The European Society of Cardiology
Rescreening of "healthy" relatives of patients with dilated cardiomyopathy identifies subgroups at risk of developing the disease
a Cardiology Division, I.R.C.C.S. Policlinico San Matteo, Pavia, Italy
b Molecular Cardiology, I.R.C.C.S. Policlinico San Matteo, Pavia, Italy
* Correspondence: Eloisa Arbustini, MD, Molecular Diagnostic, Cardiovascular and Transplant Pathology Laboratory, Transplant Research Area I.R.C.C.S. Policlinico San Matteo, Via Forlanini 16, 27100 Pavia, Italy. Tel.: +39 0382 503829; fax: +39 0382 525866 (E-mail: e.arbustini{at}smatteo.pv.it).
Abstract
OBJECTIVES: To test the diagnostic impact of the non-invasive rescreening of relatives of index patients consecutively diagnosed as having dilated cardiomyopathy.
BACKGROUND: The aim of rescreening asymptomatic healthy relatives of DCM patients is to diagnose newly affected subjects and evaluate the predictive significance of the instrumental abnormalities found at the first screening.
METHODS AND RESULTS: Two hundred and three healthy relatives of 73 consecutive index patients with DCM (18 with familial disease at first screening) underwent rescreening involving a clinical examination, electro- and echocardiography, and biochemical tests a median of 29.3 months after the first screening.
Seven relatives had developed the diagnostic criteria for DCM during the screening–rescreening interval. Of the 24 healthy relatives with left ventricular end-diastolic diameter enlargement and normal function at the first screening, nine had normalised, seven showed persistent enlargement, three had worsened, and five had developed the disease criteria at rescreening. Of the three relatives with atrioventricular block at the first screening, one had developed DCM. Finally, one of the relatives with normal echocardiographic and electrocardiographic results at the first screening, had developed the disease. Three of the newly diagnosed subjects came from families with evidence-based familial DCM, and four from families with what was defined as sporadic DCM at the first screening.
CONCLUSIONS: Medium-term rescreening of the relatives of DCM patients can identify a significant number of newly affected patients (3.5%).
Keywords Dilated cardiomyopathy; Family screening; Rescreening
Introduction
Cardiological screening of the relatives of patients diagnosed as having idiopathic dilated cardiomyopathy (DCM) allows the identification of affected asymptomatic relatives and the carriers of echo- and electrocardiographic abnormalities that may predict the development of the disease.1–3 The majority of family members are clinically healthy and do not show any instrumental abnormalities, but a minority have an increased left ventricular end-diastolic diameter (LVEDD) and/or decreased left ventricular fractional shortening (LVFS).
Rescreening programmes help to confirm the healthy status of most relatives and elucidate the evolution and prognostic value of the echocardiographic and electrocardiographic abnormalities identified at the first screening.1,4 Furthermore, rescreening may identify newly affected relatives who were healthy at the time of the first screening.
Among the instrumental signs that have been tested in rescreening studies, LVEDD was suggested to have predictive value: 12/45 (27%) of the cases newly diagnosed at rescreening had an increased LVEDD at the first screening, whereas depressed LVFS did not appear to share the same risk of progression to DCM.1 In a large family with 68 rescreened members Crispell et al. 4 documented four newly affected relatives over a follow-up of about six years. At the first screening, two of them had left ventricular enlargement and left bundle branch block.
Clinical genetic data may help to identify "at risk" families whose members can be expected to develop the disease on the basis of the inheritance and penetrance patterns observed in available generations.
We here report the results of clinical rescreening and family studies of 221 relatives of 73 consecutive patients diagnosed as having non-X-linked DCM.
Methods
Rescreening strategy
Between June 1995 and June 2001, we systematically screened 559 relatives of 130 consecutive patients diagnosed as having DCM. The clinical and research plan was approved by the local Ethics Committee. The patients and families with X-linked DCM follow a dedicated programme and were excluded from the present series.5 The recreening work-up was completed by 221 members of 73 families; the other families are still being rescreened.
Definition of patients and relatives
The study population can be divided into the following groups:
- 1. Symptomatic affected subjects.
- 2. Asymptomatic affected subjects identified by screening;.
- 3. Healthy subjects with instrumental abnormalities such as an increased LVEDD or decreased LVFS insufficient for the diagnosis of DCM according to WHO criteria.6
- 4. Healthy carriers of a causative mutation with no clinical evidence of the disease, but potential candidates for disease development.
- 5. Healthy non-carriers of a causative mutation in families with a known genotype: true negative cases that are not candidates for disease development on the basis of current knowledge.
- 6. Healthy relatives in families without a known causative mutation: all potential candidates for disease development.
- 2. Asymptomatic affected subjects identified by screening;.
Rescreening timing
The timing of the rescreening was scheduled as follows:
- • Relatives diagnosed as having asymptomatic DCM: after about six months.
- • Relatives with atrioventricular or left bundle branch block (LBBB) without DCM: after 6–12 months.
- • Relatives with echocardiographic abnormalities (>LVEDD, <LVFS): after 6–12 months.
- • Healthy relatives with normal echocardiogram from families with familial and non-familial disease: after 1–3 years.
- • Relatives with atrioventricular or left bundle branch block (LBBB) without DCM: after 6–12 months.
Clinical and instrumental evaluations
All of the probands' relatives who gave their informed consent to enter the screening and rescreening programme were evaluated by means of a clinical examination, electrocardiographic and echocardiographic examinations, and biochemical tests. The main reasons for refusing consent were geographical limitations, privacy and family conflicts.
DCM was diagnosed on the basis of the WHO criteria.6 Briefly, the patients diagnosed as having DCM had no significant coronary artery disease (luminal narrowing ⩾50%) at coronary angiography, no specific heart muscle disease or myocarditis at endomyocardial biopsy, and a reduced (<45%) left ventricular ejection fraction (LVEF).
Detailed family histories were recorded by interviewing the patients and their relatives; clinical and pathological records were obtained for deceased affected relatives.
Echocardiographic examination
The two-dimensional and M-mode echocardiography examinations were performed using conventional techniques and an Esaote Biomedica AU3 and Toshiba SSA 270A or Vingmed System 5, GE. Chamber size and wall thickness were measured in the parasternal long axis view at the level of the papillary muscles. The echocardiograms were acquired by experienced operators working in the same laboratory who had no knowledge of the patients' clinical data. The percentage LVFS was calculated using standard techniques. The predicted LVEDD, corrected for age and body surface area, was calculated by means of the formula of Henry et al. 7 (corrected LVEDD=45.3xbody surface area 0.3–0.03xage–7.2); the measured LVEDD was expressed as a percentage ratio (LVEDD%=LVEDD/corrected LVEDD), with 112% being considered the upper normal limit. A limit of 117% of the predicted value for age and body surface area was also used.8
In order to test the variability of LVEDD% between the first and second screenings, the two pairs of values/subject were compared with those recorded in the 150 healthy subjects who showed no echocardiographic abnormalities at both screenings (median follow-up: 31.18 months). The mean of 100.3±6.5% recorded at the first evaluation was not significantly different from the 101.6±5.1% recorded at the rescreening (P=0.06).
Exclusion criteria
Family members with one of the following conditions were considered unsuitable for the study: arterial hypertension (⩾160/100 mmHg at repeated measurements), insulin-dependent diabetes mellitus, valvular heart disease, coronary artery disease, congenital heart disease, thyroid dysfunction, anaemia, amyloidosis or sarcoidosis, hypertrophic cardiomyopathy, drugs and substances having cardiotoxic effects, and an alcohol consumption of ⩾100 g per day. Hypertensive subjects (even if the hypertension was pharmacologically controlled) with left ventricular dysfunction were excluded.
Cardiac abnormalities in healthy relatives
The following variables were considered abnormal: (1) left ventricular dilatation (as defined above) >112% but <117% of the predicted value; (2) left ventricular enlargement >117%; (3) LVFS <28% but >25%; (4) LVFS <25%; (5) LVEF <50% but >45%; (6) atrioventricular or intraventricular conduction disturbances.1,8
Events at follow-up
The following events were considered during the follow-up: death, heart transplantation, heart transplantation waiting list, a new diagnosis of DCM, and pacemaker implantation.
Statistical analysis
The categorical variables were expressed as percentages and compared using the 
2 test. The continuous variables were expressed as mean values ±1 standard deviation, and compared using the paired or unpaired t test. A P value of <0.05 was considered statistically significant. The positive predictive value of the "minor" echo abnormalities (LVEDD >112% to <117%+LVFS <28% to >25%)8 was calculated, as was the negative predictive value of normal echo values.
Results
Familial and non-familial DCM
Two hundred and twenty-one relatives of 73 index patients underwent at least one rescreening evaluation a median of 29.3 months after the first screening, and entered the study. Twenty-four (33%) of the 73 patients were from families with proven familial DCM: 16 autosomal dominant,9–10 three of which with lamin A/C (LMNA) gene mutations; three with pathological mitochondrial DNA mutations; two sib pairs; and three with undetermined inheritance (probably recessive without parental consanguinity). At rescreening, a further four cases were defined as familial due to new diagnoses of DCM in family member unaffected at the first screening: two with autosomal dominant inheritance, including one with LMNA defect-related DCM plus atrioventricular block; and two sib pairs. The mean values of the instrumental markers recorded in the relatives of patients with familial DCM were not significantly different from those recorded in the relatives of patients with non-familial disease.
Clinical screening
Of the 221 rescreened relatives, three were diagnosed as having systemic hypertension not recorded at the first screening, and were excluded from the analysis. Of the remaining 218 relatives (116 males), 15 (mean age at first screening: 39.7±19.1 years; 10 males) had been diagnosed as having DCM at the first screening and 203 (mean age at first screening: 28.0±14.6 years; 106 males) had been found to be healthy. Of the 15 affected subjects at the first screening, four had undergone transplantation after three, 32, 36 and 54 months; one in New York Heart Association (NYHA) class IV is awaiting transplantation; one died suddenly after 21 months; six are stable in NYHA class II; and three are asymptomatic.
Screening vs rescreening echocardiographic abnormalities
Of the 203 healthy relatives, 168 showed no instrumental abnormalities at the first screening and 35 showed echocardiographic and/or electrocardiographic abnormalities after a median follow-up of 29.3 months (Table 1):
- • Fifteen had LVEDD >112% to <117% at the first screening. At rescreening, seven had normalised (LVEDD <112%), five had worsened (>117%) and three were confirmed. Two of the five with worsened abnormalities had developed the criteria for a diagnosis of DCM (Fig. 1, 2-II:3 and 3-III:2). Ten with normal values at the first screening had increased values at rescreening.
- • Nine had LVEDD >117% at the first screening; at rescreening, two had normalised (LVEDD <112%), four were confirmed and three developed the criteria for a diagnosis of DCM (Fig. 1, 1-III:1, 6-III:1 and 7-II:3). Three with normal values at the first screening had increased values at rescreening.
- • At the first screening, none of the relatives had LVFS of <25% and seven had LVFS <28% to >25%, including one with an LVEDD of >117% and LVEF of <50% to >45% (Fig. 1, 7-II:3) and one with an LVEDD of >112% to -<117% (Fig. 1, 2-II:3). At rescreening, six new relatives were found to have decreased LVFS (<25%). One of the seven relatives with LVFS of <28% to >25% but a normal LVEDD at the first screening (a 50-year-old male) died suddenly five months after the first screening; no autopsy was performed.
- • Three cases of first-degree atrioventricular block at the first screening were confirmed at follow-up. One subject developed the criteria for a diagnosis of DCM, with left ventricular enlargement and a decreased LVEF (Fig. 1, 4-III:1); his atrioventricular block worsened to a complete block and a pacemaker was implanted 29 months after the first screening. The patient inherited the maternal LMNA mutation.
- • Four relatives showed left anterior fascicular block at the first screening, and the electrocardiographic pattern remained unchanged at rescreening.
- • One relative with LBBB associated with an LVEDD of >117% and LVEF of <50% to >45% at the first screening developed overt left ventricular dysfunction (LVEF <45%) at rescreening (Fig. 1, 6-III:1).
- • Of the 168 relatives with normal echocardiographic and electrocardiographic results at the first screening, only one (a 40-year-old female LMNA gene mutation carrier; Fig. 1, 5-II:3) developed the criteria for asymptomatic disease.
- • Nine had LVEDD >117% at the first screening; at rescreening, two had normalised (LVEDD <112%), four were confirmed and three developed the criteria for a diagnosis of DCM (Fig. 1, 1-III:1, 6-III:1 and 7-II:3). Three with normal values at the first screening had increased values at rescreening.
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LVEDD, left ventricular end-diastolic diameter; LVFS, left ventricular fractional shortening; LVEF, left ventricular ejection fraction; LAH, left anterior hemiblock; LBBB, left bundle branch block. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)Newly diagnosed DCM
During the median 29.3 months of follow-up, seven new patients with a full diagnosis of DCM were identified 7–55 months after the first screening:
- • One patient with LVEDD >112% to <117%.
- • One with LVEDD >112% to <117%+LVFS <28% to >25%.
- • Two with LVEDD >117%+LVEF <50% to >45%.
- • One with LVEDD >117%+LVFS <28% to >25%+LVEF <50% to >45%+left anterior hemiblock.
- • One with first-degree atrioventricular block.
- • One with normal echocardiographic and electrocardiographic results.
- • One with LVEDD >112% to <117%+LVFS <28% to >25%.
Three of these subjects belonged to families with evidence-based familial DCM, and four came from families with sporadic disease at the first screening.
The overall positive predictive value of "minor" echocardiographic abnormalities (LVEDD >112% to <117%+LVFS <28% to >25%) was 50%; the negative predictive value of normal echocardiographic results was 94%.
Discussion
The results of the present study demonstrates that 3.5% of the healthy relatives of index patients with DCM developed the disease over a median follow-up of 29.3 months. Five had shown echocardiographic abnormalities at the first screening, whereas two had normal echocardiograms. The positive predictive value of echocardiogram abnormalities was 50%; the negative predictive value of normal echocardiographic results was 94%. This indicates that reproducible and risk-free echo-screening is a useful means of focusing clinical attention and scheduling the closer monitoring of subjects with left ventricular enlargement or decreased LVFS. However, it is not clear why 50% of the cases improved. The small variability of LVEDD% recorded at the screening and rescreening in the same subjects, excludes the possibility that 50% positive predictive value is due to the variability intrinsic in the technique. Accordingly, although alerting, this marker cannot be considered predictive per se.
On the basis of the criteria proposed by the Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy,8 at the time of the first screening, the seven new patients could have belong to the following categories:
- • affected: three had diagnostically sufficient echocardiographic signs (left ventricular dilatation >117% plus one minor criterion);
- • unknown:8 two subjects had minor criteria;
- • unaffected: one had no instrumental abnormalities (a fully healthy carrier of the LMNA mutation) and one atrioventricular block alone (a carrier of the LMNA mutation).
- • unknown:8 two subjects had minor criteria;
However, the use of the above criteria would not have predicted the diagnosis of four new cases.
The strategy of screening and rescreening the relatives of DCM patients will extend the approach to care from the individual patient to the family. The main clinical benefits of the systematic screening of relatives are an early pre-symptomatic diagnosis and the identification of echocardiographic abnormalities that can predict the development of the disease.1
The novel approach to the diagnosis and monitoring of familial DCM based on the screening and rescreening of the relatives of consecutive index patients is modifying the clinical scenario of the natural history of DCM. Our previous knowledge of the onset of DCM mainly relied on coincidence-based data between symptoms and diagnosis, but the scientifically relevant information that can be derived from rescreening the population of subjects who were healthy at first screening and affected at rescreening is the true age of disease onset, which must fall between the dates of the two screenings.
Rescreening also provides evidence supporting the predictive value of the echocardiographic abnormalities recorded at the time of first screening, and this information can be usefully translated into clinical practice: if a sub-population of relatives can be identified as being at risk of developing DCM in a given time interval, family-tailored monitoring programmes and management strategies could be developed. Furthermore, in genotyped families, the additional information could be usefully implemented in clinical practice insofar as all of the proven benefits applying to non-genotyped families can be more selectively focused: i.e. healthy carriers of a causative mutation belonging to a genotyped family should undergo different monitoring programmes from those used for non-carriers, whereas all of the relatives belonging to a non-genotyped family can be considered as sharing an identical theoretical risk of developing the disease.
The prevalence of new diagnoses was relatively low in our population (7/203 relatives found to be healthy at first screening=3.5%). All of the new patients belonged to families already identified as being affected with familial DCM at the first screening (n=3) or families previously thought to be affected by sporadic disease but found to be affected by familial disease at rescreening (n=4). These data confirm the considerable clinical value of rescreening programmes for the relatives of patients with diagnosed DCM.
In conclusion, family rescreening studies are clinically relevant for the diagnosis of new patients who are healthy or show echocardiographic abnormalities at first screening. The precise definition of the positive and negative predictive values of echocardiographic abnormalities such as an increased LVEDD requires larger populations and longer periods of follow-up.
Acknowledgments
We are indebted to the family members for their participation and collaboration, and like to thank Dr. C. Klersy of the Department of Biometry for the statistical analysis.
Footnotes
Supported by Italian Ministry of Health grants RF 1999–2001 and Progetto Strategico Scompenso Cardiaco to E. Arbustini and L. Tavazzi
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