Cardiomyopathy

Japanese: 心筋症

Cardiomyopathy was once defined as a "cardiomyocardial disease of unknown cause", but with the identification of causative gene mutations, this definition is now obsolete. In the 2006 American Heart Association Classification of Cardiomyopathy (Maron et al., 2006), cardiomyopathies are classified as hereditary, mixed (hereditary and acquired), or acquired, and genetic abnormalities now play a large role in the etiology of cardiomyopathies. Causative gene mutations are identified in approximately 60% of cases of hypertrophic cardiomyopathy (HCM) and approximately 30% of cases of dilated cardiomyopathy (DCM). Most cases are inherited in an autosomal dominant manner. Since the identification of cardiac myosin heavy chain gene mutations in a large family with HCM in 1990, linkage analysis has revealed a succession of gene mutations in sarcomere proteins such as cardiac troponin T, α-tropomyosin, and cardiac myosin-binding protein C, and HCM was initially considered to be a sarcomere disease. Even now, there is no doubt that sarcomere abnormalities are the main cause of HCM. However, genetic abnormalities in sarcomeres are also known to cause other cardiomyopathies, such as DCM, restrictive cardiomyopathy (RCM), left ventricular noncompaction (LVNC), and peripartum cardiomyopathy.
(1) Hypertrophic cardiomyopathy (HCM) (Table 5-4-2) It is characterized by myocardial hypertrophy, diastolic dysfunction, myocardial cell hypertrophy, disarray, and interstitial fibrosis. It occurs in approximately 1 per 500 people, making it the most common hereditary disease in the cardiovascular field. Clinical signs vary from asymptomatic to severe cases with outflow tract pressure gradient. It is the leading cause of sudden cardiac death in young people. In approximately 10% of cases, the disease progresses to resemble dilated cardiomyopathy over the course of the disease, resulting in refractory heart failure (dilated phase hypertrophic cardiomyopathy). Causative gene mutations have been identified in approximately 60% of cases. To date, more than 1,000 types of sarcomere protein gene mutations have been reported. It is an autosomal dominant inheritance pattern, with the disease occurring in heterozygotes. Mutations are often identified in the cardiac myosin heavy chain gene (MYH7), cardiac myosin-binding protein C gene (MYBPC3), and then the cardiac troponin T gene (TNNT2). There are few founder mutations that are widely distributed and inherited from one ancestor, and many are private mutations found in only one family. This is one of the reasons why genetic diagnosis is difficult to implement. Genetic mutations are often identified in sporadic cases that are not familial, but are caused by a mutation that occurred de novo in the individual and was not inherited from a parent, or in cases where the parent also has the same mutation but the individual develops the disease without the parent developing the disease (low penetrance of the mutation).
Research is ongoing into the mechanism by which sarcomere gene mutations cause HCM. Most of the causative mutations in sarcomere protein genes are missense or small deletions. The encoded mutant proteins are stably incorporated into cardiac fibers, causing impairment of sarcomere function. Analysis using isolated mutant myosin molecules showed that ATPase activity is increased, the force generated increases, and actin filament sliding becomes faster. These changes explain the hypercontractile state seen in the early stages of HCM. It has been proposed that stiff sarcomeres, enhanced stretch response, and increased calcium ion sensitivity are involved in the pathogenesis. It has also been found that fibrotic reactions are activated in the myocardial interstitium from an early stage before the onset of cardiac hypertrophy and play an important role in the pathogenesis.
It is important to note that "clinical signs vary from person to person even if they carry the same mutation." This is thought to be due to coexisting genetic modifiers or differences in the environment. However, the severity and pattern of cardiac hypertrophy and age of onset can be categorized to some extent depending on the type of mutation. It has been reported that late-onset HCM is often caused by MYBPC3 mutations, that patients with TNNT2 mutations are associated with a high rate of sudden death despite mild cardiac hypertrophy, and that ACTC Glu101Lys mutations are associated with a high rate of apical hypertrophy. Causing HCM mutations other than those in sarcomere protein genes have also been identified, but these are rare.
(2) Dilated cardiomyopathy (DCM) (Table 5-4-3)
It is characterized by impaired myocardial contraction, ventricular lumen dilation, cardiomyocyte loss, and interstitial fibrosis. It is a disease with a poor prognosis that causes refractory heart failure and arrhythmia. Many causative gene mutations have been identified using linkage analysis and candidate gene approaches. The proteins involved are extremely diverse, including not only sarcomere proteins, but also structures that transmit the force generated in the sarcomere, such as Z-line proteins, intercalated disc proteins, intermediate filaments, dystrophin-related glycoprotein complexes, and nuclear membrane components, proteins involved in the ion cycling system including Ca ions, and transcription factors. The pathology can be explained using the keywords "force generation disorder" and "force transmission disorder." Theories have been proposed that loose sarcomere, decreased stretch response, decreased Ca ion sensitivity, and metabolic stress disorder are involved in the pathology.
(3) Restrictive cardiomyopathy (RCM)
A rare myocardial disease characterized by impaired ventricular filling and reduced diastolic volume. It results in right-sided or bilateral heart failure. Ventricular wall thickness and contractility remain normal. Mutations in the troponin I (TNNI3) gene have been reported as a cause of idiopathic RCM.
(4) Glycogen storage cardiomyopathy and cardiac Fabry disease Glycogen storage disease causes cardiomyopathy with cardiac hypertrophy as its main symptom. Cases with skeletal muscle involvement are easy to diagnose, but cases with cardiomyopathy alone tend to be diagnosed as HCM. An accurate diagnosis is often made based on findings of vacuolar degeneration of cardiomyocytes and glycogen storage within the vacuoles (PAS staining) on myocardial biopsy. Unlike HCM, there is little disarray of cardiomyocytes and no significant interstitial fibrosis. It causes conduction disorders similar to those of WPW syndrome. A particular problem in adults is mutations in PRKAG2, which encodes the γ2 subunit of AMP kinase (leading to sustained activation of AMP kinase). It is inherited in an autosomal dominant manner.
Cardiac Fabry disease is a sphingolipid storage disease limited to the heart. While systemic Fabry disease is a rare disease (occurring in approximately 1 in 120,000 people) caused by a complete deficiency of α-galactosidase A activity, cardiac Fabry disease is caused by a partial deficiency of α-galactosidase A activity and is by no means a rare disease. It has been shown to be seen in approximately 3% of male cases of cardiac hypertrophy in Japan. As cardiac hypertrophy improves with α-galactosidase supplementation, this disease must be clearly differentiated from other types of cardiac hypertrophy when treating it. Numerous mutations in the α-galactosidase A gene (GLA) have been reported as a cause of systemic and cardiac Fabry disease. It is inherited as an X-linked recessive disorder.
(5) Arrhythmogenic right ventricular cardiomyopathy (ARVC)
A myocardial disease that causes right ventricular enlargement, reduced wall motion, and left ventricular block-type ventricular tachycardia due to the loss of right ventricular cardiomyocytes, fatty degeneration, cellular infiltration, and fibrosis. The incidence is thought to be 1 in 5,000, with 30-50% being familial, and accounting for 20% of causes of sudden death in young people. It is caused by genetic abnormalities in desmosome component proteins involved in cell adhesion. Mutations in the cardiac ryanodine receptor gene (RyR2) have also been reported.
(6) Left ventricular myocardial compaction disorder: A cardiomyopathy characterized by excessive reticular trabeculation and deep gaps in the ventricular wall, with reduced contractile force and a dilated, thickened left ventricle (thinning of the compact layer). This can lead to heart failure, thrombosis, arrhythmia, and sudden death. Genetic mutations in tafazzin, α-dystrobrevin (dystrophin-associated protein), Cyper/ZASP (Z-line-associated protein), and sarcomere protein have been reported to be the cause.
(7) Precautions and challenges in genetic analysis It is necessary to consider "what is the causative gene mutation" rather than "what is the causative gene". For example, the titin gene is the causative gene for DCM and HCM, but the gene mutations that cause each are different. In other words, it is necessary to consider that "this mutation causes DCM, but another mutation causes HCM". Another example is SCN5A mutations, which are known to cause congenital long QT syndrome type 3 (LQT3) and Brugada syndrome, but other SCN5A mutations are known to cause dilated cardiomyopathy, and the pathology caused by the site of the mutation is different. Currently, morphological classification is the mainstream for classification of cardiomyopathy, but if genetic analysis advances further in the future, it will be possible to perform genetic etiological classification based on that. It is expected that next-generation sequencers will make genetic analysis more efficient. However, even if detailed genomic information is known, the results of genome analysis cannot be used for genetic diagnosis unless it is integrated with accurate clinical information to establish genotype-phenotype correlation. Careful filing of clinical information is essential.
(8) Current status and challenges of genetic diagnosis Although genetic diagnosis of cardiomyopathy contributes to a definitive diagnosis, with the exception of some diseases such as cardiac Fabry disease, at present it is rarely directly linked to treatment options. However, it is expected that elucidating the pathology, beginning with identifying the causative gene mutation, will contribute to future improvements in diagnostic methods and the development of treatments. Furthermore, as genetic analysis progresses, it is not uncommon for gene mutations to be detected in asymptomatic cases. There is no evidence yet in humans as to whether early treatment (intervention) can delay or prevent the onset of such asymptomatic cases that are positive for gene mutations before the onset of symptoms, or whether it can improve the prognosis even if the disease does develop.
When conducting genetic testing, the Japanese Association of Medical Sciences Guidelines (Japanese Association of Medical Sciences, 2011) must be adhered to, and written informed consent must be obtained before testing. When familial cardiomyopathy is suspected, the patient's blood relatives may carry the same mutation as the patient. If genetic testing confirms that blood relatives do not carry the mutation, unnecessary lifelong regular checkups (electrocardiograms, echocardiograms) and exercise restrictions can be avoided. Prior consultation with a genetic counselor or specialist is recommended regarding interpretation of genetic test results and explanations to patients. [Morita Hiroyuki]
■ References
Maron BJ, Towbin JA, et al: Contemporary definitions and classification of the cardiomyopathies. Circulation, 113: 1807-1816, 2006.
Japanese Medical Association: Guidelines for genetic testing and diagnosis in medical care (2011). http://jams.med.or.jp/guideline/genetics-diagnosis.pdf

Table 5-4-2
Causative gene of hypertrophic cardiomyopathy ">

Table 5-4-2

Table 5-4-3
Causative genes and complications of dilated cardiomyopathy ">

Table 5-4-3

Cardiomyopathy (myocardial disease)

There are various classifications of cardiomyopathy, but the representative WHO/ISFC (WHO: World Health Organization, ISFC: International Society and Federation Cardiology) committee report in 1995 defines cardiomyopathy as "myocardial disease accompanied by cardiac dysfunction" and classifies it into dilated, hypertrophic, restrictive, arrhythmogenic right ventricular cardiomyopathy, and unclassified cardiomyopathy. Furthermore, myocardial diseases with a clear cause or association with a systemic disease are classified as "specific myocardial diseases." In addition, in Japan's 2005 "Cardiomyopathy, Diagnostic Guide and Commentary," cardiomyopathy is classified into 1) dilated cardiomyopathy, 2) hypertrophic cardiomyopathy, 3) restrictive cardiomyopathy, 4) arrhythmogenic right ventricular cardiomyopathy, 5) familial sudden death syndrome, 6) mitochondrial cardiomyopathy, 7) Fabry heart disease, and 8) takotsubo cardiomyopathy. Meanwhile, the AHA (American Heart Association) has proposed in its statement that primary conditions are those in which the lesions are limited to the myocardium only or mainly to the myocardium, and secondary conditions in which the myocardium is included as part of a systemic disease, and that primary conditions be further classified as genetic, mixed, or acquired. [Shinichi Hyakumura and Hiroshi Wada]
■ References <br /> Tomoike, Hitoshi, et al.: Guidelines for the management of dilated cardiomyopathy and related secondary cardiomyopathies, Japanese Circulation Society. http://www.j-circ.or.jp/guideline/pdf/JCS2011_tomoike_h.pdf
Ministry of Health, Labor and Welfare Intractable Disease Overcoming Project Idiopathic Cardiomyopathy Research Group: Cardiomyopathy, Diagnosis Guide and Commentary (Kitahata Akira et al. eds.), Karinsha, Sapporo, 2005.
McKenna WJ, et al: Report of the 1995 World Health Organization/International Society and Federation of Cardiology task force on the definition and classification of cardiomyopathies. Circulation, 93: 841, 1996.

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

かつて「原因不明の心筋疾患」と定義されていた心筋症であるが，原因遺伝子変異の同定が進み，この定義は過去のものとなった．2006年のアメリカ心臓協会の心筋症分類（Maronら， 2006）では，心筋症は遺伝性，混合性（遺伝性と後天性），後天性に分類されており，心筋症の病因において遺伝子異常は大きなウエイトを占めるに至っている．　肥大型心筋症（HCM）では約60％，拡張型心筋症（DCM）では約30％の症例に原因遺伝子変異が同定される．多くは常染色体優性遺伝形式をとる．1990年，HCMの大家系に心筋ミオシン重鎖遺伝子変異が同定されて以来，連鎖解析により心筋トロポニンT，αトロポミオシン，心筋ミオシン結合蛋白Cなどサルコメア蛋白の遺伝子変異が次々に報告され，当初は「HCM＝サルコメア病」と考えられた．現在でも，サルコメアの異常がHCMをきたす主たる原因であることは間違いない．しかし，サルコメアの遺伝子異常はHCMにとどまらず，DCM，拘束型心筋症（RCM），左室心筋緻密化障害（LVNC），周産期心筋症などほかの心筋症の原因でもあることがわかっている．
（1）肥大型心筋症
（hypertrophic cardiomyopathy： HCM）（表5-4-2）　心筋の肥大，拡張障害，心筋細胞の肥大，錯綜配列，間質線維化を特徴とする．人口500人あたり1人程度と頻度が高く，循環器領域における遺伝性疾患として最多である．無症状から，流出路圧較差をきたす重症のものまで臨床徴候は多岐にわたる．若年者心臓突然死の原因の第一位である．約10％の症例では経過中に拡張型心筋症様になり難治性心不全をきたす（拡張相肥大型心筋症）．　約60％の症例に原因遺伝子変異が同定されている．現在までに1000種類以上のサルコメア蛋白遺伝子変異が報告されている．常染色体優性遺伝形式をとり，ヘテロ型で発症する．心筋ミオシン重鎖遺伝子（MYH7），心筋ミオシン結合蛋白C遺伝子（MYBPC3），ついで心筋トロポニンT遺伝子（TNNT2）に変異が同定されることが多い．1人の祖先から代々受け継がれ広く分布するようなfounder変異は少なく，1家系だけにみられるprivate変異が多い．これが遺伝子診断の実践を困難にしている一因である．家族性ではなく，孤発する（sporadic）症例にも遺伝子変異が同定されることが多いが，これは，①親からの遺伝ではなくその個人に新規（de novo）に発生した変異による場合，または②親も同じ変異を保有しているが親には発症せず，その個人でのみ発症に至る場合（変異の浸透率が低い），にみられる．
　サルコメア遺伝子変異がHCMをきたす機序に関して検討が進められている．サルコメア蛋白遺伝子にみられる原因変異のほとんどはミスセンスないしは小欠失である．コードされた変異蛋白は安定的に心筋線維に取り込まれ，サルコメア機能の障害をきたす．単離した変異ミオシン分子を用いた解析では，ATPase活性は亢進，発生する力は大きくなり，アクチンフィラメントのスライディングは速くなる．これらの変化はHCM早期にみられる収縮亢進状態をよく説明する．stiff sarcomere，ストレッチ反応の亢進，Caイオン感受性亢進が病態に関与するという説が提唱されている．心肥大発症前の早期段階から心筋間質で線維化反応が活性化し病態形成に重要な役割を果たすこともわかってきた．
　「同じ変異を保有していても臨床徴候には個人差がある」ことに注意が必要である．併存する遺伝要因（genetic modifier）ないしはおかれた環境の違いによると考えられる．しかし，心肥大の重症度やパターン，発症年齢は変異の種類によりある程度類型化できる．late-onsetのHCMにはMYBPC3変異によるものが多い，TNNT2変異では心肥大が軽度である割には突然死が多い，ACTC Glu101Lys変異は心尖部肥厚型が多い，などが報告されている．　サルコメア蛋白遺伝子以外にもHCM原因変異が同定されているが頻度は低い．
（2）拡張型心筋症（dilated cardiomyopathy： DCM）（表5-4-3）
　心筋収縮障害，心室内腔拡張，心筋細胞脱落と間質線維化を特徴とする．難治性心不全や不整脈をきたす予後不良の疾患である．連鎖解析，候補遺伝子アプローチを用いて多くの原因遺伝子変異が同定されてきた．サルコメア蛋白だけではなく，Z線蛋白，介在板蛋白，中間径フィラメントやジストロフィン関連糖蛋白複合体，核膜構成蛋白などサルコメアで発生した力を伝達する構造物，Caイオンをはじめとするイオンサイクリング系に関与する蛋白，転写制御因子などきわめて多岐にわたる．「力発生障害」「力伝達障害」をキーワードに病態の説明が可能である．loose sarcomere，ストレッチ反応低下，Caイオン感受性低下，代謝ストレス障害が病態に関与しているという説が提唱されている．
（3）拘束型心筋症（restrictive cardiomyopathy：RCM）
　心室充満の障害と拡張容量減少を特徴とするまれな心筋疾患である．右心不全あるいは両心不全をきたす．心室壁厚と収縮能は正常に保たれる．トロポニンI（TNNI3）遺伝子変異が特発性RCMの原因として報告されている．
（4）グリコーゲン貯留性心筋症および心Fabry病
　グリコーゲン貯留性疾患は心肥大を主徴とする心筋症をきたす．骨格筋病変を伴うケースは診断がつきやすいが，心筋症単独症例ではHCMと診断されがちである．心筋生検での心筋細胞の空胞変性，空胞内のグリコーゲン貯留（PAS染色）所見をもって正確な診断に至ることが多い．HCMとは異なり，心筋細胞の錯綜配列は少なく，間質線維化も有意でない．WPW症候群様の刺激伝導障害をきたす．成人において特に問題になるのはAMP キナーゼのγ2サブユニットをコードするPRKAG2の変異（AMP キナーゼの持続的活性化をきたす）である．常染色体優性遺伝形式をとる．
　心Fabry病は心臓限局性のスフィンゴ脂質蓄積症である．全身性のFabry病がα-ガラクトシダーゼA活性の完全欠損によって起こるまれな疾患（約12万人に1人）であるのに対し，心Fabry病はα-ガラクトシダーゼA活性の部分欠損によって起こり，決してまれな疾患ではない．わが国では心肥大男性症例の3％程度にみられることが明らかにされている．α-ガラクトシダーゼの補充により心肥大の改善をみるので，本症はほかの心肥大と明確に鑑別して治療にあたる必要がある．全身性のFabry病，心Fabry病の原因としてα-ガラクトシダーゼA遺伝子（GLA）の変異が多数報告されている．X染色体劣性遺伝形式をとる．
（5）不整脈源性右室心筋症（arrhythmogenic right ventricular cardiomyopathy： ARVC）
　右室心筋細胞の脱落，脂肪変性，細胞浸潤と線維化により右室拡大，壁運動低下および左室ブロック型心室頻拍をきたす心筋疾患．頻度は5000人に1人，30〜50％が家族性，若年者突然死原因の20％を占めるとされる．細胞接着に関与するデスモソーム構成蛋白の遺伝子異常による．その他，心リアノジン受容体遺伝子（RyR2）変異の報告もある．
（6）左室心筋緻密化障害
　心室壁の過剰な網目状肉柱形成と深い間隙（trabeculation）を特徴とする，収縮力低下と拡張した肥厚左室（緻密層菲薄化）を呈する心筋症．心不全，血栓症，不整脈，突然死をきたす．tafazzin，α-ジストロブレビン（ジストロフィン関連蛋白），Cyper/ZASP（Z線関連蛋白），サルコメア蛋白などの遺伝子変異が原因として報告されている．
（7）遺伝子解析の注意点と課題
　「原因遺伝子は何か」ではなく，「原因遺伝子変異は何か」という視点が必要である．たとえば，タイチン遺伝子はDCMおよびHCMの原因遺伝子であるが，おのおのの原因となる遺伝子変異は別箇である．すなわち，「この変異はDCMをきたすが，別の変異はHCMをきたす」というとらえ方が必要である．別の例をあげる．SCN5A変異は先天性QT延長症候群3型（LQT3），Brugada症候群の原因として知られるが，SCN5Aの別の変異は拡張型心筋症の原因として知られるなど変異の部位によって引き起こされる病態が異なる．心筋症の分類は現在形態的分類が主流であるが，遺伝子解析が今後さらに進めばそれに基づいた遺伝病因学的分類を行うことが可能になる．次世代型シークエンサーによる遺伝子解析の効率化が期待される．ただし，ゲノム情報が詳細にわかっても，正確な臨床情報と統合してgenotype-phenotype連関を確立しないと，ゲノム解析の成果を遺伝子診断に活かすことはできない．臨床情報の丹念なファイリングが不可欠である．
（8）遺伝子診断の現状と課題
　心筋症における遺伝子診断は，診断確定に貢献するものの，心Fabry病など一部の疾患を除いて，現時点で治療選択に直結することは少ない．しかしながら，原因遺伝子変異同定に始まる病態解明は将来の診断法改良，治療開発に貢献することが期待される．また，遺伝子解析を進めると，未発症例に遺伝子変異が検出されることもまれではない．このような遺伝子変異陽性未発症例に対して発症前から何らかの早期治療（介入）を行えば発症を遅らせることができるのか，予防できるのか，また発症したとしても予後を改善させうるのか，ヒトではいまだエビデンスが得られていない．
　遺伝子検査を行う際には日本医学会ガイドライン（日本医学会， 2011）を遵守し，検査前に必ず文書によるインフォームドコンセントを得る必要がある．家族性心筋症が疑われる場合，患者の血縁者は患者と同じ変異を有している可能性がある．血縁者がその変異を有していないことが遺伝子検査で確認されれば，生涯にわたる不必要な定期検診（心電図，心エコー検査）の反復や運動制限を避けることができる．遺伝子検査の結果解釈や患者への説明に関しては，遺伝カウンセラーや専門医への事前コンサルトが勧められる．［森田啓行］
■文献
Maron BJ, Towbin JA, et al: Contemporary definitions and classification of the cardiomyopathies. Circulation, 113: 1807-1816, 2006.
日本医学会：医療における遺伝学的検査・診断に関するガイドライン（2011）．http://jams.med.or.jp/guideline/genetics-diagnosis.pdf

表5-4-2
肥大型心筋症の原因遺伝子">

表5-4-2

表5-4-3
拡張型心筋症の原因遺伝子と合併症">

表5-4-3

心筋症(心筋疾患)

分類
　心筋症の分類にはさまざまなものがあるが，代表的なWHO/ISFC（WHO：World Health Organization，ISFC：International Society and Federation Cardiology）の1995年委員会報告書では心筋症は「心機能障害を伴う心筋疾患」と定義され拡張型（dilated），肥大型（hypertrophic），拘束型（restrictive），不整脈源性右室心筋症（arrhythmogenic right ventricular cardiomyopathy）と分類不能の心筋症（unclassified cardiomyopathy）に分類されている．さらに，原因または全身疾患との関連が明らかな心筋疾患は“特定心筋疾患”として区別される．またわが国の2005年「心筋症，診断の手引きとその解説」では心筋症は①拡張型心筋症，②肥大型心筋症，③拘束型心筋症，④不整脈源性右室心筋症，⑤家族性突然死症候群，⑥ミトコンドリア心筋症，⑦心Fabry病，⑧たこつぼ心筋障害に分類されている．一方，AHA（米国心臓協会）はそのステートメントで心筋のみあるいはおもに心筋に病変が限られるprimary（一次性）と全身疾患の一部として心筋が含まれるsecondary（二次性）に分け，primaryをさらにgenetic（遺伝性）， mixed（混合性）， acquired（後天性）に分類することを提唱している．［百村伸一・和田　浩］
■文献
友池仁暢，他：拡張型心筋症ならびに関連する二次性心筋症の診療に関するガイドライン，日本循環器学会．http://www.j-circ.or.jp/guideline/pdf/JCS2011_tomoike_h.pdf
厚生労働省難治性疾患克服事業特発性心筋症調査研究班：心筋症，診断の手引きとその解説（北畠顕他編），かりん舎，札幌， 2005.
McKenna WJ, et al: Report of the 1995 World Health Organization/International Society and Federation of Cardiology task force on the definition and classification of cardiomyopathies. Circulation, 93: 841, 1996.

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