Hypertrophic Cardiomyopathy And Hypertension Secondary To Left Ventricular Hypertrophy In Molecular Genetics And Pathogenesis Research

BACKGROUNDHypertrophic cardiomyopathy (HCM) is a genetic disease with an autosomaldominant mode of inheritance characterized by myocardial hypertrophy usuallyinvolving in the interventricular septum. Based on genotype-phenotype correlationsstudy in large HCM pedigrees, genetic defects causing HCM could represent theprimary determinant and stratifying marker of prognosis, sudden cardiac death andheart failure. Mutations in different genes or specific regions of one gene may havedifferent clinical features. Certain mutations of MYH7 have been associated with asignificantly shorter life span in patients with HCM. Whereas mutations in theMYBPC3 have been associated with late onset of hypertrophy and a relatively benignprognosis. Recently, large studies on HCM patients do not supportgenotype-phenotype correlation.The published clinical data assembled over clinical implications of HCM and thetreatment strategies were most from few selected tertiary centers in North America orEurope. Clinical stable and asymptomatic, elderly patients and patients other thanNorth America or Europe were under-represented.At present, it is not clear whether there is a particular prognosis for the adultsharboring different mutant HCM genes but having neither left ventricular hypertrophynor other clinical phenotypes of HCM, or for HCM patients carrying differentmutations.OBJECTIVESTo prospectively investigate if different gene mutations confer distinct prognosis. METHODSThe HCM patients were consecutively recruited in FuWai Hospital andCardiovascular Institute, Chinese Academy of Medical Sciences. At base-line, a totalof 100 patients with HCM and 356 family members of 25 pedigrees of the 100 HCMpatients were recruited. A total of 70 HCM patients and 46 genetically affected familymembers harboring mutations in MYH7 or MYBPC3, without HCM-phenotype, werefollowed up at Cardiovascular Institute and FuWai Hospital, Chinese Academy ofMedical Sciences from July-1997 to January-2006.The diagnosis of HCM was based on echocardiography, that is maximal thickness ofthe left ventricular wall was＞13 mm, measured in diastole in the region of greatesthypertrophy in absence of any other causes of ventricular hypertrophy. A bloodsample for DNA analysis was taken from patients and family members of patientsafter informed written consent. Clinical records and family history were obtained todetermine the disease-related deaths and the age at death for all affected individuals ineach family.ResultsThe mean duration of follow-up was 5.9±1.8 years in patients with MYH7 mutationsand 5.7±1.7 years in patients with MYBPC3 mutations (p＞0.05). During follow-up,patients with MYH7 mutations had more surgical intervention (8/52 versus 0/18,p＜0.001) than did those with MYBPC3 mutations, including surgical septal myectomy(3/8), alcohol septal ablation (1/8), and DDD pacemaker (4/8). Fourteen patients died,10 of them were with MYH7 mutations and four with MYBPC3 mutations. The sudden death ratio was higher (7/52 versus 0/18, p＜0.001) and the age at death was younger(45.1±14.0 vs 73.5±7.5 years, p=0.03) in patients with MYH7 mutations than in thosewith MYBPC3 mutations. The patients with MYBPC3 mutations had a normal lifespan (73.5±7.5 years, range 67.4 to 84.5 years). Sudden death occurred only in thepatients carrying mutations of R663C (1/7), A26V (3/7), Q734P (2/7) and R719Q (1/7)in MYH7.At base-line, 46 subjects carry the mutations either in MYH7 (27) or in MYBPC3 (19)with no clinical, electrocardiographic and echocardiographic HCM manifestations.During follow-up, 9 subjects with MYH7 mutations (4 with A26V, 3 with R143Q and2 with R663H) developed symptoms including dyspnea (3/9), angina (1/9), palpitation(4/9) or syncope (1/9) and abnormal electrocardiography (5/9) or thickerinterventricular septum (7/9) in echocardiography. All 9 new patients carry MYH7mutations and their mean onset ages were 37.3±5.6 years old. MYBPC3 mutationcarriers had neither clinical symptoms nor presentations of HCM during the entireperiod of follow-up. The mean age of those MYBPC3 mutation carriers were 46.8±9.7years old at the last time of evaluation.According to the mutation location, patients with MYH7 mutations were subclassedinto the mutation in the global region (41/52) and that in rod region (11/52); withcharge change (24/52), and without charge change (28/52). At base-line, the maximalwall thickness was thicker in the patients with mutations in the global region than inthose with mutations in rod region (21.5±6.6 versus 15±6.1 mm, p＜0.05). Duringfollow-up, total 10 patients died, 3 died of heart failure and 7 sudden death. All 7sudden death patients carry MYH7 mutations in the global region, only one patient inthe rod region who died of heart failure.At the final evaluation, 7 of 29 patients with mutations in the global region hadNYHA ClassⅠ～Ⅱat base-line and were developed to ClassⅢ～Ⅳduring follow-up, whereas no patient with mutation in the rod region had cardiac function NYHA ClassⅢ～Ⅳ(p＜0.01 between the two groups) during follow-up.The charges of the mutated amino acids had no significant influence on clinicalpresentation and prognosis at base-line and after 6-year follow-up.CONCLUSIONSThis prospective study implies that patients with mutations in MYH7, particularly inthe global region, had malignant clinical manifestation, shorter longevity and highrisk of sudden death, not MYBPC3. Our results provide potential guidance on riskstratification of patients with HCM and subjects carrying gene mutations with noclinical phenotypes. BACKGROUNDHypertrophic cardiomyopathy (HCM) is a primary autosomal dominant inheritantmyocardial disorder with heterogeneity in clinical manifestations, natural history andprognosis. Even carrying an identical gene mutation, inter- and intra-family variationshave been noticed worldwide in the presence and the severity of left ventricularhypertrophy and sudden death in patients with HCM. Modifier genes may contributeto the diversity. Which modifier gene responsible and how many genes involved arestill unknown. Echocardiographic left ventricular hypertrophy (LVH) is associatedwith cardiovascular morbidity and mortality, as well as all-cause mortality.Hypertension is the major cause of LVH, it may be responsible for up to 25% of thevariance of left ventricular mass in a given population. However, the degree ofhypertension is no parallel to the level of blood pressure. Genetic factors have beenestimated to be responsible for about 60% of blood pressure-independent variance ofcardiac mass. Previous study indicates that PPAR-αgene influences human leftventricular growth in response to exercise and hypertension, and PPAR-γsuppressescardiac growth in a cardiomyocyte-specific PPAR-γ-knockout mouse mode.OBJECTIVESWe hypothesized that polymorphisms of Rs9615784, rs4253654 and rs4253778 ofPPAR-αgene, Pro12Ala,rs7649970 and rs10865710 of PPAR-γgene andGly482Ser and Thr394Thr of PGC-1αgene may modify the diversity of HCM orLVH. To test our hypothesis, the associations of these polymorphisms with cardiachypertrophy were tested in case-control studies. SUBJECTS AND METHODSTotal of 270 consecutive HCM patients established in FuWai Heart Hospital wererecruited, and 2486 hypertensive patients, comprised 1180 patients with LVH and1306 without LVH which came from a community-based cross-sectional study, aswell as 894 healthy controls were successfully investigated. The DNA was extractedfrom peripheral blood leukocytes. The polymorphisms of PPAR-αgene, PPAR-γgene and PGC-1αgene were genotyped by PCR-RFLP and confirmed by sequencing.Logistic regression analysis was performed to identify the independent risk factors forHCM and LVH.RESULTSOur results indicated that the Ser482 allele (rs8192678) and CC genotype ofThr394Thr (rs2970847) conferred increasing risk for HCM (OR 1.52, 95% CI1.11-2.11; OR 1.49, 95% CI 1.15-1.98, respectively) and were associated with thickermaximal wall thickness of HCM (20.7±4.1 mm versus 19.1±4.3 mm, p＜0.05 and20.9±4.6 versus 19.0±4.2, p＜0.05, respectively). No association was found betweenthe two polymorphisms with hypertension with or without LVH. Polymorphisms ofRs9615784, rs4253654 and rs4253778 of PPAR-αgene, Pro12Ala,rs7649970 andrs10865710 of PPAR-γgene were not associated with increasing risk of HCM andLVH.CONCLUSIONSOur data indicate that the variations of PGC-1αgene are correlated with theincreasing risk for HCM independently, not with hypertension with or without LVH.The variations of PGC-1αgene may be the genetic modifier for the development ofHCM. Backgroud: Left ventricular hypertrophy (LVH) is associated with morbidity andmortality of cardiovascular disease and stroke. Hypertension is the major cause ofLVH. The prevalence and risk factors for LVH are unknown in Chinese hypertensivepopulation in the rural area. The objective of our study was to investigate theprevalence and the risk burden of LVH in community-based Chinese hypertensivepopulation.Methods: The study was a community-based cross-sectional study, 5440hypertensive patients were enrolled. Left ventricular mass was measured by usingtransthoracic echocardiography. LVH was defined as that the left ventricular masswas more than 49.2 g/m^2.7 for men and more than 46.7 g/m^2.7 for women. Thegeometric patterns, normal, concentric remodeling, concentric or eccentrichypertrophy, were calculated according to LVH and relative wall thickness. Logisticregression model was used to determine the odds ratio (OR) and 95% confidenceintervals (CI) of the risk factors of LVH.Results: The prevalence of LVH was in 4270 hypertensive patients, with 37.4% inmales and 45.4% in females, respectively. The prevalence of concentric remodeling,concentric or eccentric hypertrophy was 24.7%, 20.2%, and 22.6% respectively. Afteradjustment for conventional risk factors of cardiovascular diseases, female (OR 1.3,95%CI 1.2-1.5, P＜0.01), age (OR 1.2, 95%CI 1.1-1.3, P＜0.01), body mass index (OR1.4, 95%CI 1.3-1.5, P＜0.01), systolic blood pressure (OR 1.2, 95%CI 1.1-1.3,P＜0.01), and serum triglyceride (OR 1.1, 95% CI 1.0-1.2, P＜0.01) remained as riskfactors of LVH as well as left ventricular geometry abnormalities. Additive effects ofage, sex, systolic blood pressure and triglyceride on LVH were identified.Conclusions: The echocardiographic LVH is the major complication of patients withhypertension in rural area of China, especially in women. Higher level of systolic blood pressure, serum triglyceride, overweight and female have additive effects onLVH. To effectively lower hypertension, control body weight and serum triglycerideis of essential important in the prevention of LVH in hypertensive population.