Clinical And Animal Studies On Diastolic Dysfunction In Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease characterized by varying degrees of myocardial hypertrophy. The estimated prevalence of HCM in general population is about0.2%and is the most common genetic cardiomyopathy. Left ventricular (LV) diastolic dysfunction is an important pathophysiological feature of HCM. In HCM patients, heart failure related symptoms appear to be largely the consequence of diastolic dysfunction. Furthermore, severe LV diastolic dysfunction is a marker of unfavorable HCM prognosis. The diverse clinical phenotype suggests the existence of some factors that modify HCM presentation. Various epidemiologic investigations have observed that female patients with HCM have more serious symptoms of heart failure at diagnosis and the peak age distribution at diagnosis seems to be older in female patients. Moreover, based on the data from healthy people and patients with hypertension, estrogen is believed to play an important role in modulating left ventricular hypertrophy and the progression of diastolic dysfunction. Therefore, postmenopausal estrogen changes have been hypothesized to be important factors that contribute to the gender difference in severity of heart failure in patients with HCM. It is also reasonable to determine whether estrogen can modify diastolic function in HCM patients. However, to our knowledge, there is no study focus on these problems.Percutaneous transluminal septal myocardial ablation (PTSMA) is an alternative therapy for patients with hypertrophic obstructive cardiomyopathy (HOCM) with sustained improvement on the global diastolic dysfunction. The regional diastolic abnormalities and the diastolic asynchrony are very common and closely related with the global diastolic dysfunction. But it is unknown whether PTSMA can improve the regional diastolic dysfunction and the diastolic asynchrony in patients with HCM. Atrial fibrillation (AF) is the most common clinical complication in HCM patients. Diastolic dysfunction leads to sustained elevated left atrial pressure that largely contributes to atrial remodeling and AF. FTSMA can results in long-term improvement in diastolic dysfunction and also partially reverses LA remodeling. Atrial electromechanical delay (AEMD), is a novel indicator in cardiac ultrasound practice. Previous studies have proven that AEMDs are predictors of AF. However, AEMD has not been evaluated in HCM patients and there is no study focused on the effects of PTSMA on AEMDs.To address these gaps in knowledge, the present study was designed with following5subtopics:Part I:Effects of estrogen on left ventricular diastolic function in patients with hypertrophic cardiomyopathy1.1、The clinical characters of7years accumulated patients with hypertrophic cardiomyopathy and the comparisons between age matched pre-and postmenopause female patients from a single centre in Chinese mainland1.2、The correlations between plasma17β-estradiol levels and cardiac structure and function in male patients with hypertrophic cardiomyopathy1.3、The effects of17β-estradiol on left ventricular diastolic function in the cTnTR92Q transgenic mouse model of hypertrophic cardiomyopathyPart Ⅱ:Long-term echocardiographic studies following percutaneous transluminal septal myocardial ablation2.1、Effect of septal ablation on regional diastolic dysfunction and diastolic asynchrony in patients with hypertrophic obstructive cardiomyopathy:a follow-up study using speckle tracking echocardiography 2.2、Assessment of atrial conduction abnormalities in patients with hypertrophic cardiomyopathy before and long-term after alcohol septal ablationPart I:Effects of estrogen on left ventricular diastolic function in patients with hypertrophic cardiomyopathy1.1、The clinical characters of7years accumulated patients with hypertrophic cardiomyopathy and the comparisons between age matched pre-and postmenopause female patients from a single centre in Chinese mainlandObjective:The goal of this study was to assess the gender related difference of clinical characters in a single population with hypertrophic cardiomyopathy (HCM) and compare the cardiac structure and function between age matched pre-and postmenopause female patients. Methods:We performed a cross-section survey that included441consecutive HCM patients. Furthermore, we selected263pairs of age-matched pre-and postmenopausal female subjects for subgroup analysis.Results:Among the441HCM patients, there was a predominance of male patients (n=315) compared with female patients (n=216). Female patients were older and more symptomatic than male patients. The plasma NT-proBNP concentration was higher in female patients (1879.44vs999.02fmol/ml). Female were more frequently showed left ventricular outflow obstruction. Among female patients there were52.4%patients≥50years old, however the proportion in male patients was40%. However, the symptoms and cardiac structure and function were not significantly difference between age matched pre-and postmenopause female patients.Conclutions:Our data show the gender-specific difference of clinical characters in a single centre patients with HCM. Moreover, we did not find the menopause could affect the cardiac structure and function in female HCM patients. But the sample size was too small that limited our ability to make confirm conclution. 1.2、The correlations between plasma17β-estradiol levels and cardiac structure and function in male patients with hypertrophic cardiomyopathy Objective:170-estradiol can modulate diastolic function in general population and patients with hypertension. The study evaluated the plasma17β-estradiol levels and its impact on diastolic function in patients with hypertrophic cardiomyopathy (HCM).Methods:56male patients with HCM were included in this study. By radioimmunoassay, the plasma17β-estradiol and the markers of collagen turnover (PICP, ICTP and MMP-1) were measured. All patients underwent echocardiography.Results:Plasma17β-estradiol levels were negatively correlated with left atrial volume (LAV) and left atrial volume index (LAVI) which were indicators of sustained elevated left atrial pressure. Patients were divided into quintiles of plasma estradiol (quintile1, average13.48pg/mL; quintile2, average21.86pg/mL; quintile3, average27.59pg/mL; quintile4,36.01pg/mL). Compared with quintile1patients with lowest17β-estradiol level, quintile4patients with highest17β-estradiol level had larger LAV, LAVI and higher PICP concentration.Conclutions:17β-estradiol can modulate the left ventricular diastolic function probably by changing collagen turnover in patients with HCM. 1.3、The effects of17β-estradiol on left ventricular diastolic function in the cTnTR92Q transgenic mouse model of hypertrophic cardiomyopathy Objective:The aim of this study was investigate to the effects of17β-estradiol on modulating the progression of diastolic dysfunction in cTnTR92Q transgenic mouse model of HCM.Methods:Nine cTnTR92Q transgenic mice were randomly divided into3groups. The mice in1st and2ed groups underwent bilateral oophorectomy (OVX) at12weeks of age.17β-estradiol was administrated to the mice in2ed group subcutaneously from12weeks to24weeks of age.Results:Compared with wild-type mice,24weeks old cTnTR92Q transgenic mice exhibited a) hypertrophic left ventricular wall; b) longer DT, lower E and Ea by Doppler analysis, suggesting diastolic dysfunction; c) myocyte disarray and interstitial fibrosis; d) lower myocardial ATP concentrate; e) lower PPARα、p-AMPK and higher TGFβ levels. Compared with mice underwent OVX+17β-estradiol and mice did not underwent OVX, mice underwent OVX shown more serious diastolic dysfunction, lower myocardial ATP concentration, lower PPARa and p-AMPK level. However, the level of hypertrophy of left ventricular wall, interstitial fibrosis and TGFβ were not significantly different among the three groups of transgenic mice.Conclusions:17β-estradiol can modulate the progression of diastolic dysfunction in transgenic mice of HCM probably by improving the energy metabolism in myocardium. However,17β-estradial cannot reveres myocardial hypertrophy and interstitial fibrosis in transgenic mice of HCM. Part Ⅱ:Long-term echocardiographic studies following percutaneous transluminal septal myocardial ablation2.1、Effect of septal ablation on regional diastolic dysfunction and diastolic asynchrony in patients with hypertrophic obstructive cardiomyopathy:a follow-up study using speckle tracking echocard i ographyObjective:The aim of this study was to examine the effect of percutaneous transluminal septal myocardial ablation (PTSMA) on regional diastolic dysfunction and diastolic asynchrony in patients with hypertrophic obstructive cardiomyopathy (HOCM) using speckle tracking echocardiography.Methods:Strain rate curves were obtained for18different segments of the left ventricular myocardium in27HOCM patients several days before and at least half a year after PTSMA. The peak strain rate during the isovolumic relaxation period (SRIVR), the peak early diastolic strain rate (SRE), and the time from the onset of the QRS wave to SRE (TSRE) were measured for each segment. The left atrial volume indexed to the body surface area (LAVI) was measured as a global diastolic index.Results; Long-term after PTSMA, there was significant improvement of the global SRIVR (0.21±.08vs0.13±0.06%/s, P<0.001) and SRE (0.83±0.19vs0.67±0.22%/s, P=0.001). The coefficient of variation of TSRE (CVTSRE) decreased significantly. The changes in the regional myocardial diastolic deformation and CVTSREcorrelated well with the reduction in the LAVI.Conclusions: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 HOCM patients after PTSMA. 2.2、Assessment of atrial conduction abnormalities in patients with hypertrophic cardiomyopathy before and long-term after alcohol septal ablation Objectives:The aim of this study was to investigated the intra-and inter-atrial electromechanical delay (AEMD) of hypertrophic obstructive cardiorayopathy (HOCM) patients before and long-term after percutaneous transluminal septal myocardial ablation (PTSMA) using tissue Doppler imaging.Methods:Conventional echocardiographic and AEMD parameters were obtained in25healthy controls and28HOCM patients before and at least half a year after septal ablation procedures.Results:Compared with the healthy controls, the left atrial volumes indexed by body surface area (LAVI), the intra-and inter-AEMD were significantly higher in the HOCM patients. Long-term after PTSMA, the LAVI was decreased. Moreover, the intra-and inter-AEMD were significantly decreased (16.03±7.12vs24.57±7.33ms, P<0.001;27.93±9.17vs37.10±8.62ms, P<0.001) following PTSMA. These changes in the intra-and inter-AEMD correlated well with the reductions in LAVI.Conclusions:Both the intra-and inter-AEMD were significantly prolonged in the HOCM patients. PTSMA could improve the prolonged and inhomogeneous propagation of sinus impulses in atria.