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 Wilson’s 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.

The persistence of P-wave duration is an accepted indicator of a disturbance in the interatrial conduction[12]. 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)[3–7]. Therefore, it has been suggested that PWD can be used to diagnose patients with a high risk of AF[8–13]. 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 intra-atrial conduction disturbance in patients with Wilson’s disease.

The study included 18 patients (age: 49 ± 26 years, range 10-49 years) with Wilson’s disease and 15 healthy controls (age: 44 ± 11 years, range 25-50 years). In Wilson’s disease patients, the patients’ age at the diagnosis was 42 ± 18 years (range, 2.5-42 years), the mean disease duration was 9.6 ± 7 years (range, 1-29 years). Serum copper, ceruloplasmin and urinary copper excretion were 1670 ± 800 &mgr;g/L, 300 ± 120 mg/L, 167 ± 80 &mgr;g/dL, respectively. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), hemoglobin, total cholesterol, low density lipoprotein, high density lipoprotein, and triglyceride levels were 53.2 ± 42 IU/L, 45.6 ± 35 IU/L, 138 ± 18 mg/L, 131 ± 37 mg/dL, 50 ± 31 mg/dL, 66 ± 23 mg/dL, and 95 ± 16 mg/dL respectively.

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 Wilson’s patients have been treated with D -penisilamine (0.75-1 g p.o., t.i.d.) and one patient was switched to trientine (750 mg, p.o. t.i.d.) of because drug related thrombocytopenia.

P_max and PWD were significantly higher in Wilson’s patients than controls. However, there was no significant difference in P_min 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.

The intra-observer standard deviation for P_max, P_min and PWD were 10.3, 6.5, and 11 ms, respectively, and the corresponding intra-observer variability was 0.05%, 0.06%, and 0.2%, respectively. The inter-observer standard deviation for P_max, P_min and PWD were 10.5, 11.0, and 13.9 ms, respectively, and the corresponding inter-observer variability was 0.04%, 0.2%, and 0.5%, respectively. The percentage difference in P_max, P_min and PWD were 2.4%, 3.5%, and 6% within observers and 3%, 5.2%, and 5.9% between observers.

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[1920]. 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[1419]. 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[2122]. 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[8–102324]. Prolonged P wave duration and increased PWD have been reported to carry an increased risk for atrial fibrillation[5–717]. Therefore, it has been suggested that PWD can be used to diagnose patients with a high risk for developing AF[8–10]. 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 P_max 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[32526].

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[8–102324] and therefore, it has been suggested that PWD can be used to diagnose patients with a high risk for developing AF[8–10].

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, P_max 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.