Is it possible to optimise the diagnosis and treatment of relatives from genetically confirmed hypertrophic cardiomyopathy (HCM) patients using an efficient preventive risk stratification?

BACKGROUND. Hypertrophic Cardiomyopathy (HCM; prevalence 1:500, approx. 32,000 Dutch individuals) is an inherited cardiac disease that often results in sudden cardiac death (SCD) at young age (<50 years). 50% of the relatives of HCM-patients also carry the mutations. The risk of SCD among mutation carriers is approx. 1% annually in unselected HCM-patients but increases to 5% annually in a high-risk population. SCD can be prevented by regular cardiological diagnostics and effective prophylactic treatment (e.g. medication, internal cardioverter defibrillator [ICD]) once a mutation carrier becomes high risk. The ACC/ESC Consensus Report suggests that all mutation carrying relatives should be identified and yearly undergo cardiological diagnostics. One may question that advise as 75% of the HCM-population consists of low risk carriers, and cardiological diagnostics and prophylactic treatment are far-reaching and burdensome. As more than 90% of Dutch mutation carriers still await identification, timely risk stratification could be helpful to optimise the efficiency of diagnostic care. OBJECTIVE. To optimise anamnestic and cardiological diagnostics and surveillance in family members with genetically confirmed HCM. QUESTIONS. (1) Can the process of presymptomatic DNA-testing, cardiologic follow-up and treatment be optimised by distinguishing (triage) mutation carrying relatives into those with a low initial risk and those with a high initial risk for SCD? (2) Can the prognostic accuracy of the initial risk stratification be improved if relatives carry a Dutch founder mutation (2373insG, R943X, or 2864-2865del CT mutation in the MyBPC3-gene)? (3) What are the consequences of various diagnostic and treatment strategies for the screenee?s burden, risk perception, quality of life and efficiency (cost-effectiveness)? DESIGN. Prospective follow-up study. All relatives undergo cardiologic diagnostics annually and risk status is prospectively estimated. For analytical purposes, relatives are distinguished in a group with a high initial risk and a low initial risk. Over time, low risk relatives may stay low risk or migrate to high risk. STUDY POPULATION. Asymptomatic mutation carrying 1st degree relatives of index-patients with proven HCM. OUTCOME MEASURES. (1) Relative with cardial event (aborted sudden cardiac death) or SCD; (2) Relative with a final high risk status who are eligible for prophylactic treatment. POWER. Equivalence study design. Using a one sample test with alpha=0.05 (one-sided), beta=1-0.80, and rho=0.05 and an expected proportion of endpoint of 1%, a proportion of endpoints of 2% or higher can be excuded with 95% confidence if (at least) n=268 family members in the initially low risk group are included. Hence, (at least) 400 family members have to included in the study. Relatives are invited for participation in the AMC (Amsterdam), ErasmusMC (Rotterdam) and AZ Groningen. ANALYSIS. (1) cumulative number of relatives with a final high risk status distinguished by initially low versus initially high risk status; (2) comparison of survival curves (event= final high risk, time to event=time spent in low risk. (3) sensitivity and specificity of initial risk risk stratification. POTENTIAL BENEFIT. If the risk stratification proves succesful, HCM-relatives may need less cardiological diagnostics, less frequent cardiological diagnostics, or no diagnostics at all, without an increase in the risk of SCD in that group. If a risk stratification is impossible to achieve, all carriers of HCM-mutations must be identified in the coming years and must receive annual cardiological follow-up, delivering considerable workloads on clinical geneticists and cardiologists, and pose a major financial burden to the health care system and severely compromise psychosocial health to individuals. :