Progressive nature of myocardial fibrosis in pediatric hypertrophic cardiomyopathy: from mutation carrier to myocardial fibrosis

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy found in adults (1). Due to a wide variety of genetic defects and penetration, phenotypic manifestations or symptoms rise to the surface at a different time point during the lifetime (2). Early studies in adult HCM population focused on clinical manifestation and prognosis of patients with overt left ventricular hypertrophy (LVH). However, by virtue of easy accessibility to gene sequencing techniques and widely available family screening tool in HCM patients, researchers became interested in the genetically affected family members without overt LVH (3). From the perspective of a continuum of genetic disease, studies in the pediatric HCM patients and individuals carrying HCM-causing mutation without overt LVH (so-called preclinical or nonhypertrophic HCM) are of great importance to understand the pathophysiology and dynamic nature of HCM. Despite the absence of LVH, abnormal test results such as ST-segment depression, decreased myocardial tissue velocity and the elevated NT-proBNP level were demonstrated in the preclinical stage of HCM population (4). In addition, pediatric HCM patients showing apparent LVH in the early childhood showed dismal outcome early after the diagnosis (5). Thus, the clinical features of pediatric HCM seem to be much more dynamic and diverse than those of adult HCM patients.

Cardiovascular magnetic resonance (CMR) is an emerging diagnostic tool for accurate differential diagnosis and risk stratification in a wide variety of myocardial diseases. Thanks to its unique ability of tissue characterization, especially detection and quantification of the myocardial scar using late gadolinium enhancement (LGE) (6), CMR has been adopted as a main evaluation tool in the assessment of HCM. Though not established as a sole risk factor, LGE was suggested to predict sudden cardiac death risk in adult HCM patients (7,8). Due to a lack of the robust, single risk stratification strategy for sudden cardiac death, LGE has emerged as a highly possible prognosticator (9). Recently, in low-/intermediate-risk adult HCM patients (based on ESC sudden cardiac death criteria) with preserved left ventricular ejection fraction (10), LGE extent was significantly associated with prognosis, providing incremental prognostic utility (11). In a recent issue of Circulation, Axelsson Raja et al. reported CMR features of pediatric overt HCM and preclinical HCM population with a special focus on LGE (12). The authors addressed that LGE on CMR was detected in not a few pediatric HCM patients (46%), and the presence of which was also associated with symptoms, adverse outcomes and ventricular tachycardia in pediatric HCM patients (13-15). Although the association between LGE and adverse outcome was not statistically significant in this study, the follow-up of 3.4 years might not be enough to see the link between LGE and adverse events considering that the study population is children. Furthermore, LGE did not exist in the preclinical HCM subjects in this study (12). This finding is consistent with the previous report of 40 HCM-causing mutation carriers (16). The notion that LGE, irreversible myocardial fibrosis, was not detected without overt LVH is consistent with our belief that a disease process may be continuous from simple genetic abnormality, the overt hypertrophic stage with myocardial fibrosis, to the final burn-out stage. Besides, maximal left ventricular wall thickness was the only independent predictor of LGE and its extent in overt HCM group (12), suggesting that myocardial fibrosis develops in the advanced stage of disease following LVH. They noted that 3 of 4 preclinical HCM patients (75%) who underwent follow-up CMR scans showed progression to the overt HCM, a very high probability of progression (12). However, caution should be taken in the interpretation of reported progression rate of mutation carriers because not all preclinical HCM patients underwent CMR in this retrospective study. Notwithstanding, we need to keep in mind that disease progression does occur, requiring longitudinal follow-up. One more thing that we need to remember is that not only LVH but also myocardial fibrosis is a dynamic phenomenon (17,18), and thus the time when CMR is performed can be a determinant of the presence or extent of LGE. This is why the incidence and extent of LGE should be interpreted with care in cross-sectional studies.

Genetic factor or type of mutation is another component determining the onset of LVH and outcomes in individual adult HCM patients (19). Because sarcomeric proteins produced by each mutation have a distinct role in the myocardial contraction and relaxation, disease progression rate may also be different according to the type of mutations, and so is the LGE increment. In this study, more than half of the subjects with preclinical HCM have MYBPC3 mutation (12), which was well-known to cause elderly-onset HCM (19). Unfortunately, genetic information in mutation carriers who experienced disease progression was not reported in this study.

Axelsson Raja et al. also reported the results of follow-up CMR in the pediatric overt HCM patients. Only two studies were hitherto published regarding the dynamic change of LGE in adult HCM patients over time (17,18). In the current study, the authors elegantly showed the progressive nature of LGE in the pediatric HCM patients (12). Because we do not have any groundbreaking medication to improve the outcome of overt HCM patients, pathophysiology regarding LGE progression should be investigated in depth. This is especially important in pediatric HCM population, in whom the effect of new treatment for blocking progressive LVH can be maximal. A large-scale registry of CMR in adult HCM patients has already been kicked off (20), and now it is time for a large, prospective CMR registry for pediatric HCM patients to be considered.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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