CLINICAL RESEARCH: HEART RHYTHM DISORDER
Prolonged Signal-Averaged P-Wave Duration as an Intermediate Phenotype for Familial Atrial Fibrillation
Dawood Darbar, MD, FACC*,*,
Amanda Hardy, RN*,
Jonathan L. Haines, PhD and
Dan M. Roden, MD, FACC
* Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Manuscript received July 23, 2007;
revised manuscript received November 12, 2007,
accepted November 12, 2007.
* Reprint requests and correspondence: Dr. Dawood Darbar, Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Room 1285A MRB IV, Nashville, Tennessee 37323-6602. (Email: dawood.darbar{at}vanderbilt.edu).
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Abstract
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Objectives: This study sought to perform a genome-wide linkage analysis in a large atrial fibrillation (AF) kindred using AF and abnormally prolonged signal-averaged (SA) P-wave duration as the phenotype.
Background: Although inherited forms of AF exist, phenotypic complexity has limited efforts to ascertain mutation carriers and thus identify causal genes. The identification of intermediate or endophenotypes may accelerate this effort.
Methods: A genome-wide linkage analysis was performed in a 4-generation AF kindred of 27 individuals, 8 with AF documented by electrocardiogram. The analysis was performed using AF as the phenotype, and repeated using an abnormally prolonged SA P-wave duration as the phenotype.
Results: Linkage analysis and fine mapping generated a maximum multipoint logarithm of the odds (LOD) score of 3.0 at chromosome 5p15 between markers D5S406 and D5S635. Importantly, 8 heterozygous carriers had a prolonged SA P-wave (203 ± 21 ms) compared with 17 noncarriers (116 ± 12 ms, p < 0.00001). Using prolonged SA P-wave (conventionally defined as >155 ms) as an endophenotype, a maximum LOD score of 3.6 was obtained in the same region of chromosome 5p15, a span of 5.75 centi-Morgans.
Conclusions: In a large AF kindred, we have identified a novel AF locus on chromosome 5p15 and shown that affected individuals with AF and mutation carriers can be identified by a prolonged SA P-wave duration. Importantly, identification of an endophenotype in this kindred not only aided ascertainment of additional family members but also increased the LOD score, providing increased support for linkage at this locus. Identification of the causal gene, mapped to chromosome 5p15, will advance our understanding of the molecular basis of AF.
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Abbreviations and Acronyms
| | AF = atrial fibrillation | | ECG = electrocardiogram | | LOD = logarithm of the odds | | SA = signal-averaged |
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Atrial fibrillation (AF), the most common cardiac arrhythmia, affects approximately 2 million Americans (1) and results in substantial morbidity and mortality (2). Atrial fibrillation is also the most common arrhythmia requiring drug therapy, and the limited success of drug therapy for AF may in part reflect poor understanding of its diverse molecular underlying pathophysiology. Recent studies have provided evidence of a genetic contribution to AF (3,4). Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF (5–9). In addition, a number of loci that confer increased vulnerability to AF have been described (9,10). Although Mendelian forms of AF are not rare (3), large kindreds such as those used to identify disease genes in other inherited arrhythmia syndromes, such as congenital long QT syndrome (11,12), are unusual. One possible reason for such complexity is reduced penetrance with less apparent heritability, and thus a smaller genetic contribution to the ultimate clinical phenotype. Another possible mechanism is that the phenotype may be the result of interaction of several genes, that is, polygenic, each with a small overall contribution. Finally, AF may require additional environmental events to reduce the AF threshold sufficiently to trigger an episode of AF (13).
The paroxysmal nature and variable symptoms in AF, a high prevalence in the general population, and a late age of onset in many individuals all make assignment of the clinical phenotype challenging. A number of strategies can be used to minimize misphenotyping, including affected-individuals-only analysis and diagnosis by offspring, all of which reduce the power and maximum logarithm of the odds (LOD) score. This complexity has compelled a search for new, more effective methods for investigating the genetics of complex diseases such as AF (14). One approach is to use the families of affected individuals as an enriched target population for the definition and evaluation of novel phenotypes. The psychiatric field has pioneered systematic approaches to phenotyping in an attempt to discover intermediate or endophenotypes, that is, subtle or novel phenotypes that are causally related to the poorly penetrant classical clinical syndromes (15). One such example is impaired attention, which has proved useful for genetic studies of schizophrenia (16). In the case of AF, examples of potential endophenotypes include signal-averaged (SA) P-wave duration, pulmonary venous anatomy as assessed by computed tomography or magnetic resonance imaging, and profiles of biomarkers (17,18). If such markers of a reduced threshold for AF can be defined, then not only will they be clinically useful (e.g., to categorize subsets of patients with AF), but they will also accelerate the identification of causal genes.
Signal-averaged P-wave electrocardiograms (ECGs) have been shown to have a potential role in identifying patients at risk of developing paroxysmal AF and those likely to progress from paroxysmal AF to chronic AF (19). The SA P-wave ECG measures delayed potentials indicative of delayed intra-atrial and interatrial conduction. Because conduction delays are critical for the initiation of re-entrant arrhythmias, evidence of a prolonged P-wave duration using signal-averaging techniques provides a means by which patients at risk of developing AF can be identified. In this study, we describe the identification of a novel locus for familial AF that is inherited in an autosomal-dominant manner. In addition, we show that affected individuals with AF can be identified by a prolonged SA P-wave, whereas noncarriers have normal P-wave duration, supporting a primary defect in atrial activation as the cause of AF in this kindred.
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Methods
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Clinical evaluations.
All studies were performed with the approval of the Institutional Review Board of Vanderbilt University Medical Center. Each family member had a physical examination and gave a detailed history to identify past medical conditions, symptoms while in AF, and the medical history of first-degree relatives. Each subject was evaluated by 12-lead ECG, echocardiogram, P-wave SA ECG, and laboratory studies including thyroid-stimulating hormone.
The proband and relatives were clinically classified using a consistently applied set of definitions. The AF was defined as replacement of sinus P waves by rapid oscillations or fibrillatory waves that varied in size, shape, and timing and were associated with an irregular ventricular response when atrioventricular conduction was intact. Documentation of AF on an ECG, rhythm strip, event, or Holter monitor was required. Lone AF was defined as AF in individuals <60 years of age without hypertension or overt structural heart disease by clinical examination, ECG, and echocardiography. The upper limits of normal for cardiac chamber dimensions were based on age and body surface area (20). We defined as affected those individuals with ECG-documented AF. We defined as unaffected only those individuals >60 years of age with no personal history of AF and no offspring with a history of AF. All other family members were defined as unknown for the purpose of initial genetic analyses.
Signal-averaged P-wave duration.
All subjects were in sinus rhythm at the time of the SA P-wave recording. In addition, all cardioactive drugs, including antiarrhythmic drugs, were withdrawn for at least 5 half-lives before the recordings were performed. The methodology of SA P-wave duration recording and analysis has been described previously (19,21). This was recorded using the MAC 5000 (GE Medical Systems, Milwaukee, Wisconsin). In brief, the SA P-wave duration was obtained from a relaxed patient in a supine position in a quiet room, free from electrical interference. It incorporates 3 bipolar orthogonal leads referred to as the X, Y, and Z leads, which correspond to those used for the acquisition of the standard ECG. The signal from each lead was amplified to 5 µV/cm, passed through a low-bandpass filter of 300 Hz and a high-bandpass filter of 40 Hz, and then converted from analog-to-digital data to a 12-bit accuracy at the sampling rate of 1 kHz. A specially filtered P-wave derived from the selected dominant sinus P-wave of lead II served as a reference signal for all processing. After passing through a P-wave recognition program to eliminate ectopic atrial beats, >200 beats were averaged on a trigger point within the specially filtered P-wave. If the noise level remained >0.5 µV, even after 200-beat averaging, the averaging was continued until the peak noise was reduced to <0.5 µV. The filtered signals for the X, Y, and Z leads were combined into a vector magnitude, the root mean square value. The filtered P-wave duration in this vector was calculated. Previous studies have identified an abnormal SA P-wave filtered duration as >155 ms (22).
Genetic analyses.
Whole blood for genomic deoxyribonucleic acid (DNA) extraction was obtained from the proband and all consenting family members. Genetic analyses were performed on all available individuals, regardless of affection status. A genome-wide scan was performed by deCODE (Reykjavik, Iceland) using their 546-marker panel and corresponding genetic map (23,24). These microsatellite markers span the human genome by every approximately 8 centi-Morgans (cM). Genotypes were ascertained without knowledge of clinical status. Fine mapping was performed at candidate loci using additional markers identified at the Genethon and Center for Medical Genetics, Marshfield Medical Research Foundation databases.
Statistical analyses.
Two-point and multipoint LOD scores were calculated assuming a disease penetrance of 0.95. Allele frequencies were estimated from the population. Two-point LOD scores were calculated with the MLINK program (25,26). To estimate the most likely location for disease, multipoint LOD scores were calculated using the program SIMLINK (27,28). The parameters used for multipoint linkage analysis were identical to those for 2-point linkage analysis. The distance (cM) between markers was based on the data from the Center for Medical Genetics, Marshfield Medical Research Foundation database. Data for the SA P-wave duration are presented as the mean value ± SD. Comparison of means was performed using the Student t-test.
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Results
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Clinical characteristics of the pedigree.
In the 4-generation family, AF segregated as an autosomal-dominant trait (Fig. 1). The family originated from the middle Tennessee region of the U.S. In total 27 family members (18 male, 9 female; ages from 12 to 70 years) were involved in the study, 26 of whom provided DNA samples. Nine family members had the diagnosis excluded as discussed above. One consanguineous marriage occurred in this family. There were 8 individuals with documented AF on the ECG. Patient I:1 was coincidentally diagnosed with paroxysmal AF at the age of 41 when her ECG was recorded for occupational reasons. Although the patient had noticed fatigue and decreased exercise tolerance, these complaints had not prompted her to see a physician. At the present time, Patient I:1 has chronic AF that is managed with rate-control therapy. Patient I:2 was diagnosed with symptomatic paroxysmal AF at the age of 45 years. He initially had a response to antiarrhythmic drugs, but gradually over the next decade his AF became drug resistant and he was placed on rate-control therapy for chronic AF. Because he died at the age of 56, probably of a cardiovascular cause, a DNA sample was not available for this subject. The proband (II:18) developed symptoms of palpitations, lightheadedness, and dizziness at the age of 32 but did not seek medical attention until he was in his 40s. At the present time, he continues to have symptomatic paroxysmal AF that is adequately controlled with a combination of digoxin and beta-blockers.
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Figure 1 Pedigree and Haplotypes for Family VAF-1
Filled symbols indicate individuals with atrial fibrillation (AF), square or round dashed symbols indicate obligate carriers, and diagonal lines indicate deceased individuals. Proband is indicated by the arrow. Underlined numbers indicate unaffected individuals used in linkage analyses. Results of genotypic analysis are shown for markers D5S2088, D5S406, D52054, D5635, D5807, and D5S1486 below each individual. The vertical black line to the left of some series of numbers indicates disease haplotype. One consanguineous marriage is indicated by an equals sign. VAF = Vanderbilt atrial fibrillation.
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In affected individuals, the mean age of onset of AF was 32 ± 10 years (range 18 to 45 years). In this kindred AF began with paroxysmal episodes, but in 2 family members (I:1 and I:2) became chronic over time. The QT interval was normal in all affected individuals. In most affected subjects, there was evidence of mild left atrial dilation and no other evidence of structural heart disease. However, echocardiography did reveal mild concentric left ventricular hypertrophy in 2 subjects (II:16 and II:20). In both of these subjects, AF was diagnosed at least 2 years before treatment for hypertension was initiated. No members of this kindred have undergone invasive electrophysiological evaluation.
Linkage analysis.
We identified preliminary evidence of linkage with the marker D5S2054 (maximum LOD score = 2.4, theta = 0) on chromosome 5p15. Additional markers, including D5S2088, D5S406, D5S635, D5S807, and D5S1486 were used for fine mapping. The peak multipoint LOD score of 3.0 was obtained for a region between markers D5S406 and D5S635. These results indicate that the autosomal-dominant AF gene is located between markers D5S406 and D5S635, a region 5.75 cM in length (Fig. 2).
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Figure 2 Ideogram of Chromosome 5 With Giemsa Banding Patterns and Localization of the AF Locus
Genetic map with chromosome 5p15 markers; location of putative AF gene is shown on the right. AF = atrial fibrillation.
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Signal-averaged P-wave duration.
This was performed in 25 family members, including 8 family members with documented AF and 17 individuals in whom the diagnosis was ruled out. Because Patient I:1 was in chronic AF and I:2 was deceased, no SA P-wave duration was obtained in these individuals. In individuals carrying the AF haplotype and with a documented history of AF, the SA P-wave duration was prolonged (Table 1) (Fig. 3). Importantly, 8 heterozygous carriers had a prolonged SA P-wave (203 ± 21 ms) compared with 17 noncarriers (116 ± 12 ms, p < 0.00001). Using prolonged SA P-wave (conventionally defined as >155 ms [22]) as an endophenotype for AF, genome-wide linkage was performed with 8 individuals classified as affected and 17 unaffected. We identified evidence of linkage with the marker D5S2054 (maximum LOD score = 3.6, theta = 0) in the same region of chromosome 5p15 (Table 2). This LOD score is robust to changes in penetrance or allele frequency, and even analyses of affected individuals only result in 2-point LOD scores of >2.8. Because this marker was fully informative, a multipoint calculation achieved no higher LOD score. Although a prolonged SA P-wave duration allowed us to improve the LOD score for this kindred, it did not narrow the region of interest.
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Figure 3 Representative Tracings of Signal-Averaged P-Wave Duration
This patient (II:13) had no history or symptoms of AF, did not carry the AF haplotype, and had a normal P-wave duration (top). A patient (II:20) with AF and the disease haplotype who had prolonged SA P-wave duration (bottom). AF = atrial fibrillation.
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Discussion
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In this study, we have identified a novel locus for AF that is mapped to chromosome 5p15 and characterized by early onset of AF. In addition, we have also shown that prolongation of the SA P-wave duration cosegregates with AF and seems to be an intermediate marker (endophenotype) for identifying individuals at increased risk for developing AF in this kindred. Importantly, identification of an endophenotype not only aided ascertainment of additional family members but also increased the LOD score, providing increased support for linkage at this locus. Identification of the causal gene, mapped to chromosome 5p15, will not only advance our understanding of the molecular basis of AF but may also provide new therapeutic approaches to treat this common and morbid condition.
The locus we have defined on chromosome 5p15 currently extends over 5.75 cM. On the basis of the locations of the recombinant boundaries and the sequence of the human genome, the region includes 5 annotated genes. One putative candidate gene is A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 16 (ADAMTS-16) (29), whose functions include collagen processing as procollagen N-proteinase and cleavage of the matrix proteoglycans aggrecan, as well as inhibition of angiogenesis and blood coagulation homeostasis (30). However, we have been unable to identify transcripts of this gene in a human cardiac complementary DNA library. We have also performed direct DNA sequence analysis on the remaining 4 genes (LOC340094, FLJ33360, KIAA0947, and MED10) in affected subjects II:10 and II:18 with unaffected II:22 as the control. However, no mutation was identified in the coding and intron splice sequences of these genes.
Several lines of evidence raise the possibility that AF and some forms of dilated cardiomyopathy may be allelic. For example, this region of 5p is close to but does not overlap with a previously reported locus for neonatal AF that is associated with sudden death and variable cardiomyopathy (31). However, in our AF kindred, dilated cardiomyopathy was not a feature of the clinical presentation. Support for this has also recently come from identification of mutations in the cardiac sodium channel (SCN5A) that manifest as early onset dilated cardiomyopathy and AF (32,33). The cloning of the causative genes at the 10q22, 6q14-16, and 5p13 loci will further clarify the relationship between AF and cardiomyopathy (9,10,31).
Study limitations.
The genetic basis for the majority of patients with AF remains unknown. Although familial AF has been mapped to 3 other loci, identification of the causative genes has proved elusive. One possible reason relates to phenotypic complexity of AF with the lack of a biological basis for the classification of the disease. Others include reduced penetrance of the gene and polygenic nature of the disease. Consequently, the identification of well-defined endophenotypes that cosegregate with AF has been proposed to aid gene mapping (14). An endophenotype should not only cosegregate with the condition but also be present in an individual whether or not AF is present. Although it is possible that as the left atrial size increases secondary to AF, the P-wave duration may lengthen, in our study there was no uniform increase in left atrial size despite prolongation of the SA P-wave duration in individuals carrying the AF haplotype. In fact, the 1 individual with the AF haplotype (IV:1) but no documented history or symptoms of AF had a normal left atrial size. Therefore, in this study, we showed that not only individuals with AF but also those who do not carry the AF haplotype could be identified by SA ECG.
Abnormalities of the P-wave, such as increased duration and right and left atrial hypertrophy, are associated with an increased incidence of AF (34). In our kindred, strikingly abnormal P-wave durations occurred in the absence of other pathology. The routine ECG may, however, not identify many other P-wave abnormalities that are risk factors for AF and are seen during intracardiac recording after programmed stimulation. These abnormalities not only reflect structural abnormalities of the atria but also alterations in electrical properties, the most important of which are intra-atrial and interatrial conduction abnormalities and abnormalities of refractoriness throughout the atria. Because the SA P-wave ECG is able to record low-level electrical signals, more precise measurements of duration and amplitude of the P-wave can be made. Furthermore, SA P-wave duration has been shown, in retrospective and prospective studies, to be able to discriminate between those at risk and those without risk of developing AF (35,36).
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Conclusions
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Our study showed that in this kindred, SA P-wave duration was able to identify affected individuals and carriers of the AF haplotype. However, validation studies will need to be performed in additional cohorts before it can be concluded that it is a useful endophenotype for genetic studies of AF.
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Footnotes
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This work was supported by National Institutes of Health grant HL075266 to Dr. Darbar and UO1 HL65962 to Dr. Roden.
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References
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