Introduction
Methods
Study population
Genetic testing and analysis
HCM gene panel (nDNA) design
DNA preparation
Library construction and sequencing of the HCM gene panel and mtDNA
Identification of potential pathogenic mtDNA variants
Data analysis of the HCM gene panel
Data analysis of the mitochondrial genome
Echocardiographic analysis
Cardiac magnetic resonance imaging (CMR)
Mitral leaflet length measurement
LV geometry and mitral valve wall stress assessment
Statistical analysis
Results
Baseline characteristics
Genetic characteristics
Correlation with mitral leaflet size
Total (n = 211) | Sarcomere protein gene variant group (n = 67) | |||||
---|---|---|---|---|---|---|
Presence of sarcomere protein gene variant group (n = 67) | Absence of sarcomere protein gene variant group (n = 144) | P | Thick filament gene variant group (n = 52) | Thin filament or regulatory gene variant group (n = 15) | P | |
Age, years | 54.8 ± 14.3 | 61.3 ± 12.8 | 0.001 | 55.3 ± 13.0** | 52.9 ± 18.5* | 0.557 |
Women, n (%) | 25 (37) | 38 (26) | 0.106 | 23 (44)* | 2 (13)†† | 0.029 |
Hypertension, n (%) | 28 (42) | 91 (63) | 0.004 | 22 (42)** | 6 (40)** | 0.873 |
Diabetes, n (%) | 12 (18) | 27 (19) | 0.884 | 9 (17) | 3 (20) | 0.811 |
Body surface area, m2 | 1.76 ± 0.18 | 1.78 ± 0.21 | 0.596 | 1.74 ± 0.19 | 1.82 ± 0.13 | 0.135 |
FHx of SCD-1st, n (%) | 6 (9) | 8 (6) | 0.356 | 4 (8) | 2 (13) | 0.500 |
Syncope, n (%) | 6 (9) | 4 (3) | 0.049 | 6 (12)* | 0 (0)† | 0.168 |
5-year SCD risk, % (n = 123) | 2.64 ± 1.51 | 2.01 ± 1.66 | 0.040 | 2.56 ± 1.38 | 2.88 ± 1.92 | 0.538 |
Echocardiography and CMR | ||||||
ApHCM, n (%) | 21 (31) | 79 (55) | 0.001 | 13 (25)** | 8 (53)†† | 0.037 |
LVOT PPG (rest), mmHg | 9.9 ± 11.6 | 15.0 ± 23.3 | 0.041 | 10.1 ± 12.4 | 9.5 ± 8.7 | 0.874 |
LVOT PPG (Valsalva), mmHg | 15.9 ± 19.2 | 28.2 ± 37.5 | 0.005 | 16.7 ± 20.8 | 12.8 ± 11.0 | 0.556 |
Dynamic obstruction, n(%) | 13 (19) | 36 (25) | 0.370 | 12 (23) | 1 (7) | 0.157 |
LVEDV, mL | 70.6 ± 28.1 | 66.5 ± 21.9 | 0.252 | 71.1 ± 28.7 | 68.7 ± 26.6 | 0.770 |
LVESV, mL | 25.4 ± 12.0 | 23.1 ± 8.8 | 0.106 | 26.1 ± 12.9 | 23.0 ± 7.9 | 0.374 |
LA volume index, mL/m2 | 41.0 ± 22.0 | 34.8 ± 15.0 | 0.042 | 39.5 ± 19.1 | 46.1 ± 30.4* | 0.307 |
MR grade | 0.52 ± 0.35 | 0.47 ± 0.26 | 0.216 | 0.51 ± 0.39 | 0.57 ± 0.18 | 0.585 |
LV ejection fraction, % | 63.8 ± 7.3 | 64.9 ± 5.8 | 0.239 | 63.0 ± 7.8 | 66.6 ± 4.5 | 0.096 |
s′, cm/s | 6.6 ± 1.6 | 6.8 ± 1.8 | 0.408 | 6.6 ± 1.6 | 6.6 ± 1.9 | 0.905 |
E/e′ | 15.4 ± 6.7 | 14.6 ± 5.5 | 0.371 | 15.2 ± 6.6 | 16.3 ± 7.2 | 0.571 |
Maximal thickness, mm | 19.7 ± 3.7 | 18.6 ± 3.4 | 0.035 | 20.1 ± 3.5** | 18.1 ± 4.1†† | 0.061 |
LV mass index by CMR, g/m2 (n = 132) | 88.0 ± 21.1 | 84.9 ± 23.9 | 0.458 | 83.8 ± 18.3 | 102.9 ± 24.3* | 0.014 |
AML lengths | ||||||
AML-PLX, mm | 31.4 ± 4.6 | 32.5 ± 4.4 | 0.109 | 30.8 ± 4.5* | 33.5 ± 4.6 | 0.046 |
AML-3CH, mm | 28.7 ± 3.9 | 28.1 ± 3.4 | 0.230 | 28.4 ± 3.9 | 30.0 ± 3.9 | 0.187 |
AML-average, mm | 30.1 ± 3.9 | 30.2 ± 3.5 | 0.848 | 29.6 ± 3.8 | 31.9 ± 3.8 | 0.045 |
iAML-PLX, mm/m2 | 18.0 ± 2.8 | 18.5 ± 2.8 | 0.222 | 17.8 ± 2.8 | 18.4 ± 2.6 | 0.453 |
iAML-3CH, mm/m2 | 16.5 ± 2.4 | 16.0 ± 2.3 | 0.164 | 16.5 ± 2.6 | 16.5 ± 1.7 | 0.941 |
iAML-average, mm/m2 | 17.2 ± 2.4 | 17.2 ± 2.3 | 0.907 | 17.1 ± 2.5 | 17.5 ± 1.9 | 0.599 |
Genetic relevance to mitral leaflet length
Univariate analysis | Multivariable | Univariate analysis | Multivariable | |||||
---|---|---|---|---|---|---|---|---|
AML-PLX (r) | AML-3CH (r) | AML-average (r) | AML-average (β, p value) | iAML-PLX (r) | iAML-3CH (r) | iAML-average (r) | iAML-average (β, p value) | |
Age | −0.123 | − 0.221** | − 0.198** | 0.145* | 0.081 | 0.117 | ||
BSA | 0.299** | 0.281** | 0.329** | 0.292 (< 0.001) | ||||
LVEDV | 0.246** | 0.297** | 0.315** | |||||
LVESV | 0.257** | 0.340** | 0.341** | 0.207 (0.002) | ||||
LVESWS | 0.239** | 0.323** | 0.317** | |||||
LV ejection fraction | −0.118 | −0.190** | −0.164* | |||||
LA volume | 0.132 | 0.197** | 0.174* | 0.124 | 0.189** | 0.180** | ||
Maximal thickness | 0.146* | 0.225** | 0.189** | |||||
LVOT-PPG (Resting) | 0.039 | 0.044 | 0.033 | 0.244** | 0.225** | 0.230** | ||
LVOT-PPG (Valsalva) | 0.050 | 0.044 | 0.047 | 0.248** | 0.240** | 0.254** | 0.110 (0.203) | |
MR grade | 0.072 | 0.181** | 0.147* | 0.201 (0.004) | 0.280** | 0.390** | 0.373** | 0.146 (0.069) |
E/e’ | 0.023 | −0.049 | −0.007 | 0.238** | 0.188** | 0.239** | ||
LA wall stress | 0.079 | 0.071 | 0.096 | 0.242** | 0.243** | 0.275** | 0.212 (0.012) | |
CMR findings (n = 132) | ||||||||
LV mass | 0.301** | 0.289** | 0.338** | 0.227 (0.013)† | ||||
LVEDV | 0.156 | 0.365** | 0.291** | |||||
LVESV | 0,104 | 0.309** | 0.228** |
No pathogenic or likely pathogenic variant group (n = 110) | 1Only mitochondria related nDNA or mtDNA variant group (n = 33) | 1Only sarcomere gene variant group (n = 58) | 1Both sarcomere and mitochondria-related gene variant group (n = 9) | §P | |
---|---|---|---|---|---|
Age, years | 61.1 ± 12.9 | 61.5 ± 12.3 | 54.4 ± 14.7**, † | 57.0 ± 11.8 | 0.014 |
Women, n (%) | 31 (28) | 6 (18) | 21 (36) | 4 (44) | 0.227 |
Hypertension, n (%) | 69 (63) | 21 (64) | 26 (45) | 2 (22) | 0.019 |
Diabetes, n (%) | 21 (19) | 6 (18) | 10 (17) | 2 (22) | 0.982 |
Body surface area, m2 | 1.78 ± 0.21 | 1.79 ± 0.20 | 1.77 ± 0.19 | 1.70 ± 0.11 | 0.679 |
FHx of SCD-1st, n (%) | 6 (6) | 2 (6) | 5 (9) | 1 (11) | 0.820 |
Syncope, n (%) | 3 (3) | 1 (3) | 5 (9) | 1 (11) | 0.270 |
5-year SCD risk, % (n = 123) | 2.01 ± 1.72 | 2.02 ± 1.45 | 2.73 ± 1.58* | 2.10 ± 0.97 | 0.163 |
Echocardiography and CMR | |||||
ApHCM, n (%) | 57 (52) | 22 (67) | 19 (33) | 2 (22) | 0.004 |
LVOT PPG (rest), mmHg | 17.4 ± 26.5 | 8.0 ± 7.4* | 10.5 ± 11.9 | 5.2 ± 2.1 | 0.005 |
LVOT PPG (Valsalva), mmHg | 31.2 ± 40.7 | 17.4 ± 23.4 | 18.5 ± 21.1* | 6.2 ± 2.9 | 0.025 |
Dynamic obstruction, n (%) | 31 (28) | 5 (15) | 13 (22) | 0 (0) | 0.142 |
LVEDV, mL | 66.8 ± 22.5 | 66.2 ± 20.6 | 69.9 ± 27.1 | 71.3 ± 34.1 | 0.730 |
LVESV, mL | 22.5 ± 8.4 | 24.8 ± 9.9 | 24.6 ± 10.2 | 29.2 ± 20.3 | 0.145 |
LA volume index, mL/m2 | 35.2 ± 14.9 | 31.8 ± 11.1 | 40.6 ± 22.9† | 43.6 ± 15.7 | 0.051 |
MR grade | 0.49 ± 0.28 | 0.40 ± 0.21 | 0.52 ± 0.36 | 0.56 ± 0.17 | 0.217 |
LV ejection fraction, % | 65.7 ± 5.0 | 62.5 ± 7.6* | 64.3 ± 6.9 | 61.2 ± 8.7* | 0.021 |
s′, cm/s | 6.8 ± 1.7 | 6.9 ± 2.1 | 6.6 ± 1.7 | 7.0 ± 1.4 | 0.748 |
E/e′ | 14.8 ± 5.5 | 13.9 ± 5.3 | 15.6 ± 6.9 | 13.5 ± 4.6 | 0.462 |
Maximal thickness, mm | 18.7 ± 3.6 | 18.1 ± 2.6 | 19.6 ± 3.8† | 19.8 ± 3.5 | 0.164 |
LV mass index by CMR, g/m2 (n = 132) | 85.1 ± 23.9 | 84.3 ± 24.3 | 88.5 ± 22.0 | 84.7 ± 15.9 | 0.885 |
AML lengths | |||||
AML-PLX, mm | 32.4 ± 4.5 | 32.5 ± 4.3 | 31.7 ± 4.7 | 29.7 ± 3.7 | 0.260 |
AML-3CH, mm | 28.2 ± 3.5 | 27.7 ± 3.0 | 28.8 ± 3.9 | 28.4 ± 4.3 | 0.633 |
AML-average, mm | 30.2 ± 3.6 | 30.2 ± 3.2 | 30.3 ± 3.9 | 29.1 ± 3.6 | 0.834 |
iAML-PLX, mm/m2 | 18.4 ± 2.7 | 18.4 ± 2.9 | 18.0 ± 2.9 | 17.5 ± 2.1 | 0.671 |
iAML-3CH, mm/m2 | 16.1 ± 2.4 | 15.7 ± 1.9 | 16.4 ± 2.4 | 16.8 ± 2.5 | 0.408 |
iAML-average, mm/m2 | 17.2 ± 2.3 | 17.0 ± 2.2 | 17.2 ± 2.4 | 17.1 ± 2.1 | 0.981 |