CLINICAL STUDY: CARDIOMYOPATHY
Periodic rescreening is indicated for family members at risk of developing familial dilated cardiomyopathy
Kathy A. Crispell, MDFACC*,
Emily L. Hanson, MS*,
Kelly Coates, BS*,
Warren Toy, BS* and
Ray E. Hershberger, MD, FACC*,*
* Department of Medicine/Cardiology, Oregon Health and Science University, Portland, Oregon, USA
Manuscript received September 6, 2001;
revised manuscript received January 31, 2002,
accepted February 6, 2002.
* Reprint requests and correspondence: Dr. Ray E. Hershberger, Department of Medicine/Cardiology, UHN-62, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon USA97201.
hershber{at}ohsu.edu
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Abstract
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OBJECTIVES: This study evaluated the role of clinical rescreening of family members at risk for familial dilated cardiomyopathy (FDC).
BACKGROUND: Familial dilated cardiomyopathy is a genetic cardiomyopathy that usually is transmitted in an autosomal dominant pattern and may underlie from one-quarter to one-half of idiopathic dilated cardiomyopathy (IDC) diagnoses. Thus, FDC may present with advanced heart failure (HF) or sudden cardiac death (SCD). Because FDC may respond to medical intervention, we have previously recommended that screening of first-degree relatives (parents, siblings, children) of patients diagnosed with IDC be undertaken to rule out FDC, and that with a diagnosis of FDC in the kindred, unaffected but at-risk family members be rescreened every three to five years.
METHODS: Follow-up screening (history, examination, electrocardiogram, echocardiography) of a large family with FDC was performed six years after initial screening.
RESULTS: Of 68 family members who underwent rescreening, two (one with left ventricular enlargement only, one with a left bundle branch block) presented with advanced HF and SCD, respectively. Two additional subjects, asymptomatic at initial screening, were also affected with FDC at follow-up.
CONCLUSIONS: Considerable vigilance for disease presentation and progression is indicated in at-risk members of a kindred with FDC, especially those with incipient FDC.
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Abbreviations and Acronyms
| | ACE | | angiotensin-converting enzyme | | AD | | autosomal dominant | | DCM | | dilated cardiomyopathy | | ECG | | electrocardiogram | | FDC | | familial dilated cardiomyopathy | | HF | | heart failure | | IDC | | idiopathic dilated cardiomyopathy | | LBBB | | left bundle branch block | | LVE | | left ventricular enlargement | | LVEDD | | left ventricular end-diastolic dimension | | LVEF | | left ventricular ejection fraction | | NYHA | | New York Heart Association | | SCD | | sudden cardiac death |
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Dilated cardiomyopathy (DCM), characterized by ventricular dilation and impaired contractility, frequently presents with heart failure (HF) or sudden cardiac death (SCD), and causes considerable morbidity and mortality. Idiopathic dilated cardiomyopathy (IDC) is DCM after identifiable causes have been excluded. Familial dilated cardiomyopathy (FDC) is defined as DCM in two or more closely related family members who otherwise meet diagnostic criteria for IDC. Until recently, the genetic transmission of DCM was thought to be uncommon, but at least 20% of subjects with IDC have first-degree family members who meet rigorous diagnostic criteria for IDC (1). With less rigorous criteria, 35% to 48% of patients with IDC have been suggested to have FDC (2,3), which is transmitted in an autosomal dominant (AD) pattern in >90% of families studied (2–4). Considerable evidence now supports a genetic basis for FDC, with eight different autosomal genes and eight additional FDC chromosomal loci implicated (Table 1).
When DCM is discovered, a thorough family history in at least first- and second-degree relatives should be obtained (heart failure, DCM, SCD, arrhythmia, stroke, etc.) to assess for FDC. Because the family history is much less sensitive than echocardiographic screening of relatives (1), and because FDC usually follows an AD inheritance pattern, clinical screening of first-degree relatives (parents, siblings, children) by history, examination, electrocardiogram (ECG), and echocardiography has been recommended (5). However, both the age of onset and clinical presentation of FDC can be highly variable even within the same family. For these reasons, the rescreening of at-risk relatives was proposed to be undertaken every three to five years (5).
We now report the results of clinical rescreening in a large family with FDC six years after initial screening. In this family we have excluded a mutation in LMNA, the gene that encodes lamin A/C and the most common FDC disease gene to date (6–10), as well as linkage to loci of other known FDC disease genes and other previously reported FDC loci (11–26) (Table 1) (Hershberger and Jakobs, data not shown). Hence, both the screening and the detection of FDC in this study were not aided by genotypic data but were based only on clinical (phenotypic) data, a situation that parallels the issues of FDC in clinical practice. We present these observations to add further support to the rescreening of at-risk members of other FDC kindreds.
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Methods
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After informed consent was obtained, 107 subjects in a family with FDC underwent initial clinical screening in 1994 and 1995, as previously reported (FDC-1, in Crispell et al. [5]). Follow-up clinical screening (medical history, a physical examination, ECG and a two-dimensional and M-mode echocardiogram) was offered to all family members in 2000 and 2001. For this study, left ventricular enlargement (LVE) was defined as a left ventricular end-diastolic dimension (LVEDD) >the 95th percentile of a gender- and height-matched Framingham population (27); DCM was defined as LVE with systolic dysfunction (LVEF [left ventricular ejection fraction] <0.50). The diagnosis of FDC was assigned with systolic dysfunction, DCM, or LVE >97.5th percentile (28), after other possible confounding factors had been excluded (5,28).
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Results
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Demographic data of the 107 subjects screened in 1994 and 1995 and the 68 rescreened in 2000 and 2001 are shown in Table 2. Subjects with the affected phenotype and their first-degree relatives are shown in an abbreviated pedigree (Fig. 1) from one previously published (5). Of the eight subjects who were assigned affected status at baseline screening during 1994 and 1995, five (subjects III-1, III-17, III-20, IV-12, V-3) again met criteria for affected status at rescreening, and three (subjects III-18, IV-1, IV-8) were not available for rescreening; one (subject IV-3) had baseline screening in 2000 (Table 3).
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Figure 1 Pedigree including subjects with the affected phenotype and their first-degree relatives. Squares = males; circles = females; fully filled symbols = affected status at baseline screening; half-filled symbols = a change to affected status based on follow-up screening, 2000 to 2001; N = unaffected status; ? = unknown status; blank symbol = that the subject was not screened.
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Two subjects, both asymptomatic at initial screening, had developed advanced HF. At initial screening, subject IV-2 (Table 3, Fig. 1) had LVE without systolic dysfunction and a normal ECG. Six years later she presented with decompensated heart failure and required hospitalization. She was noted to have a first-degree atrioventricular block and a left bundle branch block (LBBB), further LVE and marked systolic dysfunction (Table 3); coronary angiography was normal. She was treated with diuretics, angiotensin-converting enzyme (ACE) inhibitors and beta-blockers and improved to New York Heart Association (NYHA) functional class III. One year later, she showed further improvement to a NYHA functional class II, her LVEDD decreased to 58 mm, and her LVEF improved to 0.40. The second subject (III-9) (Table 3, Fig. 1), asymptomatic with a LBBB on initial screening, presented six years later with SCD. She was successfully resuscitated but suffered chronic neurologic impairment. Comprehensive cardiovascular evaluation demonstrated normal coronary arteries, LVE and marked systolic dysfunction (Table 3). She was treated with conventional medical therapy.
A third subject (III-5), without LVE and intact systolic function at our initial screening, developed criteria for DCM at rescreening (Table 3). A fourth subject (III-7) developed systolic dysfunction (Table 3).
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Discussion
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Central findings.
This work emphasizes that considerable vigilance for disease presentation and progression is indicated in at-risk members of a kindred with FDC. Two subjects presented with advanced disease, SCD with residual neurologic injury (III-9) and decompensated HF (IV-2), whereas six years previously both subjects were observed to have cardiovascular abnormalities (LBBB and LVE, respectively), but neither met usual criteria for DCM, and both were asymptomatic. These observations also reemphasize the need for cardiovascular specialists to assess genetic risk for DCM, and to integrate family history data into diagnostic and therapeutic care plans of individual patients.
Screening recommendations.
As previously recommended (5), the rescreening of first-degree relatives of subjects with known or suspected DCM every three to five years will likely yield the greatest benefit (5). For example, the SCD and new diagnosis of DCM (in subject III-9) suggested that screening of her siblings and children was indicated; indeed, two siblings (III-5, III-7) were discovered to have disease not apparent at initial screening.
Key disease indicators.
Left ventricular enlargement may be a key indicator of disease (1,2,11). Michels et al. (1) suggested that asymptomatic LVE may represent the earliest stage of FDC. In a linkage pedigree, Krajinovic et al. (11) observed that family members with isolated LVE carried the disease genotype. In a prospective follow-up study of asymptomatic family members, 27% of those with LVE developed FDC over a period of 39 ± 14 months (2). In our study, we have observed the development of DCM in a subject (IV-2) who had isolated LVE at initial screening. Therefore, we suggest that subjects with newly identified LVE in an FDC kindred warrant ongoing medical surveillance for symptomatic disease (examination, ECG and echocardiography) every one to three years. Whether conduction system disease is a key disease indicator is more difficult to assess, but based on our experience, a LBBB in a subject at risk (IV-9) may be a harbinger of further disease and deserves close follow-up.
Medical treatment.
For subjects diagnosed with FDC, we have proposed generic treatment with ACE inhibitors and/or beta-blockers (5), based on current American College of Cardiology/American Heart Association guidelines for patients with IDC and asymptomatic LVE, or IDC and symptomatic heart failure (29).
Counseling.
Family members should be counseled that: 1) FDC has an unpredictable clinical course and an age-dependent penetrance, and that normal screening results do not exclude the possibility of developing future disease; 2) symptoms may be highly variable and result from left ventricular dysfunction and HF, or from symptomatic arrhythmias (presyncope, syncope or SCD); 3) new cardiovascular symptoms should prompt evaluation by an informed physician; 4) for AD FDC, affected subjects should be informed that their children have a 50% probability of inheriting the disease gene; and 5) for more specific questions pertaining to the clinical or genetic aspects of FDC, family members may be referred to a cardiovascular specialist with expertise in genetic cardiomyopathies, a genetic counselor or a geneticist (30).
Study limitations.
The multiple FDC disease genes and chromosomal loci, indicating substantial genetic heterogeneity, raise doubt about whether these clinical recommendations based on one family can be generalized to all instances of FDC. However, FDC (like IDC or ischemic cardiomyopathy) usually responds to conventional medical therapy once signs and symptoms are present. Also, these generic screening recommendations may be tailored to a specific kindred (e.g., to screen younger family members in a kindred with a much earlier age of onset, etc.).
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Acknowledgments
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We are indebted to all family members and thank them for their continued participation. We thank Dr. Don Wagoner and staff (Burlington, Indiana) and Drs. Minor Matthews, Richard Schaefer and Brian Gross (Medford, Oregon); their assistance has made it possible to continue this work. We also thank Diana Dutton, RN, Donna Burgess, RN, and Deirdre Nauman, RN, who assisted with the screening of these subjects.
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Footnotes
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Supported in part by a National Institutes of Health grant 1RO1HL58626 (Dr. Hershberger) and an Oregon Health and Science University Medical Research Foundation grant (Dr. Crispell).
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References
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Abstract
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