Risk Stratification of Type 2 Long-QT Syndrome Mutation Carriers With Normal QTc Interval : The Value of Sex, T-Wave Morphology, and Mutation Type

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d9000693e176">Background</h5> <p id="P1">Long QT syndrome (LQTS) mutation carriers have higher risk of cardiac events than unaffected family members even in the absence of QTc prolongation. Changes in T wave morphology may reflect penetrance of LQTS mutations. We aimed to assess whether T-wave morphology may improve risk stratification of LQT2 mutation carriers with normal QTc interval. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d9000693e181">Methods</h5> <p id="P2">LQT2-mutation carriers with QTc&lt;460 ms in men and &lt;470 ms in women (n=154) were compared with unaffected family members (n=1007). Baseline ECGs recorded at age ≥18 years underwent blinded assessment. Flat, notched or negative T-waves in leads II or V5 were considered ’abnormal’. Cox regression analysis was performed to assess the association between T-wave morphology, the presence of mutations in the pore region of <i>KCNH2</i> and the risk of cardiac events defined as syncope, aborted cardiac arrest, defibrillator therapy or sudden cardiac death. Gender-specific associations were estimated using interactions terms. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d9000693e189">Results</h5> <p id="P3">LQT2 female carriers with abnormal T-wave morphology had significantly higher risk of cardiac events compared to LQT2 female carriers with normal T waves (HR=3.31; 95% CI: 1.68–6.52; p=0.001) whereas this association was not significant in males. LQT2 males with pore location of mutations has significantly higher risk of cardiac events than non-pore location males (HR=6.01; 95%CI: 1.50–24.08; p=0.011) whereas no such association was found in females. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d9000693e194">Conclusion</h5> <p id="P4">The risk of cardiac events in LQT2 carriers with normal QTc is associated with abnormal T wave morphology in females and pore location of mutation in males. The findings further indicate sex-specific differences in phenotype and genotype relationship in LQT2 patients. </p> </div>