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Disease penetrance and risk stratification for sudden cardiac death in asymptomatic hypertrophic cardiomyopathy mutation carriers

Michels M, Soliman OII, Phefferkorn J, Hoedemaekers YM, Kofflard MJ, Dooijes D, Majoor-Krakauer D and Ten Cate FJ. European Heart Journal;30(21):2593-8, 2009


Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder and sudden cardiac death (SCD) probably the most feared complication of HCM. SCD occurs in about 1% of HCM patients per year. Algorithms for assessing risk for SCD in HCM patients have been developed to identify high risk individuals who would benefit from preventive measures, especially from implantable cardioverter defibrillator (ICD) therapy.The increasing availability of DNA tests for HCM –causing gene defects  has facilitated diagnostic testing of HCM patients. Alongside, predictive genetic testing of asymptomatic individuals has become common. In their recent article, Michels et al. demonstrate that some asymptomatic mutation carriers without HCM have SCD risk factors. The authors point out that follow-up studies are needed to evaluate the risk stratification for SCD in these individuals.

Myocardial Disease

Summary of the paper

Michels et al. describe the outcome of cardiac evaluation and the risk stratification for sudden cardiac death (SCD) in asymptomatic hypertrophic cardiomyopathy (HCM) mutation carriers.
Cardiac evaluation was performed to 76 individuals from 32 families. The subjects had been tested predictively and they were shown to be HCM mutation carriers. Cardiac assessment comprised medical history, examination, electrocardiography (ECG), Doppler echocardiography, exercise testing and 24h Holter monitoring. HCM in adult members of these families was diagnosed according to previously published criteria by McKenna et al.

The SCD risk stratification was carried out in accordance with guidelines. A syncope was defined as unexplained loss of consciousness. Three different definitions for a positive family history of SCD were used: 1) SCD in one or more relatives, not depending on the age or degree of relatedness, 2) SCD in a first-degree relative less than 40 year or 3) SCD in more than one first-degree relative less than 40 year. An abnormal blood pressure response in exercise test was defined as a failure to increase systolic pressure over 20mmHg or a fall in blood pressure during upright testing. Non-sustained ventricular tachycardia (NS-VT) was defined as three or more consecutive beats at a rate 120/min or over, lasting less than 30 s. A maximal wall thickness of >/= 30 mm or over in echocardiography was considered as a risk factor.
Index patients (n=32) had a mean age of 35 + 14 years at diagnosis. SCD was the first presentation in almost one third of the cases. Twenty-six index patients (81%)  had some myosin binding protein C gene (MYBPC3) mutation (one patients was a compound heterozygote), four (13%) a cardiac beta-myosin heavy chain gene (MYH7)mutation, one a mutation in cardiac troponin T gene (TNNT2) and one in tropomyosin gene (TPM1).
Seventy-six asymptomatic HCM mutation carriers (thirty-three men and 43 women with an age range of 16-79 years and a mean age of 40 years), were identified and referred to cardiac evaluation and risk stratification. HCM was diagnosed in 31 (41%) asymptomatic subjects. Men had more often HCM than women (p=0,04). However, there was no significant difference in age between affected men and women.

MYBPC3 mutations were involved in 23 (74%) relatives with HCM and mutations in MYH7 were present in six (19%) relatives with HCM. MYH7 gene mutation carriers were affected at an significantly earlier age at onset than those with mutations in MYBPC3 (p=0.01). Both relatives carrying a mutation in the TNNT2 and the TPM1 genes were affected.
The HCM diagnosis was based in about half of the carriers both on echocardiographic and ECG criteria. Twelve (39%) carriers fulfilled only ECG criteria, 9% of the carriers only echocardiographic criteria. Two carriers had significant left ventricular outflow tract obstruction. In 33 mutation carriers (43%) ECG or echocardiography did not reveal any minor or major criteria compatible with HCM. These subjects were significantly younger and more often female than mutation carriers presenting the HCM phenotype. The majority of subjects without HCM (88%) carried a mutation in MYBPC3.
In risk stratification for SCD, four (5%) carriers had one first-degree relative that experienced SCD below 40 years, two with and two without HCM. Fifty-six (74%) carriers had a relative who had died suddenly not depending on the degree of the relationship or the age or the deceased relative. NS-VT was observed during 24h ECG monitoring in three subjects (4%), one without HCM. During upright exercise test an abnormal blood pressure response was observed in four (5%) carriers, one without HCM.

Discussion, comments

The authors reported HCM in 41% of asymptomatic carriers. The younger age of mutation carriers without ECG or echocardiographic criteria was compatible with age-dependent penetrance, warranting repeated cardiac evaluation up to advanced age. In regard to genotype-phenotype relations, the founder mutations were concluded to have mild effects during first three decades of life although some mutation carriers would later develop a severe disease. The MYH7 mutation carriers were affected at a younger age than MYBPC3 carriers, but the clinical expression of the mutations was variable suggesting that environmental or epigenetic factors could affect the development of HCM. These findings emphasize the variability of the clinical picture associated with HCM mutations.

The annual rate of SCD among HCM carriers varies between 0,5-1,5% The risk stratification in HCM patients aims at identifying  patients in high risk for SCD, who might benefit from an ICD. So far, the algorithms have been based on HCM patients, not asymptomatic mutation carriers. Even in this group, positive predictive value has been low and additional new criteria have been sought.
In this study Michels et al. describe the results of conventional risk stratification for SCD in asymptomatic HCM mutation carriers with and without HCM. They point out that the value of traditional risk factors needs to be evaluated also in this specific population.


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Notes to editor

Presented by Tiina Heliö, Helsinki University Central Hospital, Helsinki, Finland.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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