Abstract
Background Paroxysmal episodes of atrial fibrillation frequently occur in Emery-Dreifuss muscular dystrophy (EDMD). Although previous studies have documented a variety of electrocardiographic abnormalities in EDMD, little is still known about P-wave dispersion (PD), an independent risk factor for the development of atrial fibrillation. The aim of our study was to evaluate the P-wave duration and PD in patients with EDMD with conserved systolic and diastolic cardiac function.
Methods The study involved 36 patients with EDMD (age, 20 [SD, 12] years; 26 men) and 36 healthy subjects used as controls, matched for age and sex. P-wave dispersion was carefully measured using 12-lead electrocardiogram. Compared with the healthy control group, patients with EDMD presented increased maximum P-wave duration (108.2 [SD, 22.2] vs 97.8 [SD, 11] milliseconds, P = 0.04) and PD (51.4 [SD, 12.8] vs 39.3 [SD, 9.7] milliseconds, P = 0.004) values. No statistically significant differences in left atrium diameter (37.1 [SD, 2.9] vs 34.1 [SD, 4.2] mm, P = 0.3) and maximum left atrium volume (15.2 [SD, 3.8] vs 14.1 [SD, 4.2] mL/m2, P = 0.4) were found between the 2 groups. We divided our study population into 2 subgroups, according to the different genetic diagnosis, patients with laminopathy EDMD (n = 17) or with emerinopathy EDMD (n = 19). No statistically significant differences were found in PD between the 2 subgroups (54.6 [SD, 15.6] vs 50.2 [SD, 11.5] milliseconds, P = 0.4).
Conclusions Our study showed a significant increase of maximum P-wave duration and PD in patients with EDMD with conserved systolic and diastolic cardiac function.
Emery-Dreifuss muscular dystrophy (EDMD)-as firstly described by Emery and Dreifuss in 1966-is a hereditary muscle disorder characterized by slowly progressive muscle wasting and weakness with humeroperoneal distribution the early stages, early contractures of the elbows, Achilles tendon and postcervical muscles, and cardiomyopathy.1Emery-Dreifuss muscular dystrophy can be inherited either as an X-linked recessive disorder, caused by mutations in the STA gene that encodes the nuclear protein emerin on chromosome Xq28, or as an autosomal dominant trait, caused by mutations in the gene encoding of the nuclear protein lamin A/C on chromosome 1q21.2.2Cardiomyopathy, presenting most often as atrioventricular block, is the most serious and life-threatening clinical manifestation of the disease and usually appears later compared with muscle impairment. Cardiac abnormalities have been described in both variants of the disease. Specific cardiac arrhythmias associated with EDMD include sinus node dysfunction, atrial flutter, atrial fibrillation (AF), heart block, ventricular tachycardia, and ventricular fibrillation.3Previous studies have documented the specific histopathologic pattern, valued by cardiac muscle biopsy, characterized by diffuse fibrosis and fatty acid infiltration,4which could be responsible of the paroxysmal episodes of AF that frequently occur in patients with EDMD. P-wave dispersion (PD) is defined as the difference between the maximum and minimum P-wave duration on a standard 12-lead electrocardiogram (ECG). P-wave dispersion is considered to reflect the discontinuous and inhomogeneous propagation of sinus impulses and the prolongation of atrial conduction time.5In previous studies, it was shown that PD prolongation is an independent risk factor for the development of AF.6,7The aim of our study was to evaluate the P-wave duration and PD in patients with EDMD with conserved systolic and diastolic cardiac function.
MATERIALS AND METHODS
Study Population
Seventy-one patients with EDMD observed by the Cardiomyology and Medical Genetic Section of the Second University of Naples were screened to participate in the study. Subjects with a history of hypertension (n = 2), obesity (n = 2), previous AF (n = 3), electrolyte imbalance (n = 1), valvular heart disease (n = 1), diabetes mellitus or impaired glucose tolerance (n = 2), severe chronic renal insufficiency (n = 1), thyroid disorders (n = 1), chronic obstructive pulmonary disease (n = 3), cardiomyopathy (n = 7), sick sinus syndrome (n = 7), left bundle branch block (n = 2), and atrioventricular conduction abnormalities on ECG (n = 3) were excluded from the study. The study involved 36 subjects with EDMD (26 men), with a mean age of 20 [SD, 12] years and a mean body mass index (BMI) of 20 [SD, 5] kg/m2. Thirty-six age- and sex-matched healthy subjects without EDMD were also recruited as controls. All patients were in sinus rhythm and asymptomatic for palpitations, chest pain, and dyspnea; none of them were taking medications known to affect ECG intervals. Eighteen patients with EDMD had no apparent muscular involvement. Nine patients with EDMD had only muscle wasting and weakness with humeroperoneal distribution and contractures of postcervical muscles. Five patients with EDMD had flexion deformities of both elbows, plantar flexion deformities of both feet, and a mild degree of kyphoscoliosis with a consequent mild respiratory involvement; in this group, the pulmonary spirometry showed a mild degree restrictive pattern with a similar reduction of all lung volumes and unchanged Tiffeneau and Motley indices. Four patients with EDMD presented contractures of both elbows and Achilles tendons, associated with a lumbar lordosis. Electroneuromyographic findings showed mixed patterns with fibrillations and fasciculations; motor units seemed prolonged in duration, very polyphasic, increased in amplitude and moderately reduced in numbers in all muscles tested in our cohort of patients EDMD, except for the eighteen patients with EDMD with no apparent muscular involvement. The motor nerve conduction velocities and sensory latencies were normal. Despite these abnormalities, their mobility was not very limited. All subjects gave their written informed consent.
Study Protocol
Medical history, physical examination, anthropometric evaluation, 12-lead surface ECG, 2-dimensional color Doppler echocardiography, ECG Holter monitoring, electroneuromyography, and pulmonary spirometry were performed in the study population. The patients were rested for at least 15 minutes before cardiovascular assessments, including ECG and echocardiography.
ECG Measurements
All subjects underwent a routine standard 12-lead body surface ECG recorded at a paper speed of 50 mm/s and a gain of 10 mm/mV in the supine position and were breathing freely but not allowed to speak during the ECG recording. To avoid diurnal variations, we generally performed the ECG recordings at the same time (9-10 am). The analysis was performed by 1 investigator only without knowledge of the subjects' clinic status. Electrocardiograms were transferred to a personal computer by an optical scanner and then magnified 400 times by Adobe Photoshop software (Adobe Systems Incorporated, San Jose, CA). P-wave duration measurement was manually performed with the use of computer software (configurable measurement system). Intraobserver coefficients of variation for P-wave variables were found to be less than 5% and nonsignificant. In each ECG lead, the analysis included 3 consecutive heart cycles wherever possible. Electrocardiogram with measurable P wave in less than 10 leads were excluded from the analysis. The onset of P wave was defined as the junction between the isoelectric line and the start of P-wave deflection, and the offset of the P wave as the junction between the end of the P-wave deflection and the isoelectric line.8,9If starting points and end points were not clear, the derivations including these points were taken as excluding criteria from the study. Maximum and minimum P-wave durations were measured. Maximum P-wave duration was defined as the longest P-wave duration, and minimum P-wave duration was defined as the shortest P-wave duration. P-wave dispersion was defined as the difference between the maximum P-wave duration and the minimum P-wave duration.
Echocardiographic Measurements
Images were gathered with a standard ultrasound machine with a 3.5-MHz phased-array probe (M3S; GE Vivid Seven, General Electric, Waukesha, WI). All the echocardiographic studies were digitally stored, and all the measurements were performed offline by 2 independent observers who were blinded to the clinical status of the subjects. Left atrium diameter (LAD) was measured during systole along the parasternal long-axis view from the 2-dimensional guided M-mode tracing; LA length was measured from the apical 4-chamber view during systole. The maximum LA volume (LAV) was calculated from apical 4- and 2-chamber zoomed views of the LA using the biplane method of disks. Left ventricular end-systolic diameter (LVESD), interventricular septal end-diastolic thickness (IVSEDT), and left ventricular posterior wall end-diastolic thickness (LVPWEDT) were measured by M-mode echocardiography according to the recommendation of the American Society of Echocardiography.10Ejection fraction was measured using a modified Simpson biplane method. Each representative value was obtained from the average of 3 measurements. Left ventricular mass was determined and indexed to height (in meters) to the power of 2.7 (LVM/H 2.7). Pulsed-wave Doppler examination was performed to obtain the following indices of LV diastolic function: peak mitral inflow velocities at early (E) and late (A) diastole and E/A ratio. Average values of these indices obtained from 5 consecutive cardiac cycles were used for analysis.
Statistical Analysis
Continuous variables were expressed as mean (SD) values. Pearson simple correlation allowed studying the association between 2 variables. Comparisons between continuous variables were performed using paired Student t test. Differences were considered to be significant at P < 0.05. Analyses were performed using the statistical package SPSS 9.0 software for Windows (SPSS Inc, Chicago, IL).
RESULTS
Clinical and Echocardiographic Parameters
Clinical and echocardiographic characteristics of the study population are summarized in Table 1. Healthy control group did not significantly differ from EDMD group in BMI, heart rate (HR), and blood pressure. No significant differences in LVPWEDT (7.2 [SD, 0.8] vs 5.9 [SD, 1.2] mm, P = 0.3), IVSEDT (7.5 [SD, 1.2] vs 6.3 [SD, 0.8] mm, P = 0.4), left ventricular end-diastolic diameter (49.4 [SD, 5.1] vs 43.4 [SD, 4.5] mm, P = 0.3), LVESD (34.4 [SD, 5.7] vs 32.2 [SD, 4.8] mm, P = 0.4), LVM/H (35.7 [SD, 10] vs 32.5 [SD, 9] g/m 2.7, P = 0.3), LV fractional shortening (34.8% [SD, 4.1%] vs 32.3% [SD, 4.2%], P = 0.2), and ejection fraction (64.56% [SD, 5.1%] vs 63.39% [SD, 8.1%], P = 0.1) between the 2 groups were observed. These data indicate compensated normal systolic function in the EDMD group. Compared with controls, the EDMD group did not show significant E wave (82.3 [SD, 16.5] vs 92.4 [SD, 10.8] cm/s, P = 0.2), A wave (57.9 [SD, 12.5] vs 52.03 [SD, 9.72] cm/s, P = 0.3), and E/A ratio (1.5 [SD, 0.4] vs 1.8 [SD, 0.38], P = 0.3) variations. These data indicate normal diastolic function in the EDMD group. No statistically significant differences in LAD (37.1 [SD, 2.9] vs 34.1 [SD, 4.2] mm, P = 0.3) and maximum LAV (15.2 [SD, 3.8] vs 14.1 [SD, 4.2] mL/m2, P = 0.4) were found between the 2 groups.
P-Wave Duration and PD
Electrocardiographic characteristics of the study population are shown in Table 2. Compared with healthy control group, patients with EDMD presented increased maximum P-wave duration (108.2 [SD, 22.2] vs 97.8 [SD, 11] milliseconds, P = 0.04) and PD (51.4 [SD, 12.8] vs 39.3 [SD, 9.7] milliseconds, P = 0.03) values. No statistically significant difference was found in HR (77.8 [SD, 5.3] vs 74.9 [SD, 6.5] bpm, P = 0.3), PR interval (149 [SD, 12] vs 143 [SD, 9] milliseconds, P = 0.4), and minimum P-wave duration (55.8 [SD, 20.7] vs 61.4 [SD, 7] milliseconds, P = 0.3). No correlation between PD, LAD (r = 0.1, P = 0.1) and LAV (r = 0.2; P = 0.3) was found. No statistically significant differences in PD (54.6 [SD, 15.6] vs 50.2 [SD, 11.5] milliseconds, P = 0.4) between the laminopathy EDMD subgroup (n = 17) and emerinopathy EDMD subgroup (n = 19) were found.
DISCUSSION
Atrial fibrillation is the rhythm abnormality increasingly recognized in primary myopathies, which occurs either as a permanent abnormality or paroxysmal, or as a disorder with a detectable cause or without any comprehensible cause. According to recent MEDLINE review by Finsterer and Stöllberger,11the prevalence of AF in patients with primary myopathies amounted to 6.1% and, in studies with more than 10 patients, the frequency of AF was 70% in EDMD. The degree of cardiac involvement does not seem to be affected by the degree of muscular involvement; indeed, AF/atrial flutter occurs even in patients classified, according to the modified Walton scale of muscle function,12as M0 (not apparent muscular involvement). The risk of stroke/embolism is increased 5-fold in patients with AF compared with subjects in sinus rhythm. The cardioembolic stroke can be the first clinical manifestation of EDMD in young adults, with an incidence of 36%, and can frequently be disabling.13No data are currently available regarding the prophylactic efficacy of aspirin or anticoagulants for the prevention of thromboembolism related to AF in patients with EDMD, and this now requires dedicated study. The 12-lead resting ECG remains the most frequently used study in the evaluation of patients for cardiovascular disease and, because of its relatively low cost, has the greatest potential to be used as a screening tool. The ability to predict the onset of AF may identify a group of patients with EDMD whose stroke risk can be modified. Prediction of AF could help to identify the patients who would benefit most from prophylactic use of these medical interventions. In our study, we evaluated P-wave duration and PD in patients with EDMD with conserved systolic and diastolic function.
ECG AF Predictors
Dilaveris et al.14firstly showed that prolonged P-wave duration may be used as predictor of frequently relapsing AF. One recent population-based study confirmed this data, identifying maximum P-wave duration and P-wave morphologies as very strong predictors of AF.15In a large cohort of patients, Perez et al.16confirmed prior observations that P-wave duration, PD, abnormal P axis, and LA enlargement were predictive of AF and introduced the P-wave index, defined as the SD of P-wave duration across the 12 leads, as novel measurement that could better represent the atrial heterogeneity. According to their findings, P-wave index more than 35 was one of the strongest predictor of AF (hazard ratio, 2.7). P-wave dispersion is a noninvasive indicator of intra-atrial conduction heterogeneity producing substrate for reentry, which is a pathophysiological mechanism of AF.6,7P-wave dispersion has been studied in some other conditions such as hypertension,17obesity,18diabetes mellitus,19metabolic syndrome,20dilated cardiomyopathy,21myocardial infarction,22atrial septal defect,23hypertrophic cardiomyopathy,24obstructive sleep apnea,25β thalassemia major,26and Wilson disease.15The exact mechanism of PD prolongation in these clinical conditions is not well known, but it is thought that structural and electrophysiological changes in the atrial myocardium caused by elevated plasma volume,27ventricular diastolic dysfunction,28and enhanced neurohormonal activation,29which accompany these diseases, may contribute to LA enlargement and electrical instability.
ECG Findings in Patients With EDMD
Previous studies have documented several ECG abnormalities associated with EDMD diagnosis. Low-amplitude P-waves and first-degree heart block are usually early findings in patients with EDMD.30Sinus node dysfunction, complete atrioventricular block, atrial standstill, supraventricular tachyarrhythmias, as atrial flutter and AF, and ventricular arrhythmias are related to progression of the disease.3,31The ECG features of patients with EDMD, as low-amplitude or biphasic P waves, make the analysis of P axis and LA enlargement difficult, so we preferred to evaluate maximum P-wave duration and PD in our study population. To our knowledge, no information is present in literature about the P-wave duration and PD in patients with EDMD with normal systolic and diastolic function.
Main Findings
Our data showed a significant increase in maximum P-wave duration and PD in patients with EDMD with conserved systolic and diastolic cardiac function, compared with sex- and age-matched healthy controls; these findings suggested the hypothesis that the cardiac diffuse fibrosis and fatty acid infiltration per se influences earlier the propagation of sinus impulses and the atrial conduction time than mechanical cardiac function in patients with EDMD. The lack of correlation between PD, LA diameter, and LA volume indicates that the atrial electrophysiological remodeling is an early finding in patients with EDMD, which is evident before the atrial structural remodeling.
Limitations
The small number of patients included is certainly a limitation, and it may have influenced the statistical significance of the subgroup analysis. More extensive study with higher statistical power is needed to confirm our data and reduce the possible β error; however, we specify that in literature there are no at the moment studies with more than 41 patients with EDMD. P-wave dispersion reflects only the intra-atrial conduction heterogeneity but does not provide the other atrial electrophysiological properties. P-wave dispersion measurement errors done with manual evaluation may be a potential bias for observed results, although according to Dilaveris et al.,14scanning and digitizing ECG signals from paper records using an optical scanner is a feasible and accurate method for measuring P-wave duration. The relationship between cardiac diffuse fibrosis and fatty acid infiltration, cellular cardiac electrophysiological properties and cardiac structural changes are complex and still waiting for investigation.
CONCLUSIONS
Our study showed a significant increase in P-wave duration and PD, ECG parameters considered to reflect the discontinuous and inhomogeneous propagation of sinus impulses and the prolongation of atrial conduction time, in patients with EDMD with conserved systolic and diastolic cardiac function. These simple and useful ECG markers could be used to early identify patients with EDMD at high risk of developing AF, who might benefit from prophylactic anticoagulant or antiarrhythmic therapy to prevent strokes. Further data are necessary to determine the effectiveness of relationship between PD and AF risk in patients with EDMD.