134 | Chapter 7 Arrhythmogenic cardiomyopathy Early detection in relatives at risk for ACM is of particular interest, because these relatives are at risk of developing life-threatening ventricular arrhythmias before the onset of overt structural disease. Most studies on ACM and its right dominant subform arrhythmogenic right ventricular cardiomyopathy (ARVC) included relatives with (likely-)pathogenic variants in desmosomal genes (typically plakophilin-2, Table 3). Global RV deformation was investigated in four studies. Sarvari et al.42 and Reant et al.43 found reduced RV free wall strain in genotype-positive relatives compared to control subjects (Figure 4). Lie et al.35 investigated RV free wall strain in a subgroup of genotype-positive relatives and it was reduced in all four relatives who developed lifethreatening ventricular arrhythmia during follow-up. The reduction in RV free wall strain seems to be driven by regional alterations, particularly in the subtricuspid region. Mast et al.44 described three distinct morphologies of regional deformation patterns in the RV: a type I pattern represents normal deformation while type II/ III represents abnormal deformation. An abnormal deformation pattern was found in half of the preclinical relatives in the subtricuspid area (Figure 4). A follow-up study noted that normal deformation in the subtricuspid area could exclude disease progression with a high negative predictive value in relatives.39 The role of the subtricuspid region is in line with cardiovascular magnetic resonance (CMR) and electrophysiological data that identified the subtricuspid region as one of the first affected regions in the disease.56 Besides regional deformation patterns, the regional abnormalities can also be detected by measurement of contraction heterogeneity, expressed by RV mechanical dispersion (Figure 4). Sarvari et al.42 showed greater RV mechanical dispersion in genotype-positive relatives compared to healthy controls. RV mechanical dispersion was found to be an independent predictor of arrhythmic events in a mixed group of ACM patients and asymptomatic genotypepositive relatives. Leren et al.36 showed that greater RV mechanical dispersion was associated with arrhythmic events in genotype-positive relatives, and had incremental value on top of electrical parameters according to the 2010 Task Force Criteria for ARVC. The aforementioned methods of RV deformation were developed and tested in two centres and recently externally validated.57 Both showed independent associations with life-threatening ventricular arrhythmias, and the combination of these methods increased the association with arrhythmia outcome. External validation has been a key step towards clinical implementation of deformation imaging in relatives at risk for ACM. LV deformation has also been investigated in ACM relatives (Figure 4). Reduced GLS42,43, impaired regional LV deformation37,43, and increased LV mechanical dispersion (LVMD)42 was seen in relatives with (likely-) pathogenic variants of desmosomal genes. LVMD was greater in relatives who developed a life-threatening ventricular arrhythmia during follow-up, and predicted structural disease progression during follow-up.35,38 Non-compaction cardiomyopathy Relatives of NCCM patients were investigated in one study (Table 4).52 In 30 relatives, many deformation imaging parameters were slightly more abnormal compared to controls, including GLS, global circumferential and rotational strain. These results have not yet been replicated by other studies.
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