Echocardiographic Evaluation in Asymptomatic Relatives of Patients with Dilated Cardiomyopathy Reveals Preclinical Disease

Context Idiopathic dilated cardiomyopathy is familial in 25% of cases. However, identifying asymptomatic affected relatives is difficult because there is no specific molecular marker for the disease and penetrance of the genetic defect is incomplete. The natural history of asymptomatic disease is poorly defined. Contribution Clinical evaluation of asymptomatic relatives of patients with dilated cardiomyopathy showed that those with left ventricular enlargement or depressed fractional shortening were nearly 8 times as likely to progress to dilated cardiomyopathy as those with normal findings. Implications Screening of asymptomatic relatives of patients with dilated cardiomyopathy seems useful since early treatment may improve prognosis in affected individuals. The Editors Idiopathic dilated cardiomyopathy frequently presents at an advanced stage as severe heart failure or a catastrophic event, such as sudden death or stroke (1). The preclinical stage of dilated cardiomyopathy may last several years, even when the eventual clinical syndrome is acute. Although advances in heart failure management have improved the prognosis for patients presenting late, additional benefit might result from treatment before the onset of symptoms, making the identification of at-risk individuals a major focus of current research in heart failure. Recent studies have demonstrated that dilated cardiomyopathy is familial in at least 25% of cases (2-5). Most families exhibit an autosomal dominant mode of inheritance. Genetic analyses in extended kindreds have defined several dilated cardiomyopathy disease loci and genes (6-16). However, in most families with dilated cardiomyopathy, disease penetrance is incomplete and age-related, hampering attempts to identify the responsible gene defects. Without molecular markers, the diagnosis of familial dilated cardiomyopathy and the detection of early asymptomatic disease depend on clinical evaluation. Initial echocardiographic studies of the family members of patients with dilated cardiomyopathy noted an unusually high incidence of asymptomatic minor abnormalities of the left ventricle (3-5). These abnormalities may represent preclinical disease or formes frustes of dilated cardiomyopathy. We prospectively examined a large series of unselected patients with dilated cardiomyopathy and their family members to determine the prevalence and natural history of echocardiographic abnormalities among asymptomatic, apparently healthy relatives. Methods The human research committee at St. George's Hospital Medical School, London, United Kingdom, reviewed and approved the entire study protocol. We obtained informed consent from each patient to contact family members and subsequently from each family member who agreed to participate in the study. Echocardiographic Criteria Experienced operators, who were unaware of the clinical context, performed all study echocardiography. We obtained chamber measurements at the mitral valve tip level from 2-dimensional guided M-mode or short-axis view recordings. We corrected dimensions for age and body surface area according to the formula of Henry and colleagues (17): percentage of predicted left ventricular end-diastolic dimension = measured left ventricular diastolic dimension/predicted left ventricular diastolic dimension 100; and predicted left ventricular diastolic dimension = (45.3 body surface area0.3) (0.03 age) 7.2. We classified individuals in accordance with earlier reports as follows. Dilated cardiomyopathy was defined as percentage of predicted left ventricular diastolic dimension of 112% or greater and fractional shortening less than 25%; left ventricular enlargement was defined as percentage of predicted left ventricular diastolic dimension of 112% or greater and fractional shortening of 25% or greater; depressed fractional shortening was defined as percentage of predicted left ventricular diastolic dimension less than 112% and fractional shortening less than 25%; and healthy was defined as percentage of predicted left ventricular diastolic dimension less than 112% and fractional shortening of 25% or greater. Proband Enrollment We recruited probands from 370 consecutive patients with dilated cardiomyopathy who were referred to the heart failure clinic at St. George's Hospital. All patients underwent a comprehensive evaluation, including clinical history, physical examination, 12-lead electrocardiography, 2-dimensional echocardiography, 24-hour Holter monitoring, symptom-limited metabolic exercise testing, and laboratory investigation (including creatine kinase level measurement), to screen for asymptomatic skeletal muscle disease and iron studies to exclude hemochromatosis. We performed coronary angiography to exclude atherosclerotic heart disease in those older than 40 years of age or in those with features suggestive of coronary disease. We excluded individuals with documented coronary disease, systemic arterial hypertension, primary valvular disease, pericardial disease, cor pulmonale, or a history of excess alcohol consumption (regular intake >40 g/d for women and >80 g/d for men). Family Member Enrollment We offered family screening to all patients with dilated cardiomyopathy, regardless of an overt family history, and we based inclusion on the willingness to participate and geographic availability. Of the patients, 189 probands and their families fulfilled inclusion criteria, resided in the United Kingdom, and were willing to participate. A trained research nurse constructed extended pedigrees based on each proband by using Cyrillic 2.1 (Cherwell Scientific Ltd., Oxford, United Kingdom), and we contacted at-risk first- and second-degree relatives and offered them noninvasive evaluation. Assessment of asymptomatic relatives who agreed to participate included medical history, clinical examination, 12-lead electrocardiography, and 2-dimensional echocardiography. Relatives with abnormalities proceeded to a full evaluation as described for probands. We reviewed medical records and autopsy findings to confirm or refute the diagnosis of dilated cardiomyopathy for all deceased relatives. Definition of Familial Dilated Cardiomyopathy We classified dilated cardiomyopathy as familial if at least 1 relative (in addition to the proband) had documented disease during life or at postmortem or if there was a history of unexplained sudden cardiac death before the age of 30 years. Follow-up of Asymptomatic Relatives All relatives with left ventricular enlargement and depressed fractional shortening (but not initially healthy relatives) underwent prospective annual evaluation. They were asymptomatic and did not receive treatment unless criteria for dilated cardiomyopathy developed. After initial observation of progression to dilated cardiomyopathy (approximately 9% over 40 months) among this group, we determined that initially healthy individuals should also be reevaluated to verify that left ventricular enlargement and depressed fractional shortening were risk markers for development of dilated cardiomyopathy. Accordingly, a nurse who had not been involved in the original screening project and who did not know the families randomly contacted 238 relatives whose initial echocardiograms were entirely normal from a list of all initially healthy relatives and invited them for reevaluation at a median of 57 months from their initial assessment. Follow-up evaluations consisted of repeated history and physical examination, 12-lead electrocardiography, and 2-dimensional echocardiography. Statistical Analysis To determine the number of initially healthy relatives requiring follow-up, we based power calculations for analysis of progression on the 9% rate of progression over 40 months observed among 140 study participants with left ventricular enlargement and depressed fractional shortening, a hypothesized rate of progression of 2% or less among those relatives with initially normal echocardiograms, and an level of 0.05. We determined the requirement of follow-up of 235 relatives or more who were initially classified as healthy at a power of 0.85 (that is, total population of 375 patients, with 140 patients with left ventricular enlargement and depressed fractional shortening and 235 healthy patients). We confirmed all quantitative variables to be normally distributed by using a 1-sample KolmogorovSmirnoff test and expressed them as means and SDs. For comparisons of continuous and discrete variables, we used the Student t-test, chi-square test, or Fisher exact test as appropriate. To account for the nesting of individuals within families, we estimated 95% CIs for prevalence of dilated cardiomyopathy, left ventricular enlargement, and depressed fractional shortening among relatives by fitting a hierarchical model for each condition using WinBUGS 1.4 (Imperial College and Medical Research Council, London, United Kingdom). We estimated prediction intervals from the posterior distribution for mean disease prevalence and presented them as 95% CIs. We used the KaplanMeier method to construct survival curves for risk for progression for relatives with left ventricular enlargement and depressed fractional shortening and healthy relatives. We fitted a Cox proportional hazards regression model to perform further analysis of progression to dilated cardiomyopathy. We used the Efron approximation to deal with ties. Covariates included in the initial model were initial diagnosis and age. A backward stepwise procedure converged upon a model, which only included initial diagnosis. To account for the clustering of related individuals within families, we used frailty models. A frailty model is a random-effects model that accounts for a familial effect in the analysis. These models allow for the lack of independence between events observed in members of the same family. Henderson and Oman (18) have discussed their use in more detail. The frailty was introduced into the model as an unobserved, no