Genotype-Driven Pathogenesis of Atrial Fibrillation in Hypertrophic Cardiomyopathy: The Case of Different TNNT2 Mutations

Abstract

Atrial dilation and atrial fibrillation (AF) are common in Hypertrophic CardioMyopathy (HCM) patients and associated with a worsening of prognosis. The pathogenesis of atrial myopathy in HCM remains poorly investigated and no specific association with genotype has been identified. By re-analysis of our cohort of thin-filament HCM patients (Coppini et al. 2014) AF was identified in 10% of patients with sporadic mutations in the cardiac Troponin T gene (TNNT2), while AF occurrence was much higher (25–75%) in patients carrying specific “hot-spot” TNNT2 mutations. To determine the molecular basis of arrhythmia occurrence, two HCM mouse models expressing human TNNT2 variants (a “hot-spot” one, R92Q, and a “sporadic” one, E163R) were selected according to the different pathophysiological pathways previously demonstrated in ventricular tissue. Echocardiography studies showed a significant left atrial dilation in both models, but more pronounced in the R92Q. In E163R atrial trabeculae, in line with what previously observed in ventricular preparations, the energy cost of tension generation was markedly increased. However, no changes of twitch amplitude and kinetics were observed, and there was no atrial arrhythmic propensity. R92Q atrial trabeculae, instead, displayed normal ATP consumption but markedly increased myofilament calcium sensitivity, as previously observed in ventricular preparations. This was associated with reduced inotropic reserve and slower kinetics of twitch contractions and, importantly, with an increased occurrence of spontaneous beats and triggered contractions that represent an intrinsic arrhythmogenic mechanism promoting AF. The association of specific TNNT2 mutations with AF occurrence depends on the mutation-driven pathomechanism (i.e., increased atrial myofilament calcium sensitivity rather than increased myofilament tension cost) and may influence the individual response to treatment.

High-resolution cryo-EM structure of the junction region of the native cardiac thin filament in relaxed state

“…5H and Table 1 ), which is expected to disrupt TnT1 interaction with actin rather than with Tm (Fig. 5F ), does not change the affinity of TnT 70-170 fragment to Tm while conferring increased Ca 2+ sensitivity ( 54 ).…”

“…Not surprisingly, the TnT1 region is a major hotspot for cardiomyopathy causing mutations ( 52 ) with a high incidence of sudden cardiac death ( 53 ) and atrial fibrillation ( 54 ). Due to the absence of a high-resolution structure of the junction region of the cTF, the underlying molecular mechanisms of these mutations were unknown.…”

“…5H ). hR92Q and hR92L pathogenic variants markedly increase myofilament Ca 2+ sensitivity ( 54 , 62 ). An alternative explanation would be that these HCM-linked mutations may affect the interaction of the TnT1 with Tm in the activated cTF when TnT1 dissociates from the actin surface ( 5 , 6 ).…”

Genetic variants, pathophysiological pathways, and oral anticoagulation in patients with hypertrophic cardiomyopathy and atrial fibrillation

“…Indeed, a subsequent study by Lee et al ( 13 ) further demonstrated that HCM patients with likely pathogenic or pathogenic MYH7 variants had a higher risk of incident AF than other sarcomeric genes (MYBPC3, thin filament genes). In addition, patients with sarcomeric gene (e.g., MYH7, TNNT2) variants in hot spot sites that are more frequently associated with HCM development may have higher AF vulnerability in the future than those with gene variants in non-hot spot sites ( 13 , 15 ).…”

“…Furthermore, the SGCG gene is thought to be linked to AF in a large genome-wide association study ( 24 ). In addition, prior clinical and genetic studies indicated that pathogenic variants in other sarcomere protein genes, including TNNT2, TNNI3, TPM1, MYL2, MYL3 and ACTC1, were associated with the occurrence of ventricular and atrial arrhythmias (particularly AF) ( 15 , 23 ).…”