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P wave dispersion is prolonged in patients with Wilson's disease.

AIM
To investigate the P wave dispersion as a non-invasive marker of intra-atrial conduction disturbances in patients with Wilson's disease.


METHODS
We compared Wilsonos disease patients (n = 18) with age matched healthy subjects (n = 15) as controls. The diagnosis was based on clinical symptoms, laboratory tests (ceruloplasmin, urinary and hepatic copper concentrations). P wave dispersion, a measurement of the heterogeneity of atrial depolarization, was measured as the difference between the duration of the longest and the shortest P-waves in 12 lead electrocardiography.


RESULTS
All the patients were asymptomatic on cardiological examination and have sinusal rhythm in electrocardiography. Left ventricular and left atrial diameters, left ventricular ejection fraction and left ventricular mass index were similar in both groups. The Wilson's disease patients had a significantly higher P wave dispersion compared with the controls (44.7 +/- 5.8 vs 25.7 +/- 2.5, P < 0.01).


CONCLUSION
There was an increase in P wave dispersion in cardiologically asymptomatic Wilson's disease patients which probably represents an early stage of cardiac involvement.


INTRODUCTION
The persistence of P-wave duration is an accepted indicator of a disturbance in the interatrial conduction [1,2] . P wave dispersion (PWD) constitutes an important contribution to the field of noninvasive electrocardiology and is defined as the difference between the longest and shortest P wave duration recorded from surface electrocardiogram (ECG) leads. PWD has been thoroughly examined in a number of diseases including hypertension, coronary artery disease, coronary artery bypass surgery, and paroxysmal atrial fibrillation (AF) [3][4][5][6][7] . Therefore, it has been suggested that PWD can be used to diagnose patients with a high risk of AF [8][9][10][11][12][13] . Wilson's disease is a severe genetic metabolic disorder, which is associated with intracellular copper overload and multiple organ involvement. Cardiac manifestations in Wilson's disease include arrhythmias, cardiomyopathy, cardiac death, and autonomic dysfunction [14] . To our knowledge, no previous studies have compared P wave duration and PWD of Wilson's disease patients to healthy controls. The aim of this study was to investigate the PWD as a non-invasive marker of intraatrial conduction disturbance in patients with Wilson's disease.

Subjects
Eighteen cardiologically asymptomatic patients with Wilson's disease and 15 healthy subjects were included in the study. We excluded patients with previous acute myocardial infarction, thyroid dysfunction, uncontrolled diabetes mellitus, chronic renal disease, valvular heart disease, cardiomyopathy, chronic obstructive pulmonary disease, systemic www.wjgnet.com or pulmonary hypertension and alcohol abuse. All of the patients were in sinus rhythm and none were taking medications like antiarrhythmics, tricyclic antidepressants, antihistaminic and antipsychotics. The diagnosis of Wilson's disease was established based on the clinical manifestations, family history of neuropsychiatric manifestations, jaundice, and premature death attributable to Wilson's disease, evidence of Kayser-Fleischer rings on slit lamp examination, low serum copper and ceruloplasmin assay, and increased 24-h urinary excretion of copper. Radiologic investigations included a cranial computed tomography (CT) scan with or without iodinated contrast and/or magnetic resonance imaging (MRI) and X-rays of long bones, pelvis, and chest to evaluate for skeletal abnormalities [15] . The diagnosis is confirmed by the liver biopsy and quantitative liver copper assay [16] .

Echocardiographic measurements
In all subjects, two-dimensional, M-mode pulsed and color flow Doppler echocardiographic examinations (Vivid 7 Dimension, GE, Horten, Norway) were performed by the same examiner. Internal left ventricular (LV) end-diastolic and end-systolic diameters and interventricular septal and posterior wall thickness at end-diastole, and left atrial dimension were measured from parasternal long axis window in M-mode echocardiography [17] . The ejection fraction of the left ventricle was obtained using modified Simpson's method [18] .

Conventional Doppler echocardiography
Early diastolic wave peak velocity (E), late diastolic wave peak velocity (A), early to late velocities (E/A) ratio and E wave deceleration time of left ventricular inflow velocities were measured by pulse wave Doppler placing the sample volume in-between the tips of the mitral valve leaflets in apical four-chamber window. Isovolumic relaxation time (IVRT) was obtained from the apical-five-chamber view by placing the sample volume between the tip of the mitral anterior leaflet and left ventricle outflow tract.

Electrocardiography
Twelve-lead ECGs of all patients at rest, with 1 mV/cm amplitude and 50 mm/s rate, were obtained. The P-wave onset was defined as the first atrial deflection from the isoelectric line and the offset was the return of the atrial signal to baseline. Patients whose measurements could be performed in at least 8 derivations were included in the study. In all patients, derivations were excluded if the beginning or the ending of the P wave could not be clearly identified.
Maximum P wave duration (Pmax) is defined as the longest and minimum P wave duration (Pmin) is defined as the shortest P wave duration. PWD defined as difference between Pmax and Pmin. All the measurements were repeated three times and average values were calculated for each of electrocardiographic parameter. All of the measurements were performed using the same experienced investigators blind to the subject's clinical status. Intra-observer and inter-observer variability was assessed in a random sample of 15 ECG (10 from patients who have Wilson's disease and 5 from control subjects) by a second investigator. The study was approved by the local ethics committee of our institution, and all patients gave written informed consent.

Statistical analysis
The SPSS statistical software package (11.0) was used to perform all statistical calculations. Number of sample is expressed as n, continuous variables were expressed as mean ± SD, and categorical variables as percentages. Pearson correlations were used to compare the association between indexes. Categorical variables were compared by Pearson Chi-square test. Comparisons of continuous variables between two groups have been performed by means of unpaired Student's t test. For all tests, P < 0.05 was considered statistically significant.
The demographic and clinical characteristics of the Wilson's patients and the controls were shown in Table 1. There was no significant difference between the two groups in regard to gender, age, body mass index (BMI), heart rate or blood pressure. All Wilson's patients were treated with copper chelation therapy. Seventeen of the Pmax and PWD were significantly higher in Wilson's patients than controls. However, there was no significant difference in Pmin between the two groups ( Table 1; A = Transmitral late diastolic peak velocity, E = Transmitral early diastolic peak velocity, EDT = E wave deceleration time, IVRT = Isovolumic relaxation time).
PWD was considerably correlated only with the age at diagnosis (r = -0.606, P = 0.048), serum copper level (r = -0.801, P = 0.009) and mitral E wave velocity (r = -0.724, P = 0.027) in patients with Wilson's disease. We were not able to find any statistically significant correlation between PWD and other clinical and echocardiographic parameters.

DISCUSSION
Wilson's disease is a severe genetic multisystem disorder associated with intracellular copper storage. Wilson's disease is characterized by an inadequate excretion of absorbed dietary copper via bile resulting in the accumulation of toxic amounts of copper in the liver and other organs. It is inherited as a rare autosomal recessive condition with an incidence of one in 40 000 live births in most populations, and with a calculated carrier frequency in the general population of one in 90 [19,20] . Copper is an essential micronutrient but ionic copper is toxic. The toxic effects are thought to be mediated by the generation of reactive oxygen free radical species in Wilson's patients [19] . Cardiac involvement in Wilson's disease has rarely been recognized. Cardiac manifestations in Wilson's disease include arrhythmias, cardiomyopathy, cardiac death, and autonomic dysfunction [14,19] . Electrocardiographic abnormalities occurred in 34 percent, including left ventricular hypertrophy, biventricular hypertrophy, early re-polarization, ST depression and T inversion, premature atrial or ventricular contractions, atrial fibrillation, sino-atrial block and Mobitz type 1 atrio-ventricular block. Asymptomatic orthostatic hypotension, an abnormal response to the Valsalva maneuver, ventricular fibrillation, and dilated cardiomyopathy can be occurred in Wilson's disease [14] .
The major pathological findings of the myocardium in Wilson's disease included the presence of interstitial and replacement myocardial fibrosis, intra-myocardial small vessel disease, focal myocarditis and cardiac hypertrophy, AV nodal degeneration and occlusive atherosclerosis in early ages [21] . These alterations are non-specific, but they are similar to those observed in other cardiomyopathies [21,22] . Their existence in a relatively young group of patients without other significant etiology for the development of heart disease, suggests the possibility of a direct relationship between Wilson's disease and cardiac degeneration [20] .
Therefore, we investigated PWD in patients with Wilson's disease patients. PWD is a new electrocardiographic marker that has been associated with the heterogeneous and discontinuous propagation of sinus impulses. Furthermore, the correlation between the presence of intra-atrial conduction abnormalities and the induction of paroxysmal AF has been well documented [8][9][10]23,24] . Prolonged P wave duration and increased PWD have been reported to carry an increased risk for atrial fibrillation [5][6][7]17] . Therefore, it has been suggested that PWD can be used to diagnose patients with a high risk for developing AF [8][9][10] . To our knowledge, this is the first study that has investigated the P wave duration and PWD changes in Wilson's disease patients. This study shows that Pmax and PWD are higher in Wilson's disease patients than control subjects. These results suggest that Wilson's disease patients may be under the risk for atrial fibrillation. This study also shows that PWD was correlated with mitral E wave velocity which is a parameter of left ventricular diastolic function and the serum copper level. Previously, it has been reported that PWD was associated with diastolic dysfunction and coronary artery disease [3,25,26] .
The precise mechanism of arrhythmias seen in Wilson's disease patients is not clear. A recent report Kaduk et al [27] describing cardiomyopathy in Wilson's disease, suggested that mitochondrial alterations were the consequence of the accumulation of myocardial copper These alterations are non-specific, and in some cases of limited severity; however, in previous study it was concluded that cardiac degeneration might have contributed to the death of Wilson's patients [27] . PWD may well be associated with autonomic dysfunction in patients with Wilson's disease [27] . Dysautonomia, often subclinical, is only one of the many features of Wilson's disease [28] . A central, rather than peripheral mechanism is hypothesized. Sympathetic and parasympathetic arms are affected equally. The abnormality is independent of involvement of the liver and the duration and severity of Wilson's disease [29] .
Previous experiments showed that electrical remodeling of atrial myocardium could be induced by autonomic nervous transmitters and suggested that autonomic nerve activity was an important factor to promote AF episodes [30] . This study population is relatively small and therefore our results should not be extrapolated to all Wilson's patients. Further studies are necessary to investigate the frequency of atrial arrhythmias by rhythm holter in patients with Wilson's disease, who have or do not have high PWD.
Furthermore, one of the relative limitations of our study was that we could not use the method of digital recording and storing of 12-lead electrocardiograms with onscreen measurement of P waves duration which provides the most accurate method for PWD calculation [31] . Secondly, the ability of P wave duration and PWD to predict future atrial fibrillation episodes was not checked in present study, since the patients included in this work were not followed-up. But, it has been well documented previously that prolonged P wave duration and increased PWD carry an increased risk for atrial fibrillation [8][9][10]23,24] and therefore, it has been suggested that PWD can be used to diagnose patients with a high risk for developing AF [8][9][10] .
Consequently, involvement of the heart may be seen in patients with Wilson's disease even in the absence of clinical cardiac manifestations. In this study, Pmax and PWD were found to be higher in patients with Wilson's disease than healthy control subjects. Therefore, the patients with Wilson's disease who have increased PWD should be closely followed for atrial arrhythmias.

Background
Wilson's disease is a rare severe genetic metabolic disorder associated with intracellular copper overload and related complications. Cardiac manifestations in Wilson's disease include arrhythmias, cardiomyopathy, cardiac death, and autonomic dysfunction. P wave dispersion, a measurement of the heterogeneity of atrial depolarization.

Research frontiers
No previous studies have compared P wave duration and P wave dispersion (PWD) of Wilson's disease patients to healthy controls. The aim of this study was to investigate the PWD as a non-invasive marker of intra-atrial conduction disturbance in patients with Wilson's disease.

Innovations and breakthroughs
Prolonged P wave duration and increased PWD have been reported to carry an increased risk for atrial fibrillation. Therefore, it has been suggested that PWD can be used to diagnose patients with a high risk for developing AF. In previous reports researchers showed that electrical remodeling of atrial myocardium could be induced by autonomic nervous transmitters and suggested that autonomic nerve activity was an important factor to promote AF episodes. This study also shows that PWD was correlated with mitral E wave velocity which is a parameter of left ventricular diastolic function and the serum copper level. Previously, it has been reported that PWD was associated with diastolic dysfunction and coronary artery disease.

Applications
Prolonged P wave duration and increased PWD carry an increased risk for AF. Therefore, it has been suggested that PWD can be used to diagnose patients with a high risk for developing AF. This study shows that Pmax and PWD are higher in Wilson's disease patients than control subjects. These results suggest that Wilson's disease patients may be under the risk for atrial fibrillation.

Terminology
Wilson's disease is a severe genetic metabolic disorder associated with intracellular copper overload and multiple organ involvement. P wave dispersion was measured as the difference between the duration of the longest and the shortest P-waves in 12 lead electrocardiography.

Peer review
This report is original and has to be considered interesting. The authors aimed to investigate the P wave dispersion as a non-invasive marker of intra-atrial conduction disturbances in patients with Wilson's disease. This rather small but homogenous patient population showed promising results with the application of PWD at such a rare genetic disorder.