130 | Chapter 7 METHODOLOGY A systematic search was conducted in the MEDLINE, Embase and Cochrane databases. The search queries included keywords and synonyms for (1) deformation imaging and (2) the most common genetic cardiomyopathies, including dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM) and non-compaction cardiomyopathy (NCCM).22,23 Full search queries for the different databases are provided in the Supplementary methods. The search was conducted on April, 1, 2021. After removing duplicates, records were independently screened by two observers (K.T. and F.K.) based on title and abstract. Studies were eligible when 2D speckle tracking was performed in relatives at risk for genetic cardiomyopathy, irrespective of their age and irrespective of whether genotyping was performed. Studies in cardiac storage diseases (e.g. Amyloidosis, Fabry), muscular dystrophy (e.g. Duchenne, Becker) or congenital heart diseases were excluded. Disagreement in abstract selection between the two observers was solved by consensus. Full papers were screened for eligibility and reference lists were screened to identify additional relevant articles that were not identified by the primary search. Abstracts without available full papers in English language, case reports/series, feasibility studies, reviews and editorials were excluded. Study quality and consequent risk of bias was assessed by two observers using the Newcastle-Ottowa scale for case-control studies and/or cohort studies (Supplementary material). Included studies In all, 29 studies were identified which were all published between 2009 and 2021 (flowchart in Figure 1). The studies are summarised per disease in Tables 1-4. Most studies included relatives who are at risk for HCM (11 studies)24–34 and ACM (11 studies)35–45, followed by DCM (6 studies)46–51 and NCCM (1 study)52. All studies were case-control studies and/or longitudinal cohort studies, except for one which was a cross-sectional cohort study.36 The number of included subjects at risk varied from 14 to 251 (median 41, interquartile range 24-73). The mean/median age of subjects at risk varied between 20 and 50 years in most studies, except for one study that included genotype-positive children at risk for HCM with a mean age of 9.8 ± 4.5 years.26 Genetic data were reported in 26 studies. Dilated cardiomyopathy Most studies in DCM classified relatives as phenotype-negative on the basis of a preserved left ventricular ejection fraction (LVEF, Table 1). All studies showed that global deformation parameters of the LV, in particular global longitudinal strain (GLS), are reduced in relatives compared to controls (Figure 2). The largest study by Verdonschot et al.46 investigated 251 firstdegree relatives of genotyped DCM patients who all had normal LVEF (≥55%) at baseline. The majority of these relatives was related to an index patient without a proven (likely-)pathogenic variant. GLS was reduced in relatives compared to matched controls. Abnormal baseline GLS in relatives was associated with deterioration of LVEF <55% (with a minimum decrease of 5%) at a median follow-up of 36 months. Abnormal GLS at baseline was also associated with more cardiac hospitalizations and more deaths after a median follow-up of 40 months. While the results suggest that GLS can be used for risk stratification in relatives of DCM patients, occurrence of hard clinical endpoints during follow-up was infrequent, which is a common issue encountered in longitudinal studies of preclinical relatives. Studies with longer follow-up would strengthen the prognostic value of GLS in relatives at risk for DCM. Moreover, the role
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