In the current study, after adjusting for covariates, death of a sibling did not contribute to risk of ACA or LQTS-related death. Thus, it appears that severe symptoms in a close relative cannot be used as an indicator of personal risk for those family members affected by the same pathogenic substrate; rather, the incomplete penetrance and variable expressivity which are such consistent findings in LQTS15,16,20
preclude predicting severity of symptoms even in siblings. In contrast, an individual’s own QTc, history of syncope and gender were strong predictors of risk.
The current study extends the findings of Kimbrough’s study14
of 211 LQTS probands and 791 first degree relatives, in which severity of LQTS in the first-degree relatives was related to their own QTc, not to the severity of the probands’ symptoms. The current study benefited from a larger number of events (829 cardiac events including 213 ACA/LQTS-related deaths vs. 67 cardiac events including 17 ACA/LQTS-related deaths in the earlier study). In addition, the current study took advantage of a newer, more sophisticated method of analysis, modeling death of a sibling as a time-dependent variable. Both study size and time-dependent modeling provided the potential for a more precise analysis.
The usefulness of QTc13,17,19,21,22
and personal history of syncope1,17,19
for predicting ACA/LQTS-related death is well-established (although evidence suggests that they may not predict well in LQT3).13
In the current large study of 1915 LQTS probands and first/second degree relatives (i.e. offspring, siblings, parents, aunts/uncles, and grandparents), QTc and personal history of syncope overwhelmed all other covariates as risk predictors of a severe event. Our finding of a time-dependent effect of gender is consistent with that reported previously.11
It is not clear why subjects with a history of sibling death had a higher risk of all cardiac events (primarily syncope). It is possible that sibling death is a subtle marker of unmeasured risk. Alternatively, subjects with a history of sibling death may report syncope more vigilantly (whereas ACA/death is a more obvious endpoint). Reports of “syncope” in the Registry are characterized by abrupt onset and offset of loss of consciousness and probably represent arrhythmogenic syncope and not simply vasovagal and orthostatic events.
It may be argued that bereaved parents are not interested in relative risk but in the absolute risk of ACA/death in their remaining affected offspring. Assuming that all such offspring would be treated with beta-blockers, we analyzed the risk of ACA/death over a 5-year period that started at the time of their sibling’s death, for asymptomatic surviving affected siblings on beta-blocker therapy. There were 50 such subjects (40 with QTc 450–480 ms; 11 with QTc 490–520 ms; and 6 with QTc ≥ 530 ms). No ACA or LQT-related deaths occurred within this five-year period in the asymptomatic surviving siblings on beta-blocker therapy.
A potentially serious limitation of this study is that subjects with history of death in a sibling were more aggressively treated both with beta-blocker medication and with ICDs. This may have decreased the incidence of severe events in such subjects. So, even though history of sibling death did not contribute to risk of severe events in this study, it is possible that such an effect was masked by more aggressive therapy. We attempted to ascertain whether ICD implantation, more aggressively used in subjects with history of death in a sibling, influenced the outcome of this study. There were 189 subjects (out of 1915) who received an ICD, 140 of whom received an ICD before follow-up was censored due to ACA or age 41. Of these, follow-up ICD data were available in 137 (98%). When the primary endpoint of a severe event was redefined to include not only ACA and LQT-related death but also an appropriate shock or a shock of unknown appropriateness, the total number of endpoints increased from 213 to 229. Even so, sibling death was not predictive of the risk of reaching this endpoint.
Although we were able to incorporate beta-blocker use into the Cox model and although we verified that the disproportionate use of ICD implantation in the sibling-death group did not mask a higher risk of long QT-associated death, we were unable to exclude a protective effect of, for example, more consistent advice about avoiding QT-prolonging medications, competitive sports, and other triggers of torsades de pointes. While we acknowledge (and cannot correct for) the bias toward more aggressive treatment of the subjects with a history of death in a sibling, we recommend beta-blocker therapy and consistent advice for nearly all patients with long QT syndrome considered to be at some level of increased risk. In this study, subjects with a history of sibling death were more likely to be treated with (appropriate) beta-blocker therapy. The clinician must take care not to under-treat subjects without a history of sibling death.
The effects of beta-blockers in any registry-based study must be interpreted with caution. In 1985 Schwartz and Locati demonstrated that anti-adrenergic therapy was associated with a meaningful reduction in 15-year mortality of patients with LQTS presenting with syncope (from 53% to 9%).5
Since that time, beta-blockers have been the mainstay of treatment in LQTS, although several investigators7,8,23,24
have reported a substantial rate of beta-blocker failure among high-risk patients with a history of ACA, syncope despite beta-blockers, or LQT3. In the current study, overall there was a 50% reduction in risk associated with the use of beta-blocker. Evaluation of beta-blocker efficacy in a registry-based analysis (rather than a randomized trial) is inherently limited because clinicians assign beta-blocker therapy to patients whom they believe to be at particularly high risk. Thus, beta-blocker use may become a surrogate marker of high risk. Despite this possible bias, we found a striking and significant benefit of beta-blocker therapy (see ).