工作记录

肥厚型心肌病的临床病程与治疗

hypertrophic cardiomyopathy (HCM), the most common mono- genic cardiovascular disorder, is diverse in presentation and natural history, frequently misunderstood, and often underrecognized in clinical practice. A comprehensive clinical description of the disease was first made 55 years ago by the Braunwald group at the National Institutes of Health; at that time it was called idiopathic hypertrophic subaortic stenosis. An understanding of diagnostic features, genetic factors, clinical course, and management of the broad spectrum of HCM has evolved measurably, particularly in the past 15 years.  A vast literature (more than 18,000 reports) has emerged, and in many respects, contemporary HCM differs markedly from the disease of previous eras.

肥厚性心肌病(HCM)是最常见的单核心血管疾病，在表现上以及自然变化中呈现多样性，因此常被误诊，或在临床上诊断不出来。55年前，美国国立卫生研究院的Braunwald小组首次对HCM进行了系统的临床描述。那时它被称为特发性肥厚性主动脉瓣下狭窄。随着研究的进展，特别是在过去的15年中。对诊断特征，遗传因素，临床过程和广泛HCM管理的理解已经有了可观的发展。出现了大量的文献（超过 18，000的报告），在许多方面，现在的HCM与以前时代的HCM明显不同。

Epidemiologic features流行病学特征

Diagnosis and Prevalence

诊断和患病率

Clinical diagnosis of HCM is based on a hypertrophied, no dilated left ventricle

— which is identified by means of echocardiography or magnetic resonance imaging (MRI) — in the absence of another cardiac, systemic, metabolic, or syndromic disease. HCM的临床诊断通常是基于肥厚的没有扩张的左心室-通过心脏超声或MRI判断—在没有其他心脏，全身，代谢或综合征疾病的情况下。

Echocardiography-based epidemiologic studies have shown a disease prevalence of 1 case per 500 persons in the general population but a higher prevalence (1 case per 200) when both clinical and genetic diagnoses, including those in family members, are taken into account (Fig. 1). 以心脏超声为基础的流行病学研究表明在普通群体中每500有一人患病，但是当综合考虑临床和基因诊断因素时，这一比例提高（每200人中有1例）。

An estimated 750,000 persons in the United States may be affected by HCM. 估计美国有75万人口可能患有HCM。

However, the disease has been diagnosed in only a fraction of them (about 100,000), usually by means of noninvasive imaging, which suggests that most persons do not receive a diagnosis during their lifetime (Fig. 1). 然而只有部分人真正确诊（大概10万）通常通过非侵袭性成像，这表面大多数人在他们一生中没有得到诊断。

Under recognition of hypertrophic cardiomyopathy has disproportionately affected women and also underserved minorities, with evidence of under recognition among blacks including deaths on the athletic field of black men with undiagnosed disease and potential under referral of affected black patients for specialized hypertrophic cardiomyopathy -related  treatments.

对肥厚型心肌病的认识不足多影响女性和缺乏医疗服务的少数民族，黑人认识不足，包括未确诊疾病的黑人男性运动场死亡，以及受影响的黑人患者转介专门的肥厚型心肌病相关治疗的可能性。

Global Burden 全球化压力

HCM has been identified in 122 countries (representing approximately 90% of the world population), with spontaneous (de novo) mutations probably accounting for this disease burden (Fig. 1). It is likely that HCM affects approximately 20 million people globally, well beyond the population that was initially thought to be affected.

已有122个国家发现HCM（占世界人口的90%），自然的基因突变或许可以解释这样的疾病总量(Fig. 1)。HCM很可能影响全球约2000万人，远远超出最初认为受影响的人群。

Although the disease occurs in many countries, ethnic groups, and races and affects both sexes equally, its clinical and phenotypic expression and genetic substrate do not appear to vary substantially according to demographic characteristics. Hypertrophic cardiomyopathy has been under recognized in many parts of the world, but an awareness of the disease is now penetrating the health care systems in China, India, and other developing countries, defining an emerging frontier for diagnosis and management.

尽管这种疾病发生在许多国家、民族、种族和男女之间，但其临床表现，表型表达和遗传基质似乎并没有因人口特征而有很大的差异。肥厚型心肌病已在世界许多地方得到认可，但对这种疾病的认识正在渗透到中国，印度和其他发展中国家的医疗保健系统，从而为诊断和管理创造了一个新兴的前沿。

It is likely that HCM affects approximately 20 million people globally, well beyond the population that was initially thought to be affected.

Global Burden 全球化压力

HCM has been identified in 122 countries (representing approximately 90% of the world population), with spontaneous (de novo) mutations probably accounting for this disease burden (Fig. 1). It is likely that HCM affects approximately 20 million people globally, well beyond the population that was initially thought to be affected.

已有122个国家发现HCM（占世界人口的90%），自然的基因突变或许可以解释这样的疾病总量(Fig. 1)。HCM很可能影响全球约2000万人，远远超出最初认为受影响的人群。

Although the disease occurs in many countries, ethnic groups, and races and affects both sexes equally, its clinical and phenotypic expression and genetic substrate do not appear to vary substantially according to demographic characteristics. Hypertrophic cardiomyopathy has been under recognized in many parts of the world, but an awareness of the disease is now penetrating the health care systems in China, India, and other developing countries, defining an emerging frontier for diagnosis and management.

尽管这种疾病发生在许多国家、民族、种族和男女之间，但其临床表现，表型表达和遗传基质似乎并没有因人口特征而有很大的差异。肥厚型心肌病已在世界许多地方得到认可，但对这种疾病的认识正在渗透到中国，印度和其他发展中国家的医疗保健系统，从而为诊断和管理创造了一个新兴的前沿。

It is likely that HCM affects approximately 20 million people globally, well beyond the population that was initially thought to be affected.

图1.肥厚型心肌病的流行病学特征。

图A显示了疾病的全球分布（红色）。虽然世界上某些地区无法获得报告，但这种遗传病很可能在全球范围内传播。图B显示了临床鉴定和未鉴定病例的比例。

genetic factors遗传因素

HCM is inherited in an autosomal dominant pattern, associated with mutations (nucleotide sequence variants) in 11 or more genes encoding proteins of thick and thin myofilament contractile components of the cardiac sarcomere or Z disk, with beta-myosin heavy chain and myosin-binding protein C genes most commonly involved. Genetic testing panels show vast heterogeneity and diverse molecular pathways, with more than 2000 sarcomere mutations identified. Some of the mutations are considered to be pathogenic, but in others pathogenicity is uncertain, and many are confined to single families (Fig. 2).

HCM以常染色体显性模式遗传，与11个或更多基因中的突变（核苷酸序列变体）相关，所述基因编码心肌肌节或Z盘的厚和细肌丝收缩组分的蛋白质，具有β-肌球蛋白重链和肌球蛋白结合蛋白 C基因最常涉及。基因检测小组显示出巨大的异质性和多样化的分子途径，确定了超过2000个肌节突变。一些突变被认为是致病性的，但在其他突变中，致病性是不确定的，并且许多突变仅限于单个家族（图2）。

工作记录

These seminal insights have made it possible to diagnose HCM on the basis of laboratory test ing in patients who otherwise would be unaware of  their  genetically  affected  status.  However, genotype–phenotype correlations have been in- consistent,  and  single  (or  multiple)  sarcomere variants are unreliable in predicting prognosis, with no specific role in risk stratification. Thus, important management decisions in cases of HCM are based solely on clinical criteria.

这些开创性的见解使得有可能在患者身上进行实验室检测来诊断HCM，否则他们将不知道自己的遗传受影响状态。然而，基因型 - 表型相关性不一致，单个（或多个）肌节变体在预测预后方面不可靠，在风险分层中没有特定的作用。因此，HCM病例的重要管理决策完全基于临床标准。

Genetic testing is confined largely to next- generation (cascade) family screening, which affords the opportunity to identify family members who are unlikely to inherit HCM, as well as affected family members without left ventricular hypertrophy (Fig. 2). Such gene carriers characteristically have no cardiac events or symptoms, and many carriers will never have HCM but can nevertheless transmit disease-causing mutations to subsequent generations. Genetic  testing  can  also  identify  metabolic  and storage phenocopies that mimic HCM.

基因检测主要局限于下一代（级联）家庭筛查，这提供了识别不太可能遗传HCM没有左心室肥大的家庭成员的机会（图2）。这些基因携带者没有表现出特征性的心脏问题或症状，并且许多携带者将永远不会犯病但是仍然可以将致病突变基因传递给后代。基因检测还可以识别模拟HCM的代谢和储存表型。

With technological advances (whole-genome sequencing), variants of uncertain significance have become more numerous, making interpretation of pathogenicity increasingly complex and potentially leading to misinterpretation of benign variants as pathogenic in diverse racial, ethnic, and ancestry populations. Indeed, at present, only one third of probands with HCM have pathogenic (or probably pathogenic) mutations suitable for family screening. Sporadic (nonfamilial) HCM (i.e., sarcomere mutations in a patient without a family history of HCM) may be more common than currently thought.

随着科学技术的发展（全基因组测序），随着技术进步（全基因组测序），具有不确定意义的变异变得越来越多，致使致病性的解释变得越来越复杂并且可能导致对良性变异的错误解释，因为它们在不同的种族，民族和血统群体中具有致病性。实际上，目前，只有三分之一的HCM先证者符合家庭筛查的致病性（或可能是致病性）突变。散发性（非家族性）HCM（即没有HCM家族史的患者的肌节突变）可能比目前认为的更常见。

影像学研究的形态特征

左心室肥厚

Characterization of the HCM phenotype has been based on almost 50 years of echocardiographic imaging. High-resolution tomographic MRI can provide a more reliable assessment of left ventricular hypertrophy in some patients, as well as enhanced risk stratification through in vivo identification of myocardial fibrosis  (Fig. 2).

过去50多年HCM表型特征一直是基于心脏超声成像。高分辨率的MRI能够对左心室肥大提供更可靠的评估，同时也通过体内鉴定心肌纤维化增强风险分层（图2）。 In most clinically diagnosed cases, left ventricular wall thickness is 15 mm or more (average, 21 mm), but there is massive thickness (30 to 50 mm) in some cases.Borderline thick- ness (13 to 14 mm) often requires differential diagnosis from systemic hypertension or physiologic athlete’s heart (Fig. 2). However, any left ventricular wall thickness is consistent with the clinical spectrum of HCM, including normal dimensions in gene carriers. Greater left ventricular thickness is associated with an increased risk of sudden death but not necessar- ily of progression to heart failure.

在大多数临床诊断的病例中，左心室壁厚度为15 mm或更大（平均21 mm），但在某些情况下存在超级厚度（30至50 mm）。边界厚度（13至14毫米）通常需要从系统性高血压或生理运动员的心脏进行鉴别诊断（图2）。然而，任何左心室壁厚度都与HCM的临床谱相一致，包括基因载体中的正常尺寸。左心室厚度增加会增加猝死风险，但不一定会发展为心力衰竭。

Phenotype expression includes a myriad of asymmetric patterns of hypertrophy that are highly variable even among first-degree relatives. These patterns can be diffuse, segmental (in- cluding apical), focal, or noncontiguous or could involve extension into the right ventricle,  as well as elongated mitral leaf lets or blood-filled crypts.

表型表达包括无数不对称的肥大模式，即使在一级亲属中也是如此。这些模式可以是弥漫性的，节段性的（包括顶端的），局灶性的或不连续的，或者可能涉及延伸到右心室，以及伸长的二尖瓣叶或血液充盈的隐窝。

The preferred option for initial family screening is diagnostic imaging every 12 to 18 months from the ages of 12 to 21 years, given that left ventricular hypertrophy commonly develops during adolescence and periods of accelerated growth, although adverse events punctuating the clinical course are rare (Fig. 2). The possibility of delayed penetrance of the phenotype into midlife can justify extended imaging surveillance at 5-year intervals.

初始家庭筛查的首选方案是从12至21岁每12至18个月进行一次诊断性成像，因为左心室肥大通常发生在青春期和加速生长期，尽管在临床过程中间断的不良事件很少见（图 2）。延迟表型渗入中年的可能性可以证明延长的成像监测是间隔5年。

Echocardiographic assessment with pulsed and tissue Doppler, strain rate imaging, and digital speckle tracking has provided mechanistic and functional insights into diastolic dysfunction, global and regional myocardial mechanics, and determinants of systolic ejection. However, these initiatives have not yet substantially affected disease prognosis or management.

脉冲和组织多普勒，应变率成像和数字斑点追踪的超声心动图评估为舒张功能障碍，全局和局部心肌力学以及收缩期射血的决定因素提供了机械和功能性见解。然而，这些举措尚未显着影响疾病预后或管理。

Outflow Obstruction

HCM is predominantly an obstructive disease, with 70% of patients having mechanical impedance to left ventricular outf low (gradients ≥30 mm Hg) at rest or with physiological provocation (i.e., exercise)30 (Fig. 2). Subaortic gradients are characteristically dynamic and subject to change with physiological loading conditions (e.g., increased with reduced ventricular volume due to dehydration, alcohol or food consumption, or a change from a sitting to a standing position), and these changes are often responsible for daily fluctuations in symptoms.

Outflow obstruction is usually produced by mitral-valve systolic anterior motion and septal contact due to flow drag, also resulting in mitral regurgitation (Fig. 2). Congenital, anomalous insertion of the papillary muscle directly into the mitral valve (without interposition of chordae) is occasionally responsible for midventricular muscular obstruction and is relevant to the planning of invasive treatment strategies.

流出障碍

HCM主要是一种阻塞性疾病，70％的患者在静息时或通过生理学激发（即运动）对左心室低（梯度≥30mmHg）具有机械阻抗（图2）。主动脉下梯度具有动态特征，并且随着生理负荷条件而变化（例如，由于脱水，酒精或食物消耗导致的心室容量减少或从坐位变为站立位置而增加），这些变化通常随着每日的症状波动。

流出阻塞通常由二尖瓣收缩前运动和由于流动阻力引起的间隔接触产生，也导致二尖瓣反流（图2）。先天性，乳头肌直接异常插入二尖瓣（没有插入腱索）偶尔会导致中度肌肉阻塞，并且与侵入性治疗策略的规划相关。

临床病程和管理