The Effects Of Gender On Diastolic Function And Its Associated Mechanism In Patients With Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, with an estimated prevalence of 1:500. HCM is characterized by unexplained left ventricular hypertrophy、myocardial fibrosis and potential malignant ventricular arrhythmia, which is strongly associated with sudden cardiac death in young adults.The clinical expression and natural history of HCM are extremely heterogeneous, with patients being either asymptomatic, having normal left ventricular outflow tract (LVOT) gradient compared to those with severe obstruction and refractory heart failure. Sex is known to be a modifying factor that account for the phenotypic variability of HCM. The largest study to date was in 969 consecutive patients with HCM; they showed a higher prevalence in males than in females. In addition, the average age at diagnosis was significantly lower in males than in females. However, females were more symptomatic than males and more frequently showed LVOT obstruction. However, it is unknown about the mechanism of the sex-differences in the prevalence、severity of clinical manifestations and outcomes. An increasing body of data indicates that sex hormones seem to have profound effects on the clinical course in various kinds of cardiovascular disease. We conclude that estrogen may play an important role in the prognosis in patients with HCM.Percutaneous transluminal septal myocardial ablation (PTSMA) has been proved to reduce the LVOT obstruction effectively. Our previous study demonstrated that PTSMA has a favorable effect on regional diastolic abnormalities and diastolic asynchrony, which may partly account for the persistent improvement in global LV diastolic function in HCM patients. However, its beneficial effect on diastolic function assessed by cardiac magnetic resonance (CMR) has not been reported. Furthermore, although PTSMA has been proved to reverse LV remodeling, it remains unknown the long-term effects of PTSMA on the biventricular remodeling after successful PTSMA in patients with HCM.The first part:Left ventricular remodeling and fibrosis:sex difference and relationship with diastolic function in hypertrophic cardiomyopathyObjective:We investigated sex difference in left ventricular (LV) remodeling and fibrosis and their relationship with LV diastolic dysfunction by cardiovascular magnetic resonance (CMR).Methods:CMR imaging was performed simultaneously in 152 age-matched patients (76 men,76 women; mean age:49 ± 9 years) without LV systolic dysfunction. LV remodeling index (LVRI) was calculated as the ratio of LV mass and end-diastolic volume. Diastolic function indexes including peak filling rate (PFR) and time to PFR (tPFR) were evaluated. Extent of late gadolinium enhancement (LGE) was measured.Results:LVRI and extent of LGE were greater in women compared with men (1.48 ± 0.22 vs.1.36 ± 0.28 g/ml; 13.15 ± 2.48 vs.11.35 ± 2.34 g, respectively, both P<0.001). Women had lower PFR and higher tPFR (both P<0.001) than men. LVRI and the extent of LGE showed significant relationships with parameters of diastolic function in both sex. In a multivariate analysis, LVRI remained a strong independent predictor of PFR and TPFR in women (β=-0.272, P=0.032; β=0.348, P=0.016, respectively), and in men (β=-0.374, P<0.001; (β=0.660, P<0.001, respectively). Furthermore, the extent of LGE also remained an independent predictor of PFR in women (β=-0.283,P=0.033) and men (p=-0.492,P<0.001).Conclusions:There are prominent sex differences in LV remodeling and myocardial fibrosis. We suggest that the effects of LV remodeling and fibrosis may lead to diastolic dysfunction with greater susceptibility to worse clinical outcome in women. The second part:17β-estradiol prevents cardiac diastolic dysfunction by stimulating mitochondrial function:a preclinical study in a mouse model of a human hypertrophic cardiomyopathy mutationObjective:We investigated the effect of ovariectomy (OVX) and 17β-estradiol (E2) replacement on both mitochondrial and myocardial function in cTnT-Q92 transgenic mice generated by cardiac-restricted expression of a human hypertrophic cardiomyopathy (HCM) mutation.Methods:The cTnT-Q92 mice were ovariectomized at twenty weeks of age and were treated with either placebo (OVX group) or E2 (OVX+E2 group) for twelve weeks before being sacrificed. Wild-type and cTnT-Q92 female mice receiving sham operation were used as controls. Indices of diastolic function such as mitral early (E) and late (A) inflow as well as isovolumic relaxation time (IVRT) were measured by echocardiography.A Clark-type electrode was used to detect respiratory control, and ATP levels were determined at the mitochondrial level using HPLC. Key components related to mitochondrial energy metabolism, such as peroxisome proliferator-activated receptora (PPARa), PPARy coactivator la (PGC-la) and nuclear respiratory factor-1 (NRF-1), were also analyzed using Western blot and RT-PCR. The levels of oxidative stress markers were determined by measuring malondialdehyde (MDA) using the thiobarbituric acid assay.Results:The cTnT-Q92 mice had impaired diastolic function compared with wild-type mice (E/A ratio,1.39±0.04 vs.1.21 ± 0.01, P<0.001; IVRT,19.17 ± 0.85 vs.22.15 ± 1.43 ms, P= 0.028). In response to ovariectomy, cardiac function further decreased compared with that observed in cTnT-Q92 mice that received the sham operation (E/A ratio,1.15 ± 0.04 vs.1.21 ± 0.01, P<0.001; IVRT,28.31 ± 0.39 vs.22.15 ± 1.43 ms, P=0.002). Myocardial energy metabolism, as determined by ATP levels (3.49±0.31 vs.5.07±0.47 μmol/g, P<0.001), and the mitochondrial respiratory ratio (2.04±0.10 vs.2.63±0.11, P= 0.01) also decreased significantly. By contrast, myocardial concentrations of MDA increased significantly in the OVX group, and PGC-la, PPARa and NRF-1 decreased significantly. E2 supplementation significantly elevated myocardial ATP levels (4.55±0.21 vs.3.49±0.31 μmol/g, P=0.003) and mitochondrial respiratory function (3.93±0.05 vs.2.63±0.11, P=0.001); however, it reduced the MDA level (0.21±0.02 vs. 0.36±0.03 nmol/g, P<0.001), which subsequently improved diastolic function (E/A ratio, 1.35 ± 0.06 vs.1.15 ± 0.04, P<0.001; IVRT,18.22 ±1.16 vs.28.31 ± 0.39 ms, P=0.007).Conclusions:Our study has shown that 17β-estradiol improved myocardial diastolic function, prevented myocardial energy dysregulation, and reduced myocardial oxidative stress in cTnT-Q92 mice.A Clark-type electrode was used to detect respiratory control, and ATP levels were determined at the mitochondrial level using HPLC. Key components related to mitochondrial energy metabolism, such as peroxisome proliferator-activated receptora (PPARa), PPARy coactivator la (PGC-la) and nuclear respiratory factor-1 (NRF-1), were also analyzed using Western blot and RT-PCR. The levels of oxidative stress markers were determined by measuring malondialdehyde (MDA) using the thiobarbituric acid assay.Results:The cTnT-Q92 mice had impaired diastolic function compared with wild-type mice (E/A ratio,1.39±0.04 vs.1.21 ± 0.01, P<0.001; IVRT,19.17 ± 0.85 vs.22.15 ± 1.43 ms, P= 0.028). In response to ovariectomy, cardiac function further decreased compared with that observed in cTnT-Q92 mice that received the sham operation (E/A ratio,1.15 ± 0.04 vs.1.21 ± 0.01, P<0.001; IVRT,28.31 ± 0.39 vs.22.15 ± 1.43 ms, P=0.002). Myocardial energy metabolism, as determined by ATP levels (3.49±0.31 vs.5.07±0.47 μmol/g, P<0.001), and the mitochondrial respiratory ratio (2.04±0.10 vs.2.63±0.11, P= 0.01) also decreased significantly. By contrast, myocardial concentrations of MDA increased significantly in the OVX group, and PGC-la, PPARa and NRF-1 decreased significantly. E2 supplementation significantly elevated myocardial ATP levels (4.55±0.21 vs.3.49±0.31 μmol/g, P=0.003) and mitochondrial respiratory function (3.93±0.05 vs.2.63±0.11, P=0.001); however, it reduced the MDA level (0.21±0.02 vs. 0.36±0.03 nmol/g, P<0.001), which subsequently improved diastolic function (E/A ratio, 1.35 ± 0.06 vs.1.15 ± 0.04, P<0.001; IVRT,18.22 ±1.16 vs.28.31 ± 0.39 ms, P=0.007).Conclusions:Our study has shown that 17β-estradiol improved myocardial diastolic function, prevented myocardial energy dysregulation, and reduced myocardial oxidative stress in cTnT-Q92 mice.The third part:Effects of alcohol septal ablation on left ventricular diastolic filling patterns in obstructive hypertrophic cardiomyopathyObjective:Percutaneous transluminal septal myocardial ablation (PTSMA) has been shown to improve left ventricular (LV) diastolic function in patients with obstructive hypertrophic cardiomyopathy (HCM). However, its beneficial effect on diastolic function assessed by cardiac magnetic resonance (CMR) has not been reported. We investigated the midterm changes of diastolic function by CMR combined with echocardiography in HCM patients after PTSMA at a median of 14-month follow-up.Methods:Forty-three obstructive HCM patients were referred in our study. All HCM patients underwent echocardiographic and CMR measurement before and after the PTSMA procedure in a median of 14-month follow-up. Mitral early diastolic inflow velocity (E wave) and late diastolic inflow velocity (A wave) was obtained using color Doppler flow imaging. Mitral early mitral lateral annular velocity (E’) was obtained using tissue Doppler imaging. Meantime, all HCM patients received CMR examination. Left ventricular (LV) 2-chamber long and short axis cine images were performed. LV volume-time curves were reconstructed. Diastolic function indexes including peak filling rate (PFR) and time to PFR (tPFR) were evaluated from LV volume-time curve.Results:LV diastolic function improved significantly measured by echocardiography with the decrease in ratio of E wave to E’(14.20 ± 1.17 to 11.58 ± 1.16, P<0.001) and E-wave deceleration time (194.04 ± 19.30 to 168.45 ± 12.58 ms, P<0.001). PFR increased significantly with associated decrease in TPFR after ASA (both P<0.001) at follow-up. Furthermore, patients with larger decrease in LVOT gradients had a greater improvement of LV diastolic function, as measured by the reduction of E/E’(P<0.001) and increase of PFR (P<0.001).Conclusions:This study demonstrated that successful PTSMA resulted in both echocardiographic and CMR indices of diastolic function improvement after ASA at 14-month follow-up. ASA therapy could significantly reduce LVOT gradient and mitral regurgitation, both of which might contribute to the improvement of diastolic function. HCM patients after PTSMA at a median of 14-month follow-up.Methods:Forty-three obstructive HCM patients were referred in our study. All HCM patients underwent echocardiographic and CMR measurement before and after the PTSMA procedure in a median of 14-month follow-up. Mitral early diastolic inflow velocity (E wave) and late diastolic inflow velocity (A wave) was obtained using color Doppler flow imaging. Mitral early mitral lateral annular velocity (E’) was obtained using tissue Doppler imaging. Meantime, all HCM patients received CMR examination. Left ventricular (LV) 2-chamber long and short axis cine images were performed. LV volume-time curves were reconstructed. Diastolic function indexes including peak filling rate (PFR) and time to PFR (tPFR) were evaluated from LV volume-time curve.Results:LV diastolic function improved significantly measured by echocardiography with the decrease in ratio of E wave to E’(14.20 ± 1.17 to 11.58 ± 1.16, P<0.001) and E-wave deceleration time (194.04 ± 19.30 to 168.45 ± 12.58 ms, P<0.001). PFR increased significantly with associated decrease in TPFR after ASA (both P<0.001) at follow-up. Furthermore, patients with larger decrease in LVOT gradients had a greater improvement of LV diastolic function, as measured by the reduction of E/E’(P<0.001) and increase of PFR (P<0.001).Conclusions:This study demonstrated that successful PTSMA resulted in both echocardiographic and CMR indices of diastolic function improvement after ASA at 14-month follow-up. ASA therapy could significantly reduce LVOT gradient and mitral regurgitation, both of which might contribute to the improvement of diastolic function.The fourth part:Biventricular reverse remodeling after successful alcohol septal ablation for obstructive hypertrophic cardiomyopathyObjectives:the aim of the present study was to investigate the long-term effects of percutaneous transluminal septal myocardial ablation (PTSMA) on left ventricular (LV) and right ventricular (RV) remodeling in patients with obstructive hypertrophic cardiomyopathy (HCM) using cardiovascular magnetic resonance (CMR)Methods:Thirty-eight obstructive HCM patients were entrolled in the study. All the patients underwent CMR scanning, including short axis cine sequences and LGE sequences at baseline, and at 16-month follow-up. Left and right ventricular function including ventricular mass、end-diastolic volume and ejection fraction were measured on short axis cine sequence using Qmass software. LGE parameters, including LGE rate, total LGE mass were detected on LGE sequence. The relationships between the changes of LVOT gradient and biventricular mass were assessed using the linear regression analysis.Results:CMR was performed at baseline and 16 months after PTSMA in thirty eight patients with obstructive HCM (age 48 ± 9 years) despite optimal medical treatment. PTSMA resulted in significant reduction of left ventricular outflow tract (LVOT) gradient (89 ± 22 vs.24 ± 12 mmHg, P<0.001) and improvement of New York Heart association (NYHA) functional class (P<0.001) during the follow-up. LV remote mass and septal mass decreased from 98.34 ± 37.02 to 84.23 ± 34.71 g and 77.56 ± 16.40 to 68.43 ± 14.02 g respectively (both P<0.001) at 16-month follow-up. There were significant reductions of RV mass (53.69 ±7.12 vs.47.49 ± 6.17 g P<0.001) and improvement of RV end-diastolic volume (110.58 ± 22.47 vs.124.22 ± 24.17 ml, P<0.001) as well as RV ejection fraction (P<0.001) during 16-month follow-up. Linear regression analysis showed that LVOT gradient reduction correlated significantly with LV remote mass reduction (r=0.475, P=0.003) and RV mass reduction (r=0.535, P=0.001) respectively at 16-month follow-up.Conclusions:Successful PTSMA can lead positive biventricular reverse remodeling, showing significant reductions of RV and LV mass as well as augment of RV and LV end-diastolic volume during the follow-up.