Author + information
- Received August 5, 1997
- Revision received July 7, 1998
- Accepted July 24, 1998
- Published online November 15, 1998.
- Steven D Nelson, MD, FACC∗,* (, )
- Elizabeth A Sparks, RN∗,
- Harry L Graber, MD, FACC∗,
- Harisios Boudoulas, MD, FACC∗,
- Ali A Mehdirad, MD, FACC∗,
- Peter Baker, MD† and
- Charles Wooley, MD, FACC∗
- ↵*Address for correspondence: Dr. Steven D. Nelson, Associate Professor of Medicine, Division of Cardiology, The Ohio State University, Room 657 Means Hall, 1654 Upham Drive, Columbus, Ohio 43210
Objectives. The purpose of this study was to identify the clinical characteristics of family members at risk of sudden death.
Background. The significance of sudden death in heritable cardiac disorders with delayed expression is incompletely understood. Additional insights come from a four-decade experience of seven generations of a family of German origin with autosomal dominant (chromosome 1p1-1q1) cardiac conduction and myocardial disease.
Methods and Results. A total of 38 family members (20 males; 18 females) were identified with sudden death. Twenty-eight family members (mean age 48 ± 8 years) from earlier generations had no pacemaker at the time of sudden death. In this group, 15 subjects were asymptomatic prior to sudden death. Ten family members with sudden death, from later generations, had chronically implanted pacemakers for high grade atrioventricular block. This group was older (mean age 57 ± 2 years), with decreased functional status (New York Heart Association class II to IV), enlarged left atria, dilated left ventricles with reduced systolic function and documented ventricular fibrillation in three members. Twenty-eight family members with sudden death were descendants of sib lineages 2 or 6; 21 family members with sudden death were offspring of a parent who also suffered sudden death.
Conclusion. Sudden death is an important late outcome in heritable (chromosome 1p1-1q1) cardiac conduction and myocardial disease. Pacemaker therapy is important for the treatment of symptomatic bradycardia, but it does not prevent sudden death. Family members who are beyond the third decade of life with reduced functional capacity, left ventricular dysfunction, pacemakers and who are the offspring of a parent with sudden death appear to be at greatest risk.
With recent advances in molecular genetics, heritable disorders of the cardiovascular system are emerging as an important cause of cardiovascular disease in adults (1–14). The clinical significance of sudden death in heritable cardiac disorders is incompletely understood. The identification of heritable syndromes, which have delayed expression, requires the development of multigenerational pedigrees. We have had the unique opportunity to engage in a multigenerational study of an autosomal dominant heritable cardiac disorder with a genetic defect located on chromosome (1p1-1q1) (15). Our initial report of this syndrome in 1986 characterized affected family members as having progressive development of cardiac conduction abnormalities, which precede the development of myocardial dysfunction (16). Late affected family members eventually require permanent pacemakers for symptomatic complete heart block and asystole in the setting of chronic atrial fibrillation. Initially, sudden death did not appear to be an important feature of this disorder. As we have expanded our study, a greater number of family members have been identified with sudden death syndrome. The purpose of this study was to determine the clinical characteristics of affected family members with sudden death.
Both pedigree information and clinical history were obtained in 479 family members over seven generations. All studies were performed after obtaining human subjects review consent. In addition, 239 of the family members have had an assessment of left ventricle function (by echocardiography or nuclear studies) and electrocardiographic monitoring. Echocardiographic studies were performed by standard techniques using a Hewlett-Packard Sonos 1000 (Andover, Massachusetts). Standard echocardiographic measurements were made according to the recommendations of the American Society of Echocardiography. Presence of ventricular or atrial tachyarrhythmias was confirmed either by 12-lead electrocardiography, ambulatory monitoring or telemetry monitoring. Congestive heart failure was defined as the presence of the clinical signs of rales, peripheral edema and increased jugular venous pressure. Between 1977 and 1994, selected family members underwent invasive programmed ventricular stimulation studies employing percutaneously introduced multipolar pacing catheters positioned in the appropriate chambers. Standard stimulation protocols were employed for the induction of ventricular tachycardia.
Sudden death was defined as death occurring within minutes after symptom onset, or during sleep, and was considered to be due to the familial disease in the absence of other recognizable causes. The account of the sudden death event was usually obtained from family members closest to the victim and corroborated in some instances by family lineage records or from public records. Six of the recent sudden death victims had detailed cardiac evaluation from autopsy.
Multigenerational pedigrees for sib lineages are presented in Figures 1 to 4. ⇓⇓⇓Each family member is referenced by a three-part confidential code with respect to sib, generation and number within a generation. The number order of siblings within a generation was altered to protect confidentiality. Females are represented as circles and males as squares. Sudden death victims are denoted as solid symbols and an S. An arrow identifies family members with sudden death who have had autopsies.
Data are presented as the mean ± SD. Data between groups were compared with nonparametric methods (Mann–Whitney). A p value <0.05 was considered significant.
Thirty-eight family members (20 males, 18 females) were identified with sudden death associated with heritable conduction and myocardial disease (Fig. 5). Generation V was a transition period when pacemaker therapy became increasingly available. The overall incidence of sudden death is 13.7% in the sample of family members enrolled in our study. The mean age at sudden death was 51 ± 8 years.
Three family members died suddenly while sedentary, 6 experienced sudden death during sleep and 24 had sudden death during physical activity. The activity level was uncertain at the time of sudden death in five victims. Five sudden death victims were taking oral sodium channel blockers. Twenty-eight family members did not have a pacemaker (group A), whereas 10 family members did have a pacemaker (group B) at the time of sudden death.
Group A consisted primarily of family members from earlier generations before pacemaker therapy became widespread. There were 15 females and 13 males, with a mean age of 48 ± 8 years. Clinical characteristics of group A family members are less detailed because they were from earlier generations. Fifteen were asymptomatic prior to sudden death; nine family members had some history of cardiovascular disease (seven with palpitations, one had heart failure and one had heart failure and previous strokes). Clinical history was unknown in four family members.
Group B family members (pacemaker group; six males and four females; mean age 57 ± 2 years) were from later generations when pacemaker therapy was available. All group B family members also had evidence of cardiomyopathy, high grade atrioventricular (AV) block and evidence of reduced functional capacity (New York Heart Association [NYHA] Functional Classifications ranging from class II to class IV). All appeared to have normal pacemaker function at the time of sudden death. In three family members, ventricular fibrillation was documented at the time of sudden death.
Multigenerational pedigrees allowed us to study patterns of sudden death within the family lineage. The lineages from sib 2 and sib 6 are the most complete. Less information is available on the pedigrees for sibs 5, 7 and 9.
A total of 14 (12%) sudden death events have occurred in 117 descendants of sibling 2, who was also a victim of sudden death. Thirteen of the 14 sudden death events occurred in family members from Generations IV and V (Fig. 1). Thirteen (18%) sudden death events have been recorded in 73 descendants from sib 6 (Fig. 2). There was some clustering of sudden death events. The family member 6-III-3 lineage had three sudden deaths, and family member 6-III-6 lineage had six sudden death events.
Seven (14%) sudden deaths occurred in 51 family members from the sib 5 lineage (Fig. 3). Five of the seven sudden death victims were descendants of family member 5-III-3, who was also a victim of sudden death. Less information is known about the sib 9 lineage. A total of two sudden deaths have been identified in this lineage, one from Generation IV and one from Generation V. Twenty-eight family members with sudden death were descendants of sib 2 or sib 6 (including sib 2, who also had sudden death). Twenty-one of the 38 victims of sudden death were offspring of a parent who also had suffered sudden death.
Clinical characteristics of sudden death victims
Studies of clinical characteristics focused on later generations where clinical data were more complete. Ten of 11 sudden deaths recorded since 1974 have occurred in family members with functioning permanent pacemakers. Chronic pacemaker therapy was required for advanced high grade AV block.
We attempted to determine predictors of sudden death in affected family members with a pacemaker (group 3; n = 10) by comparing them to affected family members with pacemakers but without sudden death (group 2; n = 19) and to affected family members without pacemakers and without sudden death (group 1; n = 30). Clinical, echocardiographic and electrocardiographic features were compared by nonparametric analysis.
In comparing groups 2 and 3, no significant difference was noted between the groups with respect to age, age of onset of symptoms, age at pacemaker implant or NYHA functional classification (Table 1). Sudden death victims did tend to have longer durations of pacemaker therapy than did nonsudden death victims with pacemakers. Echocardiographic findings also varied between the groups. Sudden death victims tended to have larger end diastolic and end systolic chamber diameters, a lower %ΔD and a larger left atrial size than did the nonsudden death group with pacemakers. Even though there was considerable overlap in echocardiographic measurements between the groups, a %ΔD less than 19% and a left atrial size greater than 5.4 cm were more likely to be present in sudden death victims. Electrocardiographic presence of atrial fibrillation and nonsustained ventricular tachycardia did not differ between groups 2 and 3 (Table 1).
Between 1977 and 1996, 14 family members (3 with subsequent sudden death; 11 without) underwent programmed ventricular stimulation (PVS) for the induction of ventricular tachyarrhythmias (VT). The indication for PVS was based on clinical symptoms of palpitations, near syncope or syncope and abnormalities recorded during electrocardiographic monitoring. The family members studied were scattered throughout the multigenerational pedigree (six were from the sib 2 lineage; three from sib 6; four from sib 5; one from sib 7 lineages).
Two of 14 family members had inducible sustained monomorphic VT. Both presented with syncope; both had chronically implanted pacemakers and subsequently underwent implantation of internal defibrillators.
All three of the family members who subsequently died of sudden death did not have inducible VT at the time of PVS. One sudden death occurred within 1 year of PVS (triple extrastimuli protocol), whereas the other two sudden deaths occurred at 11 and 14 years after PVS (double extrastimuli protocol). The differences in the number of extrastimuli reflects the evolution of electrophysiology testing over the past two to three decades to include more aggressive stimulation protocols for the induction of ventricular tachycardia.
An autopsy was performed on six family members who had sudden death. Autopsies were performed between 1987 and 1996. The average age at death was 56 ± 7 years. The lineage of sudden death victims who had an autopsy are indicated by an arrow adjacent to their respective symbol on the pedigree charts. Four sib 2 and two sib 5 family members had such data.
All six hearts had significant hypertrophy (mean weight 577.1 ± 71.3 g). Five had varying degrees of sinus node fibrosis. Six hearts had marked AV node fibrosis, with fatty infiltrate in four. Moderate to severe right and left atrial dilation was observed in five specimens (total of five reported), and moderate right ventricular enlargement was noted in six. Mild to moderate left ventricular enlargement was noted in six specimens, and right and left ventricular hypertrophy was observed in three specimens. Interstitial fibrosis was observed in all six specimens (patchy in three, diffuse in three) and involved all chambers of the heart. The two most recent autopsies showed a unique pattern of fibrosis involving the middle third of the interventricular septum extending to the left ventricular posterior wall. There was no evidence of old or recent myocardial infarction. No significant coronary artery disease was detected except for a single 75% stenosis of the left anterior descending coronary artery of questionable significance in one individual.
The role of heredity in adult cardiovascular disease continues to expand. We have reported in an earlier study the phenotypic expression of the heritable (chromosome 1p1-1q1) cardiac conduction and myocardial disease (16). We have greatly expanded the number of family members enrolled since the initial report. Sudden death has emerged as an important outcome in this heritable disorder.
We have identified 38 family members from the multigenerational pedigree who have been victims of sudden death. Family members without pacemakers tended to have earlier onset of sudden death than did family members who had pacemakers. The reason for this finding may be multifactorial. Family members without pacemakers were from earlier generations before pacemaker therapy was widely available. Pacemaker therapy clearly prevents symptomatic high grade AV block that occurs in the late phases of disease; however, the role of pacing in the delay in the onset of sudden death is not clear. Improvements in medical therapy for the treatment of congestive heart failure and arrhythmias may also be important for the improvement in survival observed in later generations. Even though affected family members with pacemakers tended to live longer than did family members without pacemakers, pacemaker therapy did not prevent sudden death in a substantial number of family members with pacemakers. Nearly a third of family members with pacemakers had sudden death.
Our data suggest that sudden death is a late outcome of disease progression rather than a heritable propensity for sudden death independent of cardiomyopathy. Clearly, the fibrotic myopathy alone may be all that is required for a family member to be at risk of sudden death. Multigenerational pedigrees show some patterns in the sudden death events. Over half the family members with sudden death were direct descendants of a parent who also had sudden death. In addition, there was some evidence of clustering of sudden deaths within certain regions of the pedigree. These data suggest that multigenerational pedigrees may be of value for risk stratification of affected family members.
The mechanism of sudden death in this family remains elusive. Life-threatening bradyarrhythmias may have played a role in precipitating sudden death in family members from earlier generations without pacemakers. However, sudden death in family members from later generations with functioning pacemakers suggests that ventricular tachyarrhythmias, rather than bradyarrhythmias, are important. In fact, three family members had ventricular fibrillation as the first rhythm detected at the time of attempted resuscitation. The mechanisms of ventricular tachyarrhythmias in this family remain unclear. Disorders of repolarization, as detected by QT interval prolongation, have not been a phenotypic expression in affected family members without pacemakers in the earlier stages of disease (16). Of course, the use of the QT interval duration as a marker of abnormal repolarization is uncertain during ventricular pacing in the later stages of disease. Therefore, we cannot exclude dispersion of refractoriness or after depolarizations as potential mechanisms for lethal ventricular arrhythmias. The presence of ventricular myocardial fibrosis suggests that reentry may be a possible mechanism of lethal arrhythmias. The presence of inducible sustained monomorphic VT in two family members supports the reentry hypothesis. The value of programmed ventricular stimulation to identify high risk family members needs further study.
To date, no affected family members have had heart transplants. Sudden death has usually been an out-of-hospital event and not in the setting of severe congestive heart failure. Those family members who advance to class IV congestive heart failure are usually in the seventh decade of life, beyond the acceptable cutoff age for cardiac transplant.
Several of the sudden deaths reported in this study occurred in family members from earlier generations when cardiac diagnostics were less advanced. However, the definition of a death as “sudden” depends heavily on witness accounts. This definition has not changed significantly over the past several decades. Epstein et al. (17)highlighted some of the difficulties in sudden death classification, most of which are as appropriate today as they were decades ago.
It certainly is possible that some of the sudden deaths reported were due to noncardiac-related disorders or cardiac diseases unrelated to the heritable chromosome 1p1-1q1 disorder. Cardiac catheterization and autopsy data from this family suggest that the more common cardiac disorders such as coronary artery disease are not routinely present, increasing the likelihood that sudden death is due to the underlying heritable cardiac disorder. As genotype classification becomes more readily available in this family, some of these ambiguities will be resolved.
Even though the true incidence of sudden death in the family cannot be determined with certainty until all family members are accounted for, the remarkable consistency of sudden death rates in each sib lineage suggests our data may be a reasonable approximation. For example, the sib 2 pedigree is most complete and has a sudden death incidence of 12%. In contrast, the sib 5 lineage is less complete but still has a sudden death rate of 14%.
Sudden death emerges as an important outcome in late affected family members with heritable (chromosome 1p1-1q1) cardiac conduction and myocardial disease. Family members beyond the third decade of life with evidence of atrial and ventricular myopathy, reduced functional class, pacemakers and a parent with sudden death appear to be at highest risk for sudden death. Sudden death occurs despite pacemaker therapy. The unique pattern of midmyocardial fibrosis and midseptal fibrosis in sudden death victims may provide the substrate for predisposition to lethal ventricular tachyarrhythmias. Prophylactic implantable defibrillators may be warranted in high risk family members.
- New York Heart Association
- programmed ventricular stimulation
- ventricular tachycardia
- Received August 5, 1997.
- Revision received July 7, 1998.
- Accepted July 24, 1998.
- American College of Cardiology
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