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(Circulation. 1995;92:158-159.)
© 1995 American Heart Association, Inc.

Articles

Sudden Death and Tetralogy of Fallot

Risks, Markers, and Causes

J. Timothy Bricker, MD

From Pediatric Cardiology, Texas Children's Hospital, Baylor College of Medicine, and the Texas Heart Institute, Houston.

Correspondence to J. Timothy Bricker, MD, Chief, Pediatric Cardiology, Texas Children's Hospital, 6621 Fannin, Suite 260, Houston, TX 77030.

	Introduction

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Tetralogy of Fallot has been treated with palliative surgery for more than 50 years, and operative correction has been available for more than 30 years. Although surgical repair is now done with low mortality and excellent quality of survival, late sudden cardiac death remains a problem.^{1 2} Understanding of the causes and of the factors that predict risk for sudden death remains incomplete.

Observations by astute clinicians in the first half of this century suggested possible causes of coronary artery disease. White³ thought that tobacco was probably without influence on the development of coronary disease. It was believed that overworked business or professional men were more likely to have coronary symptoms³ and that environmental noise as well as a stressful environment might contribute to the risk of developing coronary artery disease.⁴

The term "cohors" referred to 1/10 of a Roman legion. Each cohort in the legion included 300 to 600 soldiers who would march together in defense of the empire. Initially, the use of this term in epidemiology referred to a birth cohort (eg, all children with heart disease born in 1950). Now, the term cohort often refers to any group of individuals followed longitudinally and who are "marching through time" together. Beginning in the 1940s, several large cohorts at risk for development of symptomatic coronary artery disease were carefully observed in a systematic manner.⁵ Multivariate analysis of numerous candidate variables for development of coronary artery disease in these cohorts led to our current understanding of coronary risk factors. A variable related to the development of a specific outcome may ultimately prove to be a covariable, a confounding variable, or an independent predictor of risk. For example, at one point, data from England suggested that sugar consumption was related to coronary disease risk. It was eventually determined that sugar intake was related to tea consumption and that tea breaks were a marker for smoking behavior in that cohort. When smoking was factored out as an independent predictor, the risk related to sugar consumption disappeared.⁶ Covariables are those that relate to the risk of development of disease in an indirect manner by having a relation to another risk of greater quantitative value in the multivariate model. Confounding variables are those that are related to the outcome in a spurious or noncausal manner. The independent predictors of development of atherosclerosis end points in multivariate analysis came to be considered coronary artery risk factors.

Epidemiological evidence of risk can lead to hypotheses about mechanisms. A risk factor is generally not a cause of the outcome per se at the tissue level. Several different independent risk factors could potentially contribute to the same ultimate mechanism at the cellular level. Understanding the precise mechanism of the final step of a disease process is of value but may not have the same clinical and public health impact as knowledge regarding antecedents of the outcome.

Our understanding of risk for sudden cardiac death for individuals who have had surgery for tetralogy of Fallot is more similar to the beliefs about coronary artery risks in the first half of the century than to the current understanding of coronary artery disease risk factors. The data regarding sudden death in the postoperative tetralogy of Fallot population are mostly retrospective. Attempts to sort out risk have had to be "trohoc" attempts (cohort spelled backward) to some degree. Investigators have had to look back in time for data that might be related to risk and thus had to deal with limited or incomplete information. The few prospective studies of risk of sudden death have been restricted by the small sample size as well as the fact that the development of end points (ie, the occurrence of sudden death) not only is infrequent but also seems to be declining in frequency. It has not been possible to follow adequate numbers of tetralogy patients at risk to measure each of the candidate variables to observe the development of end points as was done for coronary artery disease.

No single risk factor currently identified convincingly predicts sudden death in tetralogy of Fallot patients. Meaningful multivariate analysis of longitudinal data to identify independent predictors of risk for sudden death with tetralogy of Fallot would require long-term observation on a large cohort. The attempt to look at a multivariate model with seven or eight variables, a population in which 70 to 80 deaths would be expected, is necessary for adequate statistical power.^{7 8} Waien and coworkers⁹ in Toronto found a rate of 4.5 deaths per 1000 patient years in a 3-year prospective study of 151 adults who had surgical repair of tetralogy of Fallot. A cohort of about 1700 tetralogy of Fallot patients followed for 10 years might be required for sufficient statistical power to sort out the relative strength and independence of multiple predictors of sudden death in multivariate analysis. An annual birth cohort of tetralogy of Fallot in the entire United States from the late 1970s would probably number only about 2400.¹⁰ Application of a multivariate model to another data set to see whether the model is still predictive is the epidemiological equivalent of Koch's postulate. Risk factors identified from a given data set must subsequently be applied to analysis of data from a different population for validation.

Observations of groups of patients with surgery for tetralogy of Fallot have described a number of factors hypothesized to be related to sudden death (Table). Residual hemodynamic abnormalities and sustained ventricular arrhythmias certainly do seem to be related to sudden cardiac death in this population. The causal relation is plausible, in addition to being a strong and persistent association in the data. Several of these factors (such as conduction abnormalities and atrial arrhythmias) certainly seem to have been confounding variables and are probably not related or only very rarely related to cases of sudden cardiac death. Some of the other candidate risk factors are potentially related to each other and could be covariables. There may be more to the story than can be extracted from the data currently available. None of the proposed risk factors are 100% predictive of death, and some are probably stronger risks than others. Perhaps some factors previously discarded could be found to have some relevance when investigated in a multivariate model with adequate sample size.

View this table: [in this window] [in a new window]   Table 1. Some Factors Proposed to Be Related to the Risk of Sudden Death After Repair of Tetralogy of Fallot

Factors related to sudden cardiac death but not independent predictors could still be of clinical use in the identification of an individual who is in a high-risk subgroup. Gatzoulis and coworkers,¹¹ in this issue of Circulation, show relations between QRS prolongation, right ventricular dilation, sustained ventricular arrhythmias, and postoperative sudden cardiac death. Although there has been optimism that alterations in surgical technique and younger age at repair might make sudden death a diminishing problem in the future, ever-increasing numbers of individuals with successful tetralogy of Fallot surgery are entering the adult population. I find this study to be of potential practical value for the routine follow-up of our older tetralogy patients. The authors suggest that those with a QRS duration >180 ms on the ECG require the closest surveillance, perhaps a lowered threshold for additional investigation, and possibly a lower threshold for a decision to begin prophylactic antiarrhythmic treatment. We cannot know the strength of this association compared with other possible risk factors or whether this is a marker for factors other than right ventricular size or function (such as the size of the ventriculotomy scar or the adequacy of the myocardial preservation). The strength of the association reported suggests hypotheses of causation for additional research. The practical implications and the simplicity of obtaining the QRS duration from the routine ECG call for a study of this relation to sudden death in other tetralogy of Fallot data sets.

Sudden death remains a devastating late consequence of the surgical repair of tetralogy of Fallot. Gatzoulis and coauthors¹¹ emphasize that there is no clear method of identification of the individuals at risk. White's³ perceptions of the risks and causes of coronary artery disease in the 1930s were limited because of the data available. Fortunately, his observations led to methods of investigation that eventually provided better information about the risks for and causes of coronary artery disease. Large-scale pooling of cases in a longitudinal approach may be required for us to get the same quality of predictive information for our patients with tetralogy of Fallot.

	References

Top Introduction References

 

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3. White PD. Heart Disease. New York, NY: The MacMillan Co; 1931:414.
   
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8. Bricker JT, Fisher DJ, Garson A Jr. Statistics for the cardiologist. In: Garson A Jr, Bricker JT, McNamara DG, eds. The Science and Practice of Pediatric Cardiology. Philadelphia, Pa: Lea & Febiger; 1990:646-655.
   
9. Waien SA, Liu PP, Ross BL, Williams WG, Webb GD, McLaughlin PR. Serial follow-up of adults with repaired tetralogy of Fallot. J Am Coll Cardiol. 1992;20:295-300. [Abstract]
   
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