ヘテロ接合体性家族性高コレステロール血症とコレステリルエステル転送蛋白欠損症の合併例の血清リポ蛋白および臨床像に関する研究

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1178号, 学位授与年月日：平成7年3月25日,学位授与年：199

Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol

金沢大学大学院医学系研究科病態検査学Genetic determinants of HDL cholesterol (HDL-C) levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G(+1)-to-A mutation(Int14 A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C ≥ 100 mg/dl (n = 130) were screened by PCR single strand conformational polymorphism analysis of the CETP gene. Two other mutations were identified by DNA sequencing or primer-mediated restriction map modification of PCR products: a novel intron 14 splice donor site mutation caused by a T insertion at position +3 from the exon14/intron14 boundary (Int14 T) and a missense mutation (Asp442 to Gly) within exon 15 (D442G). The Int14 T mutation was only found in one family. However, the D442G and Int14 A mutations were highly prevalent in subjects with HDL-C ≥ 60 mg/dl, with combined allele frequencies of 9%, 12%, 21%, and 43% for HDL-C 60-79, 80-99, 100-119, and ≥ 120 mg/dl, respectively. Furthermore, prevalences of the D442G and Int14 A mutations were extremely high in a general sample of Japanese men (n = 236), with heterozygote frequencies of 7% and 2%, respectively. These two mutations accounted for about 10% of the total variance of HDL-C in this population. The phenotype in a genetic compound heterozygote (Int14 T and Int14 A) was similar to that of Int14 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Int14 T produces a null allele. In four D442G homozygotes, mean HDL-C levels (86±26 mg/dl) were lower than in Int14 A homozygotes (158±35 mg/dl), reflecting residual CETP activity in plasma. In 47 D442G heterozygotes, mean HDL-C levels were 91±23 mg/dl, similar to the level in D442G homozygotes, and significantly greater than mean HDL-C levels in Int14 A heterozygotes (69±15 mg/dl). Thus, the D442G mutation acts differently to the null mutations with weaker effects on HDL in the homozygous state and stronger effects in the heterozygotes, suggesting dominant expression of a partially defective allele. CETP deficiency, reflecting two prevalent mutations (D442G and Int14 A), is the first example of a genetic deficiency state which is sufficiently common to explain a significant fraction of the variation in HDL-C in the general population

Progressed Multivessel Spontaneous Coronary Artery Dissection That Naturally Healed in a Male Patient with Non-ST Segment Elevation Myocardial Infarction

Spontaneous coronary artery dissection (SCAD) is a rare condition that may have a serious outcome because of acute coronary syndrome. The condition especially affects young women. We evaluated a middle-aged male patient with a non-ST segment elevation myocardial infarction caused by multivessel SCAD. The SCAD had occurred in the distal right coronary artery (RCA), the mid left anterior descending artery (LAD), and the distal LAD at the same time. His culprit lesion was in the distal RCA, but the SCAD had progressed more proximally within the RCA 12 days later with no clinical symptoms. We treated the mid LAD with implantation of a drug-eluting stent on admission and the SCAD had not progressed 12 days later. Moreover, the SCAD in the distal RCA and distal LAD healed spontaneously 12 days later. He had no recurrent attack, and all SCAD lesions of the RCA and LAD had completely healed 6 months later. Given that SCAD appears in various forms over the clinical course, a strategy of intervention needs careful consideration

Increased heart rate caused by atrial pacing with the closed-loop stimulation function prevented micturition syncope

A 70-year-old man had been experiencing syncope several times a year. We implanted a DDD pacemaker with closed-loop stimulation (CLS) function. When he urinated early in the morning, his increased atrial pacing rates elevated his heart rate (HR) during and after micturition. After implantation of the DDD-CLS mode, he did not experience symptoms. In contrast, in the DDD-R mode, his intrinsic HR changed to atrial pacing after micturition but decreased to the basal rate within 2 min, and he experienced a sense of cold perspiration and presyncope. Increased HRs caused by atrial pacing with the CLS function were useful in the prevention of micturition syncope