Molecular Genetics And Clinical Study Of Hypertrophic Cardiomyopathy

Background:Hypertrophic cardiomyopathy (HCM) is defined by a hypertrophied and non-dilated left ventricular cavity, characterized with normal or supernormal systolic function. However, a small number of HCM patients progress to left ventricular thinning, cavitary dilation, and systolic dysfunction. Such a condition is referred to as end-stage HCM (ES-HCM). Previous studies suggested diverse clinical characteristics and prognosis of ES-HCM, largely proved to be poor. Early recognition of patients with high risk of mortality would improve the prognosis. To date, the sample size of most studies is small and no research has been focus on Chinese patients with ES-HCM. Furthermore, risk factors of cardiovascular mortality remain obscure. Accordingly, the prognostic factors of end-stage HCM patients need to be clarified to target early management.Aims:This study aimed to evaluate the clinical manifestations and prognostic factors in Chinese patients with ES-HCM.Methods:HCM patients were enrolled from 2002 to 2013 in Fuwai Hospital and ES-HCM were defined by a left ventricular ejection fraction<50%without coronary artery disease or septum reduction therapy. Clinical data was collected. Risk factors for cardiovascular death were analyzed by multiple Cox hazards ratio model.Results:ES-HCM was identified in 99 (5.4%) patients from a total of 1844 HCM patients, averaged at 52±16 years old at entry, and annual incidence was 0.45%. Of them,57 patients (57%) were evaluated with New York Heart Association (NYHA) class III/IV at entry,9 (9%) with mid-ventricular obstruction,11 (11%) with apical aneurysms, and 14 (14%) with left ventricular thrombi. Atrial fibrillation, non-sustained ventricular tachycardia, and sustained ventricular tachycardia were respectively observed in 53 (54%),48 (48%), and 13 (13%) patients. During 3.9±3.0 years of follow-up, systemic embolism, refractory heart failure, and death or transplantation were observed in 22 (22%),39 (39%), and 51 (52%) patients, respectively. The incidence of annual mortality was 13.2%. Kaplan-Meier analysis showed that a higher probability of cardiovascular death was observed in patients with NYHA class Ⅲ/Ⅳ (P=0.018), those with severe systolic dysfunction (LVEF<35%) (P=0.045), and those with the presence of complete left bundle branch block (.P-0.002) and an abnormal Q wave (P=0.001). Cox hazards regression analysis identified NYHA class Ⅲ/Ⅳ at entry (hazard ratio [HR]:1.99; 95% confidence interval [CI]:1.05-3.80; P=0.036), left bundle branch block(HR:2.80; 95% CI:1.47-5.31; P=0.002), and an abnormal Q wave (HR:2.21; 95% CI:1.16-4.23; P=0.016) as independent predictors of cardiovascular death.Conclusions:Heart failure and arrhythmia are common findings in Chinese ES-HCM population. Susceptibility of ES-HCM patients to mural thrombus and embolic events warrants further attention. Complete left bundle branch block and an abnormal Q wave are risk factors of cardiovascular mortality in end-stage HCM and provide new evidence for early intervention.Backgrounds:Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac disease, is the major cause of sudden cardiac death and heart failure in adolescents. Mutations in 25 or more genes with more than 1500 variants are responsible for HCM. Genetic testing is a specific means for early recognition of patients and an important method to screen familial carriers. Also, correlation between genotype and phenotype may provide evidence for predicting prognosis and early prevention. However, controversies existed in genotype-phenotype relationship and previous analyses were mainly resulted from sacomeric mutations. To date, there is no genotype-phenotype relationship based on overall genetic spectrum in HCM.Aims:The study aimed to identify the genotype by overall HCM causal genes and to explore the genotype-phenotype correlation.Methods:Patients diagnosed with HCM were prospectively included from 2011 to 2012 at Fuwai hospital. Causal gene mutations were screened by Ion Torrent Sequencing for these patients. Survival analysis was used for genotype-phenotype correlation after comprehensive clinical evaluation and follow-up for HCM patients.Results:Of the inclusive 71 patients,33 (46%) carried 34 different mutations,4 (12%) of which carried multiple gene mutations. Of all mutations, the frequency of sarcomere genes, MYH7, and MYBPC3 was 91%,35%, and 35%, respectively. Also,65% (22/33) of them were novel and 74% were missense mutations. But 75% of the mutations in MYBPC3 were deletions or splice site mutations. Compared to the mutation-negative patients, the mutation-positive patients had earlier age at symptoms onset (40±12 VS.49 ±11 years old, P=0.001), earlier age at diagnosis (41±13 VS.53±10 years old, P< 0.001), and the more frequent presence of family history of HCM (52% VS.13%, P< 0.001), family history of sudden death (50% VS.11%,P<0.001), and non-sustained ventricular tachycardia (36% VS.13%, P=0.022). Kaplan-Meier analysis demonstrated that the survival free of cardiovascular death (P=0.019), sudden cardiac death (P=0.010), and heart failure admission (P=0037) in mutation-positive patients were lower than those in mutation-negative patients. The frequency of ages less than 35 years old was higher in MYH7 carriers than in MYBPCS carriers, but there is no difference between them on other clinical characteristics or prognosis. Among four patients with multiple mutations, two patients implanted a cardiac cardioverter defibrillator with an appropriate discharge and two patients with end-stage HCM both had mural thrombus and heart failure admission with one waiting for heart transplantation.Conclusions:The frequency of multiple gene mutations was greater than expected by all causal genes screening and sarcomere mutations are the main cause of HCM. Mutation-positive patients have worse prognosis irrelative to mono-mutation type. Multiple mutations may predict systolic dysfunction.Backgrounds:Hypertrophic cardiomyopathy (HCM) is characterized by a broad spectrum of morphological features, clinical expressions, natural history, and prognosis. A unique subgroup of HCM develops left ventricular apical aneurysms (LVA) with unclear mechanisms, irrelative to coronary artery stenosis. The clinical characteristics with regard to this unique disease were not fully understood due to small sample and few serial reports. The prognosis was inconsistent in previous studies and how to early recognize patients at high risk of SCD from this entity has not been clarified yet. Up to date, the effect of medical treatment to control the progression is not optimistic and surgical therapy of apical aneurysms in HCM patients has been only confined to case reports. Although the population of HCM in China is estimated to be 100 million, there has been no study focused on this entity yet.Aims:This study aimed to evaluate the prevalence, clinical characteristics, and prognosis of apical aneurysms in Chinese HCM patients.Methods:HCM patients were consecutively collected from 2002 to 2013 in Fuwai Hospital and apical aneurysms were enrolled by diagnostic criteria. Clinical data, including medical history, electrocardiography, and echocardiography, were analyzed by chart review. Follow-up data were collected by regular outpatient and/or telephone interviews with the patients or family members.Results:Apical aneurysms were identified in 24 patients (1.3%) from a total of 1844 HCM patients, averaged at 52±14 (range 9 to 75) years old at entry. Of them,11 (46%) patients attended with family history,11 (46%) with chest pain,17 (71%) with ST-segment elevation, and 4 (17%) with New York Heart Association class III/IV at initial evaluation. Left ventricle was identified as an hourglass shape (71%) or distal hypertrophy (29%). Of them,13 (54%) had intra-ventricular pressure gradients (61±44mmHg, range 16 to 180 mmHg), including 2 (8%) by LV outflow tract obstruction and 9 (38%) by mid-ventricular obstruction. Mural thrombi, non-sustained ventricular tachycardia, and sustained ventricular tachycardia were present in 11 (46%),4 (17%), and 9 (38%) patients, respectively. During 5.0±3.4 (range:1-14) years of follow-up,14 (58%) patients experienced clinical adverse events (annual event rate,11.7%), including sudden cardiac death (n=4), appropriate implantable cardioverter defibrillation discharge (n=4), progressive heart failure (n=4) or related death (n=1), and stroke (n=4). Eleven patients evolved into systolic dysfunction. No adverse event was observed in 4 patients with myomectomy and aneurysmectomy in addition to an aneurysmal thrombus. Compared to survivals without surgery, patients experienced sudden death had a lower ejection fraction (41±12 VS.58±11, P=0.004), a larger left ventricular end-diastolic diameter (59±5 mm VS.46±4, P<0.001).Conclusions:Apical aneurysms are not rare in Chinese HCM patients. Sustained ventricular tachycardia and mural thrombus are the main manifestations. Common signs of chest pain and ST segment elevation highlight the clinical awareness. The prognosis is poor with a high incidence of sudden death. Aggressive therapeutic strategy to counter sudden death should be considered for them with dilated ventricle and systolic dysfunction, and prophylatic surgical resection may be an alternative choice.