The Mechanisms Of The Left Ventricular Outflow Tract Obstruction And Genotype-phenotype Relationship In Hypertrophic Cardiomyopathy

There are more than 1 million patients with hypertrophic cardiomyopathy (HCM) in China. HCM is the most common genetic cardiovascular disease, inherited as an autosomal dominant trait. HCM is the most common cause of sudden death (SD) in the young. The left ventricular outflow tract obstruction (gradient≥30 mmHg) is a prominent feature of hypertrophic cardiomyopathy. The severe LVOTO is a major cause of symptoms and a predictor of adverse prognosis. The septal reduction interventions (such as surgical septal myectomy and percutaneous alcohol septal ablation) have been introduced to relieve disabling symptoms associated with outflow tract obstruction. Indications for these invasive procedures are based on measurement of LVOTG. In the recent studies, latent obstruction were present during exercise echocardiography (EE) in half of patients without obstruction at rest. One-third of latent obstruction patients required invasive therapy for relief of symptoms. The evaluation of HCM patients with resting outflow tract gradients<30 mm Hg must include provocative maneuvers to identify latent obstruction, preferably by physiologic exercise. However, in our present clinical practice, the diagnosis of the LVOTO in HCM still depends on the assessment of outflow gradient under resting conditions. Consequently, the prevalence, clinical profile of latent obstruction provoked by exercise echocardiography was presently unknown in Chinese patients with HCM. It would be amount of latent obstruction patients (estimated 30000) undetected and untreated. Dobutamine stress echocardiography (DSE) as an nonphysiologic maneuver was used to provoke LVOTG in some medical institutions. However, the accuracy and difference of DSE in Comparison with EE was uncertain. Since the discovery of the first genes for HCM, much has been speculated on specific genotype-phenotype correlations. There was no study to investigate whether the phenotype (including PTSMA effect) in patients with obstructive hypertrophic cardiomyopathy was difference in different mutation carriers. To address these gaps in knowledge, the present study was designed with three parts:PartⅠ:to provoke left ventricular outflow tract obstruction by exercise echocardiography, and analysis the morphological characteristics of different types of obstruction in HCMPartⅡ:to Compare dobutamine stress echocardiography with exercise echocardiography in evaluation of left ventricular outflow tract obstruction in HCM.PartⅢ:to investigate the genotype-phenotype correlations between different mutations and clinical characteristics in patients with obstructive hypertrophic cardiomyopathyPartⅠ:Left ventricular outflow tract gradient provoked by exercise echocardiography in hypertrophic cardio-myopathyObjective:We sought to assess the prevalence and significance of left ventricular outflow tract obstruction (LVOTO) under resting conditions and with physiological exercise in HCM patients.Methods:We prospectively analyzed 60 consecutive patients with HCM and LVOT gradient<50 mm Hg at rest, measuring LV outflow gradient at rest, and with exercise echocardiography. Nine patients had rest gradients> or=30 mm Hg (resting LVOTO). Of the other 51 patients with gradients < 30 mm Hg at rest,26 developed mechanical obstruction to LV outflow after exercise (latent LVOTO), The remaining 25 patients had no or small gradients (< 30 mm Hg) both at rest and with exercise(Non LVOTO). Comparison of echocardiographic morphology of each group to analyze the morphological characteristics of different types of obstruction.Results:Patients with resting LVOTO were more likely to have systolic anterior motion of the mitral valve (SAM), narrow of LVOT, higher mitral regurgitation grade and wigle's scores than patients with gradients< 30 mm Hg at rest. (all P<0.05). Each of these factors was positively correlated with rest LVOTO (all P<0.01, all r<0.5).On multivariate logistic regression analysis, independent factors of resting LVOTO were SAM (OR 6.431,95%CI 1.226-33.721 P=0.028) and mitral regurgitation grade (OR 9.808,95%CI 1.054-91.271 P=0.045) at rest (both P<0.05). Patients with latent LVOTO were more likely to have SAM, narrow of LVOT, higher resting gradients and mitral regurgitation grade at rest than patients with non-obstructive (all P<0.05). The distribution of septal hypertrophy were different in two groups (P<0.05). Each of these factors was significantly correlated with latent LVOTO (all P<0.01, all r>0.5). On multivariate logistic regression analysis, independent predictors of latent LVOTO were SAM(OR 6.431,95%CI 2.323-291.112 P=0.002) at rest and distribution of septal hypertrophy (OR 0.011,95%CI 0.001-0.179 P =0.008)Conclusions:Approximately half of patients with non-obstructive HCM at rest have latent LVOTO. SAM and distribution of septal hypertrophy may be useful to identify patients with latent obstruction.PartⅡ:Comparison of dobutamine stress echocardio-graphy and exercise echocardiography in evaluation of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.Objective:To compare LVOT gradients induced by dobutamine stress echocardiography (DSE) and exercise echocardiography (EE) in patients with HCMMethods:Forty consecutive patients with HCM and LVOT gradient<50 mm Hg at rest completed exercise echocardiography and dobutamine stress echocardiography using Doppler echocardiography to assess the presence of left ventricular outflow gradient. LVOT gradients were measured at rest at peak exercise and during each dose of DSE.Results:Of the 36 patients with gradients< 30 mm Hg at rest,17 developed mechanical obstruction to LV outflow after exercise (latent LVOTO), and 18 developed obstruction by DSE. The results of the two maneuvers had good consistency (91.7%). The provoked gradients by DSE at dose of 800ug. min-1 and by exercise were no significant difference by paired T test (P=0.181). They had good correlation (r=0.902 P<0.001) and consistency.Conclusions:Dobutamine stress echocardiography was a safe and sensitive maneuver and could be used as an alternative provoke method for patients with hypertrophic cardiomyopathy.Part III:Genotype-phenotype relationship in patient with obstructive hypertrophic cardiomyopathyObjective:To investigate the causing-disease genes in Chinese with obstructive hypertrophic cardiomyopathy, and to analysis relationship between the genotype and the phenotype.Methods:We investigated 52 unrelated HCM patients who recieved PTSMA treatment and 50 healthy volunteers as controls by sequencing the two most frequent HCM-causing gene (MYH7, MYBPC3).The complete data of clinical and intervention procedures were collected.Results:seventeen patients (32.7%) carried 15 types of mutations in the selected genes, including 12 patients carried 10 types of mutations in MYH7 genes and 5 patients carried 5 types of mutations in MYBPC3 genes. most (9/15) were newly identified. These results suggested that MYH7 were the predominant genes responsible for HCM in Chinese, and with fewer MYBPC3 mutations in this subset. There were no differences in clinical phenotype between MYH7 and MYBPC3 mutations. The amount of alcohol used in PTSMA was more in patients with MYH7 mutations than in patients with MYBPC3 mutations. (3.1±1.3ml vs 1.7±0.6ml P=0.039) Two mutations in MYH7 (A26V and R143Q) were detected high frequence of mutation and designated as hot-spot mutations in Chinese. The unrelated patient carrying the same mutation had similar clinical manifestations. Two muslim patients carried compound heterozygosity for mutations in MYH7. They had more severe phenotype.Conclusions:It was confirmed that MYH7 were the predominant genes responsible for HCM in Chinese, especially in severe phenotype patients.