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肥満が心機能に与える影響についての検討

澤田, 直子 東京大学 DOI:10.15083/0002002402

2021.10.13

概要

心不全は悪性腫瘍に次いで本邦の死因第2位である。左室収縮の保持された心不全はHeart failure with preserved ejection fraction (HFpEF)と呼ばれ、その主な病態は、左室拡張障害と考えられている。HFpEFは心不全患者全体の約半数を占めるが、左室収縮の低下した心不全と異なり、死亡率や罹患率を低下させるような治療法で確立されたものはいまだない。そのため、臨床像を明らかにして、予防することが重要である。

肥満はHFpEFの重要なリスクファクターであることが報告されている。肥満、特に内臓脂肪蓄積と様々な健康障害との関連が知られており、その機序に内臓脂肪蓄積に伴う各種アディポサイトカインの産生・分泌異常の関与が疑われている。そのうちアディポネクチンは、心肥大抑制、線維化抑制、抗酸化、抗動脈硬化、抗炎症などの心保護作用を持ち、内臓脂肪蓄積に伴い産生が減少する善玉アディポサイトカインである。低アディポネクチン血症群で心血管イベントが多いという報告があるが、左室拡張能と内臓脂肪、アディポネクチンの関連を調べた研究は少ない。研究１では当院検診部を受診した心疾患のない健常人213名を対象に、内臓脂肪蓄積が左室拡張能にどの程度影響するのか、さらにその機序に低アディポネクチン血症が関連するかどうかについて検討した。一般的な身体所見や臨床背景、血液検査項目に加え、血清アディポネクチン総量を測定した。左室拡張能は経胸壁心エコーを用いて、左室流入血流速波形（急速流入期血流速波形（E波）と心房収縮期血流速波形（A波）の比であるE/A）と、僧帽弁輪拡張早期運動速度（e’）と、Eをe’で除した左室充満圧の指標であるE/e’の3項目を評価した。内臓脂肪は腹部CTで定量評価した。その結果、内臓脂肪増加は左室拡張能指標の低下と相関し（e’；r=-0.39、p<0.001、E/A；r=-0.38、p<0.001、E/e’；r=0.29、p<0.001）、内臓脂肪面積は年齢と並んで左室拡張能の独立規定因子であった（e’；β=-017、p=0.025、E/e’；β=0.16、p=0.012、E/A；β=-0.17、p=0.019）。一方で、アディポネクチンは左室拡張能指標との相関関係は認めなかった。心疾患のない健常人において内臓脂肪増加は左室拡張能低下と関わるということが判明したが、アディポネクチンはその主体ではなかった。その要因として、内臓脂肪はアディポネクチンのみならず他のアディポサイトカインも分泌しており、それらとのバランスや相互作用が影響している可能性が考えられる。内臓脂肪型肥満の進行に伴い、善玉アディポサイトカインであるアディポネクチンは低下し、悪玉アディポサイトカインであるTNF-αやMCP-1は上昇する。それらが脂肪組織の慢性炎症やインスリン抵抗性を惹起し、各種アディポサイトカインの血管への作用が加わることで、糖尿病や高血圧、脂質異常症が生じると考えられている。様々なアディポサイトカインを介した機序を考慮する必要がある。

また、近年右室機能が着目されている。回転楕円形である左室と比較して、右室は三角錐状の複雑な形態をしており、また低圧環境のため周囲の影響を受けやすいことから、これまで評価が困難とされてきた。近年画像診断の進歩に伴い、心臓MRIや経胸壁心エコーでの右室機能評価が可能となり、右室機能が様々な心疾患の予後規定因子であることが判明してきた。最近ではHFpEFにおいて右室機能が死亡率や再入院率に関連していたという報告もある。右室機能評価法のゴールデンスタンダードは心臓MRIであるが、経胸壁心エコーの右室機能指標は心臓MRIの計測値と良好な相関関係を示し、その中でもRVLS（right ventricular longitudinal strain）が最も有用であったとの報告がある。strainとは、組織の歪み・変形といった意味であり、Bモードエコー画像上の小斑点（speckle）を追跡することで、局所心筋自体の伸び縮みを評価できる。健常者において長軸方向のstrainは負の値をとり、その絶対値が大きいほど良好な収縮を示すことになる。虚血性心疾患や心不全患者において、収縮期のピーク速度であるRVLSの絶対値が低い群は予後不良であったとの報告がある。また、肥満が進行すると、右室収縮能が低下し右室容積が大きくなるとともに、RVLSの絶対値は小さくなることが報告されている。研究２では、当院検診部を受診した心疾患のない健常人102名を対象に、内臓脂肪蓄積が潜在的な右室機能低下に関与するかどうかを検討した。内臓脂肪は腹部CTで定量評価し、右室機能は経胸壁心エコーでRVLSに加え、従来指標である三尖弁輪の収縮期移動距離（TAPSE: tricuspid annular plane systolic excursion）、右室面積変化率（RVFAC: right ventricular fractional area change）、三尖弁収縮期弁輪部移動距離速度（RV-s’）の4項目を評価した。その結果、内臓脂肪の蓄積に伴い右室機能指標は低下し（RVLS；r=0.36、p<0.001、TAPSE；r=-0.24、p=0.015、RVFAC；r=-0.19、p=0.050、RV-s’；r=-0.22、p=0.024）、さらに心血管リスクとは独立して、内臓脂肪は右室機能に影響を与えていることが示された（内臓脂肪面積；β=0.27、p=0.0062）。アディポネクチンは右室機能指標と有意な相関関係は認めなかった。今回の結果より、内臓脂肪蓄積の影響は、これまで報告されていた左室だけでなく、右室にも影響を及ぼすことが示唆された。その機序として、先に述べたような内臓脂肪蓄積に伴う慢性炎症や、各種アディポサイトカインの異常分泌による耐糖能異常、血圧上昇、動脈硬化などが考えられるが、今回検討したアディポネクチンとは明らかな関連がなく、様々な因子を総合的に検討する必要があるといえる。

内臓脂肪を減少させる治療を行うことで、左室拡張能や右室機能を改善することができる可能性がある。今後は内臓脂肪量の継時的な変化と、左室拡張能指標や右室機能指標の関係を前向きに追跡することで、心疾患の予防や治療法の発見に貢献できるかもしれない。また、肥満の進行により、アディポネクチンだけでなく様々なアディポサイトカインの分泌異常が生じるため、それらの検討も行うことで内臓脂肪蓄積による心疾患増加の機序に迫ることが出来る可能性がある。

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