Research in molecular and genetic epidemiology of hypertrophic cardiomyopathy and other cardiomyopathies

• Project/Area Number: 17K09082
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Epidemiology and preventive medicine
• Research Institution: Kanazawa University
• Principal Investigator: FUJINO Noboru 金沢大学, 保健学系, 准教授 (40361993)
• Co-Investigator(Kenkyū-buntansha): 林 研至 金沢大学, 附属病院, 助教 (00422642) ; 山岸 正和 金沢大学, 医学系, 協力研究員 (70393238)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肥大型心筋症 / 遺伝子解析 / 次世代シークエンサー / 心筋線維化 / 心臓MRI / 拡張型心筋症 / 心不全 / 不整脈 / 突然死 / 特発性心疾患 / 左室収縮不全 / 直接シークエンス法 / 全エクソームシークエンス法 / 左室拡張機能障害 / 非弁膜症性心房細動 / 血栓塞栓症 / 抗凝固療法 / 収縮不全 / 社会医学 / 遺伝学 / 循環器・高血圧 / 遺伝子 / 内科

Outline of Final Research Achievements

Cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) revealed a variation in the extent of myocardial scarring, a pathological hallmark of hypertrophic cardiomyopathy (HCM). We aimed to investigate whether variations in the extent of LGE in HCM patients can be explained by the presence or absence of disease-causing mutations. We analyzed data from 82 unrelated HCM patients who underwent both LGE-CMR and next-generation sequencing. We identified disease-causing sarcomere gene mutations in 44 cases (54%). The extent of LGE on CMR was an independent factor for predicting mutation-positive HCM (odds ratio 2.12 [95% confidence interval 1.5-3.8], P<0.01). The area under the curve of %LGE was greater than that of the conventional Toronto score for predicting the presence of a mutation (0.96 vs. 0.69, P<0.01). Sensitivity, specificity, positive predictive value, and negative predictive value of %LGE (cutoff >8.1%) were 93.2%, 89.5%, 91.1%, and 91.9%, respectively.

Academic Significance and Societal Importance of the Research Achievements

肥大型心筋症（HCM）の一部は、心筋線維化と収縮不全をきたす。HCMの原因は心筋サルコメア遺伝子の変異で、原因遺伝子による臨床病型の違いが報告されている。最近、心臓MRIガドリニウム遅延造影（LGE）により、HCMの本態である心筋線維化が検出可能となった。本研究では、LGEの定量的評価により遺伝子変異の存在が予測可能か否かを検証した。HCM症例を対象として原因遺伝子と心臓MRI所見を解析した結果、%LGEの上昇は、原因遺伝子変異の存在を予測する独立した因子であった。本研究成果から、臨床的に汎用されている心臓MRI検査により、HCM症例における原因遺伝子変異の存在を予測できる可能性が示された。

Research Products

• [Journal Article] Impact of cardiac myosin light chain kinase gene mutation on development of dilated cardiomyopathy (2019)
  • Author(s): Hodatsu A, Fujino N, Uyama Y, Tsukamoto O, Imai-Okazaki A, Yamazaki S, Seguchi O, Konno T, Hayashi K, Kawashiri MA, Asano Y, Kitakaze M, Takashima S, Yamagishi M
  • Journal Title: ESC Heart Fail. Volume: 6 Pages: 06-415
  • DOI: 10.1002/ehf2.12410
  • Peer Reviewed / Open Access
• [Journal Article] Effect of hypertrophic cardiomyopathy on the prediction of thromboembolism in patients with nonvalvular atrial fibrillation (2019)
  • Author(s): Tsuda T, Hayashi K, Fujino N, Konno T, Tada H, Nomura A, Tanaka Y, Sakata K, Furusho H, Takamura M, Kawashiri MA, Yamagishi M; Hokuriku-Plus AF Registry Investigators.
  • Journal Title: Heart Rhythm. Volume: 印刷中 Pages: 829-837
  • DOI: 10.1016/j.hrthm.2018.11.029
  • Peer Reviewed
• [Journal Article] Late Gadolinium Enhancement for Prediction of Mutation-Positive Hypertrophic Cardiomyopathy on the Basis of Panel-Wide Sequencing (2018)
  • Author(s): Teramoto R, Fujino N, Konno T, Nomura A, Nagata Y, Tsuda T, Tada H, Sakata K, Yamagishi M, Hayashi K, Kawashiri MA.
  • Journal Title: Circ J Volume: 82 Issue: 4 Pages: 1139-1148
  • DOI: 10.1253/circj.cj-17-1012 10.1253/circj.CJ-17-1012
  • NAID: 130006528636
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access