心カテ室で微小循環指標計測を如何に行うか?─ 2020 ARIA Abbott共催セッションより ─

 心外膜血管評価(FFR)だけでなく、CFR/IMRを始めとした微小循環評価を加えたtotal assessmentを通じて、より適切な患者マネジメントが可能となり、今後の治療戦略決定に重要な付加価値をもたらすことが期待される。本セッションでは、どのような患者に微小循環評価を行うことが臨床的に必要か、またどのような方法で測定するのか等、その全貌についてphysiology expertの先生方にご解説頂いた。

東京医科大学
八王子医療センター
田中信大先生
和歌山県立 医科大学
塩野泰紹先生

心カテ室で評価する
サロゲートマーカーとしての冠微小循環指標

室屋隆浩 先生
(佐世保市総合医療センター
)

普段我々が心カテ室で視認している冠動脈造影像は心臓を養っている血管のたかだか5%程度であり、残りの95%は冠微小循環から灌流されている。この冠微小循環は、毛細血管、前細動脈、細動脈から構成されており、毛細血管を除く前細動脈、細動脈においては、それぞれ異なる因子により拡張・収縮が調節されており、そ れ 以 外 に も Neural Factor、PhysicalFactorによって複雑に制御がなされている(図1)。 2013年度のESCガイドラインでは、代表的な冠微小循環指標であるCFR測定が経胸壁心エコー図検査において、左前下行枝(LAD)のみではあるもののClass IIb、 Level Cとして推奨されていた。2019年度になると、症状が持続する正常あるいはiwFR/FFRが保持された中等度狭窄病変に対するガイドワイヤーを用いたCFR測定がClass IIa、Level Bとして推奨され、より冠微小循環指標の測定が重要視されている。実際には心カテ室で冠微小循環指標を測定する際には、特殊なワイヤーを直接冠動脈内に挿入する必要がある。圧センサー付きドップラーセンサー、あるいは圧センサー付き温度センサーが従来用いられていたが、 現在は圧センサー付き温度センサーによる熱希釈法を用いた評価のみ使用可能となっている。 冠微小循環指標を求めるためには、安静時、最大充血状態での冠内圧と冠血流量の情報が必要であり、これらを組み合わせることによって冠微小循環指標は、サロゲートマーカーとして大変有用な指標となっている。

図1 Herrmann J et al: Coronary microvascular dysfunction in the clinical setting: from mystery to reality. Eur Heart J 2012; 33: 2772

 心カテ室で計測可能な主な冠微小循環指 標 を4つ:1冠 血 流 予 備 能(CFR)、2Coronary Flow Capacity (CFC)、3冠微小血管抵抗指標(IMR)、4Resistive ReserveRatio(RRR)を紹介する。


 ①CFRは、冠動脈遮断、あるいは薬剤を用いて冠微小循環を最大限に拡張することによって得られた状態での最大冠血流量を安静時冠血流量で割った値で求められる。つまり、心筋酸素消費量の増大に対し冠血流量を増加させ得る能力を表す指標ということになる。 普段心カテ室で評価しているFFRやResting indexは主に心外膜の冠動脈を検討する指標であるが、それに対してCFRは心外膜冠動脈と冠微小循環の二つを合わせ持った指標となる。そのためにCFRで冠微小循環のみを評価するためには心外膜冠動脈に問題がないことが条件となる。一般的にCFRが低下する病態としては、1. 最大充血時に心外膜冠動脈の血流を制限するような狭窄(>50%)が存在している、2. 安静時血流量が既に増加している、3. 最大充血時に冠血流の増加が抑制されている、 という3つのケースの組み合わせとなる。
 ②CFCは単体としての直接的な冠微小循環指標ではないものの、心筋虚血を考える上で大切な指標となっている。CFCはもともとPETシンチより得られた心筋虚血に対する考え方で、CFRとStress Flowの組み合わせから成り立っている。例としてCFRがある程度保持されていてもStressFlowが極度に低下する状態であると心筋虚血になり得る可能性があり、逆にCFRが低下していてもStress Flowが増加している状態であると心筋虚血になりにくい可能性がある。 また、Resting Flowの増加、あるいは減少によっても心筋虚血に多大な影響を与えていることもわかっている。
 ③冠微小血管抵抗指標は、最大充血状態で冠内圧を冠血流量で除した値となる。圧センサー付きドップラーセンサー法で測定した指標がHMR、圧センサー付き温度センサー法を用いた指標がIMRとなる。また微小血管抵抗指標を考える上での注意点として、虚血の程度が強い場合には側副血行路の影響を加味する必要がある。そのままの式を代用すると微小血管抵抗の値が本来の値より高めに出るため、側副血行路の影響が大きい場合には計算式の補正が必要となる。
 ④虚血性心疾患症例でFFRとCFRの関係を検討した研究1) で(図2)、3割を超える病変で不一致病変が認められた。 さらにFFRが0.8を超えるHigh FFR群、つまり心外膜冠動脈に有意狭窄がない病変群でのCFR、IMRの関係でも、3割を超える病変で不一致が認められた。CFR、IMRともに冠微小血管を検討する指標であるものの、それぞれ観察しているものが異なっているのではないかと示唆される。また、STEMI症例におけるIMRについても多く検討されており、40を超えたIMR値は死亡に対する独立した予測因子となっている。さらにCFRを組み入れることによって、よりリスク層別化が可能となり、鋭敏な指標になり得ることも報告されている。
 ⑤RRRは、心外膜冠動脈と冠微小血管の2つを合わせたvasodilatory capacityとして紹介されている。算出方法は、安静時の微小血管抵抗指標を最大充血状態での微小血管抵抗指標で除した値となる。個人的には心臓を養っている血管そのものの弾力性を検討する指標であると考えている。RRRを用いた中等度狭窄病変に対する予後評価報告では、RRR値が低下した群ではイベント発生率が上昇することが報告されている2)図3)。

図2 Lee JM et al: Coronary Flow Reserve and Microcirculatory Resistance in Patients WithIntermediate Coronary Stenosis. J Am Coll Cardiol. 2016; 67: 1158-1169
図3 Lee SH et al: Prognostic Implications of Resistive ReserveRatio in Patients With Coronary Artery Disease. J Am Heart Assoc. 2020; 9

 また同論文では、High CFR症例をRRRでリスク層別化すると、低RRR値の群、いわゆる微小血管の弾力性が失われた群において、有意にイベント発生率が上昇していることが報告されている。 以上より、冠微小循環指標は普段私たちが慣れ親しんだ環境である心カテ室で測定可能であり、しかも重要な予後予測因子となっている。今後、さらなるデータの蓄積、指標の組み合わせ、または新たな指標の登場等により、より有用なサロゲートマーカーとしての重要度が増す可能性が期待されている。

塩野 ありがとうございました。微小循環評価に関する沢山の指標をご紹介いただきました。症例による使い分けに関して室屋先生のお考えがありましたら教えてください。
室屋 心カテ室で安静時、最大充血状態での冠内圧と冠血流量を測定するだけで、様々な冠微小循環指標を求めることが可能で、さらにそれらを組み合わせることも可能です。個人的には、現時点で症例による使い分けは不明ですが、1つの指標だけを用いて予後評価を行うのは非常に難しく、指標の組み合わせや病態での評価を用いてリスク層別化した報告が今後もなされてくるのではと思っていますし、多いに期待をしています。

日常臨床におけるCFRとIMRについて
~冠微小循環の評価方法としてのCFR、IMR ~

村井典史 先生
(横須賀共済病院
)

 冠微小循環障害とは、500μm以下の微細な冠動脈の循環に生じる障害であり、障害により心筋虚血などの様々なトラブルが起こることが報告されている。冠微小循環は、冠血流の調節にとって重要な場所であり、様々なメカニズムによって冠血流を調節している。微小循環障害のメカニズムは多岐にわたるが、ひとつは必要とされる血流に対して応答できない機能的障害である。これは血管内皮障害や、平滑筋の異常といわれている。もうひとつは必要とされる血流を供給できない構造的障害、心筋疾患に伴う物理的な障害によって微小循環が生じうるということが報告されている(図4)。例えば心筋の肥大によって微小循環が圧迫される病態、微小循環自体の密度が減少する病気など様々なメカニズムで微小循環の障害が起こり得ることが報告されている。

図4 Kaski JC et al: Reappraisal of Ischemic Heart Disease. Circulation 2018; 138:1463-1480


 冠微小循環の評価方法は基本的には心筋を灌流する血流の評価が大事な要素であり、冠動脈のカテーテル検査時に圧力と血流を同時に評価することが可能であるが、特に圧力データの抽出には侵襲的な測定が必要となる。現在、冠循環全体を評価するCFRや微小循環に特化した微小循環抵抗指数(IMR)が考案され、日常 臨 床 で 使 用 可 能 で あ る。CFRは、1970年代のPETの研究からでてきた概念である。横軸に冠動脈の狭窄程度、縦軸にCFRを冠血流を置いた際に、狭窄がきつくなっても、安静時の血流は一定に保たれることが示された。これは狭窄がきつくなった際に、微小循環が徐々に開き、安静時の血流を一定に保つという自動調節能が働くためである。一方で最大充血時血流は、薬で微小循環を開き、その際に流れる血流を評価するが、冠動脈の狭窄が50%を超えた場合に影響を受けてしまうことが考えられる。CFRは安静時の血流が最大充血時にどの程度血流が増えるかを示しており、微小循環の拡張度合いによって変化する。微小循環の評価に使う際には、CFRのカット値はおよそ2.0~2.5のことが多い。心外膜血管の狭窄が50%を下回る場合は、冠動脈の微小循環の評価にCFRを用いることが可能であると考えられるが、CFRを微小循環の評価に使用するにはいくつか問題点がある。最大の問題点は、安静時の血流は緊張、血圧、貧血といった患者のコンディションによって影響を受けることだ。そこで冠動脈内圧と血流から算出される微小循環抵抗指数(IMR)が20年前から提唱され、日常臨床で使用されてきた。IMRは、冠動脈の遠位の圧力、つまり微小循環に加わる圧力であり、この圧力がかかった際にどのくらい血流が流れるのかを表したものである。日常臨床にて、IMR値の基準としては、25を超えると微小循環障害の度合いが高いと判断される。
 冠動脈疾患と微小循環障害について考えてみる。FFRは、冠動脈の病変の前後で生じる圧較差、エネルギーロスを測定しており、これは冠血流に大きく依存する。微小循環障害がある場合、微小循環で血流が流れないため冠血流が低下し、圧較差が下がり、FFRは高く算出され、病変を過小評価する可能性が報告されている。微小循環抵抗が高い症例でQFRとFFRのミスマッチが大きくなるという報告3)もあり、FFRの妥当性が疑われる場合には微小循環抵抗の確認をすることも有用であると思われる。TCT2020で発表されたDEFINE-FLOW studyの結果では、FFRは保たれており、CFRが低い症候群で予後が悪いという結果が示された。以前の研究からそのような群では、びまん性病変や微小循環障害の症例が多く含まれていると報告されている。FFR良好群をIMRとCFRでさらに群分けした韓国からの研究では、IMRが高くてCFRが悪い、すなわち微小循環が悪い群が他の群と比べてイベントが多い結果であった。さらに興味深いことに、これらのイベントはTarget vesselではなく、Non-targetvesselで多かった(図5)。つまり微小循環障害と冠動脈疾患には関係性があることが示唆されている。

図5  Lee JM et al: Coronary Flow Reserve and Microcirculatory Resistance in Patients With Intermediate Coronary Stenosis. J Am CollCardiol. 2016; 67: 1158-1169


 次に、冠動脈に狭窄を伴わない微小循環障害へのアプローチについて考えてみる。冠動脈の狭窄を伴わない胸痛のある患者を、病気がないと切り捨てるのではなく、その原因を追求していくことが重要になってきている。アセチルコリンによる負荷を行い、心外膜血管、微小血管のスパズムの有無の確認、最終的にアデノシン負荷によりCFRとIMRを用いて微小循環の異常をチェックするプロトコールが提唱されており、これは、CorMicATrialで先駆け的に行われた4)。現在利用できる評価指標は、CFR、IMR、アセチルコリン負荷の3つであるが、本来、微小循環障害は様々な原因で生じるため、この3つの指標だけでは評価しきれないと考えられる。微小循環障害のメカニズムは1つではないので、IMRの数値だけでどの治療薬が有効なのかは判断が難しい。少なくとも機能的な微小循環障害なのか、あるいは構造的な微小循環障害なのかを分けて検討する必要があると考えている。微小血管狭心症だけではなく、心不全、心筋障害にも微小循環障害が関わっているという報告もあるため、今後多様な心疾患において、微小循環障害の診断から治療までのエビデンスを作っていくことが重要であると考えられる。

塩野 村井先生ありがとうございました。IMRの異常値25ということですが、使い慣れていない方のために正常値を教えていただけないでしょうか。
村井 だいたい中央値が15~20なので、おそらく20未満だったら大丈夫だと認識しております。

<文献>
1) Lee JM et al: Coronary Flow Reserve and
Microcirculatory Resistance in Patients
With Intermediate Coronary Stenosis. J Am
Coll Cardiol. 2016; 67: 1158-1169
2) Lee SH et al: Prognostic Implications of
Resistive Reserve Ratio in Patients With
Coronary Artery Disease. J Am Heart
Assoc. 2020; 9
3) Mejía-Rentería H et al: Influence of
Microcirculatory Dysfunction on
Angiography-Based Functional Assessment
of Coronary Stenoses. JACC Cardiovasc
Interv 2018; 11: 741-753
4) Ford TJ et al: Stratified Medical Therapy
Using Invasive Coronary Function Testing
in Angina: The CorMicA Trial. JACC 2018;
72: 2841-2855

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