Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease, with a prevalence of 0.2–0.5% in the general population [1
]. Because of its familial character, and to prevent potentially life-threatening complications, family screening is advised in first-degree relatives of HCM patients. Contemporary family screening is based on genetic testing and clinical evaluation (maximal left ventricular wall thickness (MWT) ≥15 mm, or ≥13 mm in first-degree relatives of HCM patients) [2
]. These absolute echocardiographic cut-off values ignore the fact that subjects differ in gender and size. Indexation is advocated in various echocardiographic measurements, particularly left ventricular and left atrial dimensions, and in the diagnosis of aortic dilatation [3
]. However, the role of body size indexation in HCM is unknown. The aims of this study are to assess the effect of gender and body size on the diagnosis of HCM in genotype-positive relatives, to compare this with normal values derived from healthy volunteers and to assess the effect of indexation on the prediction of HCM-related events.
The main findings of this study are that in genotype-positive subjects presented for cardiac screening: 1) mean MWT is higher in men than in women, and that this difference is nullified after indexation by BSA or weight; 2) body size influences the diagnosis of HCM, with the largest and heaviest subjects being diagnosed significantly less often after BSA- or weight-indexation and application of gender-specific reference values obtained in healthy controls, with the reverse being true for the lightest tertile; 3) weight is the primary determinant of these differences; and 4) indexation by BSA or weight augments the predictive accuracy for HCM-related events, suggesting superior patient identification using gender-specific cut-off values for MWTBSA (men: 6.51 mm/m2, women: 6.68 mm/m2) and MWTweight (men: 0.16 mm/kg, women: 0.18 mm/kg), instead of the conventional cut-off.
Indexation is increasingly being used in the context of cardiac disease [3
]. Left ventricular mass, calculated using septal and posterior wall dimensions, is routinely reported after correcting for BSA. Nevertheless, there is no mention of body size when reporting wall thickness alone. In this cohort, the diagnosis of HCM was predominantly altered in patients with a high BSA, but also in the lightest and heaviest group when stratifying by weight alone. The decrease of diagnoses in men, being taller and heavier than women, supports the notion that body size matters in diagnosing HCM.
Furthermore, our results imply that these differences are driven by weight variations, which is illustrated by the effects of indexation by BSA and weight and the lack thereof when indexing by height. Indexation by weight reclassified a significant number of the lightest and heaviest subjects, and subjects reclassified as no HCM were predominantly obese. Left ventricular enlargement is a well-recognised physiological adaptation aimed at optimising stroke volume to compensate for an increased oxygen demand [10
], and is also seen in HCM [14
]. Olivotto et al.
studied 275 HCM patients (age 48 ± 14 years; 70% male) and found that BMI was independently associated with magnitude of hypertrophy, defined as an increase in likelihood of having a left ventricular mass in the highest quartile (>120 g/m2
The autosomal dominant inheritance pattern of HCM implies an equal gender distribution. However, many cohorts illustrate a male predominance [15
], bringing forth potential explanations ranging from delays in clinical presentation to differences in gene expression and sex hormone receptor levels [18
]. In this cohort, less men, but not women, were diagnosed with HCM after indexation, suggesting that applying non-indexed cut-off values overestimates the prevalence of HCM in men. Moreover, in the control group, MWT was higher in men than in women. Although it is unlikely that this finding is the primary cause of the observed gender disparity, especially in light of the aforementioned hypotheses, it does offer a partial explanation.
Additionally, gender disparities are reported when comparing disease severity and outcome [15
], generally in favour of men. In a cohort of 27 women and 44 men, Nijenkamp et al.
demonstrated that tissue samples of women who underwent myectomy showed decreased expression of phospholamban (PLN) and sarco/endoplasmic reticulum Ca2+
ATPase (SERCA2), more compliant titin and more fibrosis [22
]. Absolute MWT, left ventricular and left atrial diameter were similar across gender, but BSA-corrected values were higher in women. Although we are unable to corroborate these results, our findings do support indexation when assessing gender differences.
The clinical relevance of indexation in HCM is demonstrated by the augmented predictive accuracy for HCM-related events after indexation for BSA or weight, by improving specificity without sacrificing sensitivity, indicating proper identification of HCM patients. It is reassuring that no endpoints occurred in HCM patients reclassified as no HCM after a median follow-up of 5.8 years. To our knowledge, this is the first study demonstrating the value of indexation in HCM, albeit in a single centre and with a modest size and low event rate. As the clinical spectrum of HCM is expanding with the advent of advanced genetic testing and imaging, the prevalence of HCM will increase, emphasising the importance of correct patient identification as a means of decreasing the burden on health care systems [1
], by virtue of less frequent follow-up and a decreased need for cardiac monitoring, exercise testing and imaging. Additionally, a reduction in HCM diagnoses has the potential to preclude patients from unnecessary (exercise) restrictions, simultaneously decreasing their psychological burden. Future studies in index patients (i.e. those requiring MWT measurement ≥15 mm) will potentially decrease HCM diagnoses in that group, leading to less (unnecessary) genetic testing and family screening.
This study has several limitations. In the first place, the inherent limitations of retrospective studies apply here, although some of these limitations were attenuated by a dedicated assessment of MWT in controls. Moreover, scaling cardiac size using BSA in patients with hypertensive left ventricular hypertrophy has been shown to underestimate the prevalence of left ventricular hypertrophy in obese individuals [28
], raising the possibility that the same problem occurs in our data. As there is a paucity of data on the relationship between body size and cardiac dimensions in the context of HCM, we cannot exclude the influence of obesity on our results and acknowledge that the concept of scaling MWT to body size requires further attention before it can be incorporated into clinical practice. Furthermore, body size is only one factor potentially influencing HCM diagnoses, with an individual’s prior chance of HCM likely depending on several other components (e.g. hypertension, engaging in strenuous physical activity). This includes inter-reader and intra-reader variability, which can potentially influence HCM diagnoses in our data as well as in clinical practice. Finally, although mortality data was complete for all patients, we cannot exclude the possibility of other events (mainly ICD implantations) occurring in other centres.
In conclusion, in genotype-positive subjects referred for cardiac screening, differences in MWT across gender are mitigated after correcting for body size, especially body weight. The effect of body size on the diagnosis of HCM is demonstrated by the reclassification of mainly male subjects when indexing by BSA or body weight. The improved predictive accuracy for HCM-related events after indexation by BSA or weight suggests that correcting for body size has a potential role in the diagnosis of HCM.