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P wave duration and dispersion and QT interval in multiple sclerosis

      Highlights

      • Involvement of the heart may be seen in MS patients even in the absence of clinical cardiac manifestations.
      • P wave duration and P wave dispersion was found to be higher in MS patients than healthy control subjects.
      • The patients with MS who have increased PWD should be closely followed for atrial arrhythmias.

      Abstract

      Introduction

      Multiple sclerosis (MS) is one of the most frequent disorders of central nervous system, resulting in autonomic disturbances. Some electrocardiographic changes have been reported in these patients that can lead to arrhythmia. In this study we compared P wave duration and dispersion and QT interval of MS patients to healthy control subjects.

      Material and methods

      Eighty four multiple sclerosis patients and 84 healthy, age and sex-matched volunteers were included. A 12-lead electrocardiogram was undertaken in order to measure minimal and maximal P wave duration, P wave dispersion (PWD) and QT interval.

      Results

      In patient group, mean P wave duration, maximum P wave duration and PWD were significantly longer than control group. QT interval was longer in patient group but the difference was not significant.

      Conclusion

      In this study, P wave duration and P wave dispersion was found to be higher in MS patients than healthy control subjects.

      Keywords

      1. Introduction

      Multiple sclerosis is a chronic demyelinating inflammatory disorder, presumed to be of autoimmune etiology. Abnormalities of autonomic nervous system (ANS) function in multiple sclerosis (MS) have been reported in various studies (
      • Flachenecker P.
      • Wolf A.
      • Krauser M.
      • Hartung H.P.
      • Reiners K.
      Cardiovascular autonomic dysfunction in multiple sclerosis: correlation with orthostatic intolerance.
      ,
      • Frontoni M.
      • Fiorini M.
      • Strano S.
      • Cerutti S.
      • Giubilei F.
      • Urani C.
      • et al.
      Power spectrum analysis contribution to the detection of cardiovascular dysautonomia in multiple sclerosis.
      ,
      • Gunal D.I.
      • Afsar N.
      • Tanridag T.
      • Aktan S.
      Autonomic dysfunction in multiple sclerosis: correlation with disease-related parameters.
      ,
      • Merkelbach S.
      • Dillmann U.
      • Komel C.
      • Holz J.
      • Muller M.
      Cardiovascular autonomic dysregulation and fatigue in multiple sclerosis.
      ,
      • Pentland B.
      • Ewing D.J.
      Cardiovascular reflexes in multiple sclerosis.
      ,
      • Sterman A.B.
      • Coyle P.K.
      • D.J. Panasci
      • Grimson R.
      Disseminated abnormalities of cardiovascular autonomic functions in multiple sclerosis.
      ).
      The most common manifestations of the ANS in patients with MS include bladder dysfunction, sleep disturbances, sweating, gastrointestinal and cardiovascular disturbances. Another common symptom seen in patients of MS is fatigue. Orthostatic dizziness has been reported to occur in up to 50% of MS patients (
      • Anema J.R.
      • Heijenbrok M.W.
      • Faes T.J.
      • Heimans J.J.
      • Lanting P.
      • Polman C.H.
      Cardiovascular autonomic function in multiple sclerosis.
      ,
      • Vita G.
      • Fazio M.C.
      • Milone S.
      • Blandino A.
      • Salvi L.
      • Messina C.
      Cardiovascular autonomic dysfunction in multiple sclerosis is likely related to brainstem lesions.
      ). Autonomic dysfunction has an important impact on the disability that patients with MS experience and can substantially restrict the activities of daily living in these individuals.
      Cardiovascular function will affect 10–50% of people with MS. On cardiovascular reflex testing it has been shown that both sympathetic as well as parasympathetic dysfunction can occur in patients with MS (
      • Acevedo A.R.
      • Nava C.
      • Arriada N.
      • Violante A.
      • Corona T.
      Cardiovascular dysfunction in multiple sclerosis.
      ,
      • Pomeranz B.
      • Macaulay R.J.
      • Caudill M.A.
      • Kutz I.
      • Adam D.
      • Gordon D.
      • et al.
      Assessment of autonomic function in humans by heart rate spectral analysis.
      ).
      We hypothesized that the patients with MS may be under the risk for ventricular and atrial arrhythmias. Therefore, this study was planned to investigate the P wave duration, P wave dispersion and QT interval in MS patients.

      2. Material and methods

      Eighty four patients with relapsing remitting MS who were admitted to outpatient neurology clinic of Imam Reza Hospital; affiliated to Kermanshah University of Medical Sciences, Iran, were included in this study. All of the patients with MS were diagnosed according to the 2005 McDonald׳s criteria (
      • Reingold S.C.
      • Edan G.
      • et al.
      Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald criteria.
      ). All patients were in remission and have been without any significant new symptoms and/or signs for at least 2 months and were not received corticosteroid treatment in 2 months ago. The informed consent obtained from all the patients.84 genders and age matched healthy subjects as control group were included in this study. Physical examination, medical history of subjects was evaluated in two groups to exclude systemic diseases. Persons with thyroid dysfunction, anemia, electrolyte imbalance, hypertension, diabetes mellitus, heart failure, rheumatic valve disease, primary cardiomyopathy, chronic lung disease, coronary artery disease and left bundle branch block, atrioventricular conduction abnormalities on electrocardiogram (ECG) were excluded from the study. All of the subjects have sinus rhythm and none of them were taking medications like antiarrhythmics, tricyclic antidepressants, antihistaminics and antipsychotics. The 12-lead ECG was recorded at a paper speed of 50 mm/s and gain of 10 mm/2 mV in the supine position and were breathing freely but not allowed to speak during the electrocardiographic recording. Measurement of P duration and QT interval was carried out manually using a caliper. The starting point of P wave was referred as the positive deflection crossing the isoelectric line and the end-point was referred as the end of the deflection crossing the isoelectric line. P wave duration was measured from the onset to the offset of the P wave (Figure 1). The patients were excluded if these points were not clear. Maximum P wave duration is defined as the longest P wave duration and minimum P wave duration is defined as the shortest P wave duration. P wave dispersion defined as difference between maximum P wave duration and minimum P wave duration was also calculated. QT interval was measured from the onset of the QRS complex to the offset of the T wave. Maximum QT interval was selected and was adjusted according to heart rate (QTC=QT+1.75(HR−60)) (
      • Hodges M.
      • Salerno D.
      • Erlien D.
      • Bazett’s Q.T.
      correction reviewed: evidence that a linear QT correction for heart rate is better.
      ).
      Figure thumbnail gr1
      Figure 1The P-wave durations (Pmax and Pmin) were calculated.
      All the measurements were repeated three times and average values were accepted for each of electrocardiographic parameters. All of the measurements were performed by one experienced investigators unaware of the subject׳s clinical status. Intra and inter-observer coefficients of variation (standard deviation [SD] of differences between 2 observations divided by the mean value and expressed in %) were found as 4.1% and 4.2% for P wave dispersion. Intra and inter-observer coefficients of variation were found to be less than 5%.
      The SPSS statistical software package (version 16.0) was used to perform all statistical calculations. Continuous variables were expressed as mean values±SD, and categorical variables as percentages. Pearson correlations were used to compare associations 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, a value of p<0.05 was considered statistically significant.

      3. Results

      The demographic and clinical characteristics of the MS patients and the control subjects are shown in Table 1. There was no significant difference between the two groups with regard to gender, age, heart rate or blood pressure. In MS patients, the mean disease duration was 6±5.8 years (range 0.25–23). All patients were treated with disease-modifying treatments (interferon beta).
      Table 1The demographic and clinical characteristics of the MS patients and control subjects.
      MS patients (n=84)Control group (n=84)p Value
      Female73710.564
      male11130.525
      Age (years)35±1035.3±100.231
      Heart rate (beat/min)77±774±50.121
      Systolic BP (mmHg)124±13123±130.345
      Diastolic BP (mmHg)78±977±80.234
      Disease duration (years)6±5.8
      Data are means±SD, BP indicates blood pressure.
      Maximum P wave duration and P wave dispersion were significantly higher in MS patients than control groups. However, minimum P wave duration and QT interval were not significantly different between the groups (Table 2).
      Table 2Electrocardiographic measurements of the MS patients and controls.
      MS patients (n=84)Control group (n=84)p Value
      Minimum P wave duration (ms)60.48±15.2962.41±11.850.506
      Maximum P wave duration (ms)125.78±15.78111.57±15.340.000
      P wave dispersion (ms)65.30±18.7649.16±16.620.000
      QT interval (ms)422.92±26.14416.55±19.360.077
      Data are means±SD.

      4. Discussion

      Multiple sclerosis is a progressive and disabling neurological condition associated with documented dysfunction of the autonomic nervous system. Frequent studies have shown abnormalities of cardiovascular reflexes in MS patients (
      • Pentland B.
      • Ewing D.J.
      Cardiovascular reflexes in multiple sclerosis.
      ,
      • Anema J.R.
      • Heijenbrok M.W.
      • Faes T.J.
      • Heimans J.J.
      • Lanting P.
      • Polman C.H.
      Cardiovascular autonomic function in multiple sclerosis.
      ,
      • Nordenbo A.M.
      • Boesen F.
      • Anderson E.B.
      Cardiovascular autonomic functions in multiple sclerosis.
      ).
      P wave dispersion 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 (
      • Dilaveris P.E.
      • Gialofos E.J.
      • Andrikopoulos G.K.
      • Richter D.J.
      • Papanikolaou V.
      • Poralis K.
      • et al.
      Clinical and electrocardiographic predictors of recurrent atrial fibrillation.
      ,
      • Dilaveris P.E.
      • Gialafos E.J.
      • Sideris S.K.
      • Theopistou A.M.
      • Andrikopoulos G.K.
      • Kyriakidis M.
      • et al.
      Simple electrocardiographic markers for the prediction of paroxysmal idiopathic atrial fibrillation.
      ,
      • Dilaveris P.E.
      • Gialafos J.E.
      P wave dispersion: a novel predictor of paroxysmal atrial fibrillation.
      ,
      • Leier C.V.
      • Meacham J.A.
      • Schall S.F.
      Prolonged atrial conduction: a major predisposing factor to atrial flutter.
      ,
      • Cheema A.N.
      • Ahmed M.W.
      • Kadish A.H.
      • Goldberger J.J.
      Effects of autonomic stimulation and blockade on signal-averaged P wave duration.
      ). Prolonged P wave duration and increased PWD have been reported to carry an increased risk for atrial fibrillation (
      • Dilaveris P.E.
      • Gialofos E.J.
      • Andrikopoulos G.K.
      • Richter D.J.
      • Papanikolaou V.
      • Poralis K.
      • et al.
      Clinical and electrocardiographic predictors of recurrent atrial fibrillation.
      ,
      • Dilaveris P.E.
      • Gialafos E.J.
      • Sideris S.K.
      • Theopistou A.M.
      • Andrikopoulos G.K.
      • Kyriakidis M.
      • et al.
      Simple electrocardiographic markers for the prediction of paroxysmal idiopathic atrial fibrillation.
      ,
      • Dilaveris P.E.
      • Gialafos J.E.
      P wave dispersion: a novel predictor of paroxysmal atrial fibrillation.
      ,
      • Aytemir K.
      • Ozer N.
      • Atalar E.
      • Sade E.
      • Aksoyek S.
      • Ovunc K.
      • et al.
      P wave dispersion on 12-lead electrocardiography in patients with paroxysmal atrial fibrillation.
      ). Therefore, it has been suggested that PWD can be used to diagnose patients with a high risk of AF (
      • Dilaveris P.E.
      • Gialofos E.J.
      • Andrikopoulos G.K.
      • Richter D.J.
      • Papanikolaou V.
      • Poralis K.
      • et al.
      Clinical and electrocardiographic predictors of recurrent atrial fibrillation.
      ,
      • Dilaveris P.E.
      • Gialafos E.J.
      • Sideris S.K.
      • Theopistou A.M.
      • Andrikopoulos G.K.
      • Kyriakidis M.
      • et al.
      Simple electrocardiographic markers for the prediction of paroxysmal idiopathic atrial fibrillation.
      ,
      • Dilaveris P.E.
      • Gialafos J.E.
      P wave dispersion: a novel predictor of paroxysmal atrial fibrillation.
      ). This study shows that maximum P wave duration and PWD are higher in MS patients than control subjects. The significance of an increased P wave duration and PDW in our patients is unknown.
      • Kocer A.
      • Karakaya O.
      • Kargin R.
      • Barutcu I.
      • Esen A.M.
      P wave duration and dispersion in multiple sclerosis.
      investigated P wave duration and dispersion in 31 MS patients and compared with 33 healthy subjects, their study showed that P wave duration and dispersion were prolonged significantly in MS patients compared to control subjects. We cannot find other studies which investigated P wave changes in MS patients.
      • Tukek T.
      • Akkaya V.
      • Demirel S.
      • Sozen A.B.
      • Kudat H.
      • Atılgan D.
      • et al.
      Effect of valsalva maneuver on surface electrocardiographic P wave dispersion in paroxysmal atrial fibrillation.
      suggested that increased sympathetic activity may cause significant increase in PWD. P wave dispersion may be associated with increased sympathetic nervous system activity in patients with MS. On the surface electrocardiogram, QT interval reflects time for repolarization. Several studies have shown a relationship between prolonged QTc (QT interval corrected for heart rate) and life threatening arrhythmias (
      • Bonnet M.
      • Mulcare J.
      • Mthews T.
      • Gupta S.
      • Ahmed N.
      • Yergani V.
      Heart rate variability in multiple sclerosis: evidence for decreased sympathic activity.
      ).
      • Drouin E.
      • Nataf S.
      • Lande G.
      • Louboutin J.P.
      Abnormalities of cardiovascular repolarization in multiple sclerosis: relationship with a model of allergic encephalomyelitis in rat.
      investigated ventricular repolarization for the first time in 48 multiple sclerosis patients using measurement of QTc interval on standard electrocardiographic recordings. Their study showed that the repolarization process was prolonged significantly in MS compared to control subjects (p=0.0001).We found that there was no statistically significant difference in QT interval between MS patients and control subjects. This result may be due to difference in the QT correction formulas in two studies. In Drouin et al. study correction of the QT-interval for heart rate was according to
      • Bazett H.C.
      An analysis of time relations of the electrocardiogram.
      formula. Rate correction of QT intervals using the standard Bazett formula can introduce significant errors in the QT interval measurement. It overestimated the change in QT. Numerous references recommend 420–440 ms as the threshold for reporting prolonged QTc when using Bazett׳s formula. Based on this database, 30% of apparently normal ECGs would be reported as having abnormal QT intervals for the 440 ms threshold, or 10% if 460 ms is chosen, compared to <2% for the other formula (
      • Bonow Robert O.
      • Mann Douglas L.
      ). It was also noted that QT has a linear trend with heart rate but not with RR interval. However this study population is relatively small and therefore our results should not be extrapolated to all MS patients.
      Obviously, measurement errors performed during manual evaluation may be one limitation of the study. Although acceptable intraobserver and interobserver errors in the manual measurement of P-wave duration in 12-lead ECGs have been reported (
      • Dilaveris P.E.
      • Gialafos E.J.
      • Sideris S.K.
      • Theopistou A.M.
      • Andrikopoulos G.K.
      • Kyriakidis M.
      • et al.
      Simple electrocardiographic markers for the prediction of paroxysmal idiopathic atrial fibrillation.
      ), well-known difficulties in defining P-wave onset and offset may restrict the accuracy and reproducibility of the measurements. It is better to resort to signal averaging of P-waves. However, lack of the Holter recordings may be another potential limitation of the study.

      5. Conclusions

      Involvement of the heart may be seen in MS patients even in the absence of clinical cardiac manifestations. In this study, P wave duration and P wave dispersion was found to be higher in MS patients than healthy control subjects. However, whether the patients with MS prone to development of atrial conduction abnormalities should be established by further large scale studies.

      Conflict of interest

      There is no financial interest to report.

      Acknowledgments

      We certify that the submission is not under review at any other publication. This work was supported by the Vice-chancellor for research, Kermanshah University of Medical Sciences and Health Services (Grant No. 90187).

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