Frequency of Asymptomatic Disease Among Family Members With Noncompaction Cardiomyopathy

Frequency of Asymptomatic Disease Among Family Members With Noncompaction Cardiomyopathy Kadir Caliskan, MD*, Michelle Michels, MD, PhD, Marcel L. Geleijnse, MD, PhD, Ron T. van Domburg, PhD, Robert van der Boon, MSc, Aggie H. M. M. Balk, MD, PhD, and Maarten L. Simoons, MD, PhD Noncompaction cardiomyopathy (NCC) is a primary cardiomyopathy characterized by an excessively prominent trabecular meshwork and deep intertrabecular recesses of the left ventricular walls. Most cases are inherited, with a dominant inheritance pattern. The aim of the present study was to determine the prevalence and clinical characteristics of cardiomyopathies in the close relatives of patients with NCC. We evaluated 156, mostly first-degree, family members of 44 adult patients with NCC who agreed to familial screening. A family history of cardiac disease was reported by 16 (36%) of the 44 patients, including premature sudden death in 8 families (18%). NCC (n ⴝ 32) or dilated cardiomyopathy (n ⴝ 9) was diagnosed in 41 relatives (26%) by echocardiography (n ⴝ 25), contrast echocardiography (n ⴝ 6), or magnetic resonance imaging (n ⴝ 10). Of these family members, 13 already had known cardiac symptoms and signs, but most (28 of 41) were asymptomatic. Most subjects with NCC had mild to moderate left ventricular dysfunction (n ⴝ 29, 71%). After a median follow-up of 55 months (interquartile range 43 to 93), most remained asymptomatic. Four family members were treated with prophylactic implantable cardioverter-defibrillator placement and 23 of those with NCC were treated with drugs, including angiotensin-converting enzyme inhibitors (41%), ␤ blockers (34%), and anticoagulants (17%). In conclusion, there is a high prevalence, mostly asymptomatic, of cardiac disease (26%) among first- and second-degree family members of patients with NCC. This warrants screening and offers an opportunity for early intervention. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:1512–1517) Noncompaction cardiomyopathy (NCC) is a primary cardiomyopathy, originally described in 1984, and characterized by an excessively prominent trabecular meshwork and deep intertrabecular recesses of the left ventricular (LV) walls.1–3 NCC can present with heart failure, arrhythmias, embolic events, or sudden cardiac death; however, it can also be detected in asymptomatic subjects.4 Most cases are familial, with a dominant inheritance pattern.5 Just as with other cardiomyopathies, NCC is associated with different mutations of the sarcomere genes. Some mutations have been found in patients with hypertrophic, dilated cardiomyopathy, as well as NCC.5–7 Because cardiac disease can progress for years without any symptoms, preventive cardiac screening of the asymptomatic relatives could aid in the understanding of the pathogenesis of NCC. Furthermore, an early diagnosis, before the onset of advanced symptomatic diseases, might improve patient treatment and prognosis. The aim of the present study was to determine the prevalence and clinical characteristics of cardiomyopathies in the close relatives of patients with NCC.

Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands. Manuscript received March 12, 2012; revised manuscript received and accepted July 6, 2012. *Corresponding author: Tel: (⫹31) 10-0703-5625; fax: (⫹31) 10-7034808. E-mail address: [email protected] (K. Caliskan). 0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.07.009

Methods Since 2005, adult patients with NCC and their family members have been prospectively followed up at our center, a tertiary referral center. Their data were collected and analyzed in accordance with the hospital institutional review board policies. We obtained detailed family histories from all 80 patients in the registry to construct pedigrees. The family history was considered abnormal, if it was positive for nonischemic heart failure, cardiomyopathies, documented supraventricular or ventricular arrhythmias, or pacemaker/implantable cardioverter-defibrillator placement. From 44 patients, we obtained informed consent to interview family members and completed the screening and counseling as described in the next paragraph (Table 1). Subsequently, the 44 patients were referred to a clinical geneticist for genetic counseling, to initiate family studies, and to obtain additional informed consent for DNA analysis. The results have recently been published.5 All living first-degree relatives of these 44 patients were invited to undergo a cardiac examination after appropriate counseling. When possible, “cascade screening” for cardiomyopathies was pursued. From 231 first-degrees relatives, 136 (59%) accepted the invitation for cardiac screening (median 60%, interquartile range 20% to 83%). The cardiac evaluation of the 156 relatives was done by 2 experienced clinicians (K.C., M.M.). The evaluation consisted of a review of the medical history, physical examination, electrocardiography, and 2-dimensional echocardiwww.ajconline.org

Cardiomyopathy/Family Screening in Noncompaction Cardiomyopathy Table 1 Clinical characteristics of index patients with noncompaction cardiomyopathy (NCC) Variable Mean age at presentation (years) Men Family history of cardiomyopathies Family history of sudden cardiac death Heart failure Arrhythmias Supraventricular arrhythmias Sustained ventricular tachycardia or fibrillation Thromboembolic events Miscellaneous Left atrium (mm) Left ventricular end-diastolic diameter (mm) Left ventricular end-systolic diameter (mm) Fractional shortening (%) Noncompacted segments (%) Noncompacted/compacted ratio Implantable cardioverter-defibrillator Heart transplantation Death

Family Screened (n ⫽ 44)

Not Screened (n ⫽ 36)

39 ⫾ 15 20 (45%) 16 (33%) 10 (23%)

42 ⫾ 13 19 (53%) 14 (39%) 6 (17%)

20 (45%) 11 (25%) 3 (8%) 8 (18%)

16 (44%) 7 (19%) 1 (3%) 6 (17%)

3 (7%) 10 (23%) 40 ⫾ 10 60 ⫾ 10

3 (7%) 10 (28%) 42 ⫾ 8 60 ⫾ 10

48 ⫾ 12

49 ⫾ 12

21 ⫾ 8 58 ⫾ 11 2.5 ⫾ 0.3 27 (61%) 3 (7%) 1 (2%)

20 ⫾ 9 57 ⫾ 12 2.5 ⫾ 0.3 18 (50%) 1 (3%) 2 (6%)

p ⫽ NS for all.

ography. From the electrocardiogram-derived heart rate, the PQ, QRS, and QTc intervals were measured. The QTc interval was calculated after correction for the heart rate using Bazett’s formula. The electrocardiogram was considered abnormal if it showed pathologic Q waves (⬎40 ms or ⬎25% R waves in ⱖ2 leads), left ventricular hypertrophy, complete bundle branch block, or nonspecific intraventricular conduction delay or (minor) repolarization abnormalities.8 The LV end-diastolic diameter, LV end-systolic diameter, and the presence or absence of significant valvular abnormalities were determined using 2-dimensional echocardiography. Measurements of the LV volumes and ejection fraction were not made because of the inherent problem of identifying the endocardial border in the presence of extensive trabeculation. Global LV function was estimated by visual assessment by 2 experienced observers and classified as 1, normal LV function; 2, mild LV dysfunction; 3, moderate LV dysfunction; and 4, severe LV dysfunction. Additionally, fractional shortening was measured: (LV enddiastolic diameter ⫺ LV end-systolic diameter)/LV enddiastolic diameter ⫻ 100%. The extent and severity of noncompaction was assessed by measuring the maximal noncompacted and compacted wall thickness with electronic calipers in the parasternal short-axis or apical 4-chamber view, in end-systole. A noncompacted wall thickness was diagnosed if prominent trabeculations were present with a noncompacted/compacted ratio ⬎2 at the end-systole, regardless of LV function.2 In case of a diagnosis using magnetic resonance imaging (MRI), a noncompacted/compacted ratio of ⬎2.3 at end-diastole was used.9 Because of poor echocardiographic image quality, especially at the level of the LV apical or midventricular walls,

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MRI (n ⫽ 10 [6%]) or contrast echocardiography (n ⫽ 6 [4%]) was performed for a firm diagnosis in 14 subjects (10%).10 All echocardiographic and MRI scans were reviewed by both clinicians, and the diagnosis was made by consensus. The cardiac assessment was extended with 24hour electrocardiographic monitoring and an exercise test when NCC or other heart disease was suspected because of complaints or abnormal electrocardiographic, echocardiographic, or MRI findings. The diagnosis of NCC was established according to stringent echocardiographic criteria, as described by Jenni et al2: (1) an excessively thickened LV myocardial wall with a 2-layered structure composed of a compacted epicardial layer and a noncompacted layer of prominent trabeculations on the endocardial side, (2) a noncompacted/compacted myocardial thickness ratio ⬎2 measured at the moment of maximal thickness in end-systole on the parasternal short-axis view, (3) color Doppler evidence of deep intertrabecular recesses in communication with the LV cavity, and (4) the absence of coexisting cardiac anomalies. Dilated cardiomyopathy (DC) was diagnosed in the case of myocardial abnormalities that did not fulfill the diagnosis of NCC. Continuous variables are summarized as the mean ⫾ SD or median and interquartile range (25th, 75th percentile), as appropriate. Categorical variables are presented as frequencies and percentages. A comparison of continuous variables between groups was made using the unpaired Student t test. When comparing frequencies, the chi-square test or Fisher’s exact test was used, where applicable. All tests were 2-tailed, and p ⬍0.05 was considered statistically significant. Results The baseline characteristics of the index patients, with or without family screening, were fully comparable (Table 1). A total of 156 close relatives of 44 unrelated patients with NCC accepted our invitation for cardiac screening and counseling (Figure 1 and Table 2). Cardiac screening revealed that familial disease was present in 49%. Sudden cardiac death at ⬍60 years old was reported in 8 families (18%). In 1 sibling and 2 children, congenital heart disease had been diagnosed before the family screening, including a combination of pulmonary valve stenosis and atrial septal defect in 2 subjects. NCC or DC was found in 41 relatives (26%) using transthoracic 2-dimensional echocardiography (n ⫽ 25), MRI (n ⫽ 10) or contrast echocardiography (n ⫽ 6; Figure 2 and Table 3). All the relatives diagnosed with DC had some form of prominent trabeculations (noncompacted/compacted ratio 1.0 to and 2.0), without fulfilling the diagnostic criteria for NCC (noncompacted/compacted ratio ⬎2.0). Abnormal electrocardiographic findings were observed in 51 subjects (33%). Of the 41 subjects with NCC or DC, 16 (39%) had normal electrocardiographic findings. Of the subjects with NCC, 13 (32%) already had known cardiac symptoms and signs, but most (n ⫽ 28 [68%]) were asymptomatic. The 6 patients who presented with heart failure and/or a cerebrovascular accident had previously been regarded to have DC but at revision fulfilled the Jenni criteria for NCC. Most subjects with NCC had mild (n ⫽ 21 [51%]) or moderate to severe LV dysfunction (n ⫽ 8 [20%]).

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NCC pa
ents (n= 80)

Not screenend (n=36 )

Family screening (n=44) Rela
ves (n=156) Historyy ECG Echo ( MRI)

NCC (n=32)

Valvular or other heart diseases (n=6)

DC (n=9) (n 9)

Healthyy (n=109)

Figure 1. Summary of evaluation of close relatives of patients with NCC. Table 2 Overview of screened noncompaction cardiomyopathy (NCC) relatives

Patients (n) Age at presentation (years) Male subjects History of cardiac disease* Heart failure/dilated cardiomyopathy Supraventricular arrhythmias Thromboembolic events Congenital heart disease Chest pain Valvular heart disease Coronary heart disease Syncope Abnormal electrocardiogram Abnormal echocardiogram Noncompaction Dilated cardiomyopathy Valvular heart disease Congenital heart disease Total noncompacted cardiomyopathy/ dilated cardiomyopathy

Total

Parents

Siblings

Children

Second Degree

156 41 ⫾ 19 69 (44%) 18 (12%) 6 7 2 3 1 1 1 1 51 (33%) 45 (29%) 32 (21%) 9 (6%) 2 (1%) 3 (2%) 41 (26%)

34 (22%) 60 ⫾ 8 16 (47%) 5 (21%) 3 2 1

58 (37%) 41 ⫾ 13 21 (36%) 4 (7%) 1 1

44 (28%) 24 ⫾ 12 24 (55%) 6 (14%) 2 2 1 2

20 (13) 47 ⫾ 15 8 (40) 3 (15)

1

2

1 1 1 13 (38%) 10 (29%) 7 (21%) 1 (3%) 2 (6%) 8 (24%)

17 (29%) 16 (28%) 15 (26%) 5 (9%)

1 13 (30%) 15 (34%) 12 (27%) 3 (7%)

1 (2%) 16 (28%)

2 (5%) 13 (30%)

8 (40) 4 (20) 4 (20)

4 (20)

Data are presented as mean ⫾ SD or n (%). * One or more combinations possible.

After a median follow-up of 55 months (interquartile range 43 to 93; Table 4), most (80%) of the 41 family members with NCC remained asymptomatic. Four patients had undergone prophylactic implantable cardioverter-defibrillator implantation, because of significant LV dysfunction at screening and a positive family history of sudden cardiac death. Drug therapy was prescribed in 23 (56%) of the 41 subjects with NCC, including angiotensin-converting enzyme inhibitors (41%), ␤ blockers (34%) and anticoagulants (17%). Discussion The results of the present study have confirmed a familial inheritance pattern in about ½ of patients with NCC. A

positive family history (i.e., the presence of nonischemic heart failure, cardiomyopathies, documented supraventricular or ventricular arrhythmias, pacemaker/implantable cardioverter-defibrillator placement) could suggest a familial inheritance pattern in about 1⁄3 of the patients with NCC. In the subset of 44 patients whose relatives were screened, cardiomyopathies were documented in 26%. Whether this proportion is correct remains unclear, because this might have resulted from sampling error owing to premature death of some affected relatives or their refusal to participate or, perhaps, incomplete penetration. It should be appreciated that without systematic cardiac screening, most (68%) of the diseased close relatives would have remained undetected,

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Figure 2. Close view of 4-chamber echocardiographic and 3-chamber MRI view of 25-year-old asymptomatic son of a female patient who first presented in 2010 with paroxysmal atrial fibrillation and heart failure due to severe LV dysfunction at 58 years old. MRI revealed an ejection fraction of around 40%, and he was prophylactically treated with an angiotensin-converting enzyme inhibitor and a ␤ blocker.

missing the opportunity for presymptomatic treatment. The absence of symptoms or signs of heart disease (68%) and of electrocardiographic abnormalities (39%) does not exclude the presence of NCC or another cardiomyopathy. Cardiac evaluation, including echocardiography or MRI, is indispensable to reach a correct diagnosis.2 Therefore, a complete cardiac evaluation is essential in the familial screening of patients with NCC. The published cohorts of patients with NCC are rather heterogeneous, with an 18% to 51% prevalence of familial disease reported.4,11–13 Although routine familial screening of first-degree relatives is generally recommended,14 little is known about the distribution and spectrum of cardiac abnormalities in asymptomatic relatives of patients with NCC. Using detailed history taking, electrocardiography, echocardiography, and MRI, the present study revealed frequent (26%) disease in asymptomatic relatives. Furthermore, 8% of all relatives had NCC with known cardiac symptoms such as congestive heart failure, supraventricular arrhythmias, or cerebrovascular events. The prevalence of asymptomatic disease was equally distributed among the closer and more distant relatives. This supports the expansion of familial screening beyond first-degree family members, such as was recommended in the recent guidelines, although the probability of selection bias was high in our study owing to the selective response to our invitation to undergo familial screening.15 Screening of family members of patients with nonischemic cardiomyopathy is advised because an early diagnosis provides an opportunity for early treatment. Appropriate pharmacologic therapy can significantly improve the outcomes of patients with asymptomatic LV dysfunction, defined as an LV ejection fraction ⱕ35% to 40%.16,17 In addition, placement of an implantable cardioverter-defibrillator might be appropriate to prevent sudden cardiac death.18,19 In the present study, LV dysfunction was present in 71% of NCC- or DC-positive family members. Also, prominent trabeculations were found in the DC group, probably suggesting a type of “forme fruste” of NCC such as is

also known in other familial diseases.20 No large-scale trials have specifically evaluated angiotensin-converting enzyme inhibitors or ␤ blockers for patients with nonischemic, asymptomatic LV dysfunction. Sufficient benefits, however, were observed in the Studies of Left Ventricular Dysfunction (SOLVD) prevention trial to be able to justify the use of these medications.16,17 In the SOLVD prevention trial, in 4,228 patients (83% after myocardial infarction) with asymptomatic LV dysfunction, prophylactic administration of enalapril reduced the probability of death or congestive heart failure by 29%.16 In the placebo arm, patients with asymptomatic LV dysfunction not treated with an angiotensin-converting enzyme inhibitor progressed to symptomatic heart failure at a rate of 9.7% annually. Screening family members could also help us understand the pathogenesis and development of the disease. Genetic testing is useful in families when the genetic cause of the disease has been recognized.21 Different mutations in different genes have been reported, including sarcome gene mutations in about 1/3 of patients.5,7 Some mutations related to NCC are also related to other cardiomyopathies, suggesting common genetic pathways. In most patients with a familial pattern of NCC, however, the genetic variations are as yet unknown. Therefore, the diagnosis depends on the cardiac evaluation, including cardiac imaging, to recognize the prominent trabecular mesh and deep intertrabecular recesses of the LV walls. In addition, cardiac screening is appropriate in the relatives of patients when the index patient or relatives refuse genetic testing and in asymptomatic relatives with a documented NCC mutation. Recently, we described rigid body rotation as a new echocardiographic parameter with good predictive value for the diagnosis of NCC.22 This could add an objective, quantitative functional criterion, aiding in the correct diagnosis of NCC in family members. In the present study, however, we did not use such an analysis. The current heart failure guidelines have concluded that the weight of evidence supports screening first-degree relatives of patients with all nonischemic cardiomyopathies using electrocardiography and echocardiography. Families

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Table 3 Clinical, electrocardiographic, and echocardiographic characteristics of screened noncompaction cardiomyopathy (NCC) relatives

Table 4 Clinical management and outcome of relatives with noncompaction (NCC) or dilated cardiomyopathy (DC)

Variable

Affected (n ⫽ 41)

Not Affected (n ⫽ 115)

p Value

Variable

Mean age at diagnosis (years) Men Hypertension Diabetes mellitus Coronary artery disease Congenital heart disease Asymptomatic Heart failure (New York Heart Association) I II Supraventricular arrhythmias Cerebrovascular events Miscellaneous* Abnormal electrocardiogram Atrial fibrillation First-degree atrioventricular block Bundle branch block Left ventricular hypertrophy Nonspecific intraventricular conduction abnormality T-wave inversion (lateral/ inferior) Minor repolarization abnormality Left atrium (mm) Intraventricular septum (mm) Left ventricular end-diastolic diameter (mm) Left ventricular end-systolic diameter (mm) Fractional shortening (%) Left ventricular dysfunction Mild Moderate Severe Noncompacted segments (%) Noncompacted/compacted ratio Valvular abnormalities

36 ⫾ 19 23 (56%) 2 (5%) 2 (5%) 1 (2%) 2 (5%) 28 (68%) 5 (12%)

43 ⫾ 19 46 (40%) 16 (14%) 2 (2%) 1 (1%) 1 (1%) 110 (96%) 0

0.02 0.10 Ns Ns Ns Ns ⬍0.0001 0.009

2 3 4 (10%) 2 (5%) 3 (7%) 25 (61) 2 (5%) 1 (2%)

0 0 3 (3%) 0 2 (2%) 26 (23) 1 (1%) 2 (2%)

1 (2%) 4 (11%) 5 (14%)

0 6 (5%) 7 (6%)

Ns Ns Ns

2 (5%)

0

0.08

10 (24%)

11 (10%)

0.03

40 ⫾ 8 9⫾2 56 ⫾ 7

39 ⫾ 6 9⫾2 50 ⫾ 5

Ns Ns ⬍0.0001

42 ⫾ 8

31 ⫾ 5

⬍0.0001

26 ⫾ 7 29 (71%) 21 (51%) 4 (10%) 4 (10%) 47 ⫾ 14 2.6 ⫾ 0.3

36 ⫾ 7 1 (1%) 0 1 (1%) 0 0

0.001 ⬍0.0001

4 (10%)

3 (3%)

0.08

0.08 0.08 0.06 0.0001 Ns Ns

Data are presented as mean ⫾ SD or n (%). * One or more combinations possible.

with a strong positive family history should be referred to a cardiovascular genetic center.23 The outcomes are expected to be impaired if effective therapy is delayed until patients develop overt heart failure, potentially lethal arrhythmias, and/or embolic events. Regular cardiac follow-up of at-risk relatives is advised for familial cardiomyopathies associated with sarcomeric defects. The current data support periodic cardiologic screening of unaffected at-risk relatives in the presence of familial NCC.24 However, because of possible psychological, social, legal, insurance, or employment consequences, routine family screening should only been initiated after a discussion of the possible medical benefits of the early cardiac diagnosis of cardiac disease.15 The true frequency of familial disease in cardiomyopa-

Patients Follow-up (mo) Median Interquartile range Lost to follow-up Asymptomatic Heart failure Supraventricular arrhythmias Thromboembolic events Drug treatment Anticoagulation Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker ␤ Blocker Diuretics Aldosterone antagonists Digoxin Implantable cardioverterdefibrillator Death

NCC

DC

Total

32

9

41

58 38–97 3 (9%) 24 (75%) 3 (9%) 2 (6%) 0 21 (66%) 0 17 (53%)

50 39–60 0 9 (100%) 0 0 0 4 (44%) 0 3 (33%)

55 43–93 3 (7%) 33 (80%) 3 (7%)* 2 (5%)* 0 23 (56%) 7 (17%) 20 (49%)

13 (40) 5 (16%) 1 (3%) 1 (3%) 4 (13%)

3 (33%) 0 0 0 0

16 (39%) 5 (10) 1 1 4 (10%)

1 (3%)

0

1 (cancer)

Data are presented as n (%) or median and interquartile range. * Previously known.

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