Chiara Lestuzzi , Gian Luigi Nicolosi , Antonio Neri , Daniela Pavan \ Renata Mimo , Vittorio Dall’Aglio , Sante Favero , Giovanni Castorina  and Domenico Zanuttini 
Divisione di Cardiologia e Servizio di Emodinamica, Ospedale Civile, Pordenone, Italy; 
Divisione di Medicina, Ospedale Civile, Motta di Livenza, Treviso, Italy
(Received 28 July 1989; revision accepted 24 April 1991)
International Journal of Cardiology, 33 (1991) 225-232
© 1991 Elsevier Science Publishers B.V. All rights reserved 0167-5273/91/$03.50
Lestuzzi C, Nicolosi GL, Neri A, Pavan D, Mimo R, Dall’Aglio V, Favero S, Castorina G, Zanuttini D.
Familial dilated cardiomyopathy: a transverse and longitudinal clinical and echocardiographic study. Int
Correspondence to: Dott. A.R.C., C. Lestuzzi, Div. di Cardiologia - Servizio di Emodinamica, Ospedale Civile, Via Montereale 24, 33170 Pordenone, Italy.
The familial occurrence of hypertrophic cardiomyopathy is well known; familial dilated cardiomyopathy has so far received less attention. Ten families with two or more members affected by dilated cardiomyopathy were studied by echocardiography. In 3 out of 10 families, a transverse study extended to even apparently healthy subjects was carried out, which included a total of 45 subjects. In 19 out of the 45, dilated cardiomyopathy (either symptomatic or asymptomatic) was diagnosed at echocardiography. Three more relatives, already dead of the disease, were identified through hospital records. A clinical and echocardiographic longitudinal study, lasting up to 11 years, was carried out in 5 of the 10 families. During the follow-up, 8 out of 19 patients who, at first examination were affected by dilated cardiomyopathy, died, one improved, 3 remained in stable condition and 7 were lost at follow-up. One of two patients who presented echocardiographic findings suggestive of border-line dilated cardiomyopathy returned to normality and the other developed dilated cardiomyopathy. The clinical and echocardiographic findings in our patients, and in their relatives, suggest the possibility that idiopathic dilated cardiomyopathy may be a multifactorial disease in which genetic factors might play a variable role.
Dilated cardiomyopathy occurs usually in isolated cases. In the medical literature there are only few reports of families with a high incidence of peripartum or idiopathic dilated cardiomyopathy [1-11]. Most of the reported cases were studied before the routine use of echocardiography, and the diagnostic criteria are often incompletely defined [2, 3, 5]. In our echocardiographic laboratory we examined 10 families with more than one member affected by dilated cardiomyopathy.
In order to evaluate further the prevalence of both symptomatic and asymptomatic cardiomyopathy in these families, and investigate the possibility of diagnosing early forms of the disease, we attempted an extended transverse and longitudinal clinical and echocardiographic study.
Patients affected by dilated cardiomyopathy and known to have one or more relatives affected by the disease were selected for this study. Ten families were identified and checked according to these criteria. As much detailed clinical data as
possible were assessed regarding all living and dead relatives, with particular concern to cardiovascular diseases and sudden death. Data were confirmed, as far as possible, by collecting copies of clinical records. All living relatives were invited to be examined at our laboratory. Their examination consisted of clinical history and evaluation; electrocardiogram; chest X-ray; and echocardiogram (M-mode, cross-sectional or both). All subjects examined were subsequently invited to enter a regular follow-up study. In 7 of the 10 families a transverse study extended to the apparently healthy relatives was not feasible, either because there were no living relatives or because the surviving family members, who lived in rural areas or in cities quite far from our hospital, refused to come for an examination. In the 3 remaining families 7, 11 and 10 asymptomatic relatives respectively were examined directly. All the affected subjects and their relatives were invited to be included in a regular clinical and echocardiographic follow-up: five families (C, G, H, I, L) have been lost at follow-up, five (A, B, D, E, F) have been followed up for a 2 to 130 month (mean 53) duration.
Echocardiograms were performed by using commercially available M-mode and cross-sectional equipment (Irex II, Toshiba SSH 10A, Toshiba SSL 53M, Toshiba SSH 40, Aloka SSD 720, Aloka SSD 860, Aloka SSD 870). M-mode tracings were recorded on photographic paper, cross-sectional echocardiograms were recorded on 3/4 inch or 1/2 inch videotape. Measurements of M-mode tracings were performed following the criteria recommended by the American Society of Echocardiography . Left ventricular and left atrial dimensions were corrected for body surface area both in children and in adults. Cross-sectional echocardiograms were performed using the parasternal, apical and subcostal approaches and standard and intermediate views were obtained .
For those subjects who could not be examined directly, the diagnosis of cardiomyopathy was based on autopsy data or hospital records. The report of a death caused by refractory heart failure was considered suggestive of dilated cardiomyopathy when this occurred in patients with cardiac enlargement at chest X-ray and without history or signs of ischemic, hypertensive or valvular heart disease. In all subjects who were directly examined, the presence of dilatation of the left ventricle was assessed on the basis of echocardiography, chest X-ray, and electrocardiogram. For the purpose of this study, dilated cardiomyopathy was defined using the following criteria.
Major criteria: left ventricular diastolic or systolic dimensions exceeding the 95% confidence limits of the normal values reported by Henry et al. [13,14]; shortening fraction < 25% .
Minor criteria: left ventricular diastolic or systolic dimensions between 80% and 95% of the normal values as stated by Henry et al. [13,14]; shortening fraction between 25 and 30%; E-septal distance > 10 mm both for adults and children [17,18]; enlarged left atrium; cross-sectional echocardiographic appearance of globular geometry of the left ventricle and dilated left ventricular outflow tract .
Still, for the purpose of this study, dilated cardiomyopathy was arbitrarily diagnosed when either two major criteria or one major and three minor criteria were present; one major criterion, with or without a single minor criterion or three or more minor criteria alone were considered suggestive of a border-line dilated cardiomyopathy.
We examined 45 subjects directly. At first examination, 19 patients met the echocardiographic criteria for dilated cardiomyopathy, 2 were classified as having border-line dilated cardiomyopathy, and 24 were normal. Among the relatives who could not be examined directly, 3 had proven dilated cardiomyopathy, 2 died suddenly, one was affected by ischemic heart disease and 7 had heart disease of unknown origin.
The overall prevalence of cardiomyopathies and other heart diseases in the 10 families is summarized in Table 1. Fourteen subjects had an echocardiographic follow-up lasting from 2 to 130 months (mean 53 months). They were usually checked every one to two years, but some of them came at the echocardiographic follow-up after five or six years only. During the follow-up study, one of the 2 patients classified as having borderline dilated cardiomyopathy normalized; the other, who was aged 26 at the time of the first examination, developed dilated cardiomyopathy 10 years later (Fig. 1).
The family tree of one of the families who entered the follow-up study is shown in Fig. 2.
With regard to clinical history, several differences were observed both among the family groups and in single cases.
Heart disease affected: males only in families B, C, D, E; two females only in family H; both males and females in families A, F, G, I. L.
Fig. 1. M-mode echocardiogram of a patient belonging to family D. Left: age 30, asymptomatic: borderline dilated cardiomyopathy (left ventricular dimensions at the upper normal limits, shortening fraction 25%, globular shape of the left ventricle). The echocardiogram had been unchanged for the previous four years. Right: age 36, effort dyspnea (NYHA class II-III) and tachycardia: the echocardiogram shows dilated cardiomyopathy. See text for further details. SF = shortening fraction.
Among the patients affected by dilated cardiomyopathy in families A and F, two males died 3 and 22 months respectively after diagnosis, whereas three females are still alive 84, 86 and 130 months respectively after the echocardiographic diagnosis and either they are asymptomatic or their symptoms (dyspnea and/or arrhythmias) are well controlled by medical therapies. On the contrary, symptoms rapidly worsened and were refractory to medical therapy in most affected patients belonging to families D and E, although some relatives with dilated cardiomyopathy as defined by echocardiographic criteria were asymptomatic (Fig. 3). Both patients in family C (two brothers aged 15 at diagnosis of dilated cardiomyopathy) were referred for cardiac transplantation and died while waiting for a donor: the first died of refractory congestive heart failure, 18 months after diagnosis; the second died after 2 years of oligosymptomatic disease. No follow-up data are available for the other five families.
Fig. 3. M-mode echocardiograms of three patients belonging to family E. (A) 38-year-old male, with refractory congestive heart failure (NYHA class IV). He died 3 weeks later in the intensive care unit. (B) 19-year-old male, with congestive heart failure (NYHA class IV). He underwent cardiac transplantation six months later, and survived one more year: he died suddenly at age 21.
(C) 49-year-old male, asymptomatic. He was examined because he is the brother of patient A and the father of patient B. All three subjects have as enlarged left ventricle with severe reduction of shortening fraction (SF). Calibration = 1 cm. The family included one more member only: the teenage sister of patient B. She was free from any heart disease.
Factors possibly related to dilated cardiomyopathy
Our patients drank either no alcohol at all or in very little quantity and were non-smokers. No patient had any clinical or electrocardiographic signs of symptoms suggestive of ischemic heart disease and the only risk factor was familial history in family D. There were no cases of hypertensive, valvar heart disease, metabolic diseases or chronic volume overload that could explain the left ventricular enlargement. Nine out of the 23 patients with dilated cardiomyopathy were previously healthy people aged 15 to 36; 10 patients were 37 to 55 years old and only 4 were over 55.
Only in 2 patients (both in family D) the clinical course might suggest myocarditis. The first died before 1980 and a myocardial biopsy could not be performed: the second, who had borderline cardiomyopathy at age 26, became symptomatic and showed echocardiographic signs of dilated cardiomyopathy after a flu-like syndrome at age 36 (Fig. 1). The antibody titres against coxsackie, echo and influenza viruses were normal. At cardiac catheterization the coronary arteries were normal, and myocardial biopsy showed no signs of active or healed myocarditis.
Three more patients had myocardial biopsy: no signs of myocarditis were detected. In the other patients clinical history was not suggestive of infectious diseases. Most of our patients were first observed when myocardial biopsy was performed only in few medical centres, and its use was not recommended for routine clinical evaluation of dilated cardiomyopathy; even now the usefulness of biopsy in therapeutic decisions is still debatable [19-22]. For ethical reasons, we did not suggest myocardial biopsy to asymptomatic patients or patients whose symptoms were well controlled by medical treatment.
Other heart diseases
Direct or anamnestic information about other relatives was obtained from all families except family B. In families A and D several cases of sudden death at young age, or death caused by other heart diseases were reported.
Familial dilated cardiomyopathy has been defined as a disease involving at least two members of the same family . We found 7 families with two people per family affected, but only 3 families with more than two members affected. In some instances, this could be related to a lack in the transversal study, although in families H and I, for example, even a wider clinical and echocardiographic study failed to detect other cases.
A major problem in this field is the definition of the echocardiographic criteria for diagnosing dilated cardiomyopathy, mainly in the milder and asymptomatic forms of the disease. In our study we used arbitrary criteria based on measurements derived from echocardiography; the use of "major" and "minor" criteria and the term "borderline dilated cardiomyopathy" were introduced because of the difficulty encountered in defining exactly the borderline between normal and abnormal findings. The meaning of this milder form of left ventricular dilatation and/or hypokinesia is still unclear.
After a ten-year follow-up, one of our 2 cases of borderline cardiomyopathy evolved to dilated cardiomyopathy whereas, in the other case, the echocardiographic findings had normalized. It should be noted that the latter was a child. Spontaneous regression of dilatation of left ventricular chambers and congestive heart failure in children has been reported in the literature . We also
studied in our laboratory a child with borderline dilated cardiomyopathy who, in a ten-year follow-up, met the echocardiographic criteria for dilated cardiomyopathy and subsequently normalized.
Recovery from milder forms of myocarditis in these patients cannot be excluded, even though they remained asymptomatic. A different possibility is that while these children were growing up, the dimensions of their heart did not increase at the same speed. This finally led to a normal left ventricular dimensions to body weight ratio. In this situation increased left ventricular dimensions might be due only to the different growing speeds of different organs.
Another problem in our study was the assessment of genetic aspects of the familial form of dilated cardiomyopathy. In the families reported in the literature, both dominant and recessive, autosomal and X-linked modes of inheritance have been suggested in different cases [1,23,24]. In our study an X-linked recessive gene, leading to overt disease in hemizygous males and no or milder disease in heterozygous females, cannot be excluded as regards families D, E and F. In family I an autosomic gene with low penetrance might carry the disease. In the other families we were unable to find a possible inheritance pattern because of insufficient data.
It is possible, then, that more than one gene can be related to the disease, linked to sexual chromosomes in some cases and autosomic in other cases. It is also possible that a genetic predisposition together with exogenous factors could lead to the clinical appearance of the disease, at least in some cases. Myocarditis has been reported as the cause of dilated cardiomyopathy in some families [23-26]. On the other hand, in a recent study on 11 families, no signs of myocarditis were found at histological examination of explanted hearts . This report confirms our findings in the patients who underwent endomyocardial biopsies, but we cannot exclude occult myocarditis in different patients, according to other authors [27-30].
The last problem was the clinical outcome. The prognosis of idiopathic dilated cardiomyopathy varies widely in different patients. Familiarity has been suggested to be a bad prognostic factor in one report, but not by different authors . From our data, familial cardiomyopathy seems to have an outcome similar to isolated idiopathic dilated cardiomyopathy, with a high mortality in the first years after the onset of symptoms and a better prognosis for those patients who survive longer than five years . It should also be considered that new drugs (ACE-inhibitors and antiarrhythmic drugs, for instance) that have been available for the last years, might result in a better clinical outcome for patients who had survived enough to be treated with these drugs.
In conclusion, dilated cardiomyopathy, therefore, may sometimes occur in a familial form, but among each family it is usually present only in a minority of subjects. Clinical relevance of border-line dilated cardiomyopathy is still unclear. "Idiopathic" dilated cardiomyopathy can be a multifactorial disease, in which genetic factors might play an initial predisposing role. A variety of different multiple facilitating or precipitating factors could then lead to the clinical manifestation of the disease. When a patient with dilated cardiomyopathy is first observed, detailed clinical information about living and dead relatives should be obtained. Also apparently healthy relatives should be examined clinically and by echocardiography when a familial form is suspected, and a regular follow-up is suggested for those with even border-line abnormalities. The prognosis of familial dilated cardiomyopathy
seems to be similar to that of the isolated forms, with a wide individual variability.
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Key words: Familial dilated cardiomyopathy