See Article by Camporeale et al

Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death and heart failure. Within the HCM, clinical spectrum mimics genocopies and phenocopies such as amyloid and Fabry disease (FD) that it is important to detect as there may be specific available therapies.¹ This statement highlights that modern medicine lacks disease-modifying therapy for typical sarcomeric HCM. HCM is genetically and phenotypically complex.² Our understanding about how hundreds of mutations in 11 genes lead to overt disease, morbidity and mortality is frustrated by our poor understanding of the underlying pathophysiology and stages of cardiomyopathy development. This itself is based on difficulties in “reading out” signals in vivo using imaging and other techniques to elucidate processes activated in the myocardium, confounding drug development. Since the days of William Osler, it has been highlighted that rare diseases and cleaner phenotypes may permit pattern recognition clouded in more complex, typical disease. These may still use the same basic limited portfolio of cellular clockwork and mechanisms; for example, Anderson FD and amyloid cause left ventricular hypertrophy (LVH), one starting with intracellular sphingolipid storage³ and the other with extracellular protein deposition.⁴ Like sarcomeric HCM, however, they both may lead to changes in cardiomyocytes, fibroblasts, endothelial cells, and extracellular space.⁵

Societal endeavor and medicine in particular are driven by technological advances. Several disease mechanisms in HCM have been unveiled by the technology of cardiovascular magnetic resonance. Scar imaging by means of late gadolinium enhancement has allowed the acknowledgment of different scar patterns in HCM, amyloidosis, and FD,^6–8 all potentially late disease features. But by using a different technique, T1 mapping, an unexpected finding is built on in this issue of Circulation: Cardiovascular Imaging, by Camporeale et al.⁹ The HCM genocopy FD results in a measurably low native (noncontrast) T1 in the myocardium of FD,¹⁰ and around half of subjects with a pathogenic gene mutation for FD have T1 lowering, even before LVH occurs.¹¹ Remarkably, it appears that T1 mapping provides a “read-out” of the initial disease insult in FD—myocyte lipid storage. This signal is distinct from that in amyloid⁷ and near unique—only FD and iron overload substantially lower myocardial T1,¹⁰ although athletic adaptation can reduce T1 modestly. Its presence when combined with other assessments permits staging of established disease.¹² Here, Camporeale et al⁹ address early disease. Focusing on the prehypertrophic stage, they conducted a prospective observational study of 44 LVH-negative FD patients to investigate the associations of low T1 with baseline cardiac function, exercise capacity, and cardiac arrhythmias, as well as interval change over 12 months. The authors show that low T1 was found in 59% of LVH-negative FD patients, in line with previous reports.¹¹ T1 values inversely correlated with left ventricular mass/left ventricular maximum wall thickness and left atrial volume. Patients with low T1 values also had more electrocardiographic changes, particularly repolarization abnormalities and increased voltages. Functional status as assessed by the Mainz Severity Score Index was also significantly worse in patients with low T1. These associations highlight low myocardial T1 as an early phenotype marker not only for cardiac but also for systemic FD. Even in a clean monogenic disease such as FD, there was phenotypic heterogeneity. Low T1 was more prevalent in classical mutations, and there was sex dimorphism¹² with low T1 being more prevalent in males and late gadolinium enhancement without LVH only occurring in females. Interestingly, however, both low and normal T1 groups showed markedly reduced functional capacity on cardiopulmonary exercise testing, suggesting that early limitation is not related to myocardial storage. This earlier, systemic phenotype may be musculoskeletal, inflammatory, neurological, endothelial, or indeed more complex, involving higher cortical function and motivation. Inflammatory pathways seem activated in myocardial FD once late gadolinium enhancement is present,¹³ but systemic inflammation may start earlier. Abnormal coronary microvascular function is recognized in FD patients with LVH,¹⁴ but whether this starts before LVH or T1 lowering (ie, myocyte storage) is currently unknown, although likely as endothelial cell storage appears more dynamic than terminally differentiated myocyte storage. Nevertheless, a low myocardial T1 mapping predicted clinical worsening at 12-month follow-up (as did left ventricular maximum wall thickness and left atrial volume) highlighting the links of myocardial involvement to systemic FD multi-organ involvement.

How could we take these data further? To be able to measure the earliest steps of phenotype evolution before LVH is an opportunity. Sarcomeric HCM mutations have variable penetrance making the identification of early changes and therefore potential therapeutic targets harder. Here, in FD, a cohort likely to be about to develop LVH can be recognized with the potential to identify early biomarkers and key pathways for FD, with insights transferable to more complex diseases that may lead to the development of Precision Medicines.

Within FD, the typical LVH-negative patient is currently untreated. Where there is a low T1 (storage), particularly with ECG changes (conduction disease) or late gadolinium enhancement/troponin elevation (inflammation), it is conceivable that therapy could switch disease off before the activation of potentially self-sustaining hypertrophic pathways. On the other hand, patients without storage may represent a stable, disease free, nonprogressing phenotype, confidently requiring no therapy. Clinical trials testing these hypotheses seem worthwhile.

The authors Camporeale et al⁹ should be congratulated on their study and the potential insights it and other similar studies may provide, partly for the rare disease under investigation, but also for the transferability of insights into more prevalent conditions.

Dr Moon is PI on an investigator-led grant from Sanofi Genzyme and has received honoraria from Sanofi Genzyme and Shire-Takeda. The other author reports no conflicts.

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

参见Camporeale等人的文章

肥厚型心肌病（HCM）是心脏猝死和心力衰竭的重要原因。在HCM中，临床谱图模仿基因和表型，例如淀粉样蛋白和法布里病（FD），由于可能存在特定的可用治疗方法，因此对其进行检测非常重要。¹该声明强调，现代医学对典型的肌节型HCM缺乏改善疾病的疗法。HCM是遗传和表型复杂的。^2个我们对11种基因的数百种突变如何导致明显的疾病，发病率和死亡率的理解因我们对潜在的病理生理学和心肌病发展阶段的理解不佳而受挫。这本身是基于使用成像和其他技术来阐明体内心肌激活过程，从而混淆药物开发的体内“读出”信号的困难。自从威廉·奥斯勒（William Osler）时代以来，人们就已经强调指出，罕见病和较清晰的表型可能会使模式识别模糊在更复杂的典型疾病中。这些仍然可以使用相同的基本有限的蜂窝式发条和机制。例如，安德森（Anderson）FD和淀粉样蛋白引起左心室肥大（LVH），一种起于细胞内鞘脂储存³另一个具有细胞外蛋白质沉积。⁴然而，它们像肌节型HCM一样，都可能导致心肌细胞，成纤维细胞，内皮细胞和细胞外空间发生变化。⁵

社会的努力，特别是医学受到技术进步的推动。心血管磁共振技术揭示了HCM中的几种疾病机制。通过enhancement的晚期增强对疤痕进行成像，可以确认HCM，淀粉样变性病和FD，^6-8中所有可能的晚期疾病特征的不同疤痕类型。但是，通过使用另一种技术（T1映射），在Camporeale等人的《循环：心血管成像》一期中建立了一个出乎意料的发现。⁹ HCM基因型FD导致FD心肌的天然T1低（无对比度），即使在LVH发生之前，FD的¹⁰个病原体基因突变的受试者中约有一半的T1降低。¹¹值得注意的是，似乎T1作图提供了对FD-肌细胞脂质存储的初始疾病侵害的“读出”。该信号是从不同的淀粉样蛋白⁷和近独特-仅FD和铁过载基本上较低的心肌T1，¹⁰尽管运动适应可适度减少T1。当与其他评估结合使用时，可以对已确诊的疾病进行分期。¹²这里是Camporeale等人⁹解决早期疾病。他们着眼于肥厚前阶段，对44例LVH阴性FD患者进行了一项前瞻性观察性研究，以调查低T1与基线心功能，运动能力和心律不齐以及12个月内间隔变化的关系。作者表明，在59％LVH阴性FD患者中发现低T1，与以前的报道一致。¹¹T1值与左心室质量/左心室最大壁厚和左心房容积成反比。T1值低的患者也有更多的心电图变化，尤其是复极异常和电压升高。通过Mainz严重性评分指数评估的功能状态在T1低的患者中也显着恶化。这些关联性突出显示低心肌T1是不仅对心脏而且对系统性FD的早期表型标记。即使在干净的单基因疾病（如FD）中，也存在表型异质性。低T1在经典突变中更为普遍，并且存在性别二态性¹²低T1在男性中更普遍，晚期enhancement增强在女性中没有LVH发生。然而，有趣的是，低和正常T1组在心肺运动测试中均显示出明显的功能降低，这表明早期限制与心肌存储无关。这种较早的全身表型可能是肌肉骨骼，炎症，神经，内皮或什至更复杂，涉及更高的皮层功能和动机。一旦存在late增强后期，心肌FD中的炎症途径似乎就被激活了[ ^13]，但全身性炎症可能更早开始。FD LVH患者中认识到冠状动脉微血管功能异常¹⁴但是目前尚不清楚是否在LVH或T1降低（即心肌细胞存储）之前开始，尽管可能是内皮细胞存储比终末分化的心肌细胞存储更动态。尽管如此，低的心肌T1图谱预测在12个月的随访中临床恶化（左心室最大壁厚和左心房容积也是如此）突出了心肌受累与全身性FD多器官受累的联系。

我们如何进一步获取这些数据？为了能够在LVH发生之前测量表型演变的最早步骤，这是一个机会。肌节型HCM突变的外显率可变，这使得早期变化的识别变得困难，因此潜在的治疗靶标变得更加困难。在FD中，可以识别出可能即将发展LVH的人群具有识别FD的早期生物标记物和关键途径的潜力，并将见解转移到更复杂的疾病中，从而可能导致Precision Medicines的发展。

在FD内，典型的LVH阴性患者目前未接受治疗。如果T1（储存）较低，尤其是ECG改变（传导疾病）或late增强/肌钙蛋白升高（炎症）晚期，可以想象疗法可以在激活潜在的自我维持的肥大途径之前关闭疾病。另一方面，没有储存的患者可能表现出稳定，无疾病，无进展的表型，肯定不需要治疗。测试这些假设的临床试验似乎是值得的。

Camporeale等[ ^9]的作者应受到祝贺，他们的研究以及该研究和其他类似研究可能提供的潜在见解值得祝贺，部分原因是要研究的罕见疾病，也可以是见解在更普遍的条件下的可移植性。

Moon博士是赛诺菲健赞（Sanofi Genzyme）由研究人员主导的研究员的PI，并获得了赛诺菲健赞（Sanofi Genzyme）和夏尔竹田（Shire-Takeda）的酬金。另一位作者报告没有冲突。

本文表达的观点不一定是编辑者或美国心脏协会的观点。