MANTENIMIENTO DEL AREA DE BOMBAS Y MOTORES

Sudden death in a previously asymptomatic individual is a common presentation of HCM in children and in athletes (60, 71 ) therefore these groups would be most likely to benefit from any screening and preventative strategies. Where genetic testing is possible, the pre-clinical identification of subjects with mutations known to cause HCM will permit accurate prospective observation o f disease progress thereby providing greater understanding o f the natural history. A window of opportunity for the investigation of the effects of potentially preventative treatments would also be provided. Animal studies suggest that certain medical therapies may prevent or delay the development o f left ventricular hypertrophy (202). Medical treatment with high dose propranolol (194, 195, 201), amiodarone (212) and verapamil (209) have all been reported to be associated with a low annual mortality in retrospective studies and regression o f hypertrophy has been observed in some children with HCM (194, 203). The natural history o f HCM caused by specific disease mutations and further description o f genotype-phenotype correlation would also yield information about presenting clinical features, tendency to sudden death and response to treatments associated with particular mutations and would thus add another tier to the risk stratification model (58). It has been shown using echocardiography that HCM can be rapidly progressive during childhood and adolescence in those whose echocardiograms were previously judged as normal on standard criteria (68). Therefore, suitable subjects for any intervention or treatment studies have and will continue to be identified without the use o f genetic techniques. A recent retrospective study identified such subjects during childhood using echocardiography and showed a statistically significant improvement in survival in those treated with high-dose propranolol compared with either no treatment, or other treatment regimes, in patients matched for risk factors (195). The data in this thesis suggests that the echocardiographic measurement of septum-to-cavity ratio provides a powerful tool to identify candidates of all ages for preventative and treatment purposes, including susceptible family members in families where a genetic mutation has not been found. Furthermore, once treatment regimens had commenced, the severity, progression or regression of the disease at all ages could be monitored, as indicated by the successful use o f the ratio to monitor children with HCM (194).

In addition, more accurate echocardiographic means o f identifying phenotypic characteristics of HCM are crucial to progress in the identification o f further disease mutations. This is because the process of linkage analysis requires a kindred in whom echocardiography has identified a minimum o f 3 or 4 affected family

members. Potential disease loci are then explored and the appearance at these sites in affected individuals is compared with the appearance in unaffected individuals. Septum-to-cavity ratio and systolic LV wall- to-cavity ratio appear to offer a more sensitive echocardiographic tool for this purpose at all ages. This is shown by the separation o f the first degree relatives in to more equal proportions o f "affected" and "unaffected" compared to previous echocardiographic studies (135, 159) and by the inclusion o f two subjects who fail to meet the diagnostic criteria based on absolute wall thickness measurements alone. The importance o f identifying "mildly" affected individuals is that an individual with borderline left ventricular hypertrophy who has inherited a genetic mutation associated with a high incidence o f sudden death (102, 264) may have a worse prognosis than an individual with a 32mm septum identified by all criteria as being abnormal but in whom the inherited mutation is associated with a benign prognosis (104, 263).

Early diagnosis has other advantages. I f diagnosed in childhood, a child can grow up without competitive sporting ambitions rather than having these thwarted in adolescence when considerable success or expertise may have developed along with related career aspirations. It is reasonable to counsel against vigorous exertion since up to 40% o f those < 30 years with HCM who die suddenly, do so during or after exertion (62) and therefore these individuals may be a group in whom death might have been prevented. In addition, regular medical assessment could be offered allowing symptoms to be identified and treated instead o f ignored (271).

However, in any screening strategy the disadvantages of positive identification also have to be considered. The main disadvantage of early detection of the disorder are the subsequent restrictions, limitations and fear experienced by the individual who may never overtly express the condition and whose prognosis is uncertain. As discussed above the presence of a mutation may merely be a predisposing factor to hypertrophy in the presence of other factors and so its presence alone does not allow accurate prediction of phenotype or prognosis. Employment, life insurance and loans may all be affected by the knowledge, gleaned either by genetic or echocardiographic techniques, that an individual has or is susceptible to the development of HCM. However, most companies involved in the fields of life insurance and income protection ask for a detailed family history. The policy will become null and void if details o f this are not revealed and therefore any history of a sudden death in the family due to HCM or any details of an affected family member will alert the companies to the 1 in 2 chance o f the applicant being affected. These agencies are likely therefore, to make the necessary adjustments in risks and cost or reject the application altogether based on the family history alone. In the case o f a particular employment such as that o f an airline pilot, the candidate would be subjected to the most rigorous testing available with such a family history in any case. It may be therefore that the unaffected subjects (half o f the first-degree family members) may achieve much benefit in these areas from knowing that they are not affected. In the case of the affected family members, it is likely that more knowledge regarding the natural history associated with

particular mutations, particularly the more benign ones, will assist them in these areas. For those with less benign mutations or with unidentified mutations, the development of accurate risk stratification profiles, access to detailed sequential phenotypic evaluation and the implementation of successful treatments will all help to modify the prejudice experienced by these individuals and may provide the necessary reassurance to the relevant institutions.

Despite these potential disadvantages, a very moving and honest account about the decision o f one set of parents to have their new-born baby genetically screened for HCM (411) provides significant justification for offering screening of whatever type to families. The father o f the baby in the article had himself been diagnosed with HCM at the age o f 24 years following the illness of his sister. He had, since his teenage years, experienced difficulty with exercise and believed that earlier identification of the disease would have allowed him to better adapt his lifestyle. His wife wrote, "knowledge itself can be a kind o f cure". They were in no doubt about having their daughter screened for the mutation since they perceived that this knowledge could bring only benefit to themselves and the baby. At the age of 4 weeks the baby was identified as a carrier o f the disease mutation. The parents thought that this knowledge would enable them to have their daughter carefully assessed throughout life such that any problems or symptoms could be identified and treated early and that in the event of illness experts with full knowledge o f her condition would be available quickly. They are aware that they may lose their daughter through the condition but feel that knowing about it from the start enables them to do the "very best for her" and that through knowledge and research the risks for her might be reduced. Not all families will feel the same, nor would they have made the same decision as the parents in the article but surely families and individuals should at least be offered screening of whatever type; it can be rejected if it is not wanted.