Twins with implanted pacemakers: Is there an increased mortality risk for the co-twin? A follow-up study based on the Danish Twin Registry and the Danish Pacemaker Register Free

Abstract

Background

The main indications for implanting a cardiac pacemaker are either acquired atrio-ventricular block (AVB) or sick sinus syndrome (SSS). In general, the exact aetiology of these conditions is unknown. Genetic factors may play a role. Untreated AVB is associated with increased mortality but SSS seems to have a good prognosis.

The present study was designed to assess whether first-degree relatives of these patients have an increased mortality risk.

Methods

We investigated the survival pattern of the co-twins of twins who have had a cardiac pacemaker implanted, by linking two nationwide registries in Denmark: the Danish Pacemaker Register and the Danish Twin Registry.

For each “pacemaker-twin” four control-twins matched with respect to age, sex, and zygosity were selected among the twins who were alive at the time of the pacemaker implantation.

A total of 159 twins with a pacemaker treated bradycardia of unknown aetiology were identified of which 73 had AVB and 64 had SSS. A total of 622 matched control-twins could be identified.

The survival from age six of the co-twins of the “pacemaker-twins” was compared with that of the co-twins of the control-twins. The follow-up period ended January 1st, 2000.

Findings

The survival curves for the co-twins of the “pacemaker-twins” were virtually identical to those of the co-twins of the control-twins. This finding was consistent for both AVB and SSS and for monozygotic as well as dizygotic twins.

Conclusion

No increased mortality risk could be demonstrated for first-degree relatives – including monozygotic twins – of patients with a cardiac pacemaker implanted due to either acquired AVB or SSS.

Introduction

There are two often related reasons for implanting a cardiac pacemaker: to relieve symptoms and to improve survival. Most patients treated with pacemaker implantation are elderly persons with either chronic atrio-ventricular-block (AVB) or sick sinus syndrome (SSS).

The most common cause of chronic AVB is believed to be fibrosis in the cardiac conduction system and/or calcification of the fibrous skeleton of the heart[1],[2]. Familial occurrence has been described for these arrhythmias, but they are often either congenital or occur very early in life[3]–[6]. However, adult onset conduction defects with familial occurrence have been described and linked with possible genetic mechanisms[7]–[9]. Conduction defects are also associated with other familial occurring cardiac disorders such as cardiomyopathy[10] and amyloidosis[11] and with rheumatic diseases[12]–[15].

Without pacemaker implantation the prognosis for patients with third-degree AVB is poor with reported one-year mortality as high as 50%[16],[17].

The term SSS is used for a number of conditions in all of which there is some kind of sinus node dysfunction on the electrocardiogram of the patient. Fibro-degenerative changes have also been described in SSS[18]–[20]. Unlike in chronic AVB the outlook of SSS seems rather benign[21],[22].

Due to the potentially life-threatening nature of AVB and the curability by cardiac pacemaker implantation, it is of interest to know whether the relatives of these patients have an increased mortality risk due to an unrecognized need for a pacemaker. Evidence of an increased mortality in relatives would put emphasis on an active and early detection of an incipient conduction disorder in siblings of patients with AVB.

In SSS the arrhythmia itself may not cause death but the condition might be life-threatening if untreated because syncope or near-syncope may lead to fatal accidents. Although the mortality risk in untreated AVB and SSS may be different, a substantial number of patients with both conditions experience dramatic symptoms like Stokes–Adams attacks and syncope. The siblings of these patients will obviously be concerned with their own risk of developing such disorders.

No relatives are genetically closer to each other than monozygotic twins. Therefore, we investigated the survival pattern of the co-twins of twins who have had a cardiac pacemaker implanted by using the two nationwide registries in Denmark: the Danish Pacemaker Register and the Danish Twin Registry.

Methods

The Danish Pacemaker Register

Since 1982 detailed data on all pacemaker implantations performed at all 12 pacemaker centres in Denmark have been recorded in a central register. The data collection is based upon the “European Pacemaker Patient Identification Card”, a standardized identification card made by the “European Working Group on Cardiac Pacing” now “European Heart Rhythm Association” of the European Society of Cardiology. All pacemaker patients in Europe hold this identification card. Besides technical information, data on the symptoms, the possible aetiology, and the ECG-indication leading to the implantation have been obtained. Detailed statistics from the database are published yearly[23]. A total of 26,164 patients had pacemakers implanted and in 21,650 cases the aetiology was coded as unknown (Table 1). Myocardial infarction or ischaemia was the most common aetiological factor (66.6%) among the 4514 patients with aetiology coded as known.

A total of 9934 patients had AVB with unknown aetiology. Within the AV-Block group the ECG-indications for pacemaker implantation were distributed as follows: first-degree AV-Block (1.5%), second-degree AV-Block (18.9%), third-degree AV-Block (79.3%) and atrial fibrillation with AV-Block (0.3%). A total of 8474 patients had SSS of unknown aetiology. In the SSS group the ECG-indications were distributed as follows: sino-atrial block (7.3%), sino-atrial arrest (25.5%), sinus bradycardia (21.7%), brady-tachy syndrome (36.7%) and a group where the indication was not specified (8.7%).

The Danish Twin Registry

The Danish Twin Registry is nationwide and population based. The registry was established in 1954 and comprises same sex twins born 1870–1930 and surviving till the age of 6[24]. Recently, the birth cohorts from 1931 to 1952 were included in the registry, which now holds data of more than 32,000 twin pairs born 1870–1953 and surviving till the age of 6. All twins in the registry were ascertained independently of any disease. Zygosity was established through a questionnaire with questions on the degree of similarity between twins in a pair. The validity of this zygosity classification has been evaluated by comparison with blood group determinants, and the misclassification rate has been found to be less than 5%[25].

Since 1968 all Danish citizens have been registered with a 10-digit civil registration number. This number has been used to link information between the two registries.

Study population

The study includes all twins among patients having had a pacemaker implanted in Denmark in the period of January 1st 1982 to June 30th 2000 with the aetiology coded as unknown and the electrocardiographic indication as AVB or SSS – a total of 159 twin individuals.

Control population

For each twin identified in both the AVB and SSS groups four control-twins were selected via the twin register. The four control-twins had to be alive at the time when the case-twin (the “pacemaker-twin”) had the pacemaker implanted. They were matched with respect to the age, sex and zygosity of the “pacemaker-twin”. The survival of the co-twins of the “pacemaker-twins” was then compared with the survival of the co-twins of the control-twins. Vital status was unknown for 14 co-twins of the control-twins, leaving a total of 781 persons in the analyses, namely co-twins of 159 “pacemaker-twins” and 622 control-twins. This design enables us to follow the survival pattern of the relatives of a pacemaker patient from childhood and not just from the implantation time.

Statistical analysis

The survival of the co-twins of the “pacemaker-twins” was compared with the survival of the co-twins of the control-twins. The observation time was from age six until death, emigration or end of follow-up (January 1st, 2000) whichever came first. The Kaplan–Meier method was used for survival analyses and the significance of differences in survival patterns was tested by the log-rank test. The analyses performed were also stratified for bradycardia type (AVB or SSS) and zygosity. Sex and age were controlled by the matching criteria.

Results

Among all the patients with unknown aetiology of their bradycardia a total of 159 twins was identified, of these we found 73 twins (0.73%) in the AVB group and 64 twins (0.76%) in the SSS group (Table 1). A total of five twin pairs where both the twins had a permanent pacemaker implanted was identified (Table 2). Only three pairs were found in which both the twins had unknown aetiology of the arrhythmia. The small number of twin pairs does not allow a “classic” twin study with assessment of heritability.

We performed survival analysis for all cases, and subsequently for the two largest groups AVB and SSS, and finally divided both the groups into monozygotic and dizygotic twins.

In Fig. 1 we present the survival curves for all the co-twins of the “pacemaker-twins” compared with the survival curves for the co-twins of the control-twins. Curves are shown for all twins and also divided into AVB and SSS, and the curve for monozygotic twins with AVB is also shown. There was no statistically significant difference in survival of any of the groups and no consistent difference across the curves.

Discussion

No studies have previously addressed the heredity of acquired AVB and SSS. In this study we have compared the mortality with two otherwise comparable groups of persons of which one of the groups have most of their genes in common with patients treated with a pacemaker. A familial aggregation could occur as a genetically determined acceleration of a normal age-dependent sclerosing of the conduction tissue or as a consequence of other cardiac diseases such as coronary arteriosclerosis[26].

We found no evidence of an increased mortality in twins whose co-twin has had a pacemaker implanted for either AVB or SSS. The results were the same when the analysis was restricted to monozygotic twins.

In this investigation there were too few twin pairs to permit any assessment of the hereditability of chronic AVB or SSS based on concordance rates, but the low number of concordant twin pairs indicates that the family component – if any – is modest.

Most disorders leading to implantation of a cardiac pacemaker are potentially lethal either because the arrhythmia itself will cause death if untreated or because syncope or near-syncope associated with many of the arrhythmias may lead to fatal accidents. Although the mortality risk in untreated AVB and SSS may be different, the symptoms leading to the diagnosis of both diseases are often very dramatic and traumatizing with syncope and Stokes–Adams attacks in more than 40% of the patients. The siblings of these patients will obviously be concerned with their own risk of developing a potentially life-threatening disorder.

Sudden and unexpected death is still a major medical challenge. Most of these deaths are probably due to ischaemic heart disease. From the literature it is estimated that between 20 and 30% of these are due to severe bradyarrhythmias[27],[28]. It is possible that in some cases sudden cardiac death could be due to AVB. The onset of this disorder could be sudden death in persons without prior cardiac symptoms. Based on the previous published material on the natural history of AVB, where both third-degree AV-block and second-degree AV-block have been shown to have a dismal prognosis if untreated[16],[17] one could anticipate that an excess mortality in first-degree relatives might be found in the AVB group if there is a familial component to this disorder. The AVB group in our study consists mainly (>98%) of patients with third-degree AV-block or type II, second-degree AV-block. To some degree progressive fibrosis of the cardiac conduction tissue in the AV-node and increasing calcification of the fibrous skeleton of the heart probably occur as part of normal ageing. In the majority of patients with acquired AVB the reason for the disorder could be that these processes are accelerated, and the conduction system is blocked either because there is a lack of functioning conductive tissue or because the conductive system is affected directly where the tissue penetrates the calcified fibrous skeleton. These patients have a high prevalence of coronary artery disease but this is believed to be mainly a coincidental phenomenon because of their advanced age[1],[2]. In only 12.5% of all AVB patients and 9.8% of all SSS patients registered in the Danish Pacemaker Register the aetiology is coded as myocardial infarction or cardiac ischaemia.

Worldwide SSS is probably the most frequent indication for implanting a permanent pacemaker[29]. In our study population approximately 40% had a permanent pacemaker for this indication[23]. SSS comprises a variety of cardiac arrhythmias in all of which there is a dysfunction of the sinus node leading to bradycardia or asystole. Many patients have concomitant supraventricular tachycardia that may also be responsible for some of their symptoms. Some patients do not have pauses in cardiac rhythm but are not able to increase their pulse adequately in response to stress or physical exercise.

The outlook of SSS is good and the main reason for implanting a permanent cardiac pacemaker is to relieve the often severe and disabling symptoms[21],[22]. Therefore, we would not expect an increased mortality in first-degree relatives based on the occurrence of SSS alone. In 40–50% of these patients there is no sign of concomitant heart disease. But as in AVB the most common symptom leading to implantation of a cardiac pacemaker in SSS is syncope. Even a very brief loss of consciousness or dizzy spells could be dangerous and lead to accidents e.g. in traffic and thereby indirectly cause death. Therefore, an increased mortality could occur in co-twins of twins with SSS if a genetic component was present.

With the present twin study we have addressed the question whether relatives of pacemaker patients have an increased mortality risk. The limitation of the study is the fact that we have a limited number of twins, despite the large number of pacemaker patients in the register. The unique advantage of the study is the completeness of the registries and the long follow-up period from childhood to old age. The result seems reassuring, as no evidence of increased all-cause mortality could be found in first-degree relatives of these patients. Not even in monozygotic twins who share all the genetic material and also, often, to a substantial degree environmental factors.

This study was funded by a grant from ‘Else Poulsens Mindelegat’.

References