Clinical material and methods. Departments of 1 Cardiology and 2 Anatomy, Gaziantep University, School of Medicine, Gaziantep, Turkey

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1 Interatrial Block and P-Terminal Force: A Reflection of Mitral Stenosis Severity on Electrocardiography Murat Yuce 1, Vedat Davutoglu 1, Cayan Akkoyun 1, Nese Kizilkan 2, Suleyman Ercan 1, Murat Akcay 1, Ibrahim Sari 1 Departments of 1 Cardiology and 2 Anatomy, Gaziantep University, School of Medicine, Gaziantep, Turkey Background and aim of the study: Interatrial block (IAB), a frequently overlooked conduction delay between the atria, is defined as prolonged P-wave on the electrocardiogram (ECG). Previously, IAB has been shown to be an indicator of dilated and impaired left atrial function, and a predictor of both atrial fibrillation and embolic stroke. The study aim was to test the hypothesis that, on ECG, IAB with P-terminal force can reflect the echocardiographic severity of mitral stenosis (MS). Methods: Patients with rheumatic MS who were referred to a single cardiac center for echocardiography between July and October 2009, and who met the study entry criteria (echocardiographically documented rheumatic MS), were invited to participate. Consequently, 116 such patients were studied prospectively, while a group of age- and gendermatched subjects without echocardiographic signs of rheumatic valve involvement served as controls. Transthoracic echocardiography was performed in all subjects. Results: A positive correlation was observed between IAB ( 120 ms) and the mean mitral valve gradient (R = 0.3, p <0.001). A strong negative correlation was also present between the mitral valve area (MVA) and the presence of IAB (R = -0.3, p <0.001). The presence of pulmonary hypertension and a poor NYHA functional class were associated with a high incidence of significant IAB (R = 0.4, p <0.001; R = 0.3, p <0.001, respectively), and there was a strong correlation between IAB and the P-terminal force (p <0.001). Both, the presence of significant IAB and P- terminal force were correlated with a calcific mitral valve (p <0.001). Only the MVA (β = 0.3; p = 0.008) was a predictor of IAB in multivariate analysis. Conclusion: A severe mitral gradient, a decreased MVA, an increased pulmonary artery pressure, and a poor NYHA class were shown to correlate with IAB duration and P-terminal force. Significant IAB ( 120 ms) and P-terminal force might be considered as a novel indicator of echocardiographic severity and associated complications during the follow up of MS. However, these interrelations must be clarified in further studies. The Journal of Heart Valve Disease 2011;20: : Address for correspondence: Vedat Davutoglu MD, Gaziantep University, School of Medicine, Department of Cardiology 27310/Gaziantep, Turkey davutoglu@gantep.edu.tr Interatrial block (IAB) is a frequently overlooked conduction delay between the atria which largely results from Bachmann bundle abnormality (1). IAB is defined as a prolonged P-wave ( 110 ms) on the electrocardiogram (ECG) (2), and has also been shown to be an indicator of dilated and impaired left atrial function (3), and a predictor of both atrial fibrillation (4) and embolic stroke (5). A P-wave with a negative terminal phase recorded in V1 enclosing an area of one small square on the ECG ( 40 ms 1 mm) is significantly and strongly correlated with IAB (6). Previously, the importance of IAB and P-terminal force as a reflection of echocardiographic severity in rheumatic mitral stenosis (MS) has not been established. Hence, the study aim was to test the hypothesis that, on ECG, IAB with P-terminal force could be used as an indicator of the echocardiographic severity of MS. Clinical material and methods Patients Patients with rheumatic MS, who had been referred to a single cardiac center for echocardiography between July and October 2009, were invited to participate in the study. Thus, a total of 116 consecutive patients (mean age 39 ± 11 years) with echocardiographically documented rheumatic MS was studied prospectively. A group of 92 age- and gender-matched Copyright by ICR Publishers 2011

620 Interatrial block and P-terminal force in MS subjects (mean age 37 ± 11 years), without echocardiographic signs of rheumatic valve involvement, served as controls.

concomitant organic tricuspid stenosis; history of myocardial infarction; previous cardiac surgery; blood pressure >140/90 mmhg; diabetes mellitus; heart failure; abnormal plasma creatinine level;

2 620 Interatrial block and P-terminal force in MS subjects (mean age 37 ± 11 years), without echocardiographic signs of rheumatic valve involvement, served as controls. Patients with any of the following were excluded: atrial fibrillation; the presence of moderate to severe or severe mitral regurgitation/aortic regurgitation; the presence of aortic stenosis; concomitant organic tricuspid stenosis; history of myocardial infarction; previous cardiac surgery; blood pressure >140/90 mmhg; diabetes mellitus; heart failure; abnormal plasma creatinine level; presence of moderate or severe respiratory disease; malignant or hematological disease; and presence of local or systemic infection. The presence or absence of symptoms was determined by two independent cardiologists who were blinded to the patients echocardiographic results. Patients were categorized according to their NYHA functional class. The study was approved by the University Research Ethics Committee, and all subjects provided their informed consent before being enrolled. Echocardiographic data Complete transthoracic echocardiography (TTE) was performed in all subjects (Vivid 7; GE Vingmed Ultrasound AS, Horten, Norway), who also underwent a comprehensive examination including M-mode, two-dimensional, and Doppler echocardiography. The left atrial area was estimated from the apical four-chamber view, while the ejection fraction was measured from the apical four-chamber view using the modified Simpson s single plane method (7). The mitral valve area (MVA) was measured using either planimetry or the pressure half-time method. Mitral stenosis was graded as mild if the MVA was cm 2 and the mitral mean gradient <5 mmhg; as J Heart Valve Dis moderate if the MVA was 1.1-to 1.5 cm 2 and the mitral mean gradient 5-10 mmhg; and severe if the MVA was 1.0 cm 2 and the mitral mean gradient >10 mmhg. The pulmonary artery systolic pressure was estimated from tricuspid regurgitation, according to the Bernoulli formula. Measurement of IAB and P-terminal force The IAB was defined on the routine 12-lead ECG (filter range 0.15 to 100 Hz; 25 mm/s, 10 mm/mv), using the greatest duration of P-waves from all leads. For increased specificity, a P-wave 120 ms was used to diagnose significant IAB (Fig. 1) (8). A P-terminal force biphasic P in lead V1 area of one small square on the ECG was used as a criterion to diagnose IAB (Fig. 2). The ECG was analyzed by two independent readers who were blinded to the echocardiographic findings. There was a 99.5% concordance for the ECG signs of IAB. Statistical analysis All data were analyzed using SPSS software (version 10.0; Statistical Package for Social Sciences). Numerical values were reported as mean ± SD, or as a proportion of the sample size. For the bivariable analysis, when the variables were parametric the difference of averages test (Student s t-test) was used. Discrete variables were expressed as counts or percentages, and compared using a chi-square test. The correlation between two variables was studied with the Pearson or Spearman test, depending on whether the variables had a normal (parametric) distribution, or not. In all analyses, a p-value <0.05 was considered to be statistically significant. Multivariate analysis was performed using a linear regression analysis for the dependent variable (IAB). Figure 1: 12-Lead surface electrocardiogram showing interatrial block in the inferolateral leads. Figure 2: 12-Lead surface electrocardiogram showing the P-terminal force.

3 J Heart Valve Dis Interatrial block and P-terminal force in MS 621 Table I: ECG/echocardiographic, demographic characteristics and functional status of the patients and control subjects. Parameter Patients Controls p-value (n = 116) (n = 92) Age (years) 39 ± ± 11 NS Female gender (%) NS NYHA class (%) II 35 0 III 12 0 MVA (cm 2 ) 1.5 ± Moderate MS (n) 40 (34) 0 Severe MS (n) 21 (18) 0 MMG (mmhg) 12 ± LA area (cm 2 ) 22.6 ± ± 6 <0.001 EF (%) 65 ± 6 66 ± 8 NS spap (mmhg) 45 ± 17 - IAB ( 120 ms) (n) 74 (64) 2 (2) <0.001 P terminal force (n) 95 (49) 27 (29) <0.00 Values in parentheses are percentages. EF: Ejection fraction; IAB: Interatrial block; LA: Left atrial; MMG: Mitral mean gradient; MS: Mitral stenosis; NS: Not significant; spap: Pulmonary artery systolic pressure. Results A total of 116 patients with MS and 92 normal subjects was analyzed echocardiographically. No intergroup differences were identified in terms of age and gender; the demographic characteristics, ECG/ echocardiographic features and functional status of the patients are listed in Table I. The relationship between IAB ( 120 ms) and echocardiographic parameters is shown in Table II, and that between the P-terminal force and echocardiographic parameters in Table III. A statistically positive correlation was identified between IAB ( 120 ms) and the mean mitral valve gradient (R = 0.3, p <0.001), and a strong negative correlation between the MVA and the presence of IAB (R = -0.3, p <0.001). The presence of left atrial enlargement, pulmonary hypertension and poor functional NYHA class were associated with a high incidence of significant IAB (R = 0.4, p <0.001; R = 0.4, p <0.001; R = 0.3, p <0.001, respectively). A statistically strong correlation was observed between IAB and the P-terminal force (p <0.001) (Table IV). A subgroup analysis based on valve calcification revealed that both the presence of significant IAB and P-terminal force were correlated with calcific mitral valve stenosis (p <0.001). In Discussion - text says A multivariate analysis was performed with a linear regression analysis, whereby the following variables were included as predictors of IAB (dependent vari- Table II: Relationship between IAB ( 120 ms) and echocardiographic parameters. Parameter IAB ( 120 ms) p-value MMG (mmhg) 13 ± ± MVA (cm 2 ) 1.6 ± ± 2.2 <0.001 EF (%) 65 ± 5 66 ± 7 NS LA area (cm 2 ) 24 ± 8 16 ± spap (mmhg) 48 ± ± 16 <0.001 MVA: Mitral valve area. Other abbreviations as Table I. able): mitral mean gradient; MVA; pulmonary hypertension; NYHA class; and left atrial area. Subsequently, only the MVA (β = 0.3; p = 0.008) proved to be a predictor of IAB. Discussion The study aim was to evaluate the benefit of measuring significant IAB with P-terminal force on surface ECG as an additional indicator of severity in chronic rheumatic MS. To the present authors knowledge, this is the first study to report a strong association between echocardiographically proven severe MS, poor NYHA class and increased pulmonary artery systolic pressure and the presence of significant IAB and P-terminal force. The normal P-wave duration, as classified by the World Health Organization/International Society and Federation of Cardiology Task Force, is <110 ms (2). For increased specificity, a P-wave 120 ms was used to diagnose significant IAB. Indeed, IAB denotes a delayed impulse conduction between the right and left atrium. In addition to being a predictor of atrial fibrillation, stroke, and left atrial enlargement (3-5), IAB is also correlated with severe MS, poor NYHA class, and increased pulmonary artery systolic pressure, as confirmed by the results of the present study. Table III: Relationship between P terminal force and echocardiographic parameters. Parameter P terminal force p-value MMG (mmhg) 10 ± 9 6 ± 5 <0.001 MVA (cm 2 ) 2.7 ± ± 2.1 <0.001 LA area (cm 2 ) 20 ± ± 5.5 <0.001 EF (%) 67 ± 6 66 ± 6 NS spap (mmhg) 35 ± ± 15 <0.001 Other abbrevi.ations as Table I.

4 622 Interatrial block and P-terminal force in MS Table IV: Correlation between IAB and P terminal force. Parameter P terminal force Total IAB ( 120 ms) present IAB ( 120 ms) absent Total X 2 = ; p < IAB: Interatrial block. Among the developing countries of the world, rheumatic fever and rheumatic valve disease remain significant medical and public health problems. It was demonstrated recently that rheumatic valve disease remains endemic in the region of Turkey (9), with considerable numbers of young adults suffering from the condition and its complications. Additional new indices revealing the severity of MS by means of electrocardiography that would establish the severity of rheumatic valve disease, guide any therapeutic approach, and predict any high risk of complications of the condition, would be both useful and inexpensive (10-13). Previously, in MS, the P-wave duration was shown to increase along with the progression of disease severity (14). Consequently, a partial IAB that was shown to progress with time to advanced IAB ( 120 ms) could be used as a novel additional index to monitor not only atrial enlargement (15) but also the severity of MS, poor NYHA functional class, and increased pulmonary artery pressure. To improve specificity, the precise interpretation of the P-wave duration on ECG, as reflected by the period of atrial conduction, could be considered as significant IAB if the P-wave duration were to be increased to more than 120 ms. Although the identification of IAB is relatively straightforward when compared to other ECG abnormalities, IAB is a frequently overlooked and ignored ECG finding. Hence, it is recommended that attention and consideration be given to the easily measurable IAB and P-terminal force for determining the severity of rheumatic MS and its associated complications. The presence of significant IAB and P-wave terminal force on the ECG would most likely help in guiding the timing of echocardiography in asymptomatic patients with rheumatic MS. In turn, this would provide a potentially attractive alternative screening tool for patients with rheumatic valve disease, which is endemic in many developing regions. Moreover, the absence of IAB and P-terminal force from the ECG might serve as a useful test for preventing further unnecessary examinations in patients with a history of rheumatic fever. The rational use of this modality may help the clinician to change the frequency of screening or follow up with echocardiography. J Heart Valve Dis In conclusion, a severe mitral gradient, a decreased MVA, an increased pulmonary artery pressure, and poor NYHA class were correlated with significant IAB and P-terminal force. Together, the latter two parameters might be considered as a novel indicator of echocardiographic severity and associated complication during the follow up of MS. However, these interrelations must first be clarified by conducting further studies. References 1. Waldo AL, Bush HL, Jr., Gelband H, et al. Effects on the canine P wave of discrete lesions in the specialized atrial tracts. Circ Res 1971;29: Willems JL, Robles de Medina EO, Bernard R, et al. Criteria for intraventricular conduction disturbances and pre-excitation. World Health Organization/International Society and Federation of Cardiology Task Force Ad hoc. J Am Coll Cardiol 1985;5: Goyal SB, Spodick DH. Electromechanical dysfunction of the left atrium associated with interatrial block. Am Heart J 2001;142: Agarwal YK, Aronow WS, Levy JA, Spodick DH. Association of interatrial block with development of atrial fibrillation. Am J Cardiol 2003;91: Lorbar M, Levrault R, Phadke JG, Spodick DH. Interatrial block as a predictor of embolic stroke. Am J Cardiol 2005;95: Spodick DH, Ariyarajah V, Goldberg R. Interatrial block: correlation with P-terminal force. Clin Cardiol 2009;32: Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2: Asad N, Spodick DH. Prevalence of interatrial block in a general hospital population. Am J Cardiol 2003;91: Ozer O, Davutoglu V, Sari I, et al. The spectrum of rheumatic heart disease in the southeastern Anatolia endemic region: Results from 1900 patients. J Heart Valve Dis 2009;18: Davutoglu V, Celik A, Aksoy M. Contribution of selected serum inflammatory mediators to the progression of chronic rheumatic valve disease, subsequent valve calcification and NYHA functional class. J Heart Valve Dis 2005;14: Davutoglu V, Celik A, Aksoy M, et al. Plasma NTproBNP is a potential marker of disease severity and correlates with symptoms in patients with chronic rheumatic valve disease. Eur J Heart Fail 2005;7:

5 J Heart Valve Dis Interatrial block and P-terminal force in MS Ozer O, Davutoglu V, Ercan S, et al. Plasma urotensin II as a marker for severity of rheumatic valve disease. Tohoku J Exp Med 2009;218: Sari I, Davutoglu V. Association of chronic subclinical inflammation with severity and progression of rheumatic valve disease. Int J Cardiol 2008;29: Guntekin U, Gunes Y, Tuncer M, et al. Long-term follow-up of P-wave duration and dispersion in patients with mitral stenosis. Pacing Clin Electrophysiol 2008;31: Ariyarajah V, Mercado K, Apiyasawat S, Puri P, Spodick DH. Correlation of left atrial size with p- wave duration in interatrial block. Chest 2005;128:

Relation of interatrial duration and p wave terminal force as a novel indicator of severe

European Review for Medical and Pharmacological Sciences 2012; 16: 1576-1581 Relation of interatrial duration and p wave terminal force as a novel indicator of severe mitral regurgitation M.A. ELBEY 1,