Correspondence

Risk Stratification in the Long-QT Syndrome

N Engl J Med 2003; 349:908-909August 28, 2003

Article

To the Editor:

Priori et al. (May 8 issue)1 describe a new risk-stratification algorithm for the long-QT syndrome, one based on genotype. As the authors note, the natural history of the long-QT syndrome varies not only among families with mutations that map to different loci, but also among families with mutations in the same gene. The management algorithm they describe, however, does not fully account for these types of variation.

To interpret the data presented, readers need to know the structure of the study population, whether the events seen were clustered within families, and the effect of restricting the analysis to probands. It is not clear that Kaplan–Meier methods should be applied to nonindependent data within families. In addition, it would be interesting to know how molecular diagnosis fares in comparison with a careful family history as a predictor of risk.

If genotypic risk stratification is to gain clinical acceptance, its application must be based on rigorous, well-validated techniques. Novel methods will be required for the analysis of familial risk, since families may share not only primary mutations but also many inherited and environmental modifiers.

Patrick T. Ellinor, M.D., Ph.D.
David J. Milan, M.D.
Calum A. MacRae, M.B., Ch.B.
Massachusetts General Hospital, Boston, MA 02114
cmacrae@partners.org

1 References

1. 1

   Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348:1866-1874
   Full Text | Web of Science | Medline

Author/Editor Response

Dr. Ellinor and colleagues raise a host of relevant issues pertaining to the contribution of genotyping to risk stratification. We introduced into our model the factors that are currently considered important in the modulation of the clinical phenotype.1,2 When new clinical, inherited, or environmental modifiers are identified, they will be incorporated into a novel risk-stratification scheme. In the population we studied, a family history of cardiac events was not a significant predictor of risk. This finding is in agreement with previous data showing that symptoms in probands are not predictors of events among family members.3,4

Our analysis could have been influenced by the presence of large families with several affected members. However, this problem is unlikely to have occurred, since 40 percent of the cases in the probands were sporadic, and the average number of affected persons was three per mutation per family (3.3 with a mutation at the LQT1 locus, 3.1 with a mutation at the LQT2 locus, and 2.6 with a mutation at the LQT3 locus). Furthermore, the analysis among probands showed the same trend as in the entire population, but the size of the population was insufficient for the data to reach statistical significance.

Silvia G. Priori, M.D., Ph.D.
Istituto di Ricovero e Cura a Carattere, Scientifico Fondazione Maugeri, 27100 Pavia, Italy

Peter J. Schwartz, M.D.
Istituto di Ricovero e Cura a Carattere, Scientifico Policlinico San Matteo, 27100 Pavia, Italy

Carlo Napolitano, M.D., Ph.D.
Istituto di Ricovero e Cura a Carattere, Scientifico Fondazione Maugeri, 27100 Pavia, Italy

4 References

1. 1

   Zareba W, Moss AJ, Schwartz PJ, et al. Influence of the genotype on the clinical course of the long-QT syndrome: International Long-QT Syndrome Registry. N Engl J Med 1998;339:960-965
   Full Text | Web of Science | Medline

2. 2

   Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation 1998;97:2237-2244
   Web of Science | Medline

3. 3

   Kimbrough J, Moss AJ, Zareba W, et al. Clinical implications for affected parents and siblings of probands with long-QT syndrome. Circulation 2001;104:557-562
   CrossRef | Web of Science | Medline

4. 4

   Priori SG, Aliot E, Blomstrom-Lundqvist C, et al. Task Force on Sudden Cardiac Death of the European Society of Cardiology. Eur Heart J 2001;22:1374-1450[Erratum, Eur Heart J 2002;23:257.]
   CrossRef | Web of Science | Medline