Different pathophysiologic drivers in obstructive and non-obstructive hypertrophic cardiomyopathy: implications for targeted therapy

Backgrounds

Although the recent introduction of cardiac myosin inhibitors (CMIs) has demonstrated significant therapeutic benefit in obstructive hypertrophic cardiomyopathy (OHCM), their effectiveness appears to be limited in non-obstructive hypertrophic cardiomyopathy (NOHCM). This difference is likely related to distinct pathophysiologic mechanisms underlying disease progression. This study aimed to identify factors that differentially influence disease progression in these two conditions.

Materials and Methods

A total of 212 patients were prospectively enrolled in an HCM registry, and 133 patients underwent cardiac magnetic resonance (CMR). All patients underwent genetic analysis and echocardiography. Advanced diastolic dysfunction (ADD) was defined as meeting more than half of the following four recommended parameters: mitral annular septal e′ < 7 cm/s or lateral e′ < 10 cm/s, average E/e′ ratio > 14, left atrial volume index (LAVI) > 34 mL/m², and peak tricuspid regurgitation (TR) velocity > 2.8 m/s.

Results

The mean age of the 133 participants was 58 ± 13 years, and 35 (26%) were female. Among them, 34 (26%) had OHCM, and 66 (49%) had apical HCM. There was no significant difference in the prevalence of pathogenic or likely pathogenic sarcomere variants between the two groups (OHCM 20.6% vs. NOHCM 34.3%). The prevalence of ADD was 32.4% in OHCM and 28.3% in NOHCM (p = 0.154).

In OHCM, there was no significant difference in LGE percentage according to the presence of ADD (p > 0.05). In contrast, in NOHCM, patients with ADD had a greater number of LGE segments compared with those without ADD (4.9 ± 3.6 vs. 2.5 ± 2.8, p = 0.001), and showed a trend toward higher LV mass index (LVMI) (89.6 ± 24.1 vs. 80.6 ± 20.6 g/m², p = 0.067) and higher LGE percentage (9.7 ± 9.9% vs. 6.0 ± 8.9%, p = 0.077).

In the NOHCM group, both LGE percentage and the number of LGE segments were significantly correlated with LAVI (r = 0.271, p = 0.007; r = 0.331, p = 0.002), e′ velocity (r = −0.280, p = 0.005; r = −0.390, p < 0.001), and E/e′ ratio (r = 0.223, p = 0.026; r = 0.301, p = 0.002). However, in OHCM, no association was observed between the extent of LGE and diastolic dysfunction parameters (all p > 0.05). Left ventricular global longitudinal strain (LV GLS) was associated with the number of LGE segments in both groups (OHCM: r = 0.452, p = 0.014; NOHCM: r = 0.321, p = 0.004).

Conclusion

In NOHCM, myocardial fibrosis burden is associated with diastolic dysfunction, whereas this relationship is not observed in OHCM. In OHCM, the presence of left ventricular outflow tract obstruction appears to be the strongest and most direct contributor to disease progression, whereas in NOHCM, myocardial damage—as reflected by LGE—plays a more important role. These findings may explain why the therapeutic effect of CMIs is limited in patients with NOHCM.Figure