The hypertrophic cardiomyopathy paradox: better with age

This editorial refers to ‘Clinical presentation and survival of childhood hypertrophic cardiomyopathy: a retrospective study in the United Kingdom’†, by G. Norrish et al., on page 986. Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, with a widely cited prevalence of 1/500 in adults and more recent literature suggesting that this is an underestimate.1 HCM can manifest at any age. While registry studies have provided important insights into HCM of the young,2–4 there is a paucity of data on the natural history of paediatric HCM. Current guidelines primarily focus on the screening, diagnosis, risk stratification, and treatment of adult patients with HCM, with little emphasis on differences between adults, adolescents, and pre-adolescent children.5 , 6 Should we think of paediatric HCM as an entity that is equivocal to adult HCM, but just in a smaller person? Norrish et al. present a robust addition to the available literature with one of the largest paediatric HCM studies to date: a multicentre, United Kingdom-based cohort of patients with paediatric HCM (diagnosed at ≤ 16 years of age), spanning nearly four decades.7 The studied population included a 2:1 mix of non-syndromic HCM and HCM phenocopies (comprised of RASopathies such as Noonan syndrome, inborn errors of metabolism, and neuromuscular diseases). Herein resides a major difference from adult studies of HCM, where phenocopies are either excluded or present only in very low proportions. The temporal trend of greater recognition of inborn errors of metabolism in the modern era may portend a change in the landscape of future adult studies of HCM, as previously unidentified phenocopies advance to adulthood. Recognition of this evolution will be important for HCM referral centres given differences in expected outcomes. For example, in the studied cohort, arrhythmogenic events were less commonly observed in HCM phenocopies. The majority of patients assessed by Norrish et al. were diagnosed preceding adolescence (69%). Patients with a family history of HCM presented at an older age, a finding likely attributed to current guideline recommendations for screening to begin at the onset of puberty.5 While genetic testing continues to evolve, predictive models emphasize a greater likelihood of a positive genetic test in young patients.8 Unexpectedly, the rates of pathogenic mutations in sarcomeric protein genes for non-syndromic HCM were quite low in this cohort (23%), even lower than observed in a large systematically genotyped adult HCM population (34%).8 As the authors note, these data are likely an underestimate of the true rate of pathogenic sarcomere mutations in paediatric HCM, given the higher prevalence seen throughout other paediatric HCM studies. Increased age is a significant contributor to all-cause mortality in adult populations within published literature, irrespective of specialty. Although not a modifiable risk factor, the inevitable ‘toll of time’ is widely recognized. However, the effect of age in HCM is much more complex. Elderly patients with HCM have substantially lower risk of sudden cardiac death (SCD).9 Because elderly patients have ‘weathered the test of time’ and the positive predictive value of traditional risk factors for SCD is substantially reduced, it is our practice to discontinue serial risk stratification in established patients with HCM over the age of 75. The effect of lower SCD risk with increasing age is emphasized in the HCM risk–SCD risk prediction model,10 a substantial difference between European Society of Cardiology and American College of Cardiology Foundation/American Heart Association risk stratification tools. Data presented by Norrish et al. further emphasize the age paradox seen in HCM. Although most patients (75%) were asymptomatic at the time of presentation, infants were most likely to present with heart failure. Infants diagnosed with HCM had a 16.7% 1 year mortality, a striking difference compared to adult HCM populations, among whom survival in the majority approximates that of age- and sex-matched general populations.11 SCD accounted for a lower proportion of deaths in infants, with larger contributions from congestive heart failure and non-cardiac causes. Patients with inborn errors of metabolism, seen disproportionately in this cohort compared to adult series, also had high 1 year mortality, similar to infants. The reported rate of arrhythmogenic events in the studied cohort, 1.2 per 100 patient-years, although lower than prior paediatric HCM registries, is higher than expected in adult HCM. Risk factors for SCD in paediatric HCM have been less extensively studied but include prior SCD, syncope, family history of SCD, non-sustained ventricular tachycardia, and extreme left ventricular hypertrophy as determined via use of the z-score (a quantification of the deviation of wall thickness from the age-specific population mean).12 Although guidelines exist for implantable cardioverter defibrillator (ICD) implantation within paediatric HCM,12 decision-making for ICD implantation in these patients is more complex than in adult populations, given anatomical size limitations, lead fracture risk in an active and growing patient, and the complicated psychological impact of potential defibrillation, amongst other factors. The data by Norrish et al. continue a trend in HCM literature of female underrepresentation. Expected hereditary patterns in non-syndromic HCM should be autosomal dominant (with incomplete penetrance and variable expressivity), without sex bias. However, the majority of patients were male (63%), similar to adult studies of HCM.13 It remains unclear if this represents systematic underappreciation of disease in female patients, or if there are underlying genetic or metabolic drivers of different phenotypes in males and females. Moreover, reported outcome data was not stratified by sex. Assessment of the natural history of paediatric HCM clearly reveals that it is not simply adult HCM in a smaller person. Numerous differences exist between paediatric and adult HCM (Figure 1).14 , 15 Insight into paediatric HCM benefits both paediatric and adult cardiologists, and may provide a window into the shifting landscape of HCM in the future. The age paradox of HCM is striking. Perhaps, like a fine wine, some aspects of HCM are better with age. Differences in paediatric and adult hypertrophic cardiomyopathy. There are numerous differences between paediatric and adult hypertrophic cardiomyopathy, spanning presentation, risk, and mortality. CAD, coronary artery disease; HCM, hypertrophic cardiomyopathy; LGE, late gadolinium enhancement; LVH, left ventricular hypertrophy; LVOT, left ventricular outflow tract; NYHA, New York Heart Association class; SCD, sudden cardiac death. Conflict of interest: none declared.