemented with vitamin E (1000 IU dl-alpha-tocopheryl acetate/kg) compared with controls fed the basal diet only. Although the degree of glomerular macrophage infiltration was similar in both groups, fewer proliferative cell nuclear antigen (PCNA)-positive cells were observed in the vitamin E group, suggesting that MC proliferation was suppressed via the inhibition of intracellular transduction. CONCLUSIONS: Supplemental dietary vitamin E suppresses MC proliferation and glomerular sclerosis in models of glomerular disease in rats. This action of vitamin E in experimental nephritis suggests the value of clinical trials testing the potential benefit of vitamin E in chronic GN patients.

Factors associated with calcification of the abdominal aorta in hemodialysis patients.

BACKGROUND: Cardiovascular and cerebrovascular injury caused by arteriosclerosis has been the major cause of the death in hemodialysis (HD) patients. We quantitatively analyzed and evaluated the severity of abdominal aortic calcification in HD patients in comparison to risk factors for arteriosclerosis. METHODS: One hundred thirty-seven HD patients were examined. Using image analysis software, areas of the calcified abdominal aorta were quantitatively analyzed on plain computerized tomography images. Other factors such as blood pressure (BP), lipid levels, and calcium (Ca) x phosphorus (Pi) value were also analyzed. RESULTS: Patients with a higher one-year average of systolic BP showed a higher severity of abdominal aortic calcification. That is, the severity of abdominal aortic calcification in patients with a one-year systolic BP average above 160 mm Hg was 31.5 +/- 13.6%, and this severity was significantly higher than that in patients with a one-year systolic BP average of less than 120 mm Hg (8.0 +/- 7.7%, P < 0.01). The severity of abdominal aortic calcification in patients demonstrating risk values of ectopic calcification, that is serum Ca x Pi > or = 60 (mg/dl), on more than 4 of 24 measurements within one year (25.8 +/- 13.6%) was significantly higher than the severity of aortic calcification in patients demonstrating this value less than four times in one year (P < 0.05). There was no correlation between levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, lipoprotein(a), and severity of abdominal aortic calcification. CONCLUSIONS: Systolic BP levels and the product of serum Ca and Pi were related to the severity of abdominal aortic calcification in HD patients. These observations suggested that BP control, as well as control of serum Ca and Pi levels, was important in preventing the progression of abdominal aortic arteriosclerosis.

Spatio-temporally regulated expression of receptor tyrosine kinases, mRor1, mRor2, during mouse development: implications in development and function of the nervous system.

BACKGROUND: Drosophila neurospecific receptor tyrosine kinases (RTKs), Dror and Dnrk, as well as Ror1 and Ror2 RTKs, isolated from human neuroblastoma, have been identified as a structurally related novel family of RTKs (Ror-family RTKs). Thus far, little is known about the expression and function of mammalian Ror-family RTKs. RESULTS: We have identified murine Ror-family RTKs, mRor1 and mRor2. Both mRor1 and mRor2 genes are induced upon neuronal differentiation of P19EC cells. During neuronal differentiation in vitro, the expression of mRor2 is transiently induced, although that of mRor1 increases continuously. During embryogenesis, the mRor1 gene is expressed in the developing nervous system within restricted regions and in the developing lens epithelium. The expression of mRor1 is sustained in the nervous system and is also detected in non-neuronal tissues after birth. In contrast, the expression of mRor2 is detected mainly in the developing nervous system within broader regions and declines after birth. Possible relationships of mRor1 and mRor2 genes with previously identified mutants have also been examined. CONCLUSIONS: The developmental expressions of mRor1 and mRor2, in particular in the nervous system, are differentially regulated, reflecting their expression patterns in vitro. mRor1 and mRor2 may thus play differential roles during the development of the nervous system.

Beyond category sorting and pleasantness rating: inducing relational and item-specific processing.

In most studies of relational and item-specific processing, category sorting and pleasantness rating have been the main procedures used to induce these two types of processing. Because the two types of processing have been studied in a wide range of memory phenomena (Hunt & McDaniel, 1993), it is strange that other tasks have not been proposed and tested. The present experiment demonstrates that equivalent results can be obtained with three relational processing tasks (category sorting, narrative construction, and relational imagery) and equivalent results with three item-specific processing tasks (pleasantness ratings, familiarity ratings, and single imagery).

Enhanced myocardial preservation by nicotinic acid, an antilipolytic compound: mechanism of action.

The cardioprotective effects of an antilipolytic compound, nicotinic acid, on arrested-reperfused myocardium were investigated in the isolated in situ pig heart preparation. Hearts were preperfused for 15 min in the presence of (5-3H)-glucose and (U-14C)-palmitic acid. Half of the hearts were then perfused with 0.08 mM nicotinic acid for an additional 15-min period, while the remaining control hearts received unmodified perfusion. Arrest was then induced in all animals for 2 h using hypothermic K+ cardioplegia, followed by 60 min of normothermic reperfusion. In control hearts, there were significantly greater levels of long-chain acyl Co-A and acyl carnitine and lower levels of membrane phospholipids than in the nicotinic acid group. While nicotinic acid inhibited beta-oxidation during pre-ischemia and reperfusion, it also prevented the degradation of membrane phospholipids. The net result was a reduction of free fatty acid accumulation during arrest and reperfusion in the nicotinic acid group. Glycolysis, as reflected in 3H2O production, was significantly increased by nicotinic acid administration. In the control heart as compared to the nicotinic acid group, the incorporation of 14C-label from palmitate into triglyceride and cholesterol during arrest was enhanced, while incorporation into phospholipids was depressed. The cardioprotective effects of nicotinic acid were demonstrated by decreased release of creatine kinase and improved coronary blood flow, and cardiac contractility in the reperfused myocardium supplemented with nicotinic acid compared to the control group. These results suggest that nicotinic acid significantly protects the arrested-reperfused myocardium by a) preventing elevation of myocardial fatty acid levels, b) stimulating glycolysis by limiting fatty acid oxidation, c) inhibiting degradation of membrane phospholipids, and d) preventing accumulation of fatty acid metabolites with harmful detergent properties.