Screening Relatives of Hypertrophic Cardiomyopathy Patients

By Michael H. Crawford, MD

Synopsis: A retrospective cohort study of the first-degree relatives of patients with hypertrophic cardiomyopathy (HCM) seen in screening clinics in Denmark has shown that the diagnostic yield of the first visit is 26% and subsequent visits add 4%. The best predictor of the development of HCM in relatives of families with negative genetic findings was maximal left ventricular wall thickness of ≥ 10 mm.

Source: Silajdzija E, Vissing CR, Christensen EB, et al. Family screening in hypertrophic cardiomyopathy: Identification of relatives with low yield from systematic follow-up. J Am Coll Cardiol. 2024;84(19):1854-1865.

Only about 40% of patients with clinically evident hypertrophic cardiomyopathy (HCM) will have a pathogenic (P) or likely pathogenic (LP) gene found on genetic testing. Guidelines recommend screening relatives of patients with HCM, but the appropriate way to do this in the 60% who are relatives of gene-negative patients is unclear. Thus, these investigators from a collection of inherited cardiovascular disease clinics in Denmark performed a retrospective cohort study in HCM patients to identify predictive factors for HCM development in P/LP gene-negative families to determine those who need long-term follow-up.

Three generations of relatives of HCM patients seen between 2006 and 2023 were identified, which resulted in 2,346 individuals from 735 families. After excluding those with no family members ≥ 18 years of age and those with no clinic visits, there were 1,230 relatives from 531 families (mean age 42 years, 55% women) who had an average of eight clinic visits one to five years apart over an average follow-up of seven years.

All first-degree relatives were offered follow-up, as were further generations if their relative had HCM or were P/LP gene positive. Thus, all the subjects studied were one degree of separation from an HCM or P/LP gene-positive patient.

There were 321 relatives (26%) with clinical or genetically identified HCM at the baseline visit. During follow-up, 43 more relatives developed HCM (4%). The best predictor of developing HCM was P/LP gene status (hazard ratio [HR], 4.58; 95% confidence interval [CI], 2.50-8.40; P < 0.001).

The only significant predictor in P/LP gene-negative relatives was left ventricular (LV) maximum wall thickness (MWT) by echocardiography of ≥ 10 mm (HR, 2.21; 95% CI, 2.21-1.76; P < 0.001).

Only two relatives (0.4%) with MWT < 10 mm developed HCM. In fact, those who were P/LP gene-negative with an MWT ≥ 10 mm had the same risk of developing HCM as those who were P/LP gene-positive.

The authors concluded that combined genetic and clinical evaluation of first-degree relatives of HCM patients at baseline had a 26% diagnostic yield and an average follow-up of seven years added 4%. The best predictor of developing HCM in gene-negative relatives was an MWT of ≥ 10 mm.

Commentary

Guidelines recommend screening and follow-up of relatives of HCM patients but do not specify the intensity or frequency of follow-up. This Danish study suggests that all first-degree relatives of an HCM patient be screened clinically and by genetic testing.

Those who are gene-positive should be followed frequently, as should those who are gene-negative and have an MWT ≥ 10 mm. Those who are gene-negative and have an MWT < 10 mm can be spared follow-up visits or be seen infrequently. The authors suggest that this will decrease healthcare costs and reduce psychological trauma in these relatives. These recommendations seem reasonable based on their data and leave room for individual fine-tuning.

Other studies have found that elevated diastolic blood pressure was a risk factor in gene-negative relatives, but not in the Danish study. Of course, this raises the question of which is the egg and which is the chicken, since elevated blood pressure can cause left ventricular hypertrophy. But it is possible that elevated blood pressure also could trigger or enhance the development of HCM. Perhaps blood pressure would be a factor for fine-tuning follow-up.

HCM also is more common in men, which was confirmed in the Danish study. However, the role of sex is complicated, since women generally have smaller LVs than men. The guidelines do not make any accommodation for sex, and no suggestions from the authors of the Danish study were advanced to deal with this issue.

The Danish study has limitations. Since it is retrospective, they could not exclude referral bias, unknown confounders, and ascertainment bias. Also, the population studied largely was of white Scandinavian origin, so the findings may not apply to other groups.

In addition, MWT by echocardiography is convenient, but not a highly accurate or reproducible measurement. The normal range in most labs is up to 11 mm, so the cut point for following relatives of gene-negative patients is in the normal range. Few of those in this study had cardiac magnetic resonance imaging, which may provide a more reliable anatomic marker for future HCM development.

Personally, I would not want to determine whether to follow a gene-negative HCM relative based solely on MWT by echocardiogram. The Danish study is well done, but I believe we need more data before committing to this criterion.

Michael H. Crawford, MD, is a Professor of Medicine and Consulting Cardiologist, University of California Health, San Francisco.