| BACKGROUNDFor over50years, hypertrophic cardiomyopathy (HCM) has been recognized as a familial cardiac disease with highly visible risk for sudden death and disease progression, characterizedby heterogeneous phenotypic expression, natural history, and genetic profile. Although multiple mutations was often reported in HCM patients at childhood and with severe phenotype and thereby considered with worse prognosis, its predictive value for malignant clinical outcomes had not been well explored. And cardiac remodeling is one of major pathological process in hypertrophic cardiomyopathy (HCM). Endothelin-1has been linked to cardiac remodeling. Big endothelin-1is the precursor of endothelin-1. We tested if it can become the marker for predicting the prognosis of HCM..METHODSA total of529patients from a prospectively collected HCM cohort were genotyped by screening10disease genes with multiplexing targeted resequencing and were subsequently divided into3groups based on pathogenic mutation dosage:no mutation was detected (no mutation), single mutation and multiple mutation s (≥2mutations). Mutation was considered to be pathogenic if it was absent in312healthy controls, the variant residues are highly conserved throughout evolution and segregated with disease in family. If family co-segregation analysis was unavailable, one of the following additional criteria must be met:previously reported to be pathogenic, nonsense or indels mutations, in silico prediction of damaging effect, and destroyed existing splice site predicted by Human Splicing Finder.The incidence of cardiovascular death and other adverse outcomes were recorded through a follow-up of4.7±3.2years. Correlations of multiple mutations with clinical outcomes were assessed. The families of four probands with multiple mutations were clinically and genetically screened. Twenty-six HCM-related genes were comprehensively screened for mutations in the probands with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and healthy controls. And a total of245consecutive patients with HCM were enrolled from1999to2011and partitioned to low, middle and high level groups according to their plasma big endothelin-1levels. RESULTSWe identified232mutations from256patients:38(7.2%) with multiple mutations and194(36.7%) with single mutation. Patients with multiple mutations were younger (P<10-6) and higher frequencies of carrying≥1conventional sudden cardiac death (SCD) risk factors (P=0.002). During follow-up,42cardiovascular deaths occurred. The survival rates of free of cardiovascular death at5and10years of follow up were65.0%and55.7%for patients with multiple mutations,95.8%and88.3%for those with single mutation and92.1%and86.5%for those with no mutation, respectively (P<10-6). Multiple mutations significantly increased the risk of cardiovascular death compared with single mutation (adjusted hazard ratio [HR],3.74;95%confidence interval [CI],2.51-12.231; P=0.0003). Patients with multiple mutations had higher risk for heart failure (adjusted HR,3.53;95%CI,1.25-9.92; P=0.017) and SCD (adjusted HR,3.57;95%CI,1.23-10.35; P=0.019) than those with≤1mutation. The HR ratio for SCD prediction was increased from2.74(95%CI,1.08-6.94; P=0.033) by using≥1conventional risk factors to5.52(95%CI,1.83-16.65; P=0.002) by using the presence of≥1conventional risk factors and multiple mutations. Lifelong-time analysis also showed similar associations in various adverse clinical outcomes. In the4families with multiple mutations, compared to the members with single mutation, the members with multiple mutations were younger, with severer symptom and more susceptible to heart failure.We also found that at baseline, significant associations were found between high levels of big endothelin-1and left atrium size, heart function and atrial fibrillation. Big endothelin-1was positively correlated with N-terminal B-type natriuretic peptide (r=0.291, p<0.001) and late gadolinium enhancement (LGE) on magnetic resonance imaging (r=0.222, p=0.016). During a follow-up of3(range,2-5) years, big endothelin-1level was positively associated with the risks of all-cause mortality, cardiovascular death and progression to heart failure (p=0.020,0.044and0.032, respectively). After adjusting for multiple factors related to survival and cardiac function, the significance remained in the association of big endothelin-1with the risk of all-cause mortality (hazard ratio (HR)=4.94,95%confidence interval (CI)1.07-22.88; p=0.041) and progression to heart failure (HR=4.10,95%CI1.32-12.75, p=0.015).CONCLUSIONSMultiple mutations in HCM are an independent risk factor for cardiovascular death and other adverse clinical outcomes. The positive rate for SCD prediction can be improved by adding genetic analysis into conventional frisk stratification algorithm. In the screening of a family with more than one patient who presents various phenotypes, there should not be only one proband chosen for genetic screening, for recognize all mutations correlated with HCM in the family. Our study also showed that high level of plasma big endothelin-1predicted prognosis for patients with HCM and it can be added to the marker panel in stratifying HCM patients for giving treatment priority to those at high risk. It needs to further explore whether the biomarkers could be used to evaluate the efficacy of intervention and opens a new window to look at the pathogenesis of HCM. |
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