General Discussion and Future Perspectives | 187 The genetic basis of the disease has become an important part in both diagnosis and risk stratification. Moreover, in the foreseeable future, treatment approaches are expected to undergo a paradigm shift from one-size-fits-all to individualized treatments based on molecular characteristics of the disease. Treatment will be targeted at the cause of disease, rather than the consequence (dilatation or hypertrophy). It is therefore very likely that the classical phenotypical disease classification will be replaced by a genotype-based disease classification. This is already common practice when a pathogenic variant in the phospholamban or lamin A/C gene is identified (PLN- or LMNA-cardiomyopathy, respectively). In line with most research which has been performed to this date, the studies included in this thesis are based on the phenotypical approach. The diagnostic 2010 Task Force Criteria4 which were tested in Chapter 2 and used for patient inclusion in most of the other chapters, disregard genotype and focus merely on phenotypical expression of right-sided heart disease. Patients with (likely-)pathogenic variants in genes coding for the cardiac desmosome were treated similarly to patients with nondesmosomal genetic variants or patients without a known disease causing variant. Even within the group of patients with a disease causing genetic variant in the cardiac desmosome, there is considerable heterogeneity. While variants in the plakophilin-2 (PKP2) gene typically lead to a classical right-sided ARVC phenotype, variants in the desmoplakin (DSP) gene often appear to lead to predominant LV impairment.5 It might therefore be more appropriate to distinguish PKP2-cardiomyopathy from DSP-cardiomyopathy, instead of classifying both as ARVC. Grouping all patients with a TFC-based diagnosis together may lead to important features in genetic subgroups being unrecognized. Patients with a variant in the plakophilin-2 (PKP2) gene represent the majority in most cohorts studied in this thesis. The typical abnormal deformation patterns in the subtricuspid segment of the RV lateral wall which were first classified by Mast et al.6 are commonly found as one of the first signs of disease manifestation in PKP2 variant carriers, as described in Chapter 3 and Chapter 7. While different genotypic forms of ARVC all have a final common pathway of myocardial fibro-fatty replacement and ventricular arrhythmias, the disease mechanism may be different among these patients. Not all non-PKP2 patients show typical abnormal deformation patterns in the subtricuspid segment in the early disease phase. Extrapolation of the sensitivity of subtricuspid RV deformation patterns for detection of early disease in subgroups with another genetic basis should therefore be met with caution. In future research, a genotype-specific approach might reveal specific deformation abnormalities which are characteristic for specific genetic variants. In PLN patients and family members, this approach has recently been successfully applied.7 Post-systolic shortening in the LV apex showed to be a characteristic finding in PLN p.Arg14del variant carriers, preceding any other symptom or sign of disease. In Chapter 9, we demonstrated the added value of deformation imaging on top of the ARVC risk predictor in a cohort of patients with an ARVC phenotype. In line with the studies in which the risk predictor was developed and validated, all patients fulfilled a definite ARVC diagnosis according to the 2010 TFC.4 In a validation study of the risk calculator it was pointed out that genotype should be included in future models for ARVC, since risk prediction appeared to be better in PKP2 patients compared to for instance DSP patients.8 In another recent study, it was shown that risk stratification of familial cardiomyopathies in a genotype-based approach outperformed the classical phenotype-based approach.9 Although the differences between genetic subgroups were largely driven by highly pathogenic variants in for instance the LMNA gene, this study might be an example for future approaches to risk stratification in genetic cardiomyopathies. Unfortunately, the general obstacle of this approach is that it is very difficult 9
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