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Hypertrophic Cardiomyopathy Registry Subgroups
Study Questions:
Does incorporation of cardiac magnetic resonance (CMR), genetic, and biomarker data enable identification of distinct subgroups within the National Heart, Lung, and Blood Institute Hypertrophic Cardiomyopathy Registry (HCMR)?
Methods:
The HCMR is a prospective registry with 2,755 HCM patients from 44 different sites in six countries in North America and Europe. Patients ranged from 18-65 years with an established diagnosis of HCM and with major exclusions for prior septal interventions (myectomy or alcohol septal ablation), coronary artery disease, or ventricular arrhythmias. Baseline demographics, clinical echocardiographic data, exercise stress testing, and Holter data were obtained, as well as a calculated European Society of Cardiology (ESC) risk score. CMR was performed, consisting of cine imaging for morphologic assessment, late gadolinium enhancement (LGE), and T1 mapping of extracellular volume, markers of replacement, and interstitial fibrosis, respectively. Serum biomarkers were drawn, including troponin T and N-terminal pro–B-type natriuretic peptide. Genetic analyses included core sarcomeric and well-established “phenocopy” genes.
Results:
Of 2,755 patients enrolled, 71% were male and 84% were white; 37% of patients had hypertension and 33% had a family history of HCM. Echo data revealed mean maximal wall thickness of 18.6 mm ± 4.8 mm. Only 18% had a peak gradient >30 mm Hg, with these patients having an average of 69 ± 31 mm Hg. Holter data showed atrial fibrillation and nonsustained ventricular tachycardia in 4% and 12%, respectively, while stress testing showed hypotensive response to exercise in 12%. Mean ESC risk score was 2.48 ± 0.56. Genetic analysis showed that 29.5% of patients were found to have “pathogenic” or “likely pathogenic” variants of a sarcomere gene, with the most common variants being MYBPC3 (18.5%) or MYH7 (8.0%).
CMR identified six morphological subtypes of HCM: isolated basal septal hypertrophy (46%), reverse septal curvature (40%), apical HCM (9%), mid-cavity obstruction with apical aneurysm (3%), concentric HCM (1%), and other (1%). LGE was present in 50% of patients and greatest in those with reverse septal curvature hypertrophy, with 43/46 (93%) of those with LGE mass >15% belonging to this subtype. In contrast, patients with isolated basal septal hypertrophy had less LGE and extracellular volume than other morphologies. 58% of sarcomere mutation-positive patients demonstrated reverse septal curvature morphology versus 34% isolated basal septal hypertrophy, whereas the frequencies were reversed for sarcomere mutation-negative (31% vs. 52%, respectively, p < 0.0001). Surprisingly, a smaller percentage of sarcomere mutation-positive patients had left ventricular outflow tract (LVOT) gradient >30 mm Hg than sarcomere mutation-negative patients (19% vs. 27%, p < 0.001).
Conclusions:
While many associations and interrelationships exist between CMR, genetic, biomarker, and clinical data, two relatively distinct populations emerged: 1) Patients positive for a sarcomere mutation, who were on average younger, more often female and white, had a lower body mass index, less hypertension, and more likely to have a family history of HCM. This subgroup, which represents the Mendelian form of familial HCM, was more likely to have reverse septal curvature morphology, more fibrosis, and had less significant LVOT obstruction. 2) Patients negative for sarcomere mutation, who were on average older, more often male, had a higher BMI, and more hypertension. This subgroup was more likely to have isolated basal septal hypertrophy, less fibrosis, and more LVOT obstruction.
Perspective:
HCMR is the largest and only prospective registry to include extensive CMR data in addition to biomarker, genetic, and other baseline clinical and echocardiographic characteristics. This is an impressive study with a large number of patients and the potential for major impact on the HCM field, with the first identification of distinct subgroups with disparate CMR findings, biomarkers, and genetic testing.
While the authors’ stated objective is improved risk prediction, they do not correlate subgroups with specific clinical outcomes. Moreover, applicability to higher-risk cohorts remains unclear. Further studies are needed to assess if endophenotyping of HCM or incorporation of CMR imaging and biomarkers will improve risk stratification beyond existing tools such as the ESC or American College of Cardiology/American Heart Association risk scores.
Keywords: Aneurysm, Arrhythmias, Cardiac, Atrial Fibrillation, Biomarkers, Body Mass Index, Cardiomyopathy, Hypertrophic, Coronary Artery Disease, Diagnostic Imaging, Echocardiography, Exercise Test, Gadolinium, Genetic Testing, Heart Failure, Hypertension, Hypertrophy, Magnetic Resonance Spectroscopy, Mutation, Natriuretic Peptide, Brain, Peptide Fragments, Sarcomeres, Tachycardia, Ventricular, Troponin T
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