Researchers map genetic clues to prevent sudden cardiac death in young adults

<p><strong>Background:</strong> The most common cause of sudden death in young individuals is sudden cardiac death (SCD), where hypertrophic cardiomyopathy (HCM) is the leading diagnosis and, together with dilated cardiomyopathy (DCM), the most common cardiomyopathies. The most difficult part of taking care of the HCM patient is the risk evaluation for a subsequent SCD. To improve the risk prediction factors associated with a more severe phenotype is important to find.</p><p><strong>Aims:</strong> The overall aim of this thesis was to study various aspects of genetic information, conventional and advanced electrocardiogram (ECG) and biomarkers to gain improved knowledge of cardiomyopathy in the young, especially in HCM, and to identify factors associated with a more severe phenotype.</p><p><strong>Material and methods:</strong> This thesis consists of four studies including: one presentation of a four-generation family with a strong history of DCM in all four generations (Study I), where genetic mapping and testing were performed; two retrospective single-centre studies (Study II and III), where electrographic variables from conventional ECG (the ECG Risk-score) and advanced, three-dimensional ECG (spatial mean and peaks QRS-T angles) were used to predict myocardial fibrosis expressed as late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR); and one single-centre, prospective study (Study IV) where biomarkers in biological pathways were compared between the study groups. Study II-IV include pediatric and young adult patients with familial, primary HCM, first-degree relatives with verified familial disease-causing genetic variants without developed overt HCM (genotype-positive, phenotype-negative, G+P-), and healthy volunteers.</p><p><strong>Results:</strong> Study I describe two heterozygous genetic variants, one in a previously reported pathogenic variant in TNNT2 (c.518G&gt;A) and a novel variant of unclear significance in BAG3 (c.785C&gt;T), both in the deceased infant as well as in a relative with more advanced DCM. Study II includes 42 young individuals (7-31 years): 26 HCM patients, 7 G+P- and 9 healthy volunteers. An ECG Risk-score ³3 points predicted myocardial fibrosis with a sensitivity of 85 % (95% CI 55-98%) and a specificity of 84% (95% CI 60-97%). There was a significant difference between the extent % LGE in a low-risk (0-2 p) vs high-risk ECG score (6-14 p) (p=0.001). Study III includes 34 of the individuals from Study II: 19 HCM patients, 6 G+P- and 9 healthy volunteers. The spatial mean and peaks QRS-T angles were significantly higher in HCM patients with LGE as compared to all other participants without LGE (p&lt;0.001). The spatial peaks QRS-T angle was the angle with the highest ability to indicate LGE where an angle &gt;50° indicated LGE, with 100% sensitivity, 93% specificity and an AUC 0.98 (95% CI 0.95-1.0; p&lt;0.001). Study IV includes 92 study participants: 29 HCM patients, 17 G+P- individuals and age- and gender-matched controls. Three proteins were associated with overt HCM: FGF-21 (fibroblast growth factor-21), PSGL-1 (P-selectin glycoprotein ligand-1) and Gal-9 (Galectin-9). Two proteins were associated with G+P- individuals: ADAM-TS13 (A disintegrin and metalloproteinase with thrombospondin motifs 13) and TIE2 (angiopoietin-1 receptor).</p><p><strong>Conclusions:</strong> The studies included in this thesis have shown a probable role of using the electrical phenotype as a marker of likely presence of underlying myocardial fibrosis or perfusion defects in HCM in the young. Future large-scale studies are needed to validate the results and to evaluate any incremental value of including ECG variables indicating likely presence of fibrosis in the risk prediction for SCD. The studies have illustrated the importance of genetic testing and cascade family screening, as well as the novel finding of elevated FGF-21 in overt HCM. The finding of elevated FGF-21 indicates the involvement of the Ras-MAPK pathway in young HCM patients regardless of the etiology being a primary HCM or a secondary HCM due to a RASopaty. </p>