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Long-term outcome and risk stratification in dilated cardiolaminopathies


This study, carried out in a northern Italian population, analyzes the associations between genetic and nongenetic factors and long -term outcome in DCM-affected families with lamin A/C -gene (LMNA) mutations. 
The study design was longitudinal, retrospective and observational. The study group comprised 27 consecutive families in which LMNA gene defects  and DCM phenotype were identified in the probands.
Among 164 family members, 94 LMNA mutation carriers were detected. Sixty subjects  were phenotypically affected and 34 were clinically healthy or had only minor cardiac abnormalities. Forty patients had DCM with atrioventricular block. Twelve patients had DCM with ventricular tachycardia or ventricular fibrillation and 8 subjects had cardiac and neuromuscular disease. The median follow -up was nearly five years. During this time, 49 events were observed in 43 DCM patients. The events were related to heart failure or arrhythmias: 15 heart transplants, 1 death from end -stage heart failure, 15 sudden cardiac deaths and 12 appropriate ICD (implantable cardioverter-defibrillator) interventions. These events associated with New York Heart Association (NYHA) III-IV functional class or previous competitive sports for at least ten years. The splice site mutations and competitive sports were predictors of sudden cardiac death.
The authors concluded  that DCM caused by LMNA gene defects are highly penetrant , adult onset, malignant diseases characterized by high rate of heart failure and life-threatening arrhythmias. NYHA class, competitive sports and type of mutation predicted the outcome.
Myocardial Disease

The ethiology of DCM is very heterogeneous (1). About one third of the cases are familial. Even then, the genetic background is diverse and several genes have been reported to associate with DCM. Disappointingly, many of the genes or mutations have been found only in single or few individuals and do not explain the disease at the population level. Lamin A/C gene, which codes for lamin A and C of the nuclear inner membrane by alternative splicing, is an exception to this rule. Within a decade, LMNA has turned out to be clinically the most important gene causing DCM (2-4). In earlier studies, the autosomal dominant cardiomyopathy caused by LMNA has typically been characterized by atrioventricular block, serious heart failure, atrial fibrillation, ventricular tachycardias and ventricular fibrillation and sudden death, often appearing by middle-age. Apart from DCM, defects of the LMNA gene may cause an astonishing  variety of diseases ranging from neuromuscular diseases like Emery-Dreifuss muscular dystrophy type 2, cardiac and skeletal muscle disease to rare entities like extremely early aging in Hutchinson’s progeria (5).
It has been shown that the prognosis of patients with LMNA cardiomyopathy is worse than that of DCM patients without LMNA mutations (6). The prevalence of LMNA mutations among subjects who had undergone heart transplantation has been up to 9% (7).
The study reported by Pasotti et al is so far the largest cardiologic follow-up of LMNA gene carriers. The median follow -up time was 57 months (interquartile range 36 to 107 months), allowing evalution of genetic and some nongenetic factors affecting the prognosis of these subjects. Although the study was a retrospective one, the results confirm the earlier observations demonstrating that LMNA mutations causing cardiomyopathy are highly penetrant and the disease is malignant (8). As a new finding, it was reported that previous competitive sports, lasting for at least ten years, predicted adverse cardiac events.


Clinical implications
In clinical practice, the risk stratification of individual DCM patients is often difficult. Based on the study of Pasotti et al. and other previous reports, even taking into account the fact that several different mutations have been described and the phenotype genotype-relationships are not always well known, it seems that in general cardiomyopathy caused by LMNA mutations is a serious disease with a high risk of sudden cardiac death. Identifying mutation carriers by genetic testing might affect the prognosis. The availability of genetic testing is increasing and several laboratories are capable of sequencing major disease genes causing DCM, LMNA included. Although the prices are still quite high, genetic testing for LMNA gene defects at least in DCM subjects with atrioventricular block and/or neuromuscular findings is well argumented (9). The family members of DCM patients, who could have inherited the same defect, should also be examined, either by genetic testing and /or clinically (ECG and Echo). Subjects carrying a LMNA mutation should be carefully followed up, bearing in mind the possible need of bivent/ICD therapy or even timely heart transplant. Those considering competitive sports could be informed about the possible adverse cardiac effects of competitive sports later in life.


1. Elliott P, Andersson B, Arbustini E, et al. Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial diseases. Eur Heart J. 2008; 29:270-6.
2. Fatkin D, MacRae C, Sasaki T, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999; 341:1715-24.
3. Arbustini E, Pilotto A, Repetto A, et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol 2002;39:981-90.
4. van Tintelen JP, Hofstra RM, Katerberg H, et al. High yield of LMNA mutations in patients with dilated cardiomyopathy and/or conduction disease referred to cardiogenetics outpatient clinics. Am Heart J 2007; 154:154: 1130-9.
5. Sanna T, Dello Russo A, Toniolo D, et al. Cardiac features of Emery -Dreifuss muscular dystrophy caused by lamin A/C gene mutations. Eur Heart J 2003; 24:2227-36.
6. Taylor MR, Fain PR, Sinagra G, et al. Familial Dilated Cardiomyopathy Registry Research Group. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 2003; 41:771-80.
7. Kärkkäinen S, Reissell E, Heliö T, et al. Novel mutations in the lamin A/C gene in heart transplant recipients with end stage dilated cardiomyopathy. Heart 2006; 92: 524-6.
8. van Berlo JH, de Voogt WG, van der Kooi Aj, et al. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? J Mol Med 2005; 83:79-83.
9. Mestroni L and Taylor MR. Lamin A/C gene and the heart. How genetics may impact clinical care. Editorial. J Am Coll Cardiol 2008; 52: 1261-2.

Notes to editor

By Dr. Tiina Heliö, Helsinki University Central Hospital, Helsinki, Finland.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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