Abnormal Myocardial Oxygenation Patterns in Genotype-Positive Hypertrophic Cardiomyopathy during Disease Development - revealed by Oxygenation-Sensitive Cardiac Magnetic Resonance Imaging

Background: Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease, frequently caused by pathogenic gene variants, and characterized by a highly heterogeneous disease onset and progression. Microvascular dysfunction has been observed, even at the preclinical stage, and may underlie variability in disease expression. Oxygenation-sensitive cardiac magnetic resonance (OS-CMR) is a novel non-invasive imaging technique that evaluates myocardial oxygenation during a vasoactive breathing maneuver. This approach has been shown to detect coronary vascular dysfunction in both obstructive and non-obstructive coronary artery disease [1, 2]. Here, we assessed myocardial oxygenation dynamics across the cardiac cycle using hyperventilation-induced signal intensity (SI) changes in OS-CMR images at different stages of HCM.

Methods: We included 3 HCM groups (n=10 per group) ranging from asymptomatic carriers without hypertrophy (maximum wall thickness, MWT< 12 mm) to individuals with mild (MWT 12–15 mm) and overt HCM (MWT >15 mm), and genotype-negative healthy controls (n=5). All HCM groups carried a pathogenic class 4 or 5 MYH7 or MYBPC3 variant. OS-CMR was performed on a 3T MR scanner using a standardized protocol of 1-minute hyperventilation followed by ≥30 s breath-hold. Changes in OS-sensitive SI from hyperventilation to breath hold were quantified throughout the cardiac cycle and normalized to the surface coil intensity field and to the SI in the (fully oxygenated) left ventricular blood pool. SI curves were generated for each group, aligned to the RR interval (0–100%), and used to assess both the stress response and signal heterogeneity across the cardiac cycle.

Results: Baseline characteristics are provided in Table 1. End-systolic SI during breath-hold was significantly lower in overt and mild HCM compared to carriers (0.055±0.024, 0.072±0.034 and 0.108±0.038, respectively, p=0.002 and p=0.036). Normalized SI curves revealed a progressive reduction in SI with advancing disease stage (Figure 1). Moreover, signal heterogeneity was significantly reduced in HCM patients compared to healthy controls and carriers (0.0010±0.0005, 0.0021±0.0003, and 0.0028±0.0006, p=0.002 and p< 0.001), and in mild HCM compared to carriers (0.0015±0.0002 and 0.0028±0.0006, p=0.007) (Figure 2).

Conclusion: Post-hyperventilation myocardial oxygenation as defined by the normalized SI in OS-CMR images across the cardiac cycle reveals a progressively blunted oxygenation response in mild and overt HCM, consistent with impaired tissue oxygenation due to microvascular dysfunction. In contrast, genotype-positive carriers without hypertrophy show preserved oxygenation during systole. Furthermore, reduced signal heterogeneity in mild and overt HCM may reflect diminished oxygenation dynamics. OS-CMR may thus represent a powerful tool to detect microvascular abnormalities at a relatively early HCM disease stage. Larger cohort analyses incorporating additional biomarkers are warranted to confirm our preliminary findings.

Table 1: Baseline characteristics of each patient group.

	G+/Ph+ (n=10)	G+/mild hypertrophy (n=10)	G+/Ph- (n=10)	G- controls (n=5)	P-value
Age (years)	52.6 ± 11.5	49.9 ± 11.3	45.0 ± 10.4	52.6 ± 16.4	>0.05
BMI (kg/m2)	25.9 ± 1.3	26.2 ± 3.5	23.0 ± 3.0	24.4 ± 2.9	>0.05
% male	90	80	30	60	< 0.05*
Left ventricular end-diastolic diameter (mm)	45.8 ± 2.9	47.3 ± 5.1	42.6 ± 10.2	47.8 ± 5.3	>0.05
Left ventricular end-diastolic volume (mL)	154.3 ± 17.5	182.6 ± 46.1	144.9 ± 28.2	139.8 ± 34.9	>0.05
Left ventricular end-systolic volume (mL)	48.0 ± 9.0	67.7 ± 24.6	50.3 ± 7.7	57.0 ± 17.6	>0.05
Stroke volume (mL)	106.3 ± 16.3	114.9 ± 23.8	94.6 ± 22.6	82.8 ± 17.9	>0.05
Ejection fraction (%)	68.8 ± 6.0	63.6 ± 5.7	65.0 ± 3.7	59.8 ± 3.3	>0.05
Maximum wall thickness (mm)	18.0 ± 2.2	12.7 ± 1.0	8.3 ± 1.3	9.5 ± 0.6	< 0.05*
LV mass (g)	136.3 ± 23.5	123.0 ± 21.4	83.9 ± 19.5	82.8 ± 16.4	< 0.05*

All values are mean ± SD or %. P-values by ANOVA for continuous variables or Chi-Square Test for binary variables. * p≤0.05.Figure 1: SI curve of each patient group throughout the cardiac cycle, where end-systole is represented by frame 30-40 and diastole occurs around frame 60-70.
Figure 2: Heterogeneity of each patient group throughout the cardiac cycle, where end-systole is represented by frame 30-40 and diastole occurs around frame 60-70.