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CLINICAL RESEARCH: CARDIOMYOPATHY

Long-Term Outcome and Risk Stratification in Dilated Cardiolaminopathies

Michele Pasotti, MD^_*, Catherine Klersy, MD, Andrea Pilotto, BS^_*, Nicola Marziliano, PhD^_*, Claudio Rapezzi, MD, Alessandra Serio, MD^_*, Savina Mannarino, MD^_*, Fabiana Gambarin, MD^_*, Valentina Favalli, BME^_*, Maurizia Grasso, PhD^_*, Manuela Agozzino, MD^_*, Carlo Campana, MD, Antonello Gavazzi, MD^||, Oreste Febo, MD^¶, Massimiliano Marini, MD^#, Maurizio Landolina, MD, Andrea Mortara, MD^_**, Giovanni Piccolo, MD, Mario Viganò, MD, Luigi Tavazzi, MD and Eloisa Arbustini, MD^_*,_*

^_* Centre for Inherited Cardiovascular Diseases, Molecular Diagnostic Laboratory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Department of Biometry and Clinical Epidemiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Department of Cardiac Surgery, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
^|| Cardiology Department, Ospedali Riuniti di Bergamo, Italy
^¶ Cardiology Department, IRCCS Fondazione Salvatore Maugeri, Montescano, Italy
^# Cardiology Department, Ospedale Santa Chiara di Trento, Trento, Italy
^_** Cardiology Department, Policlinico di Monza, Monza, Italy
Institute of Cardiology, University of Bologna and S. Orsola-Malpighi Hospital, Bologna, Italy
Neurology Department, IRCCS Fondazione Mondino, Pavia, Italy

Manuscript received February 6, 2008; revised manuscript received May 23, 2008, accepted June 23, 2008.

^_* Reprint requests and correspondence: Dr. Eloisa Arbustini, Centre for Inherited Cardiovascular Diseases, IRCCS Fondazione Policlinico San Matteo, Viale Forlanini 16, Pavia 27100, Italy (Email: e.arbustini{at}smatteo.pv.it).

	Abstract

Top Abstract Methods Results Discussion Conclusions References

 
Objectives: The aim of this study was to analyze the long-term follow-up of dilated cardiolaminopathies.

Background: Lamin A/C (LMNA) gene mutations cause a variety of phenotypes. In the cardiology setting, patients diagnosed with idiopathic dilated cardiomyopathy (DCM) plus atrioventricular block (AVB) constitute the majority of reported cases.

Methods: Longitudinal retrospective observational studies were conducted with 27 consecutive families in which LMNA gene defects were identified in the probands, all sharing the DCM phenotype.

Results: Of the 164 family members, 94 had LMNA gene mutations. Sixty of 94 (64%) were phenotypically affected whereas 34 were only genotypically affected, including 5 with pre-clinical signs. Of the 60 patients, 40 had DCM with AVB, 12 had DCM with ventricular tachycardia/fibrillation, 6 had DCM with AVB and Emery-Dreifuss muscular dystrophy type 2 (EDMD2), and 2 had AVB plus EDMD2. During a median of 57 months (interquartile range 36 to 107 months), we observed 49 events in 43 DCM patients (6 had a later event, excluded from the analysis). The events were related to heart failure (15 heart transplants, 1 death from end-stage heart failure) and ventricular arrhythmias (15 sudden cardiac deaths and 12 appropriate implantable cardioverter-defibrillator interventions). By multivariable analysis, New York Heart Association functional class III to IV and highly dynamic competitive sports for 10 years were independent predictors of total events. By a bivariable Cox model, splice site mutations and competitive sport predicted sudden cardiac death.

Conclusions: Dilated cardiomyopathies caused by LMNA gene defects are highly penetrant, adult onset, malignant diseases characterized by a high rate of heart failure and life-threatening arrhythmias, predicted by New York Heart Association functional class, competitive sport activity, and type of mutation.

Key Words: LMNA gene mutation • idiopathic dilated cardiomyopathy • atrioventricular block

Abbreviations and Acronyms   AVB = atrioventricular block   DCM = dilated cardiomyopathy   EDMD2 = Emery-Dreifuss muscular dystrophy type 2   HF = heart failure   ICD = implantable cardioverter-defibrillator   ins-del/stop = insertions/deletions and stop mutations   LMNA = lamin A/C   LV = left ventricular   SCD = sudden cardiac death

We investigated associations between genetic/nongenetic factors and long-term outcome in a cohort of DCM-affected families with LMNA mutations.

	Methods

Top Abstract Methods Results Discussion Conclusions References

 
Setting and study design.   This retrospective longitudinal study was conducted with a series of 27 consecutive families whose proband was diagnosed with a dilated cardiolaminopathy at our institution up to August 2006. The DCM was diagnosed based on World Health Organization criteria (18). Until 1994, we screened DCM patients and their family members when the pedigree suggested a familial disease. Since 1995, we have conducted serial family screening for all DCM patients (19). Criteria for search for the LMNA gene in DCM patients evolved during the study period according to current concepts (4–10,15–17,20,21). In brief, identification of the probands was based on the co-existence of isolated DCM with AVB (n = 21); DCM with AVB and EDMD2 (n = 4); and DCM and ventricular tachycardia/fibrillation (n = 2). We explored the associations between LMNA gene defects and phenotypic characteristics at presentation in our center and a history of highly dynamic competitive sports classified according to current guidelines (22). The patients were either phenotypically healthy or not aware of their status at the time of their athletic competitive activity. The mean interval that elapsed between the diagnosis and cessation of the competitive sport activities was 14.7 ± 10.2 years (median 12 years; range 0 to 36 years). Only 2 patients were agonistically active at the time of the diagnosis. We also assessed associations with outcome, and attempted prognostic stratification. The local ethics committee approved the study.

Family screening protocol.   After giving informed consent, all probands and relatives received genetic counseling and clinical screening and underwent peripheral blood sampling for genetic testing. On confirming full comprehension of the screening protocol, each mutated person (or legal guardians of minors) received the written and signed report describing the identified mutation. Regular clinical monitoring was planned every 24 months for children and adolescents without instrumental abnormalities, and every 12 months for adults with electrocardiographic or echocardiographic abnormalities who did not fulfill criteria for the diagnosis of DCM or had DCM in functional class I and appropriate treatment, and at shorter intervals based on clinical needs. Clinical investigation included resting cardiologic evaluation, 12-lead electrocardiogram, 2-dimensional and echocardiography study (Doppler since 1978), 24-h Holter monitoring, effort test, and serum creatine phosphokinase determination. The left ventricular end-diastolic diameter was calculated according to the formula of Henry et al. (23). Neuromuscular assessment of probands and relatives was based on detailed clinical history, physical examination, serum creatine phosphokinase and serum lactate determination, and neuromyologic examination. When possible, we traced the clinical and pathology records and autopsy samples of deceased affected relatives.

Molecular analysis.   The 12 exons of the LMNA gene were amplified from peripheral blood-derived genomic deoxyribonucleic acid by means of polymerase chain reaction, using primers derived from intronic sequences (5). The polymerase chain reaction fragments were analyzed by means of denaturing high-performance liquid chromatography using the Wave deoxyribonucleic acid fragment analysis system (Transgenomic, San Jose, California). Heteroduplex fragments were purified (QIAquick Kit, Qiagen, Santa Clarita, California) and then sequenced using a BigDye-terminator cycle sequencing system (ABI PRISM, Applied Biosystems, Foster City, California). The LMNA gene analysis was performed by direct bidirectional automated sequencing in case of probands with healthy parents, to exclude the rare possibility of recessive forms. The control series for each mutation is constituted of 196 normal persons. Reference sequences used in the study are as follows: LMNA gene: NCBI NC_000001 [GenBank] ; LMNA messenger ribonucleic acid: NCBI NM_170707 [GenBank] ; lamin A protein: NCBI NP_733821 [GenBank] ; LMNC messenger ribonucleic acid: NCBI NM 005572; lamin C protein: NCBI NP005563.

Statistical analysis.   The 94 subjects with mutations were included in the statistical analysis. Mutations were categorized in two ways, based on type and position. Mutation types were classified as: missense; intervening sequence (or splice site) mutations predicting a skipped exon; or insertions/deletions and stop mutations (ins-del/stop). The mutations were also categorized by the two position clusters reported by Hegele (24) to be associated with different phenotypic classes: mutations upstream of the nuclear localization signal spanning residues 416 to 423 (where no mutations have been found to date) versus downstream mutations (Fig. 1). Descriptive statistics were computed as mean and standard deviation for continuous variables and as counts (percentages) for categorical variables. Median (interquartile range) follow-up duration was calculated according to the inverse Kaplan-Meier method. The Student t test, Fisher exact test, and test for trend were used to compare affected patients and phenotypically healthy mutation carriers at baseline. Binomial exact confidence intervals (CIs) were computed for the age-related penetrance.

View larger version (32K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Position of LMNA Gene Mutations The position of lamin A/C (LMNA) gene mutations are shown according to the nuclear localization signal (NLS) that spans residues 416 to 423: the region upstream of the NLS encodes the central alpha-helical rod domain, and the region downstream of the NLS encodes the homology box, including the beta-immunoglobulin–like fold and a deoxyribonucleic acid binding region. In red, we show missense, insertions/deletions, and stop mutations; in blue, intervening sequence mutations. The 3-dimensional reconstruction of the LMNA/C protein was made using Cn3D software, version 4.1, by loading the 2 sequence proteins NP733821 and NP005563; in particular, the illustration emphasizes the rod domain (green worms) and the globular domain (brown and light blue worms) with respect to the NLS sequence.

The log-rank test was used for univariable comparisons. Cox regression analysis was used to identify independent predictors of events and to attempt prognostic stratification. Hazard ratios and 95% CI were calculated. Variables reaching p < 0.2 at univariable analysis were included in the multivariable model, alongside mutation categories. Collinearity was observed between left ventricular (LV) ejection fraction and LV end-diastolic volume, and between age and LV ejection fraction and AVB. Therefore, LV ejection fraction was chosen based on clinical consensus as being the most common marker of LV function, and AVB was chosen as the most prevalent and specific marker of the disease. The Huber-White sandwich robust estimator of standard errors was used to account for intrafamilial aggregation of subjects. The proportional hazards assumption was verified by means of Schoenfeld residuals. The Harrell C statistic and the shrinkage coefficient were computed to assess model discrimination and calibration. Two-sided p values <0.05 were considered statistically significant. Stata 9.2 (StataCorp, College Station, Texas) was used for all computation.

	Results

Top Abstract Methods Results Discussion Conclusions References

 
Study population and baseline characteristics.   The disease was proved to be familial autosomal dominant in 21 of the 27 families, likely familial autosomal dominant (based on pedigree and family history) in 5, and associated with a de novo mutation in 1. In 8 families, including that of the de novo case, the proband was the only living mutated member. In the other 19 families, the number of living mutated members ranged from 2 to 12. Of the 137 relatives, 67 (49%) carried the corresponding proband mutation. Thus, a total of 94 LMNA mutated subjects (i.e., 27 probands, 67 relatives) entered the main analysis. The 23 LMNA gene mutations identified in the 27 probands (6 novel and 17 known) are listed in Table 1.

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Age-Related Penetrance of Phenotypes in Patients With LMNA Gene Mutations The age-related penetrance of the phenotypes in patients with lamin A/C (LMNA) gene mutations is shown (test for trend p < 0.001). CI = confidence interval.

All events.   A total of 49 events occurred in 43 of the 60 affected patients (mean age at the event 42 ± 11 years; range 19 to 68 years), whereas no event was observed among the 34 mutated healthy subjects. Six nontransplanted patients had a later further event (heart transplantation, n = 3; death from congestive HF, n = 3) and were excluded from the statistical analysis. The mean follow-up was significantly shorter for younger healthy persons than for older mutated persons (32 ± 20 [range 1 to 84] months vs. 65 ± 78 [range 1 to 384] months, p = 0.017). The linearized event rate was 9.7 per 100 person-years (95% CI: 7.2 to 13.2). Cumulative event-free survival was 82% (95% CI: 71% to 88%) at 2 years and 60% (95% CI: 47% to 70%) at 5 years. The majority of the events were SCD/ventricular arrhythmias (27 of 43, 63%), comprising 15 SCD and 12 appropriate ICD interventions detected by the device (8 ventricular fibrillation and 4 sustained ventricular tachycardia). The remaining events were all related to end-stage HF: heart transplantation (n = 15) and death from congestive HF (n = 1). The highest percentages of total events and SCD-related events, including appropriate ICD interventions, were observed among subjects with intervening sequence mutations (64% and 57%), followed by ins/del-stop mutations (52% and 38%) and by the missense mutations (38% and 19%). The corresponding follow-up was 55 ± 98 (median 19) months, 52 ± 68 (median 33) months, and 49 ± 55 (median 36) months (p = NS).

At univariable analysis (Table 3), New York Heart Association (NYHA) functional class III to IV, any disease phenotype, atrioventricular conduction disturbances, LV ejection fraction <35%, LV end-diastolic volume >180 ml, and history of competitive sport were all associated with event occurrence.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Kaplan-Meier Event-Free Survival Kaplan-Meier event-free survival stratified by 2 independent risk factors (RF): New York Heart Association functional class III to IV and competitive sports.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Kaplan-Meier SCD Event-Free Survival Kaplan-Meier sudden cardiac death (SCD) event-free survival stratified by 2 independent risk factors (RF): splicing mutations and competitive sports.

	Discussion

Top Abstract Methods Results Discussion Conclusions References

From clinical suspicion to molecular diagnosis.   To our knowledge, this is the largest reported cardiologic follow-up study of persons with LMNA gene mutations. Identification of the cohort (probands and family members) was facilitated by institutional protocols, which incorporated evolving concepts regarding serial family screening and peculiarities ("red flags") that should arouse diagnostic suspicion of LMNA mutations. In line with current knowledge (1–6,10–13,15–17), identification of the probands was most often based on the combination of DCM and AVB in the context of non–X-linked and nonmatrilinear myopathy. Co-existent myopathy (EDMD2 or variable myopathy) (8-11) and increased serum creatine phosphokinase levels alone were also considered, after excluding an X-linked or matrilineal inheritance, especially in the presence of AVB, an unusual feature in X-linked DCM (25). In our cohort, most probands had familial disease, with only 1 case proven to be de novo. It should be noted that, due to selection bias considerations, including the characteristics of the institutional setting and the family screening protocol, the present study could not provide information regarding the prevalence of LMNA gene defects among patients with DCM.

Phenotype considerations.   Within our families, the overall penetrance was high and progressively increased with age: by 60 years, the penetrance was complete, and all mutated persons showed the phenotype, irrespective of mutation type. Among LMNA mutated subjects, DCM is rare under the age of 20 years. This observation is in line with the finding reported by Benedetti et al. (26) that onset of the cardiomyopathy phenotype tends to occur at a later age (adulthood) in comparison to the EDMD2 phenotype (early childhood). Of note, the distribution of nonmissense mutations in our cohort (44% in affected patients vs. 23% in unaffected subjects) is also broadly in line with the observation by Benedetti et al. (26) of a high prevalence in the cardiomyopathy phenotype of nonmissense mutations. The observation that the majority (78%) of our DCM-affected probands had mutations upstream of the nuclear localization signal spanning residues 416 to 423 is also in line with the study conducted by Hegele (24 using hierarchical cluster analysis, where these upstream mutations were strongly associated with class 1 (cardiac/myopathy phenotypes) with respect to class 2 laminopathies (partial lipodystrophy, progeria syndromes, and mandibuloacral dysplasia).

Our study is not informative regarding the reasons for the commonly observed phenomenon, described elsewhere (2,4,5,17), of early onset of AVB before DCM. We observed patients who first presented with AVB and later had DCM as well as patients who showed both DCM and AVB at the time of their first diagnosis (5). Prospective long-term follow-up of healthy mutated subjects should help elucidate the timing of expression of the phenotypic traits.

Outcome and prognostic stratification.   Patients with LMNA gene mutations have high rates of major cardiac events (17). The major events recorded in our cohort were related to life-threatening arrhythmias or end-stage HF and always occurred in the context of DCM. The SCD-related events, including appropriate ICD interventions for life-threatening arrhythmias, were more frequent. The high rates of SCD and other SCD-related events are in line with the meta-analysis by van Berlo et al. (17), although we observed no major cardiac event before onset of DCM. However, the spectrum of our cardiac phenotypes reflects the DCM study setting, which does not include families in which myopathy was the isolated or major phenotype and which only partially overlaps with the setting of permanent cardiac pacing in patients without DCM. In a recent study (27) including 19 patients who underwent permanent pacing and ICD implantation solely on the basis of LMNA gene mutations associated with cardiac conduction defects and normal ventricular function, 8 of 19 (42%) received an appropriate ICD intervention, suggesting high risk of SCD before onset of HF. In our cohort, only 2 unrelated healthy young mutated subjects, both sons of patients with DCM plus AVB, had first-degree AVB with normal ventricular size and function. An important difference between our young healthy mutated subjects and the patients described by Meune et al. (27) is that our 2 young mutated persons with AVB did not yet require permanent pacing, and therefore, the indication for pacemaker and ICD implantation did not seem appropriate. Regarding myopathy traits, we observed overlapping phenotypes characterized by DCM plus AVB and EDMD2 in 4 of our families; however, the myopathy was mild, and the most relevant clinical problems were the DCM and arrhythmias. It is possible that, in the myology setting, patients with less cardiac remodeling are more common or that less attention is dedicated to early cardiac dysfunction, with SCD occurring in patients with apparently normal hearts.

At univariable analysis, several factors were associated with the risk of events both related to heart failure and to life-threatening ventricular arrhythmias. Surprisingly, however, at multivariable analysis, neither AVB nor pacemaker implantation turned out to be predictors of events, supporting the concept that AVB is a clinical marker of cardiolaminopathies, rather than an event predictor. In keeping with the results of the meta-analysis by van Berlo et al. (17), the pacemaker did not appear to protect from SCD. Of note, none of our patients with ICD died suddenly, but ICD allowed us to bridge 3 patients to heart transplantation.

Only 2 factors remained significant predictors at multivariable analysis: NYHA functional class III to IV (the strongest predictor of overall events) and a history of high dynamic competitive sports of at least 10 years. This interval is somehow arbitrary, as we did not have models or prior reference data for inherited DCMs. Obviously, the age influences the lower prevalence of athletes in the group of the younger healthy mutated persons, thus helping to explain the high association with the risk of events in the multivariable analysis. However, the perception of the negative effect of competitive sport on the disease evolution was a daily experience when screening and regularly monitoring families of our series. We are aware of the beneficial effects of sport on heart performance; however, the myocyte molecular and structural derangement associated with the LMNA gene defects could interfere with the potential benefit of physical training.

NYHA functional class III to IV was the strongest predictor of total events but not of SCD, which seemed to be more influenced by competitive sport and type of mutation. Competitive sport and presence of splicing mutations appeared to help the risk stratification of SCD at Cox bivariable analysis. The possible prognostic relevance of splicing mutations is an attractive hypothesis, and nonmissense mutations were associated with the highest rate of events. However, given the particular characteristics of the setting of this single study, caution is required before the presence of a splicing mutation is used for risk stratification in clinical practice. It is noteworthy that we were unable to detect any association between the mutation regions classified by Hegele (24) and outcome. It is likely that this classification is useful for predicting phenotypes, rather than their severity or related events.

Clinical implications.   Once DCM develops in persons with LMNA gene mutations, arrhythmogenic risk seems to increase, and ICD implantation should probably be performed earlier than suggested by current guidelines (28). We think that cardiolaminopathies with DCM phenotype deserve tailored clinical monitoring, including early indications for ICD implantation so as to prevent SCD and provide a possible bridge to heart transplantation in end stage HF. This concept fits well with proposals to bring forward ICD implantation in patients who are candidates for pacemaker implantation due to AVB (17,26,27). Given the increased risk of all major events and SCD in LMNA-positive subjects with clinically overt disease, highly competitive sports should be discouraged after detection of any phenotype. For mutated healthy persons, only further follow-up will give an answer on the suitability for agonistic activity. While awaiting these data, we suggest maintaining the sport activity at a nonagonistic level.

	Conclusions

Top Abstract Methods Results Discussion Conclusions References

 
Long-term follow-up of a cohort of families with dilated cardiolaminopathies identified at a single center confirms their high risk of major events, particularly of SCD and ventricular arrhythmias. The emerging consensus in highlighting the risk of life-threatening arrhythmic events for persons with LMNA gene mutations is a warning that should lead to considering special indications for ICD implantation in this group of patients. We think that young healthy mutated patients should probably be advised to enjoy noncompetitive physical leisure activities or low dynamic, noncompetitive sport activities.

	Acknowledgments

 
The authors are grateful to patients and families for their support of the activity of the Centre for Inherited Cardiovascular Diseases and for their helpful contribution to the critical discussion about their disease during the counselings.

	Footnotes

 
Supported by grants "Ricerche Finalizzate e Correnti" from the National Ministry of Health to the IRCCS Policlinico San Matteo, and from Fondazione Cariplo, Milano, Italy.

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