Cardiovascular magnetic resonance for screening in hypertrophic cardiomyopathy: the new family plan 

This editorial refers to ‘Contemporary Family Screening in Hypertrophic Cardiomyopathy: The Role of Cardiovascular Magnetic Resonance’, by R. Huurman et al., https://doi.org/10.1093/ehjci/jeac099.

In the early 1990’s, the results of pedigree linkage analysis studies demonstrated that hypertrophic cardiomyopathy (HCM) was a monogenic heart disease in which mutations encoding sarcomere proteins risk were responsible for disease development.^1,2 Transmitted in an autosomal dominant manner, each offspring of an affected patient has a 50% chance of inheriting the disease causing mutation.^1,2 In relatives identified as having a pathogenic sarcomere mutation, the likelihood of converting to clinical expression of disease at some point in their clinical course is high.¹ In addition, young HCM patients may be at risk for a number of adverse disease related events, including sudden cardiac death, underscoring the importance of early clinical identification of disease in order to provide therapeutic interventions which may alter natural history.³

For these reasons, clinical assessment of family members for transmission of the HCM disease phenotype [i.e., left ventricular (LV) hypertrophy] has been a standard recommendation for several decades.⁴ The recent 2020 AHA/ACC HCM guidelines suggest that longitudinal screening in relatives of an HCM proband be performed with echocardiography (and ECG) as the primary cardiovascular imaging test beginning in children or adolescents and repeated every 1–2 years.⁵ If there is no phenotypic evidence of HCM by the end of physical growth period, then echocardiographic screening should continue every 3–5 years until mid-life, since a small number of patients experience delayed conversion with LV hypertrophy.⁶ In this regard, echocardiography has been the preferred modality for HCM screening protocols, with the advantages of being widely accessible, safe, and providing reliable identification of increased wall thickness and other important morphology including LV outflow tract obstruction.^3,4

However, the past two decades have witnessed the increasing penetration of cardiovascular magnetic resonance (CMR) into HCM clinical practice.^7,8 CMR provides high spatial and temporal resolution and sharp contrast between the myocardial border and blood pool, generating precise measurements of LV wall thickness unencumbered by a limited acoustic window or interference from thoracic and pulmonary parenchyma.⁷ When applied to patients suspected of having HCM, CMR can identify segmental areas of hypertrophy within the LV chamber not reliably detected by two-dimensional echocardiography.^8–10 The anterolateral free wall, apex, or posterior (inferior) septum are the three most common areas of the LV chamber where focal hypertrophy may be missed with echocardiography.⁸ In one investigation, CMR reclassified HCM diagnosis in 10% of patients by demonstrating a maximal LV wall thickness above or below HCM diagnostic criteria of 15 mm when compared with echocardiogram.¹¹ The increased sensitivity for HCM diagnosis was a major reason that the recent North America HCM guidelines strongly recommend that CMR be performed if diagnosis is suspected but echocardiography results are inconclusive.⁵ However, the utility of applying CMR as part of the screening evaluation of largely asymptomatic young HCM family members to potentially improve early detection of disease has previously not been investigated.

In this edition of the journal, Huurman et al.¹² provide an initial single centre experience characterizing the impact of CMR in the screening evaluation of HCM family members. Among a cohort of 91 young (average age, 46 years) genotype positive family members without definite LV hypertrophy on echocardiography, 25% were identified with CMR to have a regional area of increased LV wall thickness of ≥13 mm consistent with a clinical diagnosis of HCM. The notable discrepancy in maximal LV wall thickness measurements between the two imaging modalities ranged between 1 and 10 mm, including >5 mm in seven patients. Underestimation of maximal LV wall thickness by echocardiography compared with CMR was largely a result of focal hypertrophy confined to the anterolateral wall, an area of the LV chamber which has also previously been shown to be ‘echo silent’ in some HCM patients.^8,9 This phenomenon can largely be explained by the opportunity with higher spatial resolution CMR to more clearly delineate the lateral epicardial border of the LV wall from extra-cardiac structures.⁹ It is important to note that LV contrast opacification was not administered in this study, which may have contributed to the higher than anticipated rate of underdiagnoses of HCM by echocardiography. In addition, in two patients maximal LV wall thickness was overestimated by echocardiography due to poor ultrasound acoustic images, with CMR reversing HCM diagnosis in these patients.

What are the clinical implications of these findings? The observation that CMR reclassified HCM diagnosis in one out of every four genotype positive HCM family members is particularly impactful and should begin to provide rational for considering changes to the current HCM screening strategies. However, even without awaiting changes to guideline management, these data as well as other studies demonstrating similar findings,¹³ should encourage the performance at least one CMR study as part of the baseline evaluation of most HCM family members. This has indeed been the strategy that our HCM referral centre has already adopted and it is reassuring to see data supporting this practice pattern. Unfortunately, obtaining CMR studies may be challenging in some regions due to cost and access issues. Therefore, given the relatively lower yield for CMR in reclassifying HCM diagnosis in relatives with a normal ECG,¹² prioritizing CMR for those family members with abnormal (or equivocal) ECG or echocardiogram would be most practical.

Additional rational for considering CMR in the screening evaluation of young HCM family members would be to provide comprehensive baseline assessment of LV wall thickness and morphology. As CMR is associated with low reader variability for anatomic measurements, small changes in wall thickness can be reliably detected with this technique.⁷ This information could be used to compare future serial studies to best define progression of LV wall thickening.

Although the impact of these findings on HCM management strategies was not specifically addressed in this report, the potential clinical implications should be considered. Indeed, without CMR, a diagnosis of HCM in many of these family members may have been greatly delayed (or possibly not made at all). It is possible that for some of these patients important management considerations could be relevant, including the opportunity to implement sudden death prevention measures such as restriction from competitive sports and possibly primary prevention ICD therapy.^3,5 We anticipate that with greater follow up time, these investigators and others may provide greater insight on how earlier disease recognition may benefit individual patient outcomes in this disease.

The yield of CMR in this study should also be considered in light of the population studied, which were all family members who had undergone genetic testing and found to carry a pathogenic sarcomere mutation. Since gene positive status in HCM is associated with greater likelihood of disease penetrance compared with patients without a mutation,² the higher yield with CMR may not be the same when assessed in a population of families without a sarcomere mutation. Therefore, we should be cautious in extrapolating these results to the broader and much more prevalent population of HCM family members who are sarcomere mutation negative.

This study by Huurman et al.¹² underscore an important clinical principle that in select genotype positive HCM family members CMR can provide a more precise delineation of LV hypertrophy and improve reliability of HCM diagnosis compared with conventional testing. It would therefore be reasonable to consider CMR in the screening assessment of HCM family members, particularly in relatives with equivocal ECG and/or echocardiogram.

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Author notes