A novel mutation, Ser143Pro, in the lamin A/C gene is common in finnish patients with familial dilated cardiomyopathy

Satu Kärkkäinena, Tiina Heliöb, Raija Miettinena, Petri Tuomainena, Paula Peltolaa, Juha Rummukainena, Kari Ylitaloa, Maija Kaartinenb, Johanna Kuusistoa, Lauri Toivonenb, Markku S Nieminenb, Markku Laaksoa and Keijo Peuhkurinena,*

a Department of Medicine, University of Kuopio, P.O. Box 1777, Kuopio, Finland
b Department of Medicine, University of Helsinki, Helsinki, Finland

* Corresponding author. Tel.: +358-17173956; fax: +358-17173959
E-mail address: keijo.peuhkurinen{at}kuh.fi

Received 3 August 2003; revised 1 January 2004; accepted 22 January 2004 See page 812, for the editorial comment on this article.1

Abstract

Aims The mutations most frequently associated with dilated cardiomyopathy (DCM) have been reported in the lamin A/C gene. The role of variants of the lamin A/C gene was investigated in patients with DCM from eastern and southern Finland.

Methods and results All 12 exons of the lamin A/C gene were screened in 18 well-characterised familial DCM patients from eastern and southern Finland and in 72 sporadic DCM patients from eastern Finland using the PCR-SSCP method. A novel mutation, Ser143Pro (S143P), was detected in the lamin A/C gene in 24 subjects from 5 unrelated families and in one sporadic case of DCM. Sinus or atrioventricular nodal dysfunction occurred in the majority of the affected subjects, many of which required pacemaker implantation. Seven patients (28%) with the S143P mutation died suddenly or from progressive heart failure, or underwent heart transplantation. The haplotypes 5–5–5–3, 5–5–5–2, and 5–5–5–1 co-segregated with the Ser143Pro mutation, suggesting a founder effect of this mutation.

Conclusions A novel mutation S143P in the lamin A/C gene was found to be common among Finnish DCM patients. Haplotype analysis strongly suggests a founder effect of this mutation. The phenotype is characterised by severe heart failure, progressive atrioventricular conduction defects, and sudden death. Screening for the lamin A/C gene and, particularly, the S143P mutation seems warranted when patients with DCM have conduction system disturbances.

Key Words: Dilated cardiomyopathy • Lamin A/C gene

Introduction

Dilated cardiomyopathy (DCM) is a primary myocardial disease characterised by left ventricular dilatation and impaired contraction of the left ventricle.1 DCM typically has an autosomal dominant inheritance and is familial in approximately 20–35% cases of idiopathic DCM.2–4 DCM causes considerable morbidity and is one of the important causes of sudden cardiac death. The genetics of DCM has been intensively investigated, but so far only isolated mutations in 15 different genes (tafazzin, dystrophin, cardiac actin, desmin, {delta}-sarcoglycan, lamin A/C, troponin T, ß-myosin heavy chain, {alpha}-tropomyosin, titin, metavinculin, myosin binding protein-C, muscle LIM protein, telethonin, and phospholamban) have been reported to be associated with DCM.5–21

Lamin A/C is a nuclear intermediate filament that is one of the major structural components of the lamina network underlying and mechanically supporting the nuclear envelope.22 Lamin A/C probably also has a role in cell division, nuclear growth, and the anchorage of nuclear envelope proteins.23,24 Lamin A/C has three different parts: a central, {alpha}-helical, coiled-coil rod domain, a non-helical N-terminal head, and a C-terminal tail.23 Most of the mutations associated with cardiac abnormalities are located in the central rod domain.

Defects in the lamin A/C gene have been shown to be responsible for different diseases, Emery–Dreifuss muscular dystrophy, limb-girdle muscular dystrophy type 1B, Dunnigan-type familial partial lipodystrophy, Charcot–Marie–Tooth disease, mandibuloacral dysplasia, Hutchison–Gilford progeria, multisystem dystrophy syndrome, and dilated cardiomyopathy with conduction abnormalities.13,14,25–31 The lamin A/C gene is a promising candidate gene for DCM and disease-causing mutations have been reported in previous studies.13–15,32–36 Therefore, we screened for the lamin A/C gene in Finnish patients with DCM.

Materials and methods

Index patients
We studied 18 well-characterised patients with familial DCM and 72 patients with sporadic DCM from the Kuopio University Hospital region in eastern Finland and the Helsinki University Hospital region in southern Finland. The index patients were unrelated. Commonly approved diagnostic criteria, left ventricular (LV) ejection fraction (EF) 45%, and LV end-diastolic diameter 27 mm/m2 at the time of diagnosis were applied, and all secondary causes of DCM were carefully excluded.37 One patient fulfilled diagnostic criteria of DCM at autopsy and was included in the study. All DCM patients in this study were consecutive patients referred to the Kuopio or Helsinki University Hospital without any preselection (for example, conduction system disorders). The patients were evaluated by personal and family history, physical examination, 12-lead electrocardiograph (ECG), chest radiograph, and transthoracic echocardiography (M-mode, two-dimensional, and Doppler). Altogether, 88% of the study patients underwent diagnostic coronary angiography. Index subjects did not have any symptoms or signs of skeletal muscle disease and their creatine kinase (CK) levels were normal, indicating that they did not suffer from clinically significant skeletal muscle disease. The clinical characteristics, including ECG and echocardiography findings, are shown in Table 1. All available first-degree relatives of the 18 families were evaluated by physical examination, 12-lead ECG, and transthoracic echocardiography. Diagnostic criteria for family members have been previously described.38 The study protocol was approved by the Ethics Committees of the University of Kuopio and Helsinki, and was in compliance with the Helsinki Declaration.


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Table 1 Clinical characteristics and ECG and echocardiography findings of patients with dilated cardiomyopathy (DCM)

 
Controls
A group of 172 clinically healthy individuals randomly selected from subjects living in the Kuopio University Hospital region (mean age 53 years) without any family history of DCM and with a similar ethnic background formed the control group for genetic analyses to exclude the possibility that the mutations in the lamin A/C gene were not polymorphisms in patients with DCM. Echocardiography was performed in 82 of them. Control subjects were screened using the PCR-SSCP method.

Single-strand conformation polymorphism analysis
Genomic DNA was prepared from peripheral blood leukocytes. Paraffin-embedded tissues were used for DNA studies. These tissues were cut into 5- sections and one or two sections (approx. 1 cm2) were used for each extraction. Primers for the lamin A/C gene were designed on the basis of GenBank sequences L12399, L12400, and L12401. Details of the PCR have been previously described.39 PCR conditions were denaturation at 94 °C for 3 min, followed by 35 cycles of denaturation at 94 °C for 40 s, annealing at 60–66 °C for 45 s and extension at 72 °C for 45 s, with final extension at 72 °C for 4 min.

The SSCP analysis was performed as previously described.39 Our SSCP method has been previously validated against the known variants of the lipoprotein lipase gene.40,41 Genomic DNA from individuals with different SSCP patterns was re-amplified using the same primers, purified on a 2% agarose gel (NuSieve GTG, FMC Bioproducts, Rockland, Maine, USA) when necessary, and sequenced with ABI Prism BigDye Terminator Cycle Sequencing Ready Reaction Kits using the ABI Prism 310 Genetic Analyzer (Applied Biosystems, Foster City, CA).

Haplotype analysis
Primers for four microsatellite markers (D1S498, D1S305, D1S506, and D1S484) were synthesised. The lamin A/C gene is located between the D1S305 and D1S506 markers. Distances between the different dinucleotide markers were 2,955,520, 2,615,155, and 3,844,951 bp, respectively. The fluorescein-labelled, polymorphic DNA fragments were amplified with PCR and analysed with an automated laser fluorescence DNA sequencer (ALF express, Amersham Pharmacia Biotech, Uppsala, Sweden).

Statistical methods
Data are given as means±SD, or percentages. Statistical analyses were performed with statistical software packages (SPSS Win 9.0., SPSS Inc., Chicago, IL). Survival analyses were estimated by the Kaplan–Meier method. P values were derived by log-rank analysis and a p value <0.05 in 2-sided test was defined as statistically significant.

Results

Genetic screening
In this study, all 12 exons of the lamin A/C gene were screened for variants in a total of 90 DCM patients by the PCR-SSCP method. We found a formerly unreported mutation, S143P, in the lamin A/C gene (Fig. 1) in five unrelated families and in one DCM patient who had been adopted (the biological parents were unknown). With the exception of subjects <30 years, all S143P mutation carriers were clinically affected (Fig. 2). In haplotype analysis, haplotype 5–5–5–3 and five silent variants (Table 4) co-segregated with the S143P mutation in three families and in one sporadic patient (families A, B, and E and the sporadic patient=family F). In families C and D, haplotypes 5–5–5–3, 5–5–5–2, and 5–5–5–1 and five silent variants co-segregated with the S143P mutation. The haplotypes are shown in Fig. 2. The mutation was not found in more than 344 chromosomes of clinically healthy persons, indicating that the S143P is not a common polymorphism in the Finnish population.



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Figure 1 (a) SSCP film showing mutated and normal samples (M=mutation, N=Normal). (b) Sequences of normal and mutated samples showing a T to C substitution in codon 143 of the lamin A/C gene.

 


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Figure 2 Pedigrees of the six families with dilated cardiomyopathy (DCM) carrying the S143P mutation in the lamin A/C gene. Arrow indicates the proband of the family. Squares represent male family members, circles represent female family members, and slashed symbols represent deceased family members. Solid symbols indicate family members who fulfilled diagnostic criteria for DCM, open symbols indicate unaffected members, and semicircles and squares indicate members who do not yet fulfil all diagnostic criteria for DCM, but are clinically affected. N means unknown clinical and genetic status. Mutation carriers are marked by the + sign and the – sign means that family member is not a mutation carrier. Haplotypes constructed from the markers D1S498, D1S305, D1S506, and D1S484 are depicted under each individual. The haplotypes co-segregating with the Ser143Pro mutation are boxed.

 

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Table 4 Variants of the lamin A/C gene in patients with dilated cardiomyopathy (DCM)

 
Phenotypes of the S143P mutation carriers
The pedigrees and clinical data of the affected families are shown in Fig. 2 and in Table 2. The clinical characteristics of the S143P mutation carriers are shown in Table 3.


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Table 2 Family members with the S143P mutation in the lamin A/C gene

 

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Table 3 Clinical characteristics of proven or likely S143P mutation carriers

 
In family A, all members of the second generation carry the S143P mutation. Two of them (II: 2 and II: 4) fulfil all diagnostic criteria for DCM and are also symptomatic. The youngest of the siblings (II: 5) has not developed clinical disease, but she has first-degree atrioventricular (AV) block on ECG. Other mutation carriers are young, asymptomatic, and free of clinical disease. One of them (III: 3) has first-degree atrioventricular block on ECGs and two of them (III: 2 and III: 3) also have dilatation of the left atrium on echocardiography. One family member (III: 4) refused to undergo clinical and genetic studies. Family member I: 1 had third-degree AV block in her 60s and required implantation of a permanent pacemaker.

In family B, 8 members (III: 1, III: 8, III: 11, III: 13, IV: 1, IV: 2, IV: 8, and V: 1) carry the S143P mutation. Five of the mutation carriers have had pacemakers implanted because of conduction defects. Family member III: 1 had bradycardia during two pregnancies and a pacemaker was implanted for third-degree AV block. Ten years later she developed severe DCM and underwent heart transplantation. Two of her sons also developed heart failure and conduction defects, which clinically manifested as slow atrial fibrillation and necessitated pacemaker implantation. Another son died suddenly at the age of 34 years and the autopsy confirmed DCM. Recently, family member IV: 1 experienced recurrent ICD discharges (3 years after implantation) due to episodes of ventricular tachycardia and fibrillation. Family member III: 8 has severe disease and he is under consideration for heart transplantation. Two other male family members (III: 5 and IV: 11) experienced unexpected sudden death. One drowned and the other died in his sleep. Unfortunately, no DNA samples are available. Both had been considered clinically healthy, but one of them (IV: 11) had first-degree AV block in an ECG recorded six years before his death. He is considered an obligatory mutation carrier because his son (V: 1) has the mutation. Family member V: 1 is an 11-year-old male and clinically healthy. Family member II: 6 received a pacemaker for third-degree AV block and died suddenly at the age of 68 years. One mutation carrier (IV: 8) is very young and has normal ECG and echocardiographic findings. Other family members are clinically healthy and are not S143P mutation carriers.

In family C, proband III: 6 died suddenly and the autopsy revealed DCM. He did not have any symptoms or signs of the disease before his death. He was a carrier of the S143P mutation. Two of his sisters carry the same mutation and one of them (III: 4) has suffered severe bradycardia with second-degree AV block and sinus node disease, requiring a pacemaker. Another sister (III: 8) carrying the mutation has slight hypokinesia of the left ventricle and a low normal (~50%) ejection fraction, first-degree AV block, and multiple premature ventricular complexes on ambulatory ECG recording. The other S143P mutation carriers are young and do not have clinical disease. Family member II: 6 was diagnosed as having DCM and slight hypertrophy of the interventricular septum verified by echocardiography at the age of 46 years. He had left bundle-branch block, and one year later needed a pacemaker due to syncopal attacks. DCM was verified by echocardiography two years after the first symptoms. He died from a pulmonary embolism at the age of 48 years. No DNA sample is available.

In family D, two family members carry the S143P mutation. The index patient's (III: 1) first symptoms were atrial fibrillation and flutter. Two years later, AV block and episodes of polymorphic ventricular tachycardia developed, and dilatation of the right ventricle with impaired systolic function was detected in echocardiography. Due to ventricular tachycardia, an automatic implantable cardioverter-defibrillator (ICD) was implanted, and heart transplantation later became necessary because of worsening heart failure. Before heart transplantation, he suffered from several episodes of ventricular tachycardia and fibrillation, which were adequately treated with ICD. His clinical disease at first resembled arrhythmogenic right ventricular dysplasia (ARVD), but the endomyocardial biopsy specimen did not reveal fatty replacement, which is typical of ARVD. His asymptomatic sister (III: 3) also carries the mutation. She has first-second degree AV block on her ECG, but the echocardiography is normal. According to medical records, his grandfather (I: 1) had cardiomegaly on chest radiographs. Unfortunately, we do not have his DNA sample or echocardiography data. Other family members who do not carry the mutation are clinically healthy with normal echocardiographic findings.

Family E was included in the study because three family members (I: 1, II: 2 and II: 3) had a clinical diagnosis of DCM in their medical history. They all died of cardiomyopathy at the ages of 38, 43, and 57 years. Two family members (II: 1 and III: 1) were alive when this study was initiated. One family member (II: 1) did not fulfil the diagnostic criteria for DCM (LVEDD 47 mm and EF 54%), but she carried the S143P mutation. She developed the first symptoms and signs (syncopal attacks and slow atrial fibrillation) of the disease at the age of 40 years. A pacemaker was implanted at the age of 55 years. She died accidentally five years later. Her daughter is a carrier of the S143P mutation and has first-degree AV block. She is asymptomatic and has a normal echocardiography. DNA samples from other deceased family members are not available.

The sixth index patient (family F) in our study carried the same S143P mutation. She fulfilled diagnostic criteria for DCM and had slow atrial fibrillation and episodes of ventricular tachycardia. Therefore, a pacemaker (VVI+ICD) was implanted. She experienced hemiplegia due to brain infarction and several ICD shocks, but she died from advanced heart failure at the age of 51 years. She was adopted and was not aware of the identity of her biological parents. Her daughter does not carry the mutation and has normal ECG and echocardiography findings.

Other variants of the lamin A/C gene were detected, but none of them was associated with DCM. All detected variants of the lamin A/C gene are presented in Table 4.

Survival analysis
Kaplan–Meier survival analysis was performed for different endpoints. Only index patients with the S143P mutation () were included in statistical analyses to avoid the potential bias created by familiarity. Survival analysis showed that patients with the S143P mutation had a significantly poorer prognosis than non-carriers (2 deaths in 6 subjects vs. 11 deaths in 84 subjects, ) (Fig. 3(a)). The mean survival times for S143P carriers and non-carriers were 51.3 and 70.6 years, respectively. Analysis of the composite endpoint of death, heart transplantation, malignant arrhythmias, resuscitation, and ICD shocks showed a statistically significant difference between the mutation carriers and non-carriers (4 events in 6 subjects vs. 18 events in 84 subjects, ) (Fig. 3(b)). When heart failure or pacemaker implantation were included in the composite endpoint, the prognosis of carriers of the S143P mutation did not differ from that of non-carriers () (Fig. 3(c)).



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Figure 3 Kaplan–Meier cumulative survival curves for (a) death and for (b) death, heart transplantation, malignant arrhythmias, resuscitation, or ICD shocks in patients with the S143P mutation (dashed line) and patients with DCM, but no lamin A/C mutation (solid line). (c) Kaplan–Meier curve for the composite endpoint of death, heart transplantation, malignant arrhythmias, resuscitation, ICD shocks, heart failure, and pacemaker implantation in patients with the S143P mutation and other DCM patients. {blacksquare} represents mutation carriers who do not have the endpoint (censored cases) and {blacktriangledown} represents non-carriers who do not have the endpoint (censored cases). P values are derived by log rank.

 
Discussion

We screened all 12 exons of the lamin A/C gene and found a novel mutation, S143P, which was associated with DCM in six probands belonging to different families. The S143P mutation is the first DCM-associated mutation in the lamin A/C gene detected in several DCM families.

Evidence for a disease-associated founder mutation
Several of our findings support the idea that the S143P mutation is a DCM-associated mutation. First, this mutation was found in several family members of six unrelated families with a similar phenotype. Only the younger family members (under 30 years old) did not have any signs of the disease on ECG or echocardiography. Second, this mutation was not detected in 172 healthy controls, excluding the possibility of a common polymorphism. Third, the Ser143Pro mutation affects a highly conserved residue of the lamin A/C gene. Additionally, haplotype analysis strongly suggested that the S143P mutation is a founder mutation. Family histories, verified back for three generations, did not reveal a common ancestry, but it is probable that the same ancestry would have been found in earlier generations. To our knowledge, the S143P mutation is the first DCM-associated mutation reported in the lamin A/C gene that has features of a founder mutation.

DCM-associated mutations in the lamin A/C gene
The most frequent DCM-associated mutations have been reported in the lamin A/C gene.13–15,32–35,42 DCM-associated mutations in the lamin A/C gene have been reported to cause very similar phenotypes characterised by atrial fibrillation, conduction system disease, ventricular dysrhythmia, need for pacemaker implantation, and high risk of sudden death. Recently, Taylor et al.34 showed that DCM patients with lamin A/C mutations had a poor prognosis compared with other DCM patients. They also found that lamin A/C mutations were associated with supraventricular arrhythmias, conduction defects, mild DCM (slightly dilated left ventricle), and the presence of skeletal muscle disease.

Phenotype of the S143P mutation
The clinical disease caused by the S143P mutation in the lamin A/C gene resembles that reported for other mutations in this gene. The first manifestation of the disease is typically sinus node dysfunction or atrioventricular conduction defect, often progressive in nature, requiring pacemaker implantation. The combination of marked impairment of left ventricular systolic function with relatively mild dilatation of the left ventricle is a later manifestation of the disease, sometimes leading to end-stage heart failure and sudden cardiac death. Overall, the mutation carriers seem to have some abnormalities on ECG or echocardiography at the age of 20–30 years, and almost all of them develop clinical disease by the age of 40 years. One of the S143P mutation carriers (family D, III: 1) had a markedly dilated right ventricle, with a phenotype resembling that of ARVD. This has not been previously reported in DCM patients with mutations in the lamin A/C gene. However, we cannot exclude the possibility that the dilated right ventricle was due to a defect in some other gene.

The S143P mutation seems to be malignant in nature, as Taylor et al.34 previously reported concerning other DCM-associated mutations of the lamin A/C gene. Although the number of mutation carriers was limited in our study, there was a statistically significant difference in survival and in other severe endpoints between mutation carriers and non-carriers, with the exception of the third endpoint, which included heart failure and the need for pacemaker implantation.

Potential mechanisms of sudden cardiac death in carriers of the S143P mutation are likely to have rapid ventricular arrhythmias, but bradycardia and conduction system disorders cannot be excluded. This notion is supported by the clinical history of carriers of the S143P mutation because they had documented ventricular arrhythmias and two of them died although pacemakers were implanted.

Previous studies 13–15,32–34,42 and our study suggest that first-degree AV block in young patients with a family history of DCM can be clinically significant. On the other hand, familial cardiomyopathy should also be suspected in patients with a conduction system disorder and impaired systolic function, although no significant ventricular dilatation is present. Therefore, the generally accepted diagnostic criteria for DCM37 might not be applicable to all patients with lamin A/C mutations.

Potential disease-causing mechanisms of the S143P mutation
The mechanisms by which mutations in the lamin A/C gene cause DCM are not clear. It has been speculated that mutations cause dysfunction or harm the structural integrity of the nuclear membrane, leading to cell death.24,43 Other critical functions of the protein could be signal transduction between cytoplasm and nucleus, interactions with cytoplasmic proteins or protein dimerisation, and other nuclear functions.13,15,23,44 Arbustini et al.14 showed that endomyocardial specimens of the lamin A/C mutation carriers reveal delamination, focal ruptures, blebs, and nuclear pore clustering on myocyte nuclear membranes. Fibrosis, fatty infiltration, and degenerative myocyte changes were also seen in the atrioventricular junctions of those patients. Verga et al.36 have reported that loss of the integrity of myocyte nuclei is common in samples taken from hearts of lamin A/C mutation carriers. They confirmed that mutations in the lamin A/C gene were associated with a loss of protein expression in the selective compartment of non-cycling myocyte nuclei.36 Östlund et al.45 found in myoblasts that lamin A mutants can also be aberrantly localised and alter emerin localisation. Thus, mutations in the LMNA gene are associated with nuclear envelope damage.14,36,46

Almost all mutations in the lamin A/C gene associated with cardiac abnormalities have been located in the rod domain of the protein. It can be hypothesised that the proper function of the rod domain is critical for the normal conduction system of the heart. The S143P mutation is located in coil 1b of the rod domain, which participates in interaction with lamin B.47 Verga et al.36 showed that different mutations in the lamin A/C gene cause similar damage of the nuclear membrane or loss of protein expression. The mutations that they studied were located near the S143P mutation, so it is possible that this mutation has similar consequences for the nuclear envelope. However, the exact molecular mechanisms by which the S143P mutation causes DCM remain to be elucidated.

Prevalence of the S143P mutation
The Finnish population is an ideal population for investigating genetic diseases because of its genetic isolation. Especially, the population living in the eastern part of the country is genetically quite homogeneous, having descended mainly from a small number of founders of Baltic and German origin.48 In our study population from eastern and southern Finland, the S143P mutation was quite common, accounting for ~7% (6/90) of all DCM cases and ~28% (5/18) of familial cases. If only DCM probands with conduction system disease are considered, the S143P mutation accounted for 30% (6/20) of all DCM cases and 50% (5/10) of familial cases. More DCM patients from other areas of Finland need to be screened to obtain more precise estimates of the prevalence of this mutation in the general Finnish population. Because only patients fulfilling all diagnostic criteria for DCM were included in the screening, our data probably underestimate the true prevalence of the S143P mutation. On the other hand, the S143P mutation is a founder mutation, which probably explains the high prevalence of this mutation in Finnish DCM patients. Founder mutations are frequently found also in other monogenetic diseases in Finns, e.g., in hypertrophic cardiomyopathy, congenital hyperinsulinism, familial hypercholesterolaemia, and long-QT syndrome.49–52

Summary

We describe a novel mutation, S143P, in the lamin A/C gene, which is especially common in Finnish patients with familial DCM. The disease is progressive in nature and characterised by conduction system defects. The combination of a marked decrease in left ventricular systolic function with relatively mild dilatation of the left ventricle is a typical later manifestation of the disease. Due to the severe nature of the disease, we recommend screening for the S143P mutation in DCM patients and close clinical follow-up of mutation carriers.

Acknowledgments

This study was supported by the Finnish Foundation for Cardiovascular Research, Finnish Cardiac Society, Aarne Koskelo Foundation, Ida Montin Foundation, The North-Savo Fund of the Finnish Cultural Foundation, Kuopio University Hospital (EVO Grant No. 5140), and Helsinki University Hospital (EVO Grant No. T1010K0002).

Footnotes

1 doi:10.1016/j.ehj.2004.03.007. Back

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