急性心筋炎の治療戦略

急性心筋炎を疑ったら軽症でも入院のうえ、治療に臨む必要がある。心室性不整脈に対しては薬物治療を、除脈性不整脈には一時的ペーシングを行う。心不全を合併していれば、その重症度に従い治療を開始する。軽症であれば日本循環器学会の急性心不全治療ガイドラインに従い内服治療を開始する。中等症以上であれば、経静脈心血管作動薬を用い治療する。組織型により、適宜、ステロイドパルス療法や大量免疫グロブリン療法を追加する。さらに重症化するようであれば補助循環も考慮する。
DOA, ドパミン；DOB, ドブタミン；NAd, ノルアドレナリン; NTG, ニトログリセリン; hANP,ハンプ
IABP, 大動脈内バルーンパンピング; IMPELLA, 補助循環ポンプカテーテル; ECMO, 体外式膜型人工肺（心肺補助）; BiVAD, 両心室補助人工心臓; LVAD, 左室補助人工心臓
出典
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1: 著者提供

心筋炎の概念図

（注）これまで本邦と欧米との間で、慢性経過した心筋炎（慢性心筋炎、慢性炎症性心筋症、炎症性拡張型心筋症など）の概念・定義が統一されておらず混乱が生じている。したがって、最近の国際ステートメントに準じて本ガイドラインでは下記に修正している。
1）従来の慢性心筋炎は慢性活動性心筋炎と再定義する。
2）急性と慢性の境界を3カ月から30日と再定義する。

心筋炎の分類

発病初期に心筋生検を行えば組織診断に基づいた治療計画を立てることができるが、実際には発病初期には心筋生検が困難である症例や正確な組織診断が難しい症例もある。
 

心筋炎の定義

心筋炎は1）発症からの期間、2）心筋組織における炎症、3）近接する心筋細胞障害の有無に基づいて5型に分類される。
 

国内外ガイドライン・ステートメント・エキスパートコンセンサスにおける心筋炎の定義とその変遷

参考文献：
1) JCS Joint Working Group. Guidelines for diagnosis and treatment of myocarditis (JCS 2009): digest version. Circ J 2011 ; 7 5 :734-743. PMID: 21304213
2) Ammirati E, Frigerio M, Adler ED, et al. Management of acute myocarditis and chronic inflammatory cardiomyopathy: an expert consensus document. Circ Heart Fail 2020; 13: e007405. PMID:33176455
3) Caforio AL, Pankuweit S, Arbustini E, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2013; 34: 2636-2648. PMID: 23824828
 

心筋炎診断における診察と病歴聴取の推奨とエビデンスレベル

心筋炎診断における心電図の推奨とエビデンスレベル

急性心筋炎を発症した好酸球性多発血管炎性肉芽腫症の心電図

（A）急性炎症期の心電図では、胸部誘導（V3）に異常Q波（矢頭）、左軸偏位に加えて下肢誘導でrSパターン（矢印）が認められ、左脚前枝ブロックと診断された。
（B）抗炎症治療後の心電図では、入院時に認めたいずれの心電図異常も正常化している。
出典
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1: The Diagnostic Challenge of Eosinophilic Granulomatosis With Polyangiitis Presenting as Acute Eosinophilic Myocarditis: Case Report and Literature Review.
著者: Hiroyuki Yamamoto, Katsuya Hashimoto, Yoshihiko Ikeda, Jun Isogai, Toru Hashimoto
雑誌名: Front Cardiovasc Med. 2022;9:913724. doi: 10.3389/fcvm.2022.913724. Epub 2022 Jul 7.
Abstract/Text: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis involving small-to-medium-sized vessels characterized by asthma, vasculitis, and peripheral eosinophilia. EGPA-associated eosinophilic myocarditis (EM) occurs rarely, yet can be fatal if left untreated. Moreover, the accurate diagnosis of EGPA-associated EM without vasculitis is exceptionally difficult because of the overlapping features with EM of other causes. We report a case of probable EGPA with subclinical neurological involvement that presented with acute EM. The constellation of peripheral eosinophilia, left ventricular dysfunction, and normal epicardial coronary arteries raised suspicion of acute EM, which was confirmed by cardiac magnetic resonance (CMR) investigation and endomyocardial biopsy (EMB). Prompt systemic administration of corticosteroids completely restored and normalized myocardial structure and function. Although the patient's history suggested the presumed hypersensitivity myocarditis, EMB revealed EM without vasculitis, not hypersensitivity, leading to a tentative diagnosis of idiopathic hypereosinophilic syndrome. Interestingly, the characteristic findings of vasculitis on CMR imaging strongly suggested EGPA-associated EM. Although the patient had no clinical neurological manifestations, a nerve conduction study confirmed mononeuritis multiplex, leading to the final diagnosis of probable EGPA. Therefore, this case highlights the diagnostic challenge associated with EGPA and the diagnostic synergy of CMR and EMB for an exploratory diagnosis of EGPA-associated EM.

Copyright © 2022 Yamamoto, Hashimoto, Ikeda, Isogai and Hashimoto.
Front Cardiovasc Med. 2022;9:913724. doi: 10.3389/fcvm.2022.913724. Ep...

心筋炎診断における血液検査の推奨とエビデンスレベル

急性心筋炎の心エコー図

A、C：傍胸骨左室長軸像、B、D：短軸像
A、B：急性期の心エコーでは左室壁のびまん性壁肥厚に伴って左室内腔の狭小化と軽度心嚢液貯留を認める。壁運動低下も軽度低下している（LVEF 52％）。
C、D：ステロイド治療後の心エコーでは、入院時に認めていた左室のびまん性浮腫状壁肥厚の改善とともに壁運動も著明に改善している（LVEF 72％）。
LA, 左房; LV, 左室; RV, 右室; LVEF, 左室駆出率
出典
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1: Case Report: Acute Eosinophilic Myocarditis With a Low-Flow Heart Failure With Preserved Ejection Fraction Phenotype.
著者: Hiroto Aota, Hiroyuki Yamamoto, Jun Isogai, Kyoko Imanaka-Yoshida, Michiaki Hiroe, Takahiro Tanaka
雑誌名: Front Cardiovasc Med. 2021;8:678973. doi: 10.3389/fcvm.2021.678973. Epub 2021 Jun 23.
Abstract/Text: Eosinophilic myocarditis is a rare subtype of myocarditis characterized by myocardial eosinophilic infiltration, and it is potentially fatal if left untreated. Although endomyocardial biopsy (EMB) is a cornerstone for the histological diagnosis of acute eosinophilic myocarditis (AEM), as it is an invasive procedure and has a low diagnostic accuracy, the diagnosis of AEM with hemodynamic instability remains challenging. We describe a case of AEM presenting as low-flow heart failure with preserved ejection fraction (HFpEF), with rapid progression to cardiogenic shock. The constellation of peripheral eosinophilia, increased left ventricular wall thickness, and HFpEF raised the suspicion of AEM. Contrast-enhanced computed tomography (CT) scan revealed heterogeneous hypoenhancement localized in the basal-to-mid septal and mid anterolateral walls of the left ventricle, strongly suggestive of acute inflammation. Based upon these findings, we performed CT-guided EMB, which lead to a definitive diagnosis. Subsequent high-dose corticosteroids allowed a rapid and dramatic recovery and normalization of cardiac structure and function. This case highlights the clinical importance of assessing AEM as a rare cause of HFpEF and the usefulness of CT-guided EMB in patients with hemodynamic instability.

Copyright © 2021 Aota, Yamamoto, Isogai, Imanaka-Yoshida, Hiroe and Tanaka.
Front Cardiovasc Med. 2021;8:678973. doi: 10.3389/fcvm.2021.678973. Ep...

心筋炎診断における心エコー図検査の推奨とエビデンスレベル

心臓MRI（CMR）による急性心筋炎診断基準（2018年改訂版Lake Louise Criteria）

肺炎球菌ワクチン接種後に生じた急性心筋炎の心臓MRI検査

急性期（A-D）と治療後（E-H）。
A：CINE画像(（4腔像）では中等度～高度僧帽弁閉鎖不全（矢印）を認める。
B、C：4腔像と短軸像ではガドリニウム遅延造影（LGE）での非虚血性分布を示す高信号域を認め（矢頭）、左房から左室基部にかけて病変が連続していることがわかる。
D：T2強調画像（T2WI）でもLGE病変に一致して局所高信号を認めており（矢頭）、急性期炎症性心筋浮腫に合致する。以上より、急性期心筋炎のLake Louise 診断基準を満たす。
E-H：ステロイド治療後には、急性期に認められていたすべてのMRI異常所見が顕著に改善しているのがわかる。
LA, 左房; LV, 左室; RA, 右房; RV, 右室
出典
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1: A case of vaccine-associated myocarditis following pneumococcal immunization leading to acute mitral regurgitation.
著者: Hiroyuki Yamamoto, Marie Takahashi, Jun Isogai
雑誌名: ESC Heart Fail. 2022 Jun;9(3):2013-2019. doi: 10.1002/ehf2.13881. Epub 2022 Mar 14.
Abstract/Text: Vaccine-associated myocarditis (VAM) is a rare entity but can result in potentially serious sequelae if left untreated. However, the mechanisms of the complications of VAM and its treatment remain unclear. Herein, we report the first case of VAM related to pneumococcal immunization, presenting as a local and systemic inflammatory reaction, in which the patient developed significant secondary mitral regurgitation, resulting in acute heart failure. Finally, the patient recovered completely following corticosteroid treatment. This case highlights the value of cardiac magnetic resonance and the pitfall of endomyocardial biopsy in establishing the definitive diagnosis of VAM and emphasizes the importance of optimal management in understanding the mechanism and instituting the treatment for secondary mitral regurgitation caused by VAM.

© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
ESC Heart Fail. 2022 Jun;9(3):2013-2019. doi: 10.1002/ehf2.13881. Epub...

心筋炎診断における心臓MRI検査の推奨とエビデンスレベル

心筋炎における心内膜心筋生検の推奨とエビデンスレベル

心内膜心筋生検による急性心筋炎の診断基準

出典
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1: 著者提供

急性心筋炎に合併した致死性心室性不整脈に対する治療の推奨とエビデンスレベル

血行動態の安定した急性心筋炎における治療の推奨とエビデンスレベル

劇症型心筋炎における経皮的補助循環の推奨とエビデンスレベル

劇症型心筋炎における開胸を要する補助循環の推奨とエビデンスレベル

VA-ECMOの主な合併症と対策

急性心筋炎における免疫抑制療法の推奨とエビデンスレベル

急性心筋炎における免疫調整療法の推奨とエビデンスレベル

好酸球性心筋炎の診断基準

急性期レフレル心内膜炎の心エコー図検査（傍胸骨左室長軸像）

A：急性期の心エコーでは、左室壁運動良好にもかかわらず、左心内膜にびまん性血栓が生じている。血栓は乳頭筋を経て僧帽弁まで及んでいる。
B：急性期のカラードップラー心エコーでは、左室内血栓形成により乳頭筋と僧帽弁の可動制限を生じた結果、高度僧帽弁閉鎖不全を認める。
C：抗凝固療法とステロイド併用治療後の回復期の心エコーでは、入院時に認めていた左室内血栓はかなり改善した。それに伴い僧帽弁閉鎖不全も改善している。
出典
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1: Löffler's endomyocarditis.
Heart. 2005 Feb;91(2):135. doi: 10.1136/hrt.2004.041558.

慢性期レフレル心内膜炎の心エコー図検査

A：慢性期の心尖部5腔像。心室中隔から派生した左室内血栓は一見腫瘍に見える（矢印）。
B：カラードップラー心エコー（心尖部3腔像）では、左室内血栓（矢印）が乳頭筋にまで波及しており（矢頭）、乳頭筋可動制限によって生じた中等度僧帽弁閉鎖不全を認める。
Ao, 大動脈; LA, 左房; LV, 左室; RV, 右室
出典
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1: Late-Stage Löffler's Endocarditis Mimicking Cardiac Tumor: A Case Report.
著者: Takafumi Koyama, Hiroyuki Yamamoto, Manabu Matsumoto, Jun Isogai, Tadashi Isomura, Shinji Tanaka
雑誌名: Front Cardiovasc Med. 2020;7:589212. doi: 10.3389/fcvm.2020.589212. Epub 2020 Oct 29.
Abstract/Text: Löffler's endocarditis (cardiac involvement in hypereosinophilic syndrome) is rare yet life-threatening if left untreated. We describe a case of hypereosinophilic syndrome presenting as a cardiac mass with an abnormal electrocardiogram. Diagnostic studies of the cardiac mass strongly suggested a malignant cardiac tumor invading the papillary muscle. Thus, excision of the cardiac mass and endomyocardial resection with mitral valve replacement were successfully performed. Pathology revealed various stages of thrombosis and irreversible myocardial damage caused by eosinophilic infiltration with no malignancy, leading to the correct diagnosis of late-stage Löffler's endocarditis. The subsequent combination of anticoagulation and corticosteroids was effective with a favorable outcome. This case highlights pitfalls in multimodality imaging of cardiac thrombus and the clinical significance of considering Löffler's endocarditis in the diagnostic work-up of a cardiac mass.

Copyright © 2020 Koyama, Yamamoto, Matsumoto, Isogai, Isomura and Tanaka.
Front Cardiovasc Med. 2020;7:589212. doi: 10.3389/fcvm.2020.589212. Ep...

好酸球性心筋炎における治療の推奨とエビデンスレベル

巨細胞性心筋炎の組織像

炎症巣に多核巨細胞を認める。GCMはリンパ球に加えて、好酸球浸潤が目立つことが多く、かつ高度心筋壊死像を認めることが多い。

薬剤性心筋炎の分類

出典
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1: 著者提供

心筋炎を惹起する可能性のある代表的な薬物・毒物

心筋生検組織像（好酸球性心筋炎）

脱顆粒を伴う好酸球浸潤と心筋脱落壊死と置換性線維化を認める。

好酸球性心筋炎の組織像

A：ヘマトキシリン・エオジン染色による顕微鏡写真（Bar, 50μm）
脱顆粒を伴う好酸球浸潤、心筋脱落壊死、置換性線維化と心内膜肥厚を認める。
B：好酸球カチオン性タンパク質（ECP）に対する免疫染色を行った写真（Bar, 50μm）
心内膜中心としたおびただしいECPの沈着を心筋細胞間隙に認める。
C、D：透過型電子顕微鏡【Cの枠で囲んだ部分の高倍率図をDで示す】
脱顆粒した好酸球と肥満細胞が心筋細胞に近接して心筋間質に浸潤していることがわかる。好酸球が放出した顆粒（赤色矢頭）を認める。
* Cm, 心筋細胞; Eo, 好酸球; Mc, 肥満細胞
出典
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1: Case Report: Acute Eosinophilic Myocarditis With a Low-Flow Heart Failure With Preserved Ejection Fraction Phenotype.
著者: Hiroto Aota, Hiroyuki Yamamoto, Jun Isogai, Kyoko Imanaka-Yoshida, Michiaki Hiroe, Takahiro Tanaka
雑誌名: Front Cardiovasc Med. 2021;8:678973. doi: 10.3389/fcvm.2021.678973. Epub 2021 Jun 23.
Abstract/Text: Eosinophilic myocarditis is a rare subtype of myocarditis characterized by myocardial eosinophilic infiltration, and it is potentially fatal if left untreated. Although endomyocardial biopsy (EMB) is a cornerstone for the histological diagnosis of acute eosinophilic myocarditis (AEM), as it is an invasive procedure and has a low diagnostic accuracy, the diagnosis of AEM with hemodynamic instability remains challenging. We describe a case of AEM presenting as low-flow heart failure with preserved ejection fraction (HFpEF), with rapid progression to cardiogenic shock. The constellation of peripheral eosinophilia, increased left ventricular wall thickness, and HFpEF raised the suspicion of AEM. Contrast-enhanced computed tomography (CT) scan revealed heterogeneous hypoenhancement localized in the basal-to-mid septal and mid anterolateral walls of the left ventricle, strongly suggestive of acute inflammation. Based upon these findings, we performed CT-guided EMB, which lead to a definitive diagnosis. Subsequent high-dose corticosteroids allowed a rapid and dramatic recovery and normalization of cardiac structure and function. This case highlights the clinical importance of assessing AEM as a rare cause of HFpEF and the usefulness of CT-guided EMB in patients with hemodynamic instability.

Copyright © 2021 Aota, Yamamoto, Isogai, Imanaka-Yoshida, Hiroe and Tanaka.
Front Cardiovasc Med. 2021;8:678973. doi: 10.3389/fcvm.2021.678973. Ep...

過敏性心筋炎の組織像

急性心筋炎の心筋生検組織像

心筋変性・壊死像とそれに近接する炎症細胞の浸潤像が検出される。リンパ球浸潤が主体であるが、ごく少数の好酸球もみられる。

臨床および検査パラメーターに関する劇症型群と非劇症型群の比較

出典
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1: Risk factors for patients developing a fulminant course with acute myocarditis.
著者: Shigeru Kato, Shin-Ichiro Morimoto, Shinya Hiramitsu, Akihisa Uemura, Masatsugu Ohtsuki, Yasuchika Kato, Kenji Miyagishima, Yukihiko Yoshida, Shuji Hashimoto, Hitoshi Hishida
雑誌名: Circ J. 2004 Aug;68(8):734-9.
Abstract/Text: BACKGROUND: A fulminant course can be difficult to predict at the onset of acute myocarditis, so the aim of the present study was to identify the predictive clinical symptoms/signs or laboratory findings.
METHODS AND RESULTS: Thirty-nine patients with acute lymphocytic myocarditis, excluding 8 who manifested shock at admission, were studied. The fulminant group was defined as 12 patients who developed shock after admission, requiring intraaortic balloon pumping or percutaneous cardiopulmonary support, and the non-fulminant group comprised the 27 patients without shock. Various parameters at admission were compared between the 2 groups, together with multiple logistic regression analysis, excluding 6 patients with partially missing values. In the fulminant group, C-reactive protein (7.0 +/- 7.0 vs 2.3 +/- 2.2 mg/dl, p<0.01) and creatine kinase (1,147 +/- 876 vs 594 +/- 568 IU/L, p<0.05) concentrations were higher, intraventricular conduction disturbances were more frequent (9/12 vs 7/27 patients, p<0.01) and the left ventricular ejection fraction was lower (40.7 +/- 13.9 vs 50.1 +/- 10.6%, p<0.05) than in the non-fulminant group. In the multiple logistic regression analysis model with the presence/absence of a fulminant course considered as the independent variable, and C-reactive protein, creatine kinase, intraventricular conduction disturbances, and left ventricular ejection fraction as dependent variables, a high-risk group (expected proportion of fulminant course > or = 0.5) and a low-risk group (<0.5) could be differentiated. A fulminant course occurred in 9/13 (69%) patients in the high-risk group, but in only 2/20 (10%) patients in the low risk group (p<0.001).
CONCLUSIONS: The risk of a fulminant course of acute myocarditis was high in patients with elevated C-reactive protein, and creatine kinase concentrations, decreased left ventricular ejection fraction, and intraventricular conduction disturbances at the time of admission.
Circ J. 2004 Aug;68(8):734-9.

劇症型および急性心筋炎患者における受診時の二次元心エコー図

5日間の先行する感冒様症状の後、急性循環虚脱に陥った劇症型心筋炎の20歳男性の心エコー所見（a：傍胸骨長軸、b：傍胸骨短軸像）
診察時の心エコー所見では、重度左心室壁肥厚（中隔壁厚2.1 cm）を認めるものの、左心室内腔は小さい（左心室拡張末期径2.5 cm）。
強心薬点滴療法や左心補助循環装置（LVAD）による血行動態補助により、この患者はほぼ正常心機能に回復した。
3週間前から全身倦怠感・発熱があり、労作時呼吸困難が徐々に増悪したために来院した急性心筋炎の19歳男性の心エコー所見（c：傍胸骨長軸像、d：傍胸骨短軸像）
診察時の心エコー所見では、左心室壁の非薄化（中隔壁厚0.6 cm）と著明な左心室拡大（左心室拡張末期径6.9 cm）を認める。
6カ月後のフォローアップでは、左心室拡張末期径（LVEDD）は8.0 cmまで拡大し心臓移植待機となった。
出典
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1: Echocardiographic findings in fulminant and acute myocarditis.
著者: G M Felker, J P Boehmer, R H Hruban, G M Hutchins, E K Kasper, K L Baughman, J M Hare
雑誌名: J Am Coll Cardiol. 2000 Jul;36(1):227-32.
Abstract/Text: OBJECTIVES: We sought to use echocardiography to assess the presentation and potential for recovery of left ventricular (LV) function of patients with fulminant myocarditis compared with those with acute myocarditis.
BACKGROUND: The clinical course of patients with myocarditis remains poorly defined. We have previously proposed a classification that provides prognostic information in myocarditis patients. Fulminant myocarditis causes a distinct onset of illness and severe hemodynamic compromise, whereas acute myocarditis has an indistinct presentation, less severe hemodynamic compromise and a greater likelihood of progression to dilated cardiomyopathy.
METHODS: Echocardiography was performed at presentation and at six months to test the hypothesis that fulminant (n = 11) or acute (n = 43) myocarditis could be distinguished morphologically.
RESULTS: Patients with both fulminant (fractional shortening 19 +/- 4%) and acute myocarditis (17 +/- 7%) had LV systolic dysfunction. Patients with fulminant myocarditis had near normal LV diastolic dimensions (5.3 +/- 0.9 cm) but increased septal thickness (1.2 +/- 0.2 cm) at presentation, while those with acute myocarditis had increased diastolic dimensions (6.1 +/- 0.8 cm, p < 0.01 vs. fulminant) but normal septal thickness (1.0 +/- 0.1 cm, p = 0.01 vs. fulminant). At six months, patients with fulminant myocarditis had dramatic improvement in fractional shortening (30 +/- 8%) compared with no improvement in patients with acute myocarditis (19 +/- 7%, p < 0.01 for interaction between time and type of myocarditis).
CONCLUSIONS: Fulminant myocarditis is distinguishable from acute myocarditis by echocardiography. Patients with fulminant myocarditis exhibit a substantial improvement in ventricular function at six months compared with those with acute myocarditis. Echocardiography has value in classifying patients with myocarditis and may provide prognostic information.
J Am Coll Cardiol. 2000 Jul;36(1):227-32.

出典
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1: Favourable clinical outcome in patients with cardiogenic shock due to fulminant myocarditis supported by percutaneous extracorporeal membrane oxygenation.
著者: Yasuhide Asaumi, Satoshi Yasuda, Isao Morii, Hiroyuki Kakuchi, Yoritaka Otsuka, Atsushi Kawamura, Yoshikado Sasako, Takeshi Nakatani, Hiroshi Nonogi, Shunichi Miyazaki
雑誌名: Eur Heart J. 2005 Oct;26(20):2185-92. doi: 10.1093/eurheartj/ehi411. Epub 2005 Jul 13.
Abstract/Text: AIMS: The clinical outcome of severe acute myocarditis patients with cardiogenic shock who require circulatory support devices is not well known. We studied the survival and clinical courses of patients with fulminant myocarditis supported by percutaneous extracorporeal membrane oxygenation (ECMO) and compared them with those of patients with acute non-fulminant myocarditis.
METHODS AND RESULTS: Patients with acute myocarditis were divided into the following two groups. Fourteen patients who required ECMO for cardiogenic shock were defined as having fulminant myocarditis (F group), whereas 13 patients who had an acute onset of symptoms, but did not have compromised, were defined as having acute non-fulminant myocarditis (NF group). In the F group, 10 patients were weaned successfully from percutaneous ECMO. Therefore, the overall acute survival rate was 71%. Patients who were not weaned from ECMO showed smaller left ventricular end-diastolic and end-systolic dimensions, thicker left ventricular wall, and higher creatine phosphokinase MB isoform levels than those who were weaned from ECMO. When compared with patients in the NF group, the fractional shortening in the F group was more severely decreased in the acute phase [F: 10+/-4 vs. NF: 23+/-8% (mean+/-SD), P<0.001], but recovered in the chronic phase (F: 33+/-7 vs. NF: 34+/-6%). The prevalence of adverse clinical events in both groups was similar during the follow-up period of 50 months.
CONCLUSION: In patients with fulminant myocarditis, percutaneous ECMO is a highly effective form of a haemodynamic support. Once a patient recovers from inflammatory myocardial damage, the subsequent clinical outcome is favourable, similar to that observed in patients with acute non-fulminant myocarditis.
Eur Heart J. 2005 Oct;26(20):2185-92. doi: 10.1093/eurheartj/ehi411. E...

薬剤性心筋炎の治療に関する推奨とエビデンスレベル

免疫チェックポイント阻害薬関連心筋炎の病理組織像

破傷風トキソイドワクチン接種後心筋炎の病理組織像

病理組織学的にはユニークな組織学的所見が特徴的である。
A：ヘマトキシリン・エオジン染色による低倍率画像では、間質（黒矢印）または血管周囲（白矢印）に炎症細胞浸潤が巣状に複数認められる。血管周囲には心筋細胞壊死を伴う血管周囲の好酸球浸潤（白矢印）と、間質には心筋細胞壊死を伴う豊富なリンパ球浸潤（黒矢印）が心筋組織内に認める（Bar：100μm）。
B：高倍率画像（図Aの白矢印付近の拡大図）では血管周囲の炎症細胞浸潤が顕著で脱顆粒した好酸球を優位に認める（Bar：20μm）。
出典
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1: A case of biopsy-proven eosinophilic myocarditis related to tetanus toxoid immunization.
著者: Hiroyuki Yamamoto, Toru Hashimoto, Keiko Ohta-Ogo, Hatuse Ishibashi-Ueda, Kyoko Imanaka-Yoshida, Michiaki Hiroe, Tomoki Yokochi
雑誌名: Cardiovasc Pathol. 2018 Nov - Dec;37:54-57. doi: 10.1016/j.carpath.2018.10.003. Epub 2018 Oct 9.
Abstract/Text: Vaccine-associated myocarditis is an extremely rare, yet potentially lethal disease, which requires early diagnosis and prompt treatment. However, its pathogenesis remains elusive. We report the first case of biopsy-proven eosinophilic myocarditis related to tetanus toxoid immunization, with unique histopathologic findings, characterized by perivascular eosinophilic infiltrates with myocyte necrosis and abundant interstitial lymphocytic infiltrates with myocyte necrosis, separately. A systemic high-dose corticosteroid treatment had a dramatic beneficial effect on hemodynamic instability and resulted in complete recovery. This case highlights the value of endomyocardial biopsy in establishing a definite diagnosis and understanding the pathogenesis of vaccine-associated myocarditis.

Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Cardiovasc Pathol. 2018 Nov - Dec;37:54-57. doi: 10.1016/j.carpath.201...

COVID-19ワクチン接種後心筋炎の病理組織像

ほとんどの症例は軽症～中等症であり炎症細胞浸潤は少ないが心筋細胞傷害や間質の浮腫や線維化を認める。
ここでは劇症型心筋炎の症例を呈示する[1]。病理組織学的にはリンパ球性心筋炎に類似した病理像を呈する。CD3 陽性T 細胞（CD8 陽性＞ CD4陽性）とCD68 陽性マクロファージの心筋組織内炎症細胞浸潤が顕著で、CD20 陽性B 細胞浸潤も認める。
H&E：ヘマトキシリン・エオジン染色，MT：マッソン・トリクローム染色
 
文献
1) Yamamoto M, Tajiri K, Ayuzawa S, Ieda M. Pathological findings of clinically suspected myocarditis temporally associated with COVID-19 vaccination. Eur J Heart Fail. 2022 Jun;24(6):1132-1138. doi: 10.1002/ejhf.2523. Epub 2022 May 15. PMID: 35488842; PMCID: PMC9348161.

慢性活動性心筋炎（臨床的に拡張型心筋症と考えられていた症例）の組織像

慢性炎症性心筋症（臨床的に拡張型心筋症と考えられていた症例）の組織像および摘出心

病理解析による組織内のCD3陽性T細胞浸潤数に応じた層別化と予後の関係

261名の拡張型心筋症患者が心臓死または補助人工心臓を受けるまでの生存曲線。CD3陽性T細胞数＜13/mm2を軽度浸潤、13～24/mm2を中等度浸潤、≧24/mm2を高度浸潤と定義すると、炎症細胞浸潤数が多いほど予後不良であることがわかる。
 
出典
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1: Myocardial T-Lymphocytes as a Prognostic Risk-Stratifying Marker of Dilated Cardiomyopathy　- Results of the Multicenter Registry to Investigate Inflammatory Cell Infiltration in Dilated Cardiomyopathy in Tissues of Endomyocardial Biopsy (INDICATE Study).
著者: Keiko Ohta-Ogo, Yasuo Sugano, Soshiro Ogata, Takafumi Nakayama, Takahiro Komori, Kazuo Eguchi, Kaoru Dohi, Tetsuro Yokokawa, Hiromitsu Kanamori, Shigeyuki Nishimura, Kazufumi Nakamura, Yoshihiko Ikeda, Kunihiro Nishimura, Genzou Takemura, Toshihisa Anzai, Michiaki Hiroe, Kinta Hatakeyama, Hatsue Ishibashi-Ueda, Kyoko Imanaka-Yoshida
雑誌名: Circ J. 2022 Jun 24;86(7):1092-1101. doi: 10.1253/circj.CJ-21-0529. Epub 2022 Mar 10.
Abstract/Text: BACKGROUND: Dilated cardiomyopathy (DCM) associated with inflammation is diagnosed by endomyocardial biopsy; patients with this have a poorer prognosis than patients without inflammation. To date, standard diagnostic criteria have not been established.Methods and Results: This study analyzed clinical records and endomyocardial biopsy samples of 261 patients with DCM (201 males, median left ventricular ejection fraction; 28%) from 8 institutions in a multicenter retrospective study. Based on the European Society of Cardiology criteria and CD3 (T-lymphocytes) and CD68 (macrophages) immunohistochemistry, 48% of patients were categorized as having inflammatory DCM. For risk-stratification, we divided patients into 3 groups using Akaike Information Criterion/log-rank tests, which can determine multiple cut-off points: CD3+-Low, <13/mm2(n=178, 68%); CD3+-Moderate, 13-24/mm2(n=58, 22%); and CD3+-High, ≥24/mm2(n=25, 10%). The survival curves for cardiac death or left ventricular assist device implantation differed significantly among the 3 groups (10-year survival rates: CD3+-Low: 83.4%; CD3+-Moderate: 68.4%; CD3+-High: 21.1%; Log-rank P<0.001). Multivariate Cox analysis revealed CD3+count as a potent independent predictive factor for survival (fully adjusted hazard ratio: CD3+-High: 5.70, P<0.001; CD3+-Moderate: 2.64, P<0.01). CD3+-High was also associated with poor left ventricular functional and morphological recovery at short-term follow up.
CONCLUSIONS: Myocardial CD3+T-lymphocyte infiltration has a significant prognostic impact in DCM and a 3-tiered risk-stratification model could be helpful to refine patient categorization.
Circ J. 2022 Jun 24;86(7):1092-1101. doi: 10.1253/circj.CJ-21-0529. Ep...

Minds推奨グレード、Mindsエビデンス分類

参考文献：
日本循環器学会．2023年改訂版 心筋炎の診断・治療に関するガイドライン．https://www.j-circ.or.jp/cms/wp-content/uploads/2023/03/JCS2023_nagai.pdf．（2023年10月閲覧）p12　表3、4

慢性心筋炎の心筋生検組織像

大小の単核細胞の集簇があり、近接する心筋細胞の融解消失を伴っている。間質には、置換性の線維組織や脂肪組織が認められる。

プラセボ群とエナラプリル群の累積死亡率：重症心不全患者を対象としたCooperative North Scandinavian Enalapril Survival Study I（CONSENSUS I）

出典
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1: Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group.
著者:
雑誌名: N Engl J Med. 1987 Jun 4;316(23):1429-35. doi: 10.1056/NEJM198706043162301.
Abstract/Text: To evaluate the influence of the angiotensin-converting-enzyme inhibitor enalapril (2.5 to 40 mg per day) on the prognosis of severe congestive heart failure (New York Heart Association [NYHA] functional class IV), we randomly assigned 253 patients in a double-blind study to receive either placebo (n = 126) or enalapril (n = 127). Conventional treatment for heart failure, including the use of other vasodilators, was continued in both groups. Follow-up averaged 188 days (range, 1 day to 20 months). The crude mortality at the end of six months (primary end point) was 26 percent in the enalapril group and 44 percent in the placebo group--a reduction of 40 percent (P = 0.002). Mortality was reduced by 31 percent at one year (P = 0.001). By the end of the study, there had been 68 deaths in the placebo group and 50 in the enalapril group--a reduction of 27 percent (P = 0.003). The entire reduction in total mortality was found to be among patients with progressive heart failure (a reduction of 50 percent), whereas no difference was seen in the incidence of sudden cardiac death. A significant improvement in NYHA classification was observed in the enalapril group, together with a reduction in heart size and a reduced requirement for other medication for heart failure. The overall withdrawal rate was similar in both groups, but hypotension requiring withdrawal occurred in seven patients in the enalapril group and in no patients in the placebo group. After the initial dose of enalapril was reduced to 2.5 mg daily in high-risk patients, this side effect was less frequent. We conclude that the addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms. The beneficial effect on mortality is due to a reduction in death from the progression of heart failure.
N Engl J Med. 1987 Jun 4;316(23):1429-35. doi: 10.1056/NEJM19870604316...

Kaplan-Meier法による主要転帰およびその他の転帰の累積発生率の推定値（試験群別）

出典
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1: Eplerenone in patients with systolic heart failure and mild symptoms.
著者: Faiez Zannad, John J V McMurray, Henry Krum, Dirk J van Veldhuisen, Karl Swedberg, Harry Shi, John Vincent, Stuart J Pocock, Bertram Pitt, EMPHASIS-HF Study Group
雑誌名: N Engl J Med. 2011 Jan 6;364(1):11-21. doi: 10.1056/NEJMoa1009492. Epub 2010 Nov 14.
Abstract/Text: BACKGROUND: Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms.
METHODS: In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.
RESULTS: The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001).
CONCLUSIONS: Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; ClinicalTrials.gov number, NCT00232180.).
N Engl J Med. 2011 Jan 6;364(1):11-21. doi: 10.1056/NEJMoa1009492. Epu...

β遮断薬投与の有無でみた心臓死および心臓移植なしの未調整生存率

図中HTxは心臓移植を示す。
出典
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1: Predictors of outcome in patients with suspected myocarditis.
著者: Ingrid Kindermann, Michael Kindermann, Reinhard Kandolf, Karin Klingel, Burkhard Bültmann, Thomas Müller, Angelika Lindinger, Michael Böhm
雑誌名: Circulation. 2008 Aug 5;118(6):639-48. doi: 10.1161/CIRCULATIONAHA.108.769489. Epub 2008 Jul 21.
Abstract/Text: BACKGROUND: The objective of this study was to identify the prognostic indicators in patients with suspected myocarditis who underwent endomyocardial biopsy.
METHODS AND RESULTS: Between 1994 and 2007, 181 consecutive patients (age, 42+/-15 years) with clinically suspected viral myocarditis were enrolled and followed up for a mean of 59+/-42 months. Endomyocardial biopsies were studied for inflammation with histological (Dallas) and immunohistological criteria. Virus genome was detected by polymerase chain reaction. The primary end point was time to cardiac death or heart transplantation. In 38% of the patients (n=69), the Dallas criteria were positive. Immunohistological signs of inflammation were shown in 50% (n=91). Genomes of cardiotropic virus species were detected in 79 patients (44%). During follow-up, 22% of the patients (n=40) reached the primary end point. Three independent predictors were identified for the primary end point, namely New York Heart Association class III or IV at entry (hazard ratio, 3.20; 95% confidence interval, 1.36 to 7.57; P=0.008), immunohistological evidence of inflammatory infiltrates in the myocardium (hazard ratio, 3.46; 95% confidence interval, 1.39 to 8.62; P=0.008), and beta-blocker therapy (hazard ratio, 0.43; 95% confidence interval, 0.21 to 0.91; P=0.027). Ejection fraction, left ventricular end-diastolic pressure, and left ventricular end-diastolic dimension index were predictive only in univariate, not in multivariate, analysis. Neither the Dallas criteria nor the detection of viral genome was a predictor of outcome.
CONCLUSIONS: For patients with suspected myocarditis, advanced New York Heart Association functional class, immunohistological signs of inflammation, and lack of beta-blocker therapy, but not histology (positive Dallas criteria) or viral genome detection, are related to poor outcome.
Circulation. 2008 Aug 5;118(6):639-48. doi: 10.1161/CIRCULATIONAHA.108...

387名の若年運動選手に発生した突然死の原因

Maron BJ: Sudden death in young athletes. N Engl J Med. 2003 Sep 11;349(11):1064-75.を参考に作製

心筋炎患者のMRI所見

a、b：T2強調画像所見では、左心室中部側壁の心外膜下層に局所の心筋浮腫像（矢印）を認める。（a：長軸像、b：短軸像）
c、d：a、bに対応するガドリニウム造影心臓MRI（T1強調画像）では、遅延造影において典型的な信号強度の増強（LGE）像が、左心室中部側壁の心外膜下層に認められる。（c：長軸像、d：短軸像）
出典
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1: Update on myocarditis.
著者: Ingrid Kindermann, Christine Barth, Felix Mahfoud, Christian Ukena, Matthias Lenski, Ali Yilmaz, Karin Klingel, Reinhard Kandolf, Udo Sechtem, Leslie T Cooper, Michael Böhm
雑誌名: J Am Coll Cardiol. 2012 Feb 28;59(9):779-92. doi: 10.1016/j.jacc.2011.09.074.
Abstract/Text: Myocarditis is an inflammatory disease of the heart frequently resulting from viral infections and/or post-viral immune-mediated responses. It is one of the important causes of dilated cardiomyopathy worldwide. The diagnosis is presumed on clinical presentation and noninvasive diagnostic methods such as cardiovascular magnetic resonance imaging. Endomyocardial biopsy remains the gold standard for in vivo diagnosis of myocarditis. The therapeutic and prognostic benefits of endomyocardial biopsy results have recently been demonstrated in several clinical trials. Although remarkable advances in diagnosis, understanding of pathophysiological mechanisms, and treatment of acute myocarditis were gained during the last years, no standard treatment strategies could be defined as yet, apart from standard heart failure therapy and physical rest. In severe cases, mechanical support or heart transplantation may become necessary. There is some evidence that immunosuppressive and immunomodulating therapy are effective for chronic, virus-negative inflammatory cardiomyopathy. Further investigations by controlled, randomized studies are needed to definitively determine their role in the treatment of myocarditis.

Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
J Am Coll Cardiol. 2012 Feb 28;59(9):779-92. doi: 10.1016/j.jacc.2011....

急性心筋炎の診断アルゴリズム

発熱、上気道感染、消化器症状、関節痛、筋肉痛などのウイルス感染の出現後、呼吸困難や胸痛、動悸、ときに失神などの心不全や心膜刺激症状、不整脈などが出現したら積極的に急性心筋炎を疑う。胸部X線写真、心電図、採血を行うが、これらだけでは、急性心筋炎の診断は必ずしも容易ではない。心エコー、胸部CT、冠動脈CT、心臓MRIを行い類似疾患の鑑別が必要になる。最終的には心臓カテーテル検査も必要になることが多く、可能ならこの時点で心筋生検も同時に行い組織診断も加える。冠動脈CTと冠動脈造影は冠動脈狭窄の有無の確認、心筋梗塞を除外する目的であるため、どちらかで十分である。
MINOCA, myocardial infarction with non-obstructive coronary arteries

慢性活動性心筋炎および慢性炎症性心筋炎の診断アルゴリズム

急性心筋炎の治療戦略

急性心筋炎を疑ったら軽症でも入院のうえ、治療に臨む必要がある。心室性不整脈に対しては薬物治療を、除脈性不整脈には一時的ペーシングを行う。心不全を合併していれば、その重症度に従い治療を開始する。軽症であれば日本循環器学会の急性心不全治療ガイドラインに従い内服治療を開始する。中等症以上であれば、経静脈心血管作動薬を用い治療する。組織型により、適宜、ステロイドパルス療法や大量免疫グロブリン療法を追加する。さらに重症化するようであれば補助循環も考慮する。
DOA, ドパミン；DOB, ドブタミン；NAd, ノルアドレナリン; NTG, ニトログリセリン; hANP,ハンプ
IABP, 大動脈内バルーンパンピング; IMPELLA, 補助循環ポンプカテーテル; ECMO, 体外式膜型人工肺（心肺補助）; BiVAD, 両心室補助人工心臓; LVAD, 左室補助人工心臓
出典
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1: 著者提供

心筋炎の概念図

（注）これまで本邦と欧米との間で、慢性経過した心筋炎（慢性心筋炎、慢性炎症性心筋症、炎症性拡張型心筋症など）の概念・定義が統一されておらず混乱が生じている。したがって、最近の国際ステートメントに準じて本ガイドラインでは下記に修正している。
1）従来の慢性心筋炎は慢性活動性心筋炎と再定義する。
2）急性と慢性の境界を3カ月から30日と再定義する。