Fumio Okamoto

Human Heart-Type Cytoplasmic Fatty Acid-Binding Protein (H-FABP) for the Diagnosis of Acute Myocardial Infarction. Clinical Evaluation of H-FABP in Comparison with Myoglobin and Creatine Kinase Isoenzyme MB

Abstract Heart-type fatty acid-binding protein (H-FABP) is a low molecular weight cytoplasmic protein and present abundantly in the myocardium. When the myocardium is injured, as in the case of myocardial infarction, low molecular weight cytoplasmic proteins including H-FABP are released into the circulation and H-FABP is detectable in a blood sample. We have already developed a direct sandwich-ELISA for quantification of human H-FABP using two distinct types of monoclonal antibodies specific for human H-FABP. In this study we investigated the clinical validity of H-FABP as a biochemical diagnostic marker in the early phase of acute myocardial infarction (AMI). To evaluate the diagnostic usefulness of H-FABP in the early phase of AMI, blood samples were obtained from the following patients within 12 hours after the appearance of symptoms, and serum levels of H-FABP were compared with those of conventional diagnostic markers, such as myoglobin and creatine kinase isoenzyme MB (CK-MB). Blood samples were collected from patients with confirmed AMI (n=140), patients with chest pain who were afterwards not classified as AMI by normal CK-MB levels (non-AMI) (n=49) and normal healthy volunteers (n=75). The serum concentration of H-FABP was quantified with our direct sandwich-ELISA. The concentration of myoglobin mass was measured with a commercial RIA kit. The serum CK-MB activity was determined with an immuno-inhibition assay kit. The overall sensitivity of H-FA B P, within 12 hours after the appearance of symptoms, was 92.9%, while it was 88.6% with myoglobin and 18.6% with CK-MB. The overall specificity of H-FABP was 67.3%, while it was 57.1% with myoglobin and 98.0% with CK-MB. The diagnostic efficacy rates with these markers were 86.2% (H-FABP), 80.4% (myoglobin) and 39.2% (CK-MB), respectively. The diagnostic validity of H-FABP was further assessed by receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC) of H-FABP was 0.921, which was significantly greater than with myoglobin (AUC: 0.843) and CK-MB (AUC: 0.654). These parameters, such as sensitivity, specificity, diagnostic efficacy and diagnostic accuracy, obtained for patients with chest pain within 3 hours and/or 6 hours after the onset of symptoms were almost the same as those for patients within 12 hours after symptoms. H-FABP is more sensitive than both myoglobin and CK-MB, more specific than myoglobin for detecting AMI within 12 hours after the onset of symptoms, and shows the highest values for both diagnostic efficacy and ROC curve analysis. Thus, H-FABP has great potential as an excellent biochemical cardiac marker for the diagnosis of AMI in the early phase.

CD36 mediates long-chain fatty acid transport in human myocardium: Complete myocardial accumulation defect of radiolabeled long-chain fatty acid analog in subjects with CD36 deficiency

Long-chain fatty acids (LCFA) are the major energy substrate for heart and their oxidation is important for achieving maximal cardiac work. However, the mechanism of uptake of LCFA by myocardium has not been clarified. We previously reported that bovine myocardial LCFA transporter has a sequence homology to human CD36. Clinically, total defect of myocardial uptake of radiolabeled long-chain fatty acid analog [123I-BMIPP: Iodine-123 15-(p-iodophenyl)-(R,S)-methylpentadecanoic acid] has been reported in some restricted cases, but the etiology has not been clarified. In the present study, we analyzed CD36 expression and CD36 gene in subjects who showed total lack of myocardial 123I-BMIPP accumulation, and, vice versa, evaluated myocardial 123I-BMIPP uptake in subjects with CD36 deficiency. Four unrelated subjects were evaluated; Two were found to have negative myocardial LCFA accumulation by 123I-BMIPP scintigraphy, after which the expression of CD36 on their platelets and monocytes was analyzed. Remaining two subjects were identified as CD36 deficiency by screening, then 123I-BMIPP scintigraphy was performed. Expression of CD36 on platelets and monocytes was measured by flow cytometric analysis. The molecular defects responsible for CD36 deficiency was detected by allele-specific restriction enzyme analysis. CD36 expression was totally deficient in all 4 subjects on both platelets and monocytes. Two subjects were homozygous for a 478C→T mutation. One was heterozygous for the dinucleotide deletion of exon V and single nucleotide insertion of exon X, and remaining one was considered to be heterozygous for the dinucleotide deletion of exon V and an unknown gene abnormality. All cases demonstrated a completely negative accumulation of myocardial LCFA despite of normal myocardial perfusion, which was evaluated by thallium scintigraphy. In addition, all cases demonstrated apparently normal hepatic LCFA accumulation Thus, these findings suggested that CD36 acts as a major myocardial specific LCFA transporter in humans.

Human heart-type cytoplasmic fatty acid-binding protein as an indicator of acute myocardial infarction

SummaryHuman heart-type cytoplasmic fatty acid-binding protein (HH-FABPc) has been proposed as an early biochemical indicator of acute myocardial infarction (AMI). However, skeletal muscles also contain HH-FABPc identical to that found in the heart. Before HH-FABPc can be clinically employed as an indicator of AMI, its content in various tissues other than the heart must be known. Accordingly, we measured the HH-FABPc content of various human muscles and organs, using a sandwich enzyme-linked immunosorbent assay (ELISA) for HH-FABPc. HH-FABPc was abundant in the ventricles (0.46 mg/g wet weight and 1.5% of the cytoplasmic protein in the left ventricle), while the atria contained slightly less HH-FABPc (0.25 mg/g wet weight and 0.7% of the cytoplasmic protein in the left atrium). Of the skeletal muscles tested, the diaphragm contained about one-quarter of the HH-FABPc content of the heart, but other skeletal muscles contained very low levels of this protein. Other than the muscles, the kidneys contained less than one-tenth of the HH-FABPc in the heart, and negligible amounts were found in the liver and small intestine. The distribution of HH-FABPc in the heart and skeletal muscles was comparable to that of cardiac-specific creatine kinase (CK-MB) activity, and was inverse to the distribution of myoglobin. The plasma myoglobin/HH-FABPc ratio, determined in patients with AMI and those without AMI, closely reflected that in the heart and skeletal muscles. These findings indicate that HH-FABPc may be useful as a specific indicator of AMI, and the plasma myoglobin/HH-FABPc ratio could provide valuable information for the diagnosis of AMI.

Effect of sulfo-N-succinimidyl palmitate on the rat heart: Myocardial long-chain fatty acid uptake and cardiac hypertrophy

Abnormal long-chain fatty acid metabolism has been suggested as having a role in the genesis of certain cardiac diseases, and depressed myocardial long-chain fatty acid uptake has been clinically demonstrated in some patients with hypertrophic cardiomyopathy. However, the site where long-chain fatty acid metabolism is affected in cardiomyopathy remains unclear. Although cardiac hypertrophy is reported to be induced in rats by a fat-free diet, little is known of the consequences of depressed myocardial long-chain fatty acid uptake. Sulfo-N-succinimidyl derivatives of long-chain fatty acids have been shown to irreversibly inhibit long-chain fatty acid transport. To investigate the possible linkage of abnormal long-chain fatty acid uptake with cardiac hypertrophy, myocardial long-chain fatty acid uptake was blocked in rats using a sulfo-N-succinimidyl derivative of palmitate (SSP). SSP was intraperitoneally administered to rats for 12 weeks, and its effects on physiological parameters, and cardiac morphology were studied, SSP treatment (20 mg/kg) caused a 12% increase in heart weight (663.7 +/- 33.6 mg in controls v 741.2 +/- 26.5 mg after SSP treatment) and an 11% increase in the heart weight to body weight ratio (2.46 +/- 0.10 in controls v 2.72 +/- 0.17 after SSP) without any significant change of body weight. No significant differences were observed in blood pressure, heart rate, and serum hormones (insulin and triiodothyronine) between the control and SSP-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Right ventricular outflow tract prosthesis in total correction of tetralogy of Fallot.

Right ventricular outflow tract obstruction was relieved by placing outflow patches across the pulmonary annulus in 39 of 195 patients who underwent total correction of tetralogy of Fallot. The mortality rate in these 39 patients was 12.8%, which did not differ significantly from the overall mortality of 11.3% (p = 1.00). The ratio of the pulse pressure to pulmonary artery systolic pressure as an index of pulmonary insufficiency was dependent on the cross-sectional area index (CSAI) of the pulmonary annulus after enlargement, as shown in the regression equation Y = I - 0.63/(X - 0.07) (r = 0.79, p <0.05). When the CSAI was 2.5 cm2/m2 or less and a single cusp was mounted on the outflow patch, the pulmonary insufficiency was negligible and the right ventricular end-diastolic pressure was 10 mm Hg or less. In patients without outflow patches, the right ventricular-to-pulmonary arterial systolic pressure gradient and the right ventricular-toaortic systolic pressure ratio 1 month after surgery was dependent on the CSAI, as shown in the regression equations Y = 54.0/X2 + 5.6 (r = 0.76, p < 0.01) and Y = 0.42/X2 + 0.36 (r = 0.72, p < 0.01), respectively. These two equations may also be applied in the case of patients with outflow patches with a single cusp. Thus, when the outflow patch is used, the CSAI must be larger than 1.75 cm2/m2 and less than 2.5 cm2/m2, and a single cusp should be mounted on the outflow patch.

Successful surgical repair of truncus arteriosus with interrupted aortic arch in infancy by an anterior approach

A 98-day-old infant was successfully operated on for truncus arteriosus (type I) with interrupted aortic arch (type B) using a one-stage anterior approach. The interrupted aortic arch was reconstructed by direct anastomosis between the ascending and descending aorta. The ventricular septal defect was closed, and a 12-mm porcine valved conduit was placed on the right side of the ascending aorta to establish continuity between the right ventricle and pulmonary artery. Surgical procedures for the repair of this malformation are the focus of discussion.

A brimmed valved conduit in repair of fibrous skeleton abscess

Aortomitral common annular involvement, which is not uncommon in infective endocarditis, necessitates deliberate surgical procedures. To repair fibrous skeleton abscess accompanied with annuloaortic ectasia, we used a brimmed valved conduit. Tension-free reconstruction of the aortic root and aortomitral common annulus was easily performed with this method.

New modification of the Damus-Kaye-Stansel operation

We report a successful modification of the Damus-Kaye-Stansel operation for transposition of the great arteries when the coronary arteries are unsuitable for transfer. The procedure includes creation of a neoaorta with end-to-end anastomosis of the proximal pulmonary artery to the distal ascending aorta and creation of an aortopulmonary window between the proximal great arteries. A valved conduit is interposed between the right ventricle and the distal pulmonary artery.

Pulmonary stenosis after arterial switch operation for complete transposition of the great arteries(TGA).

近年,完全大血管転位症に対する動脈側スイッチ手術後,最も多くみられる合併症として肺動脈狭窄の発生が報告されている.われわれも12例の遠隔生存中4例に対し,進行性の肺動脈狭窄のため再手術を施行した.初回手術から再手術までの期間は平均2年6ヵ月であった.吻合部の狭小化または肺動脈絞扼部の発育不全による弁上狭窄を全例に認め,分岐部狭窄,弁狭窄を各1例に認めた.再手術は2例においてtransannular patchによる右室流出路再建,他の2例では主肺動脈,分岐部のパッチ拡大を行った.再手術による死亡はないが,再手術後も全例,軽度～中等度の圧較差が残存した.遠隔期の肺動脈狭窄は初回手術時の術式に起因する部分が大きいと思われ,最近では大血管の吻合を全周外面からのU字縫合とすること,冠動脈の移植に際しては,Valsalva洞の組織を可及的に温存したうえ,補綴には自己心膜を用いること,など術式の改良を試みている.