Distinct Subgroups in Hypertrophic Cardiomyopathy in the NHLBI HCM Registry

Abstract

Background: The HCMR (Hypertrophic Cardiomyopathy Registry) is a National Heart, Lung, and Blood Institute-funded, prospective registry of 2,755 patients with hypertrophic cardiomyopathy (HCM) recruited from 44 sites in 6 countries.

Objectives: The authors sought to improve risk prediction in HCM by incorporating cardiac magnetic resonance (CMR), genetic, and biomarker data.

Methods: Demographic and echocardiographic data were collected. Patients underwent CMR including cine imaging, late gadolinium enhancement imaging (LGE) (replacement fibrosis), and T1 mapping for measurement of extracellular volume as a measure of interstitial fibrosis. Blood was drawn for the biomarkers N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (cTnT), and genetic analysis.

Results: A total of 2,755 patients were studied. Mean age was 49 ± 11 years, 71% were male, and 17% non-white. Mean ESC (European Society of Cardiology) risk score was 2.48 ± 0.56. Eighteen percent had a resting left ventricular outflow tract (LVOT) gradient ≥30 mm Hg. Thirty-six percent had a sarcomere mutation identified, and 50% had any LGE. Sarcomere mutation-positive patients were more likely to have reverse septal curvature morphology, LGE, and no significant resting LVOT obstruction. Those that were sarcomere mutation negative were more likely to have isolated basal septal hypertrophy, less LGE, and more LVOT obstruction. Interstitial fibrosis was present in segments both with and without LGE. Serum NT-proBNP and cTnT levels correlated with increasing LGE and extracellular volume in a graded fashion.

Conclusions: The HCMR population has characteristics of low-risk HCM. Ninety-three percent had no or only mild functional limitation. Baseline data separated patients broadly into 2 categories. One group was sarcomere mutation positive and more likely had reverse septal curvature morphology, more fibrosis, but less resting obstruction, whereas the other was sarcomere mutation negative and more likely had isolated basal septal hypertrophy with obstruction, but less fibrosis. Further follow-up will allow better understanding of these subgroups and development of an improved risk prediction model incorporating all these markers.

Keywords: biomarkers; cardiac magnetic resonance; fibrosis; hypertrophic cardiomyopathy; late gadolinium enhancement.

Figure 1.. Steady state free precession 4-chamber long axis cine images from individual patients with the 6 different morphologic subtypes of HCM.

The six subtypes shown are: 1) localized basal septal hypertrophy 2) reverse curvature septal hypertrophy 3) apical HCM 4) concentric HCM 5) mid-cavity obstruction with apical aneurysm or 6) other

Figure 2.. Relationship of biomarkers to increasing amounts of late gadolinium enhancement (LGE).

N-terminal pro-brain natriuretic peptide (NTproBNP) and high sensitivity troponin T (cTnT) were measured in each patient as was the extent of LGE as a % of left ventricular mass on cardiac magnetic resonance imaging. Left – Median NTproBNP showing increasing levels relative to patients with increasing amounts of LGE (P<0.001 for trend). Right – similar trend shown for cTnT (separated by gender due to different normal values) with p<0.001 for trend for both.

Central Illustration.. Hypertrophic Cardiomyopathy Registry: Overall design and Findings.

2,755 patients from 44 sites in 6 countries were recruited. Two relatively distinct populations were identified as depicted in the slide. Left: 4-chamber inversion recovery gradient echo LGE image in a patient with reverse curvature asymmetric septal hypertrophy. Patchy LGE is noted in mid-septum. Right: similar orientation and image type in a patient with reverse curvature asymmetric septal hypertrophy. No LGE is noted. One group was sarcomere mutation positive, and more likely had reverse septal curvature morphology, more fibrosis, and less obstruction whereas the other was sarcomere mutation negative, and more likely had isolated basal septal hypertrophy with obstruction and less fibrosis.