ABC | Volume 112, Nº3, March 2019

Original Article Bittencourt et al Myocardial fibrosis in hypertrophic cardiomyopathy Arq Bras Cardiol. 2019; 112(3):281-289 Methods Study design Systematic review with meta-analysis of observational studies of the natural history of HCM that reported RMs of SD and severe arrhythmic outcomes. Search strategy The search used 3 databases - MEDLINE, LILACS and SciELO - contemplating prospective or retrospective studies conducted between 1980 and 2016, which analyzed the natural history of patients with HCM, regardless of sex or ethnicity. We used the PRISMA statement checklist to conduct the systematic review and meta-analysis. The detailed research adapted for each database was conducted using the following keywords of Medical Subject Heading (MeSH) and DECS: Cardiomyopathy, Hypertrophic, Familial [MeSH] OR "Cardiomyopathy, Hypertrophic" [Mesh] OR "cardiomyopathies" [MeSH] OR cardiomyopathy [MEASURE] OR "risk factors" [MeSH] Death [Text Word] OR "defibrillators, implantable" [MeSH] OR "cardioverter defibrillator, implantable" [Text Word]. Only the articles published in English, Portuguese, and Spanish were considered for the full-text review. Selection criteria We have included only observational studies (prospective or retrospective cohorts) that had a severe arrhythmic outcome equivalent to SD. The studies that also analyzed at least one of the following RMs were included: a) family history of SD, b) severe left ventricular hypertrophy, c) unexplained syncope, d) NSVT on 24-hour Holter monitoring, e) ABPRE, f) presence of left ventricular outflow tract obstruction (LVOTO), and g) presence of myocardial fibrosis on cardiacMRI. The exclusion criteria were (1) studies that were case reports or review articles, (2) studies that did not meet the previously described inclusion criteria, and (3) duplicate studies. Definitions The studies included in our meta-analysis often used variable concepts, but fit the definitions listed in Table 1. Data extraction The eligibility (using inclusion and exclusion criteria) of each study was systematically analyzed by two reviewers (MIB and SAC), initially by reading the titles and abstracts. Selected articles were read and analyzed in full to assess their eligibility and methodological quality; all references were revised to identify additional studies. Differences in opinion between the two main reviewers were independently resolved by a third reviewer (DV). After this phase, the data were extracted. The information collected from each study included study design, number of patients, demographic data, follow-up, RMs for SD, and severe arrhythmic outcomes. Authors were contacted when any additional information was needed. There was no time restriction for the severe arrhythmic outcomes. Statistical analysis The statistical analysis used relative risks (RRs) as a measure of effect with 95% confidence intervals (CIs). The meta-analysis was performed using the DerSimonian and Laird method in case of heterogeneity and the Mantel-Haenszel method in case of homogeneity. The heterogeneity was analyzed using Cochran’s Q and I 2 Higgins/Thompson tests. The risk of bias was tested using funnel plots and Egger’s linear regression test. The software used for the analysis was R 3.4.1. The level of significance was set at p < 0.05. Ethical and legal aspects The study protocol was submitted to the Medical Ethics Committee of Pedro Ernesto University Hospital and received a final opinion on November 14, 2013. Results Search results The search strategy identified 809 potentially relevant articles (Figure 1). After reading the titles and abstracts, 123 remained for the eligibility analysis. After detailed evaluation, 103 articles were excluded, and 1 article was added after reviewing the references. Thus, 21 observational studies Table 1 – Definitions of outcomes and risk markers used in the meta-analysis Severe arrhythmic outcomes SD, aborted SD, documented sustained ventricular tachycardia, or appropriate shock in patients with ICD Family history of SD Family history of SD in the first-degree relatives of patients Severe left ventricular hypertrophy Ventricular thickness > 30 mm measured using echocardiography in any left ventricular segment Unexplained syncope A history of unexplained and transient loss of consciousness with spontaneous recovery NSVT on 24-hour Holter monitoring ≥ 3 consecutive ventricular extrasystoles with heart rates of ≥ 120 bpm for < 30 seconds LVOTO Peak gradient of ≥ 30 mmHg in the left ventricular outflow tract detected on echocardiography ABPRE Increased (< 20 mmHg) or decreased (> 10 mmHg) systolic blood pressure with peak exercise Myocardial fibrosis Detection of late enhancement on MRI with gadolinium SD: sudden death; ICD: implantable cardioverter-defibrillator; NSVT: non-sustained ventricular tachycardia; LVOTO: left ventricular outflow tract obstruction; ABPRE: abnormal blood pressure response to exercise; MRI: magnetic resonance imaging. 282