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Review and Metaanalysis of the Frequency of Familial Dilated Cardiomyopathy
Review and Metaanalysis of the Frequency of Familial Dilated Cardiomyopathy Mario Petretta, MD*, Flora Pirozzi, MD, Laura Sasso, MD, Antonella Paglia, MD, and Domenico Bonaduce, MD Several studies have investigated the frequency of familial dilated cardiomyopathy (FDC). However, no systematic review and meta-analysis on this topic are available. Therefore, using the PubMed, MEDLINE, Cochrane, and the ISI Web of Science databases, relevant reports published through December 2010 were identified. For the summation of prevalence findings, prevalence point estimates and 95% confidence intervals were computed using the logit transformation formula. An aggregate estimate of clinically confirmed FDC of 23% (95% confidence interval 0.17 to 0.31) was found. However, the prevalence rates reported across these studies varied widely, ranging from 2% to 65%, and the analysis showed very high heterogeneity (Q ⴝ 295, p <0.001, I2 ⴝ 93%). Meta–regression analysis between logit event rate and year of publication explained 23% of between-study variance (p <0.05). Cumulative meta-analysis confirmed the influence of year of publication on the reported prevalence of FDC among the different studies. However, most of the observed heterogeneity may be explained by the fact that the various studies used different preselected criteria for the diagnosis of FDC. In conclusion, data obtained from trials performed using standardized criteria are needed to better define the true prevalence of FDC. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108: 1171–1176) Idiopathic dilated cardiomyopathy (IDC) is a syndrome characterized by cardiac enlargement and impaired systolic function of 1 or both ventricles, in the absence of abnormal load conditions (such as hypertension, valve disease, or congenital heart disease) or coronary artery disease of sufficient severity to cause global impairment of ventricular function. The importance of genetic factors in IDC has often been underestimated. Studies carried out from 1981 to 1985 showed a very low frequency (2%) of familial dilated cardiomyopathy (FDC).1,2 Subsequent prospective studies clearly showed familial clustering in more patients.3,4 However, the results of these latter studies were different on account of the populations enrolled and the study methods used. To our knowledge, no systematic review and metaanalysis of the frequency of FDC are actually available. In this study, our aim was to estimate the prevalence of FDC and to assess the extent of the heterogeneity in reported prevalence estimates. Methods This study was designed according to the Quality of Reporting of Meta-Analyses statement.5 We performed a search of the published research in the PubMed, MEDLINE, Cochrane, and ISI Web of Science databases. Two of the investigators (F.P. and L.S.) independently identified rele-
Department of Internal Medicine, Cardiology, Heart Surgery and Immunological Sciences, University Federico II of Naples, Naples, Italy. Manuscript received April 22, 2011; revised manuscript received and accepted June 2, 2011. *Corresponding author: Tel: 39-0817462233; fax: 39-0817462248. E-mail address: [email protected] (M. Petretta). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.06.022
vant reports published from January 1980 through December 2010. Primary key words included “FDC,” “IDC,” and “inherited dilated cardiomyopathy.” To be included, studies were required to have used samples composed exclusively of patients diagnosed with IDC or to have reported data for subgroups of patients with IDC. Criteria for selection were reporting (1) the number of patients with IDC and (2) the proportion of these patients in whom FDC was diagnosed according to the predefined criteria. R version 2.12.0 (R Foundation for Statistical Computing, Vienna, Austria) and Stata version 11.1 (StataCorp LP, College Station, Texas) served as the statistical platforms for completing all statistical tests and associated graphic results. For the summation of prevalence findings, we computed prevalence point estimates and 95% confidence intervals using the logit transformation formula: logit event rate ⫽ ln[event rate/(1 ⫺ event rate)]; the SE of logit event rate is calculated as 公1/(event rate ⫻ num tot) ⫹ 1/(1 ⫺ event rate) ⫻ num tot], and 95% confidence interval as lower limit ⫽ [logit event rate ⫺ (1.96 ⫻ logit event rate SE)] and upper limit ⫽ [logit event rate ⫹ (1.96 ⫻ logit event rate SE)]. Inverse variance weighting was used to calculate pooled estimates. To report results in untransformed units, backtransformation of the estimated average and of the lower and upper confidence limits was performed, computing event rate ⫽ 1/[1 ⫹ exp(⫺logit event rate)]. The assumption of homogeneity of prevalence among the different trials was preliminarily tested with the Q and I2 statistics. Because the assumption of homogeneity was rejected (p ⬍0.05), a random-effects model was chosen to calculate prevalence rate and the corresponding p values, and 2 and I2 values are reported. In addition to the overall random-effects model, meta–regression analysis was performed to assess the eviwww.ajconline.org
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Table 1 Demographic characteristics of study populations and criteria used to define the presence of dilated cardiomyopathy Study Fuster et al (1981)1 Keren et al (1985)14 Michels et al (1985)2 Fragola et al (1988)12 Griffin et al (1988)26 Valantine et al (1989)26* Keren et al (1990)13 Mestroni et al (1990)15* Michels et al (1992)16 Zachara et al (1993)9* Csanàdy et al (1995)11 Goerss et al (1995)17 Keeling et al (1995)18 McKenna et al (1997)19 Grunig et al (1998)20 Mestroni et al (1999)3 Monserrat et al (2002)21 Michels et al (2003)22 Michels et al (2003)23 Mahon et al (2005)4 Kushner et al (2006)24 Towbin et al (2006)27* Gimeno et al (2009)25
Male/Female
Mean Age (Years)
LVEDD
LVEF
64/40 NA 119/49 11/1 6/6 9/7 5/11 8/4 28/31 12/2 NA 47/48 28/12 NA NA NA NA 51/50 51/50 132/57 173/131 36/30 NA
49 30 NA 50 10 NA 37 36 53 42 36 55 40 NA 52 45 NA 52 52 39 47 4 40
⬎55 mm ⬎10%–15% above normal corrected range ⬎57 mm or ⬎95th percentile ⬎55 mm ⬎55 mm ⬎10%–15% above normal corrected range ⬎95th percentile ⬎2 SDs above the mean ⬎55 mm ⱖ95th percentile ⱖ112% ⬎2 SDs above the mean ⬎2.7 cm/m2 ⬎117% of predicted value ⬎55 mm ⬎95th percentile ⬎95th percentile ⱖ112% of predicted value ⱖ97.5th percentile ⬎55 mm ⱖ112% of predicted value
FS
LV Hypokinesia ⫹
⬍30% ⬍50% ⬍50% ⬍52% ⬍50% ⬍50% ⬍40% ⬍45% ⬍50% ⬍50% ⱕ50%
⫹ ⫹ ⫹ ⫹
⬍26% ⱕ25% ⬍25% ⬍25%
⬍25% ⱕ25% ⱕ25%
⫹
⫹
* Demographic data available only for probands with FDC. FS ⫽ fractional shortening; LV ⫽ left ventricular; LVEDD ⫽ left ventricular end-diastolic dimension; LVEF ⫽ left ventricular ejection fraction; NA ⫽ not available.
dence of prevalence modifiers. Cumulative meta-analysis, in which the cumulative evidence at the time each study was published is calculated, was also performed. The presence of publication bias was graphically assessed using a funnel plot, a simple graphical display of a measure of study size against logit event rate. the interpretation of funnel plots is facilitated by the inclusion of diagonal lines representing the 95% confidence limits around the summary treatment effect. These show the expected distribution of studies in the absence of heterogeneity or of selection biases. Because these diagonal lines are not strict 95% limits but rather a region in which 95% of the observed effects are expected to fall if the true effects are homogenous, they are referred to as “pseudo 95% confidence limits.”6 To evaluate potential publication bias, we also performed a test proposed by Egger et al7 on the basis of a linear regression approach and a test proposed by Begg and Mazumdar8 on the basis of a rank correlation method. Results Of the initial 2,320 studies identified, 1,750 were excluded on the basis of title, 502 on the basis of abstract, and 45 on the basis of text. These latter studies were excluded because of a lack of data on the percentages of patients with FDC in the populations examined. Thus, a total of 23 studies evaluating the prevalence of FDC were selected according to the aforementioned criteria. For each study, demographic characteristics and the echocardiographic criteria used to define the presence of FDC are listed in Table 1. These data were not available in all studies; in particular, age and gender in some studies were reported for the pro-
Table 2 Criteria used to define the presence of familial dilated cardiomyopathy Study Fuster et al (1981)1 Keren et al (1985)14 Michels et al (1985)2 Fragola et al (1988)12 Griffin et al (1988)26 Valantine et al (1989)26 Keren et al (1990)13 Mestroni et al (1990)15 Michels et al (1992)16 Zachara et al (1993)9 Csanàdy et al (1995)11 Goerss et al (1995)17 Keeling et al (1995)18 McKenna et al (1997)19 Grunig et al (1998)20 Mestroni et al (1999)3 Monserrat et al (2002)21 Michels et al (2003)22 Michels et al (2003)23 Mahon et al (2005)4 Kushner et al (2006)24 Towbin et al (2006)27 Gimeno et al (2009)25
Criteria DC in ⱖ1 first-degree relative Family history of congestive heart failure DC in ⱖ1 relative at physicians statement or medical records DC in ⱖ1 relative according to echocardiographic criteria Family history Family history Family history of congestive heart failure DC in ⱖ1 relative DC in ⱖ1 relative DC in ⱖ1 relative and confirmed at biopsy DC in ⱖ2 relatives with frankly abnormal left ventricular function DC symptomatic or asymptomatic in ⱖ1 relative DC in ⱖ1 relative DC in ⱖ1 first-degree relative DC in ⱖ1 first- or second-degree relative confirmed at biopsy or catheterization DC in ⱖ2 relatives DC in ⱖ1 relative DC in ⱖ1 relative DC in ⱖ1 relative DC in ⱖ1 relative or sudden death ⬍30 years Medical records in ⱖ2 relatives NA DC in ⱖ2 relatives or in 1 relative with sudden death
DC ⫽ dilated cardiomyopathy; NA ⫽ not available.
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Figure 1. Forest plot of prevalence rate of FDC in 22 studies. Horizontal lines represent 95% confidence intervals (CIs). Each box represents the prevalence rate point estimate, and its area is proportional to the weight of the study determined by inverse variance weighting. The diamond represents the overall summary estimate, with the 95% CI given by its width.
bands and in some studies for the entire study population. The criteria used to define the presence of FDC are listed in Table 2. The prevalence rates of clinically confirmed FDC patients for each of the 23 studies are reported in Figure 1. As shown, we found an aggregated estimate of 23% (95% confidence interval 0.17 to 0.31). The prevalence rates reported across these studies varied widely, ranging from 2%1 to 65%.3 Moreover, the analysis showed very high heterogeneity (Q ⫽ 295, p ⬍0.0001, I2 ⫽ 93%). The funnel plot appears symmetrical (Figure 2), without evidence of bias using the Egger (weighted regression) as well as the Begg (rank correlation) methods for small-study effects (p ⫽ 0.42 and p ⫽ 0.67, respectively). Meta-regression analysis between logit event rate and year of publication explained 23% of between-study variance (p ⬍0.05), with a logit event rate increase of 0.06 for each year (Figure 3). The Q test for moderator was 6.15 (p ⬍0.05), and the estimate of the residual amount of heterogeneity (2) was 0.69 ⫾ 0.25 (Q test for residual heterogeneity 222, p ⬍0.001). Cumulative meta-analysis confirmed the influence of year of publication on the reported prevalence of FDC among the different studies (Figure 4). Discussion According to this meta-analysis, the estimated prevalence of FDC in patients with IDC is 23%, with very high heterogeneity (from 2% to 65%). In retrospective studies, Fuster et al,1 Michels et al,2 and Zachara et al9 found that the familial form accounted for 2%, 6%, and 13% of patients with IDC, respectively. Also, Valantine et al10 performed a retrospective study in 184 patients who underwent cardiac transplantation and identified a familial origin in 9% of patients. Csanàdy et al11 in a retrospective survey of 240
IDC patients found a prevalence of FDC of 13%. Studies based on prospective family screening revealed that the frequency of genetic transmission of the disease was greater than previously reported. Fragola et al12 found a familial form in 33% of patients and Keren et al13,14 in 40% and 56% of patients with IDC. However, in these studies, the numbers of index patients considered were very small. The first prospective study that enrolled consecutive IDC patients was performed by Mestroni et al,15 who found that of 165 patients with IDC, 7% had ⱖ1 relative affected by FDC. However, in this study, only relatives with suspected myocardial disease were evaluated. Michels et al16 studied 325 relatives of 59 index patients with IDC; 18 relatives from 12 families were shown to have IDC; therefore, 12 of 59 index patients (20.3%) had familial disease. However, 22 relatives had left ventricular cavity enlargement with preserved (⬎50%) left ventricular ejection fractions. Goerss et al17 examined data obtained in 95 families with 457 relatives: the diagnosis of FDC was made in 7 probands according familial history and in 16 more after echocardiographic evaluations of relatives. Therefore, in this study, FDC was diagnosed in 24% of patients. Similar results were obtained by Keeling et al18 in 236 relatives from 40 families of IDC patients. McKenna et al19 enrolled 56 patients with IDC. If the relatives fulfilled 2 echocardiographic criteria, the diagnosis of FDC was considered definite, and if only 1 criterion was fulfilled or if families gave histories of sudden unexplained death in a first relative, it was considered possible. Accordingly, the familial prevalence resulted definite in 25% and possible in further 27% of patients. Grunig et al20 confirmed the diagnosis of definite FDC in 10.8% of 445 index patients. However, no quantitative criteria for the diagnosis of left ventricular function impairment was sig-
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Figure 2. Detecting publication bias using the funnel plot. The funnel plot displays the study prevalence on a logit scale against its standard error for each study included in the meta-analysis. The vertical line indicates the pooled estimate of the overall prevalence rate, with the diagonal lines representing the expected pseudo 95% confidence limits around the summary.
nified. In a survey by Mestroni et al,3 the occurrence of an inherited trait was detected in 39 of 60 (65%) families of patients with IDC. However, the selection of the families was based on their availability for family screening. Monserrat et al21 considered IDC patients who had undergone heart transplantation. IDC was familial in 11 probands (25.6%) and possibly familial in other 11 (25.6%). Michels et al22,23 reported follow-up data from 101 patients with IDC. On the basis of the original study, FDC was observed in 20% of patients,22 while after 10 years, this proportion had increased to 30% as additional relatives developed the disease during the follow-up period.23 Mahon et al4 evaluated 767 asymptomatic relatives of 189 IDC patients, of whom 37% had evidence of FDC. In this study, IDC was considered familial if ⱖ1 relative had documented disease or if there was a history of unexplained sudden cardiac death before the age of 30 years. Interestingly, also in this study, many relatives showed left ventricular enlargement or reduced fractional shortening. Kushner et al24 enrolled 304 subjects with suspected FDC. One hundred twenty-five were confirmed to have FDC, 48 were considered probable and 72 possible, and 59 were considered to have sporadic IDC. Recently, Gimeno et al25 offered familial screening to
Figure 3. Meta–regression analysis between year of publication and logit of event rate. Logit of event rate (i.e., the logit of prevalence of the familial form of dilated cardiomyopathy in the index patients) is reported on the y axis and the covariate on the x axis. Meta-regression explained 23% of between-study variance (p ⬍0.05) and the logit event rate increases of 0.066 (SE 0.026) for each year. The size of the circle for each study is proportional to the inverse of the variance.
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Figure 4. Cumulative meta-analysis of relation between year of publication and the prevalence rate of FDC. These studies are added 1 at a time in a specified order (according to date of publication) and the results are summarized as each new study is added.
493 consecutive patients with different cardiomyopathies. Familial disease was confirmed in 47% of 70 patients with IDC. Two studies were performed in children; Griffin et al26 found a 25% prevalence of FDC in 12 patients. Towbin et al27 evaluated children diagnosed as having IDC and aged ⬍18 years; of the 485 patients with IDC, 14% had FDC. Certainly, the detection of a familial trait represents a major advance in understanding the origin of IDC.28 However, the study of pedigrees of FDC is a difficult task considering that the phenotype of affected patients is not specific for the disease, the families tend to be small, the penetrance is variable, and there is no consensus on diagnostic criteria. The Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy28 suggested a 3-generation pedigree and echocardiographic and electrocardiographic screening of firstdegree relatives of IDC patients. In 2010, the European Society of Cardiology Working Group on Myocardial and Pericardial Disease proposed a stepwise screening based on genetic testing.29 Until now, no study has followed these clinical28 and/or genetic29 criteria for the diagnosis, and genetic testing is actually not recommended in the absence of established or probable familial disease.30 In the studies considered for this meta-analysis, the diagnosis of FDC was made on the basis of different preselected criteria, explaining the marked heterogeneity observed when pooling the data. In 2008, a multicenter study aiming to perform clinical and molecular characterization of FDC patients in the Portuguese population using a stepwise screening was initiated,31 but at this time, data are not available. Of note, we found a good correlation between the year of publication and estimated prevalence of FDC; we hypothesize that in recent years, the more correct use of
diagnostic criteria has increased the diagnosis of the familial form. The effects of other possible confounders on prevalence of FDC, such as gender, heart failure severity, and age, were not tested in this study given the lack of available data in many studies. 1. Fuster V, Gersh BJ, Giuliani ER, Tajik AJ, Brandenburg RO, Frye RL. The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981;47:525–531. 2. Michels VV, Driscoll DJ, Miller FA. Familial aggregation of idiopathic dilated cardiomyopathy. Am J Cardiol 1985;55:1232–1233. 3. Mestroni L, Rocco C, Gregori D, Sinagra G, Di Lenarda A, Miocic S, Vatta M, Pinamonti B, Muntoni F, Caforio ALP, McKenna WJ, Falaschi A, Giacca M, Camerini F; The Heart Muscle Disease Study Group. Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. J Am Coll Cardiol 1999;34:181–190. 4. Mahon NG, Murphy RT, MacRae CA, Caforio ALP, Elliot PM, McKenna WJ. Echocardiographic evaluation in asymptomatic relatives of patients with dilated cardiomyopathy reveals preclinical disease. Ann Intern Med 2005;143:108 –115. 5. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF, for the QUOROM Group. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Lancet 1999;354:1896 –900. 6. Sterne JAC, Harbord RM. Funnel plots in meta-analysis. Stata J 2004;2:127–141. 7. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629 – 634. 8. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088 –1101. 9. Zachara E, Caforio ALP, Carboni GP, Pellegrini A, Pompili A, Del Porto G, Sciarra A, Bosman C, Boldrini R, Prati PL, Mc Kenna WJ. Familial aggregation of idiopathic dilated cardiomyopathy: clinical features and pedigree analysis in 14 families. Br Heart J 1993;69: 129 –135. 10. Valantine HA, Hunt SA, Fowler MB, Billingham ME, Schroeder JS. Frequency of familial nature of dilated cardiomyopathy and
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usefulness of cardiac transplantation in this subset. Am J Cardiol 1989;63:959 –963. Csanàdy M, Hogye M, Kallai A, Forster T, Szarazajtai T. Familial dilated cardiomyopathy: a worse prognosis compared with sporadic forms. Br Heart J 1995;74:171–173. Fragola PV, Autore C, Picelli A, Sommariva L, Cannata D, Sangiorgi M. Familial idiopathic dilated cardiomyopathy. Am Heart J 1988; 115:912–914. Keren A, Gottlieb S, Tzivoni D, Stern S, Yarom R, Billingham ME, Popp RL. Mildly dilated congestive cardiomyopathy. Use of prospective diagnostic criteria and description of the clinical course without heart transplantation. Circulation 1990;81:506 –517. Keren A, Billingham ME, Weintraub D, Stinson EB, Popp RL. Mildly dilated congestive cardiomyopathy. Circulation 1985;72:302–309. Mestroni L, Miani D, Di Lenarda A, Silvestri F, Bussani R, Filippi G, Camerini F. Clinical and pathologic study of familial dilated cardiomyopathy. Am J Cardiol 1990;65:1449 –1453. Michels VV, Moll PP, Miller FA, Tajik AJ, Chu JS, Driscoll DJ, Burnett JC, Rodeheffer RJ, Chesebro JH, Tazelaar HD. The frequency of familial dilated cardiomyopathy in a series of patients with idiopathic dilated cardiomyopathy. N Engl J Med 1992;326:77– 82. Goerss JB, Michels VV, Burnett J, Driscoll DJ, Miller F, Rodeheffer R, Tajik AJ, Schaid D. Frequency of familial dilated cardiomyopathy. Eur Heart J 1995;16:2– 4. Keeling PJ, Gang Y, Smith G, Seo H, Bent SE, Murday V, Caforio ALP, McKenna WJ. Familial dilated cardiomyopathy in the United Kingdom. Br Heart J 1995;73:417– 421. McKenna CJ, Codd MB, McCann HA, Sugrue DD. Idiopathic dilated cardiomyopathy: familial prevalence and HLA distribution. Heart 1997;77:549 –552. Grunig E, Tasman JA, Kucherer H, Franz W, Kubler W, Katus HA. Frequency and phenotypes of familial dilated cardiomyopathy. J Am Coll Cardiol 1998;31:186 –194. Monserrat L, Hermida M, Bouzas B, Mosquera I, Mahon N, Peteiro J, Alvarez N, Penas-Lado M, Crespo M, Castro-Beiras A. Familial dilated cardiomyopathy in patients transplanted for idiopathic dilated cardiomyopathy. Rev Esp Cardiol 2002;55:725–732. Michels VV, Olson TM, Miller FA, Ballman KV, Rosales AG, Driscoll DJ. Frequency of development of idiopathic dilated cardiomyopathy among relatives of patients with idiopathic dilated cardiomyopathy. Am J Cardiol 2003;91:1389 –1392.
23. Michels VV, Driscoll DJ, Miller FA, Olson TM, Atkinson EJ, Olswold CL, Schaid DJ. Progression of familial and non-familial dilated cardiomyopathy: long term follow up. Heart 2003;89:757–761. 24. Kushner JD, Nauman D, Burgess D, Ludwigsen S, Parks S, Pantely G, Burkett E, Hershberger RE. Clinical characteristics of 304 kindreds evaluated for familial dilated cardiomyopathy. J Card Fail 2006;12: 422– 429. 25. Gimeno JR, Lacunza J, Garcìa-Alberola A, Cerdàn MC, Oliva MJ, Garcìa-Molina E, Lopez-Ruiz M, Castro F, Gonzàlez-Carrillo J, de la Morena G, Valdés M. Penetrance and risk profile in inherited cardiac diseases studied in a dedicated screening clinic. Am J Cardiol 2009; 104:406 – 410. 26. Griffin ML, Hernandez A, Martin TC, Goldring D, Bolman RM, Spray TL, Strauss AW. Dilated cardiomyopathy in infants and children. J Am Coll Cardiol 1988;11:139 –144. 27. Towbin JA, Lowe AM, Colan SD, Sleeper LA, Orav EJ, Clunie S, Messere J, Cox GF, Lurie PR, Hsu D, Canter C, Wilkinson JD, Lipshultz SE. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA 2006; 296:1867–1876. 28. Mestroni L, Maisch B, McKenna WJ, Schwartz K, Charron P, Rocco C, Tesson F, Richter A, Wilke A, Komajda M, on behalf of the Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy. Guidelines for the study of familial dilated cardiomyopathies. Eur Heart J 1999;20: 93–102. 29. Charron P, Arad M, Arbustini E, Basso C, Bilinska Z, Elliott P, Helio T, Keren A, McKenna WJ, Monserrat L, Pankuweit S, Perrot A, Rapezzi C, Ristic A, Seggewiss H, van Langen I, Tavazzi L. Genetic counseling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2010;31:2715–2726. 30. Gollob MH, Blier L, Brugada R, Champagne J, Chauhan V, Connors S, Gardner M, Green MS, Gow R, Hamilton R, Harris L, Healey JS, Hodgkinson K, Honeywell C, Kantoch M, Kirsh J, Krahn A, Mullen M, Parkash R, Redfearn D, Rutberg J, Sanatani S, Woo A. Recommendations for the use of genetic testing in the clinical evaluation of inherited cardiac arrhythmias associated with sudden cardiac death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society joint position paper. Can J Cardiol 2011;27:232–245. 31. Martins E, Silva-Cardoso J, Bicho M, Bourbon M, Ceia F, Rebocho MJ, Moura B, Fonseca C, Correia MJ, Brito D, Perdiga˘o C, Madeira H, Abreu-Lima C. Estudo Português de Miocardiopatias Dilatadas Familiares. Estudo FATIMA. Rev Port Cardiol 2008;27:1029 –1042.
Department of Internal Medicine, Cardiology, Heart Surgery and Immunological Sciences, University Federico II of Naples, Naples, Italy. Manuscript received April 22, 2011; revised manuscript received and accepted June 2, 2011. *Corresponding author: Tel: 39-0817462233; fax: 39-0817462248. E-mail address: [email protected] (M. Petretta). 0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2011.06.022
vant reports published from January 1980 through December 2010. Primary key words included “FDC,” “IDC,” and “inherited dilated cardiomyopathy.” To be included, studies were required to have used samples composed exclusively of patients diagnosed with IDC or to have reported data for subgroups of patients with IDC. Criteria for selection were reporting (1) the number of patients with IDC and (2) the proportion of these patients in whom FDC was diagnosed according to the predefined criteria. R version 2.12.0 (R Foundation for Statistical Computing, Vienna, Austria) and Stata version 11.1 (StataCorp LP, College Station, Texas) served as the statistical platforms for completing all statistical tests and associated graphic results. For the summation of prevalence findings, we computed prevalence point estimates and 95% confidence intervals using the logit transformation formula: logit event rate ⫽ ln[event rate/(1 ⫺ event rate)]; the SE of logit event rate is calculated as 公1/(event rate ⫻ num tot) ⫹ 1/(1 ⫺ event rate) ⫻ num tot], and 95% confidence interval as lower limit ⫽ [logit event rate ⫺ (1.96 ⫻ logit event rate SE)] and upper limit ⫽ [logit event rate ⫹ (1.96 ⫻ logit event rate SE)]. Inverse variance weighting was used to calculate pooled estimates. To report results in untransformed units, backtransformation of the estimated average and of the lower and upper confidence limits was performed, computing event rate ⫽ 1/[1 ⫹ exp(⫺logit event rate)]. The assumption of homogeneity of prevalence among the different trials was preliminarily tested with the Q and I2 statistics. Because the assumption of homogeneity was rejected (p ⬍0.05), a random-effects model was chosen to calculate prevalence rate and the corresponding p values, and 2 and I2 values are reported. In addition to the overall random-effects model, meta–regression analysis was performed to assess the eviwww.ajconline.org
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Table 1 Demographic characteristics of study populations and criteria used to define the presence of dilated cardiomyopathy Study Fuster et al (1981)1 Keren et al (1985)14 Michels et al (1985)2 Fragola et al (1988)12 Griffin et al (1988)26 Valantine et al (1989)26* Keren et al (1990)13 Mestroni et al (1990)15* Michels et al (1992)16 Zachara et al (1993)9* Csanàdy et al (1995)11 Goerss et al (1995)17 Keeling et al (1995)18 McKenna et al (1997)19 Grunig et al (1998)20 Mestroni et al (1999)3 Monserrat et al (2002)21 Michels et al (2003)22 Michels et al (2003)23 Mahon et al (2005)4 Kushner et al (2006)24 Towbin et al (2006)27* Gimeno et al (2009)25
Male/Female
Mean Age (Years)
LVEDD
LVEF
64/40 NA 119/49 11/1 6/6 9/7 5/11 8/4 28/31 12/2 NA 47/48 28/12 NA NA NA NA 51/50 51/50 132/57 173/131 36/30 NA
49 30 NA 50 10 NA 37 36 53 42 36 55 40 NA 52 45 NA 52 52 39 47 4 40
⬎55 mm ⬎10%–15% above normal corrected range ⬎57 mm or ⬎95th percentile ⬎55 mm ⬎55 mm ⬎10%–15% above normal corrected range ⬎95th percentile ⬎2 SDs above the mean ⬎55 mm ⱖ95th percentile ⱖ112% ⬎2 SDs above the mean ⬎2.7 cm/m2 ⬎117% of predicted value ⬎55 mm ⬎95th percentile ⬎95th percentile ⱖ112% of predicted value ⱖ97.5th percentile ⬎55 mm ⱖ112% of predicted value
FS
LV Hypokinesia ⫹
⬍30% ⬍50% ⬍50% ⬍52% ⬍50% ⬍50% ⬍40% ⬍45% ⬍50% ⬍50% ⱕ50%
⫹ ⫹ ⫹ ⫹
⬍26% ⱕ25% ⬍25% ⬍25%
⬍25% ⱕ25% ⱕ25%
⫹
⫹
* Demographic data available only for probands with FDC. FS ⫽ fractional shortening; LV ⫽ left ventricular; LVEDD ⫽ left ventricular end-diastolic dimension; LVEF ⫽ left ventricular ejection fraction; NA ⫽ not available.
dence of prevalence modifiers. Cumulative meta-analysis, in which the cumulative evidence at the time each study was published is calculated, was also performed. The presence of publication bias was graphically assessed using a funnel plot, a simple graphical display of a measure of study size against logit event rate. the interpretation of funnel plots is facilitated by the inclusion of diagonal lines representing the 95% confidence limits around the summary treatment effect. These show the expected distribution of studies in the absence of heterogeneity or of selection biases. Because these diagonal lines are not strict 95% limits but rather a region in which 95% of the observed effects are expected to fall if the true effects are homogenous, they are referred to as “pseudo 95% confidence limits.”6 To evaluate potential publication bias, we also performed a test proposed by Egger et al7 on the basis of a linear regression approach and a test proposed by Begg and Mazumdar8 on the basis of a rank correlation method. Results Of the initial 2,320 studies identified, 1,750 were excluded on the basis of title, 502 on the basis of abstract, and 45 on the basis of text. These latter studies were excluded because of a lack of data on the percentages of patients with FDC in the populations examined. Thus, a total of 23 studies evaluating the prevalence of FDC were selected according to the aforementioned criteria. For each study, demographic characteristics and the echocardiographic criteria used to define the presence of FDC are listed in Table 1. These data were not available in all studies; in particular, age and gender in some studies were reported for the pro-
Table 2 Criteria used to define the presence of familial dilated cardiomyopathy Study Fuster et al (1981)1 Keren et al (1985)14 Michels et al (1985)2 Fragola et al (1988)12 Griffin et al (1988)26 Valantine et al (1989)26 Keren et al (1990)13 Mestroni et al (1990)15 Michels et al (1992)16 Zachara et al (1993)9 Csanàdy et al (1995)11 Goerss et al (1995)17 Keeling et al (1995)18 McKenna et al (1997)19 Grunig et al (1998)20 Mestroni et al (1999)3 Monserrat et al (2002)21 Michels et al (2003)22 Michels et al (2003)23 Mahon et al (2005)4 Kushner et al (2006)24 Towbin et al (2006)27 Gimeno et al (2009)25
Criteria DC in ⱖ1 first-degree relative Family history of congestive heart failure DC in ⱖ1 relative at physicians statement or medical records DC in ⱖ1 relative according to echocardiographic criteria Family history Family history Family history of congestive heart failure DC in ⱖ1 relative DC in ⱖ1 relative DC in ⱖ1 relative and confirmed at biopsy DC in ⱖ2 relatives with frankly abnormal left ventricular function DC symptomatic or asymptomatic in ⱖ1 relative DC in ⱖ1 relative DC in ⱖ1 first-degree relative DC in ⱖ1 first- or second-degree relative confirmed at biopsy or catheterization DC in ⱖ2 relatives DC in ⱖ1 relative DC in ⱖ1 relative DC in ⱖ1 relative DC in ⱖ1 relative or sudden death ⬍30 years Medical records in ⱖ2 relatives NA DC in ⱖ2 relatives or in 1 relative with sudden death
DC ⫽ dilated cardiomyopathy; NA ⫽ not available.
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Figure 1. Forest plot of prevalence rate of FDC in 22 studies. Horizontal lines represent 95% confidence intervals (CIs). Each box represents the prevalence rate point estimate, and its area is proportional to the weight of the study determined by inverse variance weighting. The diamond represents the overall summary estimate, with the 95% CI given by its width.
bands and in some studies for the entire study population. The criteria used to define the presence of FDC are listed in Table 2. The prevalence rates of clinically confirmed FDC patients for each of the 23 studies are reported in Figure 1. As shown, we found an aggregated estimate of 23% (95% confidence interval 0.17 to 0.31). The prevalence rates reported across these studies varied widely, ranging from 2%1 to 65%.3 Moreover, the analysis showed very high heterogeneity (Q ⫽ 295, p ⬍0.0001, I2 ⫽ 93%). The funnel plot appears symmetrical (Figure 2), without evidence of bias using the Egger (weighted regression) as well as the Begg (rank correlation) methods for small-study effects (p ⫽ 0.42 and p ⫽ 0.67, respectively). Meta-regression analysis between logit event rate and year of publication explained 23% of between-study variance (p ⬍0.05), with a logit event rate increase of 0.06 for each year (Figure 3). The Q test for moderator was 6.15 (p ⬍0.05), and the estimate of the residual amount of heterogeneity (2) was 0.69 ⫾ 0.25 (Q test for residual heterogeneity 222, p ⬍0.001). Cumulative meta-analysis confirmed the influence of year of publication on the reported prevalence of FDC among the different studies (Figure 4). Discussion According to this meta-analysis, the estimated prevalence of FDC in patients with IDC is 23%, with very high heterogeneity (from 2% to 65%). In retrospective studies, Fuster et al,1 Michels et al,2 and Zachara et al9 found that the familial form accounted for 2%, 6%, and 13% of patients with IDC, respectively. Also, Valantine et al10 performed a retrospective study in 184 patients who underwent cardiac transplantation and identified a familial origin in 9% of patients. Csanàdy et al11 in a retrospective survey of 240
IDC patients found a prevalence of FDC of 13%. Studies based on prospective family screening revealed that the frequency of genetic transmission of the disease was greater than previously reported. Fragola et al12 found a familial form in 33% of patients and Keren et al13,14 in 40% and 56% of patients with IDC. However, in these studies, the numbers of index patients considered were very small. The first prospective study that enrolled consecutive IDC patients was performed by Mestroni et al,15 who found that of 165 patients with IDC, 7% had ⱖ1 relative affected by FDC. However, in this study, only relatives with suspected myocardial disease were evaluated. Michels et al16 studied 325 relatives of 59 index patients with IDC; 18 relatives from 12 families were shown to have IDC; therefore, 12 of 59 index patients (20.3%) had familial disease. However, 22 relatives had left ventricular cavity enlargement with preserved (⬎50%) left ventricular ejection fractions. Goerss et al17 examined data obtained in 95 families with 457 relatives: the diagnosis of FDC was made in 7 probands according familial history and in 16 more after echocardiographic evaluations of relatives. Therefore, in this study, FDC was diagnosed in 24% of patients. Similar results were obtained by Keeling et al18 in 236 relatives from 40 families of IDC patients. McKenna et al19 enrolled 56 patients with IDC. If the relatives fulfilled 2 echocardiographic criteria, the diagnosis of FDC was considered definite, and if only 1 criterion was fulfilled or if families gave histories of sudden unexplained death in a first relative, it was considered possible. Accordingly, the familial prevalence resulted definite in 25% and possible in further 27% of patients. Grunig et al20 confirmed the diagnosis of definite FDC in 10.8% of 445 index patients. However, no quantitative criteria for the diagnosis of left ventricular function impairment was sig-
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Figure 2. Detecting publication bias using the funnel plot. The funnel plot displays the study prevalence on a logit scale against its standard error for each study included in the meta-analysis. The vertical line indicates the pooled estimate of the overall prevalence rate, with the diagonal lines representing the expected pseudo 95% confidence limits around the summary.
nified. In a survey by Mestroni et al,3 the occurrence of an inherited trait was detected in 39 of 60 (65%) families of patients with IDC. However, the selection of the families was based on their availability for family screening. Monserrat et al21 considered IDC patients who had undergone heart transplantation. IDC was familial in 11 probands (25.6%) and possibly familial in other 11 (25.6%). Michels et al22,23 reported follow-up data from 101 patients with IDC. On the basis of the original study, FDC was observed in 20% of patients,22 while after 10 years, this proportion had increased to 30% as additional relatives developed the disease during the follow-up period.23 Mahon et al4 evaluated 767 asymptomatic relatives of 189 IDC patients, of whom 37% had evidence of FDC. In this study, IDC was considered familial if ⱖ1 relative had documented disease or if there was a history of unexplained sudden cardiac death before the age of 30 years. Interestingly, also in this study, many relatives showed left ventricular enlargement or reduced fractional shortening. Kushner et al24 enrolled 304 subjects with suspected FDC. One hundred twenty-five were confirmed to have FDC, 48 were considered probable and 72 possible, and 59 were considered to have sporadic IDC. Recently, Gimeno et al25 offered familial screening to
Figure 3. Meta–regression analysis between year of publication and logit of event rate. Logit of event rate (i.e., the logit of prevalence of the familial form of dilated cardiomyopathy in the index patients) is reported on the y axis and the covariate on the x axis. Meta-regression explained 23% of between-study variance (p ⬍0.05) and the logit event rate increases of 0.066 (SE 0.026) for each year. The size of the circle for each study is proportional to the inverse of the variance.
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Figure 4. Cumulative meta-analysis of relation between year of publication and the prevalence rate of FDC. These studies are added 1 at a time in a specified order (according to date of publication) and the results are summarized as each new study is added.
493 consecutive patients with different cardiomyopathies. Familial disease was confirmed in 47% of 70 patients with IDC. Two studies were performed in children; Griffin et al26 found a 25% prevalence of FDC in 12 patients. Towbin et al27 evaluated children diagnosed as having IDC and aged ⬍18 years; of the 485 patients with IDC, 14% had FDC. Certainly, the detection of a familial trait represents a major advance in understanding the origin of IDC.28 However, the study of pedigrees of FDC is a difficult task considering that the phenotype of affected patients is not specific for the disease, the families tend to be small, the penetrance is variable, and there is no consensus on diagnostic criteria. The Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy28 suggested a 3-generation pedigree and echocardiographic and electrocardiographic screening of firstdegree relatives of IDC patients. In 2010, the European Society of Cardiology Working Group on Myocardial and Pericardial Disease proposed a stepwise screening based on genetic testing.29 Until now, no study has followed these clinical28 and/or genetic29 criteria for the diagnosis, and genetic testing is actually not recommended in the absence of established or probable familial disease.30 In the studies considered for this meta-analysis, the diagnosis of FDC was made on the basis of different preselected criteria, explaining the marked heterogeneity observed when pooling the data. In 2008, a multicenter study aiming to perform clinical and molecular characterization of FDC patients in the Portuguese population using a stepwise screening was initiated,31 but at this time, data are not available. Of note, we found a good correlation between the year of publication and estimated prevalence of FDC; we hypothesize that in recent years, the more correct use of
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