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Medical Science Monitor: International Medical Journal of Experimental and Clinical Research logoLink to Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
. 2025 Aug 12;31:e947360. doi: 10.12659/MSM.947360

Electrocardiographic Indicators of Left Atrial Remodeling in Ischemic Stroke Patients with Atrial Fibrillation

Sebastian Sawonik 1,A,B,C,D,E,F,G,*, Andrzej P Wysokiński 2,A,D,G, Tomasz Zapolski 2,A,B,C,D,E,F,G,*,✉
PMCID: PMC12357521  PMID: 40790861

Abstract

Background

Left atrial (LA) remodeling (LAR) is a risk factor for atrial fibrillation (AF) and ischemic stroke (IS). LAR can be detected on electrocardiogram (ECG) by P wave indices. The aim of this study was to search for noninvasively assessed LAR markers associated with the history of IS in patients with AF, considering differences between males and females.

Material/methods

This retrospective study included a group of 256 patients, aged 76.19 (±9.64) years, with documented AF and after IS. The control group consisted of 70 people aged 68.43 (±7.38) years with AF but without IS. The collected study material included ECG (longest P wave duration [Pmax], P wave duration [PWD], P wave dispersion [PWDI], P wave terminal force in lead V1 [PWTFV1], negative phase duration of the P in V1 [PWDNV1]) and trans-thoracic echocardiography. Results were compared among both sexes and the control group.

Results

In the study group, electrophysiological LAR was more advanced than in the control group, with significantly higher PWDI (80.60(±23.05) vs 62.49(±14.92) ms; p<0.001) and lower percentage of patients with normal Pmax/PWTFV1/PWDNV1/PWDI indices (2.73 vs 11.43%; p<0.05) respectively. LA area was larger (28.33(±7.50) vs 21.26(±2.79) cm2; p<0.001) and LVEF was lower (54.85(±9.14) vs 58.17(±6.40); p<0.05) in the study group compared to the control group. PWTF (4801.6(±3695.4) vs 4127.8(±3689.6) mcV*ms; p=0.049) was higher in males than in females. In multivariable logistic regression analysis, predictors significantly associated with IS occurrence in patients with AF were: higher PWDV1 values (95% CI: 1.02–1.08, p<0.001), Pmax (95% CI: 0.90–0.97, p<0.001), and LVEF (95% CI: 0.84–0.99, p=0.030).

Conclusions

In patients with IS, higher indices of both structural and electrophysiological LAR are observed. There are significant differences between the sexes in the severity of LAR indices.

Keywords: Atrial Fibrillation, Gender Role, Stroke

Introduction

Atrial fibrillation (AF) is a modern epidemic related to the aging of society, and is particularly dangerous due to the direct connection between arrhythmia and ischemic stroke (IS). AF is an arrhythmia that causes adverse remodeling of the left atrium (LAR), known as atrial cardiomyopathy (AC) [1]. LAR refers to the spectrum of pathophysiological changes in atrial structure and mechanical function and the electric, ionic, and molecular milieu of the left atrium (LA) that most often occurs in response to stresses imposed by conditions such as hypertension, heart failure, diabetes mellitus, and obesity [2]. Remodeling forms the basis of AC, defined by a multi-society, expert consensus statement as any complex of structural, architectural, contractile, or electrophysiological changes affecting the atria with the potential to produce clinically relevant manifestations [2]. LAR is the link between morphological changes and electrophysiological abnormalities that contribute to the triggering and maintenance of AF, creating a vicious circle between AC and cardiac arrhythmias. Therefore, the pathomechanism of arrhythmia resulting from structural, functional, and electrophysiological remodeling may be reflected in specific P wave changes in the electrocardiogram (ECG) [3,4]. The presence of atrial fibrosis and fatty infiltration is the anatomic substrate of both AF and advanced interatrial block [4]. In patients with AF and after IS, structural and functional remodeling of both LA and right (RA) atria (AR) causes large differences in P indices, which are a manifestation of electrophysiological AR [5,6]. Prolongation of the P wave duration ≥110 ms, the dispersion of P ≥40 ms, and the P wave terminal force (PWTF) in the V1 lead (PWTFV1) ≤4000 mcV*ms are risk factors for recurrent AF, which increases the risk of embolic complications [7,8]. PWTFV1, P wave duration, and maximum P wave area are useful electrocardiographic markers that can be used to stratify the risk of incident IS [9]. The ARCADIA trial (AtRial Cardiopathy and Antithrombotic Drugs in prevention After cryptogenic stroke) use one of these measures, PWTFV1, as a key eligibility criterion for identifying cryptogenic stroke patients with potential underlying AC [10]. Although several clinical studies have shown the value of some ECG P wave markers in assessing the risk of IS, patients with atrial abnormalities without evident AF are not placed on oral anticoagulation [11]. This is controversial because it is a major diagnostic and therapeutic inconsistency, which potentially poses a risk of IS. There is an unresolved gap – whether the indication for anticoagulation should be the occurrence of AF or whether anticoagulation should be started earlier, after the electrophysiological and structural AR has been detected. More important, however, are the potential clinical consequences of changing the paradigm of anticoagulation initiation.

The sex differences in AF are vast. There are conflicting data as to whether sex plays a role in the association of various risk factors and the development of AF [12]. There are also female-/male-specific factors that contribute to the development of AF [13]. There are many gaps in our knowledge of the sex differences in AF, and many opportunities for future research.

The main aim of this study was to assess differences in LA enlargement indicating LAR markers based on the occurrence of IS among patients with AF and to evaluate sex differences in these markers. The results of this study may suggest future research directions for screening tools for patients at increased risk of AF and cardioembolic complications.

Material and Methods

Study Design and Data Collection

The study material consisted of the medical histories of patients hospitalized in the Department of Neurology for cardioembolic stroke with a history of AF. These patients were selected because AR is to be expected in this group. The study included a group of 731 patients, with documented AF and after IS, hospitalized between 2000 and 2020 at the Department of Neurology. The exclusion criteria were: undocumented AF in the ECG, no ECG with sinus rhythm (SR) in the peri-stroke period (±6 months), implanted pacemaker or cardioverter-defibrillator, hemodynamically significant heart defects, and unsatisfactory quality of the ECG recording. Finally, the data of 256 patients (183 females and 73 males) over 18 years of age were evaluated (Figure 1). The collected study material involved medical documentation, which included ECG and trans-thoracic echocardiography (TTE) performed at admission to the hospital, as well as data considered in the study: age and comorbidities. The control group consisted of 70 people (44 females and 26 males) aged 68.43(±7.38) years with AF but without IS. The selection of the control group was based on a study of people with AF and after IS hospitalized for AF in the Department of Cardiology. Women predominated in both the study group and the control group, which facilitates comparison between the 2 groups and corresponds to similar proportions of patients in the daily treatment of people with similar conditions. Patient data from the study and control groups were manually extracted from the medical records archives. Patient documentation also contained information about the time between first diagnosis of AF and IS (in the study group) or hospitalization (in the control group). The study assessed structural AR (eg, LA diameter, area) and electrical remodeling (P wave indices). Results were compared among both sexes due to the well-known differences between males and females. Structural remodeling was assessed by echocardiographic parameters and electrical remodeling was assessed based on ECG parameters. The ECG and echocardiographic parameters considered in the study are listed in detail below.

Figure 1.

Figure 1

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Patient flow diagram. The process of identifying a cohort of 731 patients and selecting 256 individuals for the study group is shown in the diagram of patient flow. The selection criterion was ECG with SR available on file. The full inclusion criteria are given above. AF – atrial fibrillation; ECHO – echocardiography; ECG – electrocardiogram; SR – sinus rhythm.

Electrocardiographic Assessment

An ECG was routinely performed upon admission of patients to the hospital using the Aspel AsCard Orange v.07.105 device. The ECG was set for a paper speed of 25 mm/s and sensitivity of 1 (1 cm=1 mV). The ECG measurements were always performed by the same cardiologist blinded to clinical data. A magnifying glass with a scale of 0.1 mm, a scale length of 10 mm, and a lens diameter of 15 mm were used to measure the P wave in the ECG recording. This enables the analysis of the morphology of the P wave in available ECGs with an accuracy of 0.1 mm, which corresponds to 0.004 s of the duration of the P wave and enables the measurement of the P amplitude with an accuracy of 0.01 mV. The P wave duration was measured from the beginning of the ECG curve until its return to the isoelectric line. P amplitude was measured from the isoelectric line to the peak of the P wave (positive P amplitude) and from the isoelectric line to the lowest point on the P wave curve (negative P amplitude). For biphasic P waves, positive and negative P amplitudes were reported. PWDI was measured manually by subtracting the minimal P wave (Pmin) duration from the maximal P wave (Pmax) duration (Pmax - Pmin), measured by 12-lead surface ECG, from a single beat, and mean values for 3 complexes were calculated. The duration of the negative phase of the P wave in the V1 lead was measured from the onset of the negative P wave in V1 to the return of the wave to the isoelectric line. The amplitude of the negative phase of P in V1 was measured from the isoelectric line to the deepest point of the P wave. The PWTFV1 is the product of negative phase duration of the P wave in V1 (ms) and negative phase amplitude of the P wave in V1 (mcV).

All 12 ECG leads were analyzed. Then, the most commonly used P wave indices were calculated from the available parameters (Figure 2) [3,4]:

Figure 2.

Figure 2

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Methodology for calculating of P wave indices (A – PWD, B – PWDNV1, C – PWDNV1A). PWD – P wave duration; PWDNV1 – negative phase duration of the P in V1; PWDNV1A – negative phase amplitude of the P in V1.

  • P wave duration [ms] (PWD),

  • PWD in the lead I <110 ms [n (%)]

  • P wave dispersion [ms] (PWDI),

  • the longest P wave duration [ms] (Pmax),

  • the shortest P wave duration [ms] (Pmin),

  • negative phase duration of the P in V1 [ms] (PWDNV1),

  • negative phase amplitude of the P in V1 [mcV] (PWDNV1A),

  • P wave terminal force in the V1 lead [mcV *ms] (PWTFV1),

  • PWTFV1 <4000 μV*ms [n (%)]

  • Pmax/PWTFV1/PWDNV1 in normal range [n (%)]

  • Pmax/PWTFV1/PWDNV1/PWDI in normal range [n (%)]

Echocardiographic Protocol

Echocardiographic examinations were performed upon admission to the hospital using a Philips Epiq 7c Ultrasound System with a Philips X5-1 Sector Array Probe. Echocardiographic measurements were always performed by the same cardiologist, a different one from the one analyzing the ECG recordings and blinded to the clinical data. Measurements and calculations were performed based on current recommendations for cardiac chamber quantification by echocardiography in adults [14]. The following parameters were analyzed (Figure 3):

Figure 3.

Figure 3

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Echocardiographic measurements. A – Trans-thoracic echocardiography: LAD calculation in M-mode in parasternal long axis view – PLAX; B – Trans-thoracic echocardiography, two-dimensional apical 4-chamber view: LAA calculation; C – Trans-thoracic echocardiography, two-dimensional apical 4-chamber view: RAA calculation. LAD – Left atrium diameter; LAA – left atrium area; RAA – right atrium area.

  • LA dimension in M-mode presentation in the parasternal long axis view (LAD),

  • RA area in the apical four-chamber view (RAA),

  • LA area in the apical four-chamber view (LAA),

  • left ventricular (LV) ejection fraction (LVEF) calculated by the Simpson method.

Atrial Fibrillation Burden

In the simplest sense, AF burden refers to the amount of AF that an individual has. Classical AF burden indicators include the percentage of AF time in a specific period of observation [15]. Due to the retrospective nature of the study, continuous recording using telemonitoring or retrospective analysis of records in implantable devices was impossible [15]. Patients with implanted intracardiac devices were excluded from the study because the stimulated P waves would have impaired the assessment of P wave indices and thus falsified the assessment of electrical AR. Under these conditions, an attempt was made to estimate the burden of AF based on available data. Estimated AF burden was defined as the time from first AF diagnosis to IS onset, defined as a percentage of lifetime (estimated AF% burden). The time from first AF diagnosis to stroke onset was defined as estimated AF burden. In other words, 2 alternative indicators were used, which could be precisely determined based on available documentation:

  • time from AF diagnosis to IS (years) – estimated AF burden,

  • time from AF diagnosis to IS-to-age ratio (%) – estimated AF% burden.

Statistical Analysis

Categorical variables are presented as counts (percentages). Normality was tested using the Shapiro-Wilk test. All continuous variables had normally distributed data. Descriptive statistics were reported as means with standard deviations (SD) for continuous variables for normally distributed data. For comparative studies involving 2 groups, the Mann-Whitney U test (for independent samples) was used. Correlations between categories were examined using the chi-square test (χ2) with Yates’ correction. Univariate comparisons between patients with and without stroke were performed using the Wilcoxon rank-sum test due to non-normal data distribution, and were assessed via the Shapiro-Wilk test with p<0.05 indicating statistical significance.

A multivariable logistic regression model was fitted to assess predictors of IS occurrence, using a binomial distribution with a logic link function. Predictors were selected based on their established clinical relevance to IS risk in AF, as evidenced by significant associations in univariate analysis, and informed by prior literature and clinical guidelines. Model fit was evaluated using the Hosmer-Lemeshow goodness-of-fit test (10 groups), with a non-significant p value (p>0.05) indicating adequate fit. The Tjur’s R2 was calculated to estimate explained variance, and the rank correlation coefficient (rho) assessed agreement between observed and predicted probabilities.

Multicollinearity was examined using variance inflation factors (VIFs) and tolerance values, with VIF <3 and tolerance >0.1 as thresholds for acceptable collinearity. The time between first AF diagnosis and hospitalization – to-age ratio (AF% burden) was excluded from the final model due to high multicollinearity (preliminary VIF >10.0) with age and time from AF to IS. Model discrimination was evaluated via the area under the receiver operating characteristic (ROC) curve (AUC), with 95% confidence intervals (CI) computed using the DeLong method.

Statistical Tool

Analyses were conducted using the R Statistical language (version 4.3.3; R Core Team, 2024) on Windows 11 x64 (build 26100), using the packages sjPlot (version 2.8.15) [16], performance (version 0.12.3) [17], report (version 0.5.8;) [18], pROC (version 1.18.5) [19], gtsummary (version 1.7.2) [20], gofcat (version 0.1.2) [21], MASS (version 7.3.60.0.10 [22], and dplyr (version 1.1.4) [23].

Ethical Consideration

The consent to conduct the research was obtained from the local bioethics committee (Bioethical Committee at the Medical University of Lublin) – KE-0254/27/2013. The research was conducted in accordance with the principles contained in the Declaration of Helsinki [24,25]. After being fully informed about the aims, research methods, possible adverse effects and potential scientific, medical, and social values of this project, informed consent was obtained from all individuals included in the study. Because this was a retrospective study conducted at a university clinical center, consent to use for research purposes the data routinely obtained during a standard hospitalization is obtained from each patient in the hospital documentation upon admission.

Results

Patients with IS were older and most (222, 86.72%) had hypertension, resulting in a significant difference to the control group. Nevertheless, it cannot be concluded that patients with IS were characterized by multimorbidity, as heart failure, diabetes and ischemic heart disease occurred in only 1/4 to 1/3 of patients and similarly frequently in both groups (Table 1). The results of the presented study confirm that LAE in the study group is reflected in higher PWTFV1 values. 52,34% of the subjects in study group had a rate above 4000 mcV*ms (Table 1). PWD in the lead II and PWD in the lead III had a statistically significantly lower value in the group with IS compared to the control group. In contrast, patients with IS were characterized by a significantly higher value of PWD in the lead V1. As a result, the calculated PWDI was statistically significantly higher in the study group. Pmax was significantly longer in the control group than in the IS group. The proportion of patients with all 4 indices in a normal range (Pmax/PWTFV1/PWDNV1/PWDI) was higher in the control group than in the study group. Taken together, these data imply that electrophysiological remodeling was more advanced in the study group than in the control group.

Table 1.

Clinical data and echocardiographic and electrocardiographic indices in study group and control group.

Category Value With stroke n=256 Control group (without stroke) N=70 Test p value
Age [years] 36–97 76.19 (±9.64) 68.43 (±7.38) MWU: 2286.50; z=4.69 p<0.001
Heart failure [n (%)] 58 (22.66) 18 (25.71) χ2=0.04 p>0.05
Hypertension [n (%)] 222 (86.72) 46 (65.71) χ2=8.69 p<0.01
Diabetes mellitus [n (%)] 62 (24.22) 8 (11.43) χ2=2.19 p>0.05
Ischemic heart disease [n (%)] 79 (30.86) 30 (42.86) χ2=1.15 p>0.05
Echocardiographic parameters LAA [cm2] 16–49 28.33 (±7.50) 21.26 (±2.79) MWU: 97.00; z=4.08 p<0.001
RAA [cm2] 12–26 20 (±4.78) 18.83 (±2.47) MWU: 114.50; z=0.78 p>0.05
LAD [cm] 2.70–6.10 4.22 (±0.63) 4.12 (±0.42) MWU: 1966.50; z=0.84 p>0.05
EF [%] 28–75 54.85 (±9.14) 58.17 (±6.40) MWU: 1569.50; z=−2.27 p<0.05
PWD in the lead I [ms] 54.48 (±41.81) 95.83 (±16.50) MWU: 4374.50; z=−0.22 p>0.05
PWD in the lead I <110ms [n (%)] 220 (85.94) 62 (88.57) χ2=0.02 p>0.05
PWD in the lead II [ms] 68.36 (±38.17) 79.20 (26.60) MWU: 1742.00; z=−5.86 p<0.001
PWD in the lead III [ms] 58.44 (±36.08) 84.09 (±21.46) MWU: 2768.50; z=−3.66 p<0.001
PWD in the lead aVF [ms] 63.44 (±36.41) 69.71 (±28.09) MWU: 4218.50; z=0.56 p>0.05
PWD in the lead aVL [ms] 47.16 (±36.13) 63.86 (±23.64) MWU: 3776.00; z=−1.51 p>0.05
PWD in the lead aVR [ms] 67.19 (±39.58) 69.23 (±25.85) MWU: 4021.00; z=0.98 p>0.05
PWD in the lead V1 [ms] 82.82 (±25.62) 72.69 (±26.49) MWU: 3284.50; z=2.56 p<0.05
PWD in the lead V2 [ms] 49.11 (±33.70) 57.06 (±21.35) MWU: 4127.00; z=−0.75 p>0.05
PWD in the lead V3 [ms] 54.34 (±33.10) 61.46 (±17.60) MWU: 4371.00; z=−0.22 p>0.05
PWD in the lead V4 [ms] 56.45 (±33.45) 68.09 (±24.74) MWU: 4046.00; z=−0.93 p>0.05
PWD in the lead V5 [ms] 57.41 (±34.78) 68.37 (±25.23) MWU: 4214.50; z=−0.57 p>0.05
PWD in the lead V6 [ms] 57.09 (±36.77) 68.20 (±23.60) MWU: 4167.00; z=−0.67 p>0.05
Pmax [ms] 101.08 (±21.03) 106.35 (±17.48) MWU: 2305.50; z=−4.66 p<0.001
Pmin [ms] 20.48 (±23.00) 44.09 (±15.46) MWU: 3778.00; z=−1.50 p>0.05
PWDI [ms] 80.60 (±23.05) 62.49 (±14.92) MWU: 2488; z=4.27 p<0.001
PWDNV1 [ms] 50.70 (±26.82) 48.51 (±18.33) MWU: 3676.50; z=1.72 p>0.05
PWNV1A [mcV] 79.58 (±39.91) 85.67 (±29.45) MWU: 4103.00; z=−2.45 p<0.05
PWTFV1 [mcV*ms] 4320.71 (±3696.64) 3957.14 (±1644.47) MWU: 4286.00; z=−0.38 p>0.05
PWTFV1 <4000 mcV*ms [n (%)] 133 (51.95) 36 (51.43) χ2=0.06 p>0.05
Pmax/PWTFV1/PWDNV1 in normal range [n (%)] 82 (32.03) 16 (22.86) χ2=0.82 p>0.05
Pmax/PWTFV1/PWDNV1/PWDI in normal range [n (%)] 7 (2.73) 8 (11.43) χ2=4.23 p<0.05
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LAA – left atrium area; LA – left atrium; LAD – left atrial dimension [M-mode in parasternal long axis view – PLAX]; LVEF – left ventricular ejection fraction; n – the total number of patients in the sample; Pmax – the longest P wave duration; Pmin – shortest P wave duration; PWD – P wave duration; PWDI – P wave dispersion; PWDNV1 – duration of the negative P phase in V1; PWDNV1A – the negative phase amplitude of P in V1; PWTFV1 – P wave terminal force in V1; RAA – right atrium area.

Comparative analysis between sexes showed that females were older than males. In contrast, there were no significant differences in the incidence of cardiovascular disease and diabetes (Table 2).

Table 2.

Clinical data and echocardiographic and electrocardiographic indices in relation to sex.

Category Value Female
n=183		 Male
n=73		 Test P value
Age [years] 36–97 77.5 (±9.2) 72.9 (±9.9) MWU: z=3.255 p=0.001
Heart failure [n (%)] 39 (21.3) 19 (26.0) χ2=0.421 p=0.517
Hypertension [n (%)] 161 (88.0) 61 (83.6) χ2=0.542 p=0.462
Diabetes mellitus [n (%)] 45 (24.6) 17 (23.3) χ2=0.003 p=0.954
Ischemic heart disease [n (%)] 51 (27.9) 28 (38.4) χ2=2.221 p=0.136
Echocardiographic parameters LAA [cm2] 16–49 27.8 (±6.2) 29.5 (±10.3) MWU: z=0.140 p=0.925
RAA [cm2] 12–26 18.0 (±5.8) 22.0 (±2.9) MWU: z=−1.299 p=0.243
LAD [cm] 2.7–6.1 4.1 (±0.6) 4.4 (±0.6) MWU: z=−2.319 p=0.020
EF [%] 28–75 56.5 (±8.1) 51.3 (±10.2) MWU: z=2.513 p=0.012
PWD in the lead I [ms] 55.0 (±40.5) 53.1 (±45.1) MWU: z=0.308 p=0.756
PWD in the lead I ≥110ms [n (%)] 174 (95.1%) 63 (86.3) χ2=4.647 p=0.031
PWD in the lead II [ms] 70.9 (±36.0) 62.1 (±42.7) MWU: z=0.800 p=0.416
PWD in the lead III [ms] 61.0 (±33.9) 51.9 (±40.5) MWU: z=1.085 p=0.272
PWD in the lead aVF [ms] 64.9 (±34.4) 59.7 (±41.1) MWU: z=0.085 p=0.932
PWD in the lead aVL [ms] 48.8 (±34.6) 43.1 (±39.7) MWU: z=0.927 p=0.344
PWD in the lead aVR [ms] 69.4 (±37.4) 61.7 (±44.5) MWU: z=0.682 p=0.492
PWD in the lead V1 [ms] 82.2 (±25.1) 84.8 (±26.9) MWU: z=−1.077 p=0.277
PWD in the lead V2 [ms] 52.3 (±32.4) 41.0 (±35.7) MWU: z=2.009 p=0.042
PWD in the lead V3 [ms] 56.1 (±32.2) 50.0 (±35.2) MWU: z=0.299 p=0.763
PWD in the lead V4 [ms] 57.7 (±30.5) 53.4 (±39.9) MWU: z=0.213 p=0.830
PWD in the lead V5 [ms] 57.7 (±32.4) 56.7 (±40.4) MWU: z=−0.660 p=0.504
PWD in the lead V6 [ms] 58.3 (±34.9) 54.0 (±41.1) MWU: z=0.253 p=0.798
Pmax [ms] 100.4 (±22.4) 102.8 (±17.2) MWU: z=−1.146 p=0.242
Pmin [ms] 43.0 (±15.0) 48.5 (±16.6) MWU: z=−2.570 p=0.008
PWDI [ms] 57.4 (±23.5) 54.3 (±21.8) MWU: z=0.724 p=0.467
PWDNV1 [ms] 48.3 (±26.9) 56.7 (±25.9) MWU: z=−2.445 p=0.014
PWNV1A [mcV] 80.30 (±39.5) 80.63 (±36.9) MWU: 7723; z=0.17976 p=0.857
PWTFV1 [mcV*ms] 4127.8 (±3689.6) 4801.6 (±3695.4) MWU: z=1.962 p=0.049
PWTFV1 <4000 mcV*ms [n (%)] 103 (56.6) 30 (41.1) χ2=4.413 p=0.036
Pmax/PWTFV1/PWDNV1 in normal range [n (%)] 72 (39.3) 10 (13.7) χ2=9.685 p=0.002
Pmax/PWTFV1/PWDNV1/PWDI in normal range [n (%)] 7 (3.8) 0 (0.0) χ2=2.431 p=0.119
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LAA – left atrium area; LA – left atrium; LAD – left atrial dimension [M-mode in parasternal long axis view – PLAX]; LVEF – left ventricular ejection fraction, n – the total number of patients in the sample; Pmax – the longest P wave duration; Pmin – shortest P wave duration; PWD – P wave duration; PWDI – P wave dispersion; PWDNV1 – duration of the negative P phase in V1; PWDNV1A – the negative phase amplitude of P in V1; PWTFV1 – P wave terminal force in V1; RAA – right atrium area.

There were several significant differences in P wave indices among patients with IS based on sex. PWTFV1 and Pmin were higher in the male group than in the female group, whereas values of PWD in the lead V2 were longer among females (Table 2). The PWDNV1 was significantly shorter in females than in males. There were also interesting differences in the frequency of certain abnormalities between females and males. A statistically significantly larger percentage of women had a higher prevalence of PWD in the lead I ≥110 ms than in males (Table 1). A lower percentage of PWTFV1 <4000 mcV*ms was recorded in males. Males were less likely than females to have at least 1 of the studied parameters in the normal range (considering PWTFV1, Pmax, PWDNV1). Only 13.7% of males had all 3 parameters in the normal range, while among females the percentage was 34.1% (p=0.002) (Table 2). The differences between the sexes were statistically significant (p<0.05).

Most patients had enlarged atria on TTE. Females had a significantly smaller LA and higher mean LVEF than males (Table 2).

Table 3 presents a comparison of clinical data and echocardiographic and electrocardiographic parameters in the study group with IS and in the female control group. The analogous comparison of clinical data and echocardiographic and electrocardiographic parameters in the study group with IS and in the male control group is presented in Table 4.

Table 3.

Clinical data and echocardiographic and electrocardiographic indices in female study group and control group.

Category Value Total women
n=227		 With stroke
n=183		 Control group (without stroke)
N=44		 Test p value
Age [years] 55–97 76.9 (±9.15) 77.5 (9.2) 72.3 (±5.4) MWU: 1260.00; z=2.86 p<0.01
Heart failure [n (%)] 46 (2.4) 39 (21.3%) 14 (31.8) χ2=0,72 p>0.05
Hypertension [n (%)] 176 (85.9) 161 (88.0%) 30 (68.2) χ2=4.81 p<0.05
Diabetes mellitus [n (%)] 48 (23.4) 45 (24.6%) 6 (13.6) χ2=0.77 p>0.05
Ischemic heart disease [n (%)] 61 (29.8) 51 (27.9%) 20 (45.5) χ2=2.13 p>0.05
Echocardiogra phic parameters LAA [cm2] 16–40 23.1 (±5.4) 27.8 (6.2) 20.5 (±2.4) MWU: 30.00; z=3.66 p<0.001
RAA [cm2] 12–26 18.5 (±2.8) 18.0 (5.8) 18.5 (±2.2) MWU: 33.00; z=−0.75 p>0.05
LAD [cm] 2.70–6.10 4.1 (±0.6) 4.1 (0.6) 4.0 (±0.4) MWU: 847.50; z=0.67 p>0.05
EF [%] 33–75 56.7 (±7.8) 56.5 (8.1) 57.6 (±6.61) MWU: 803.50; z=0.67 p>0.05
PWD in the lead I [ms] 59.5 (±40.7) 55.0 (40.5) 96.3 (±15.2) MWU: 701.00; z=−4.00 p<0.001
PWD in the lead I ≥110 ms [n (%)] 180 (87.8) 174 (95.1%) 38 (86.4) χ2=0.02 p>0.05
PWD in the lead II [ms] 71.7 (±40.7) 70.9 (36.0) 78.7 (±27.1) MWU: 1987.00; z=0.09 p>0.05
PWD in the lead III [ms] 63.6 (±33.5) 61.0 (33.9) 84.8 (±19.6) MWU: 1175.00; z=−3.19 p<0.01
PWD in the lead aVF [ms] 65.7 (±33.9) 64.9 (34.4) 71.6 (±29.65) MWU: 1972.00; z=0.15 p>0.05
PWD in the lead aVL [ms] 50.5 (±34.0) 48.8 (34.6) 65.0 (±24.4) MWU: 17.66; z=0.15 p>0.05
PWD in the lead aVR [ms] 69.5 (±36.4) 69.4 (37.4) 70.4 (±27.8) MWU: 17.71; z=0.92 p>0.05
PWDNV1 [ms] 48.3 (±26.3) 48.31 (±26.88) 48.4 (±21.6) MWU: 1758.00; z=0.97 p>0.05
PWD in the lead V1 [ms] 80.5 (±25.8) 82.2 (25.1) 66.9 (±27.8) MWU: 1250.00; z=2.90 p<0.01
PWD in the lead V2 [ms] 52.6 (±31.5) 52.3 (32.4) 55.3 (±23.7) MWU: 19.85.50; z=0.10 p>0.05
PWD in the lead V3 [ms] 56.3 (±30.8) 56.1 (32.2) 58.1 (±14.6) MWU: 1893.00; z=0.46 p>0.05
PWD in the lead V4 [ms] 58.3 (±30.8) 57.7 (30.5) 63.7 (±22.9) MWU: 1985.00; z=0.10 p>0.05
PWD in the lead V5 [ms] 58.5 (±31.6) 57.7 (32.4) 64.9 (±23.8) MWU: 1964.50; z=−0.18 p>0.05
PWD in the lead V6 [ms] 59.2 (±33.9) 58.3 (34.9) 66.4 (±)23.5 MWU: 1959.00; z=−0.20 p>0.05
P max [ms] 100.9 (±22.0) 100.4 (22.4) 105.5 (±17.9) MWU: 1718.00; z=−1.12 p>0.05
P min [ms] 23.6 (±)23.8 43.0 (15.0) 47.9 (±18.0) MWU: 809.00; z=−4.58 p<0.001
PWDI [ms] 77.3 (±24.2) 57.4 (23.5) 57.6 (±15.5) MWU: 946.00; z=4.06 p<0.001
PWDNV1 [ms] 48.3 (±26.3) 48.3 (26.9) 48.4 (±21.6) MWU: 1758.00; z=0.97 p>0.05
PWTF [mcV*ms] 4130.7 (±3533.4) 4127.8 (3689.6) 4154.6 (±1829.8) MWU: 1714.50; z=−1.10 p>0.05
PWTF <4000 mcV*ms [n (%)] 123 (54.2) 103 (56.6%) 20 (45.5) χ2=0.62 p>0.05
Pmax/PWTFV1/PWDNV1 in normal range [n (%)] 86 (37.81) 72 (39.3%) 14 (31.8) χ2=0.04 p>0.05
Pmax/PWTFV1/PWDNV1/PWDI in normal range [n (%)] 13 (5.7) 7 (3.8%) 6 (13.6) χ2=2.23 p>0.05
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LAA – left atrium area; LA – left atrium; LAD – left atrial dimension [M-mode in parasternal long axis view – PLAX]; LVEF – left ventricular ejection fraction; n – the total number of patients in the sample; Pmax – the longest P wave duration; Pmin – shortest P wave duration; PWD – P wave duration; PWDI – P wave dispersion; PWDNV1 – duration of the negative P phase in V1; PWTFV1 – P wave terminal force in V1; RAA – right atrium area.

Table 4.

Clinical data and echocardiographic and electrocardiographic indices in male study group and control group

Category
Value		 Valuwe Total men
n=99		 With stroke
n=73		 Control group (without stroke)
n=26		 Test p value
Age [years] 36–92 71.3 (±10.1) 72.9 (±9.9) 66.9 (±5.3) MWU: 127.00; z=4.18 p<0.001
Heart failure [n (%)] 21 (24.4) 19 (26.0) 4 (15.4) χ2=0.22 p>0.05
Hypertension [n (%)] 69 (80.2) 61 (83.6) 16 (61.5) χ2=2.32 p>0.05
Diabetes mellitus [n (%)] 18 (20.9) 17 (23.3) 2 (7.7) χ2=0.82 p>0.05
Ischemic heart disease [n (%)] 33 (38.4) 28 (38.4) 10 (38.5) χ2=0.09 p>0.05
Echocardiographic parameters LAA [cm2] 18–49 24.7 (±6.8) 29.5 (±10.3) 22.5 (±3.0) MWU: 22.50; z=1.40 p>0.05
RAA [cm2] 15–26 19.9 (±3.1) 22.0 (±2.9) 19.3 (±3.0) MWU: 15.50; z=1.13 p>0.05
LAD [cm] 3.30–5.70 4.4 (±0.6) 4.4 (±0.6) 4.3 (±0.5) MWU: 215.50; z=0.79 p>0.05
EF [%] 28–66 53.3 (±9.9) 51.3 (±10.2) 59.2 (±6.1) MWU: 116.50; z=−2.81 p<0.01
PWD in the lead I [ms] 59.4 (±44.7) 53.1 (±45.1) 95.1 (±19.2) MWU: 217.00; z=−3.10 p<0.01
PWD in the lead I >110ms [n (%)] 71 (82.6) 63 (86.3) 24 (92.3) χ2=0.37 p>0.05
PWD in the lead II [ms] 64.8 (±41.1) 62.1 (±42.7) 80 (±26.8) MWU: 424.50; z=−0.60 p>0.05
PWD in the lead III [ms] 56.6 (±40.1) 51.9 (±40.5) 82.9 (±25.2) MWU: 305,50; z=−2.03 p<0.05
PWD in the lead aVF [ms] 60.7 (±39.2) 59.7 (±41.1) 66.5 (±26.3) MWU: 428.00; z=0.55 p>0.05
PWD in the lead aVL [ms] 46. (±38.2) 43.1 (±39.7) 61.9 (±23.1) MWU: 365.50; z=−1.31 p>0.05
PWD in the lead aVR [ms] 62.5 (±41.9) 61.7 (±44.5) 67.2 (±23.1) MWU: 463.00; z=0,13 p>0.05
PWD in the lead V1 [ms] 84.5 (±26.1) 84.8 (±26.9) 82.5 (±21.6) MWU: 438.50; z=0.43 p>0.05
PWD in the lead V2 [ms] 43.9 (±34.2) 41.0 (±35.7) 60.1 (±17.16) MWU: 349.00; z=−1.51 p>0.05
PWD in the lead V3 [ms] 52.6 (±33.9) 50.0 (±35.2) 67.1 (±21.3) MWU: 403.00; z=−0.86 p>0.05
PWD in the lead V4 [ms] 56.8 (±38.9) 53.4 (±39.9) 75.5 (±16.9) MWU: 353.00; z=−0.46 p>0.05
PWD in the lead V5 [ms] 59.3 (±39.1) 56.7 (±40.4) 74.3 (±27.4) MWU: 435.50; z=−0.46 p>0.06
PWD in the lead V6 [ms] 56.6 (±39.4) 54.0 (±41.1) 71.3 (±24.5) MWU: 408.50; z=−0.46 p>0.05
P max [ms] 103.7 (±17.2) 102.8 (±17.2) 108.5 (±17.3) MWU: 390.00; z=−1.01 p>0.05
P min [ms] 24.5 (±25.1) 48.5 (±16.6) 50.2 (±14.4) MWU: 180.50; z=−3.54 p<0.001
PWDI [ms] 79.2 (±21.8) 54.3 (±21.8) 58.2 (±17.2) MWU: 171.50; z=−3.65 p<0.001
PWDNV1 [ms] 55.5 (±24.4) 56.7 (±25.9) 48.7 (±11.6) MWU: 308.00; z=2.00 p<0.05
PWTF [mcV*ms] 4623.5 (±3460.5) 4801.6 (±3695.4) 3623.1 (±1269.0) MWU: 382.50; z=1.10 p>0.05
PWTF <4000 mcV*ms [n (%)] 46 (46.5) 30 (41.1) 16 (61.6) χ2=0.30 p>0.05
Pmax/PWTFV1/PWDNV1 in normal range [n (%)] 12 (12.1) 10 (13.7) 2 (7.7) χ2=0.51 p>0.05
Pmax/PWTFV1/PWDNV1/PWDI in normal range [n (%)] 2 (0.2) 0 (0.0) 2 (7.7) χ2=0.96 p>0.05
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LAA – left atrium area; LA – left atrium; LAD – left atrial dimension [M-mode in parasternal long axis view – PLAX]; LVEF – left ventricular ejection fraction; n – the total number of patients in the sample; Pmax – the longest P wave duration; Pmin – shortest P wave duration; PWD – P wave duration; PWDI – P wave dispersion; PWDNV1 – duration of the negative P phase in V1; PWTFV1 – P wave terminal force in V1; RAA – right atrium area.

Univariate analysis of patient characteristics in an AF cohort (Table 5) revealed significant differences between those with and without IS. Patients with IS were older (mean age 76.20 years, SD=9.64) compared to those without (mean 68.43 years, SD=7.38; W=6673.5, p<0.001).

Table 5.

Comparison of patient characteristics by stroke status in atrial fibrillation cohort.

Characteristic N Overall (N=291) Stroke (N=256) No stroke (N=70) Test statistic (W) p
Age (years) 291 75.26 (9.72) 76.20 (9.64) 68.43 (7.38) 6673.5 <0.001
AF burden (years) 291 2.19 (1.18) 2.33 (1.15) 1.18 (0.83) 6892.0 <0.001
AF% burden (%) 291 2.87 (1.49) 3.03 (1.46) 1.70 (1.16) 6688.0 <0.001
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Data are presented as mean (SD) unless otherwise specified. Comparisons between IS and No-IS groups were performed using the Wilcoxon rank-sum test. AF – atrial fibrillation; SD – standard deviation; W – Wilcoxon test statistic.

The time between first AF diagnosis and hospitalization was significantly longer in the IS group (mean 2.33 years, SD=1.15) than in the no-IS group (mean 1.18 years, SD=0.83; W=6892.0, p<0.001), indicating that prolonged AF duration increases IS risk, potentially due to progressive AR (Table 5). Similarly, the AF% burden was higher in the IS group (mean 3.03%, SD 1.46) versus the no-IS group (mean 1.70%, SD=1.16; W=6688.0, p<0.001), indicating that the relative duration of estimated AF exposure, adjusted for age, may further amplify risk (Table 5).

To further evaluate the results, multivariable analysis was conducted. We assessed predictors of IS occurrence using a multivariable logistic regression model. The model included 153 observations and 8 predictors, explaining 42.7% of the variance in IS occurrence. Predictors were selected based on their established clinical relevance to IS risk in patients with AF, including demographic factors (sex, age), comorbidities (hypertension), echocardiographic measures (LVEF, LAD), electrocardiographic parameters (PWDV1, Pmax), and the AF burden.

Model fit was evaluated using the Hosmer-Lemeshow test (÷ (8)=5.17, p=0.739), indicating no evidence of lack of fit (H0 not rejected). The rank correlation coefficient (rho) between observed and predicted probabilities was 80%, demonstrating good predictive accuracy.

Multicollinearity was assessed using variance inflation factors (VIFs) and tolerance values (Table 6). All included predictors had VIFs below 2 (range: 1.26–1.99) and tolerance values from 0.50 to 0.79, indicating low multicollinearity. The 95% confidence intervals for VIF and tolerance further support model stability, with no values indicating significant collinearity (eg, tolerance <0.1). However, the AF% burden was excluded from the final model due to high multicollinearity with age and time from AF diagnosis to hospitalization, as evidenced by preliminary VIF values exceeding 10.0.

Table 6.

Assessment of multicollinearity in regression analysis: variance inflation factors, tolerance, and associated confidence intervals for key clinical variables.

Predictor VIF VIF 95% CI Increased SE Tolerance Tolerance 95% CI
Sex 1.29 [1.13, 1.65] 1.14 0.77 [0.61, 0.88]
Age 1.30 [1.14, 1.66] 1.14 0.77 [0.60, 0.88]
Hypertension 1.27 [1.12, 1.62] 1.13 0.79 [0.62, 0.90]
AF burden 1.31 [1.14, 1.66] 1.14 0.77 [0.60, 0.88]
LVEF 1.26 [1.11, 1.61] 1.12 0.79 [0.62, 0.90]
LAD 1.27 [1.12, 1.62] 1.13 0.79 [0.62, 0.90]
PWDV1 1.99 [1.64, 2.54] 1.41 0.50 [0.39, 0.61]
Pmax 1.99 [1.64, 2.54] 1.41 0.50 [0.39, 0.61]
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VIF – Variance Inflation Factor, a measure of multicollinearity in regression analysis. Values <3 indicate low multicollinearity. VIF 95% CI – 95% confidence interval for the Variance Inflation Factor. Increased SE – increase in standard error due to multicollinearity. Tolerance – measure of collinearity, calculated as 1/VIF. Values <0.1 imply significant multicollinearity. Tolerance 95% CI – 95% confidence interval for tolerance. LVEF – left ventricle ejection fraction; LAD – LA dimension in M-mode presentation in the parasternal long axis view; PWDV1 – P wave duration in lead V1; Pmax – the longest P wave duration.

The results of multivariable logistic regression analysis in Table 7 identified several predictors significantly associated with IS occurrence in patients with AF. A higher AF burden in the group with IS than in the group without IS (OR: 2.66, 95% CI: 1.54–5.20, p=0.001) indicates increased IS risk, demonstrating that prolonged exposure to AF can amplify thromboembolism risk. Hypertension (OR: 5.30, 95% CI: 1.27–24.34, p=0.025) also markedly elevated IS odds, reinforcing its role as a critical modifiable risk factor. Additionally, higher P wave duration in the lead V1 (PWDV1) values (OR: 1.05 per ms, 95% CI: 1.02–1.08, p<0.001) and lower Pmax length (OR: 0.94 per ms, 95% CI: 0.90–0.97, p<0.001) were linked to increased IS risk. The area under the curve (AUC) was 0.908 (95% CI: 0.861–0.955), reflecting excellent model performance (Figure 4)

Table 7.

Results of multivariable logistic regression model.

Predictor OR 95% CI p
Intercept 1.38 0.34–5.91 0.656
Sex (Male vs Female) 1.91 0.58–7.08 0.303
Age (per year, centered at 74.0) 1.08 1.00–1.17 0.043
Hypertension (Yes vs No) 5.30 1.27–24.34 0.025
AF burden (per year, centered at 2.0) 2.66 1.54–5.20 0.001
LVEF (per%, centered at 58) 0.92 0.84–0.99 0.030
LAD (per cm, centered at 4.1) 0.88 0.28–2.72 0.829
PWDV1 (per ms, centered at 80.0) 1.05 1.02–1.08 <0.001
Pmax (per ms, centered at 100.0) 0.94 0.90–0.97 <0.001
Model summary:
Observations 153
R2 (Tjur) 0.427
Outcome Stroke occurrence
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OR – odds ratio: exponentiated regression coefficient representing the change in odds of stroke occurrence per unit increase in the predictor (or for categorical variables, relative to the reference group). 95% CI – 95% confidence Interval for the odds ratio. p value – probability of observing the result under the null hypothesis. P-values <0.05 are considered statistically significant. AF –atrial fibrillation; LVEF – left ventricle ejection fraction; LAD – LA dimension in M-mode presentation in the parasternal long axis view; PWDV1 – P wave duration in lead V1; Pmax – the longest P wave duration. Predictors are centered at their median values to improve interpretability. Reference categories: For categorical variables, Sex (female) and Hypertension (No) are the reference groups.

Figure 4.

Figure 4

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ROC curve of the fitted multivariable logistic regression model (Nobs=153).

Conversely, higher LVEF (OR: 0.92 per%, 95% CI: 0.84–0.99, p=0.030) was associated with reduced IS odds, suggesting a protective effect of preserved cardiac function. Age was associated with IS risk (OR: 1.08 per year, 95% CI: 1.00–1.17, p=0.043), consistent with its established role as a risk factor, but the effect size was small. Sex (OR: 1.91, 95% CI: 0.58–7.08, p=0.303) and LAD size (OR: 0.88 per cm, 95% CI: 0.28–2.72, p=0.829) were not significantly associated with IS, but echocardiography showed the LAA was larger in the IS patients compared to the control group (Table 7).

Discussion

The unique contribution of this study is the evaluation of patients with stroke and documented AF compared to patients without IS. Thromboembolic complications are an expression of AR. We found that LAR in the study group is reflected in higher PWTFV1 values: 52.34% of the subjects in the study group had a rate above 4000 mcV*ms, whereas in the control group it was 48.57% of patients. The reason for this is the difference in the duration of the negative phase of the P wave. In the study group, this was an average of 50.7 ms and in the control group it was an average of 48.51 ms. An additional value of the study is the comparison of parameters in groups of both sexes. Among males, the difference was even more pronounced (56.7 ms PWDNV1 in the study group and 48.7 ms in the control group). Similar results were reported by Kamel et al, namely, PWTFV1 >4000 mcV*ms was associated with older age, male gender, black race, and more frequent other risk factors [26]. Opposite, in the ARCADIA trial no statistically significant interactions were found when modeling the AC biomarkers as continuous variables NT-proBNP, PWTFV1 and LA diameter index for treatment with apiksaban vs aspirin [10]. Although the study innovatively included PWTFV1, no statistical assessment was made of the impact of this indicator on the occurrence of IS, limiting itself to comparing this indicator between patients treated with apixaban and aspirin [10]. Given the results of the ARCADIA trial, these previously demonstrated links between AC and IS may have reflected unmeasured confounding by subclinical AF, which was probably more thoroughly ruled out by continuous heart rhythm monitoring in potential trial participants than in earlier cohort studies. However, the prevailing data indicate an association between ECG parameters related to the P wave and LAR and AF, and consequently IS. The Cardiovascular Health Study (CHS) also showed that the risk of IS increases with increasing PWTFV1 [26]. PWTFV1 was associated with prevalent infarcts of any type and more so with prevalent non-lacunar infarcts. Among 1839 participants with 2 MRI scans, PWTFV1 was also associated with worsening leukoaraiosis, but not with incident infarcts. Sensitivity analyses adjusting for incident AF found similar results [26]. This study has important implications that are consistent with the premise of the current study. Combinations of ECG markers such as PWTFV1, echocardiographic measurements of LA size (LAVI), LA appendage function, and serum biomarkers such as NT-pro-BNP may predict the risk of vascular brain injury better than the presence or absence of apparent AF alone. Therefore, further confirmation and characterization of AC as a risk factor for vascular brain injury may help accelerate efforts to prevent IS.

The P wave dispersion (PWDI) value is usually defined as 29±9 ms [27]. Aytemir et al. indicate a maximum normal PWDI value to be up to 36 ms [28]. In the present study, P wave dispersion reached mean value in the study group 80,60 ms and 62,49 ms in control group. Again – the differences are more pronounced among male (82.90 ms PWDI in the group with IS and 58.23 ms in the control group). The differences were statistically significant. Similar conclusions were obtained by Puerta et al, citing PWDI >40ms as an indicator of variable electrical activity, which may be the reason why greater susceptibility to the occurrence of tachyarrhythmias [29]. Our findings address a previously existing gap between the known association of abnormal P wave indices and AC, clearly suggest that patients with abnormal P wave parameters have a greater risk of IS. Studies have shown a high prevalence of abnormal P wave parameters, including P wave duration >118 ms, P wave dispersion >40 ms and advanced interatrial block, was detected in patients with thrombus/spontaneous echocardiographic contrast (SEC) in LA appendage, which are recognized markers of IS [30]. Confirming the significance of the data presented is the fact that only 2.73% of patients with IS had all parameters in the normal range of the 4 Pmax/PWTFV1/PWDNV1/PWDI. Among non-IS patients, the percentage was 11.43% (p<0.05). It also seems interesting that, in all groups, Pmax was longer in those without IS than in the control group, which may indirectly indicate a less fibrotic atrium and a better visible P wave. Perhaps the more fibrotic atrial substrate in the group with IS inhibits full LA depolarization and, on the other hand, the lower potential in the LA may not allow the prolonged conduction time to be visualized on the ECG.

Patients with IS were characterized by a significantly higher value of PWDV1 than in control group without IS (respectively: 82.82(±25.62) vs72.69(±26.49) ms; p<0.05). Pmax was higher in the control group than in the IS group (101.08(±21.03) vs 106.35(±17.48); p<0.001). Multivariate logistic regression analysis performed in the current study showed that among the numerous indicators related to the P wave, only the higher PWDV1 values (OR: 1.05 per ms, 95% CI: 1.02–1.08, p<0.001) and the lower Pmax length (OR: 0.94 per ms, 95% CI: 0.90–0.97, p<0.001) were associated with an increased risk of IS. Most patients with AF and after IS have enlarged LA and RA atria on TTE, which may indicate proarrhythmic and prothrombotic effects of the arrhythmia substrate. Regarding echocardiography, the area of both the LA and RA was larger in the IS patients compared to the control group, which may indicate LA enlargement as a sign of structural LAR. According to the available literature LAR was associated with greater risk of recurrent IS [31,32]. Andlauer et al. found an ambiguous relationship between PWD and LAR [33]. The systematic review and meta-analysis by He et al. demonstrated that common ECG markers including PWTFV1 and PWDV1 are predictive of IS [9]. A significant association with IS was observed when PWD was analyzed as a categorical variable (>110–120 ms; odds ratio 1.86; 95% CI 1.37–2.25; p<0.0001) [9]. PTFV1 and PWD are simple electrocardiographic markers that can be used to predict the occurrence of IS. These findings support the notion of an atrial cardiomyopathic process in which thromboembolism risk is elevated even in the absence of AF. Observations indicating that a shorter Pmax translates into a greater risk of IS also require comment. This seemingly paradoxical phenomenon may be justified by structural remodeling at the tissue level [2]. Histologically, in AC fibrotic changes are the most obvious alteration [2]. The fibrosis accompanying AR is nothing more than a reduction in the number of electrically active myocytes and, consequently, a reduction in the Pmax duration.

The present study has shown that female have smaller atria and higher LVEF, which should be considered manifestations of less advanced functional and structural remodeling of the heart. AR as well as low LVEF may promote blood stasis and hypercoagulability, triggering the thrombogenic cascade, even in patients without AF. Studies have shown a high prevalence of abnormal P wave parameters, including PWD >118 ms, PWDI >40 ms and advanced interatrial block, was detected in patients with thrombus/SEC in LA appendage, which are recognized markers of IS [30].

Current research also showed that most markers of electrophysiological remodeling also have lower values in females than in males. Moreover, among males, normal values of P wave parameters in ECG were significantly less frequently recorded. Ahmadi et al found PWD were higher among males (p<0.0001). AF was more prevalent among males compared to females [8]. Faulkner et al found higher maximum P wave duration in males (109.6±2.3 ms) compared to females (103±1.8 ms) [34]. In the study by Meel et al, females had a higher LA volume index (LAVI) compared with males (20.9±6.3 vs 18.6±5.3 mL/m2, P = 0.04) [35]. Laureanti reported that males with persistent AF compared to females had higher PWTFV1 (2.1±1.2 mcV*ms vs 1.8±1 μV*ms, p=0.007) [36]. P wave indices and LA dimensions on echocardiography reached significantly higher values in the male group than in the female group, which is associated with an earlier occurrence of cardiovascular disease in males.

Our findings address a previously existing gap between the known association of abnormal P wave indices and AC, clearly suggesting that men have a greater risk of IS. The analysis of echocardiographic parameters and electrocardiographic P wave indices indicates that unfavorable structural and electrophysiological remodeling of the LA is more pronounced in males. P wave indices may therefore help identify patients at risk of IS who have AC. It is difficult to prove the usefulness of a single P wave indicator as a predictor of AF, and a combined analysis of the 4 indicators tested in this study may be associated with a high probability of AR that leads to arrhythmias such as AF.

While ECG markers can predict IS risk, this effect is minimal compared to hypertension and estimated AF burden, which also appear to be strong predictors (respectively: OR: 5.30, 95% CI: 1.27–24.34, p=0.025 and OR: 2.66, 95% CI: 1.54–5.20, p=0.001).

Although data on electrocardiographic indices generated from the P wave of the ECG are still quite scarce, the importance of echocardiographic indices has been known for a long time. Reduced LVEF is 1 of 5 echocardiographic indices associated with an increased risk of IS in patients with AF. The others are LA enlargement, decreased LA appendage flow velocity <20 cm/s, increased SEC intensity, and the presence of atherosclerotic plaque in the aorta [30,37]. The results of multivariable logistic regression analysis identified that higher LVEF (OR: 0.92 per%, 95% CI: 0.84–0.99, p=0.030) was associated with reduced IS odds, suggesting a protective effect of preserved cardiac function. Our results are consistent with numerous previous observations indicating that reduced LVEF is associated with a higher risk of IS in patients with AF [38]. However, in relation to the current studies in patients who experienced IS, had AF but currently have SR enabling the assessment of individual P wave indices, the relatively recent observation is extremely important. Low LVEF is an independent factor of IS [39], as shown in our group with SR.

Previous studies, although they have shown that the size of LA in patients with IS is larger than in the control group, in multivariate logistic regression analysis no significant relationship between LAD and IS was noted, probably because LA size was not adjusted to the body surface area (BSA). More importantly, however, the American Society of Echocardiography and the European Association of Cardiovascular Imaging recommendations no longer recommend using planimetric dimensions, but rather use LAVI [14]. Although it seems obvious now, due to the retrospective nature and time distance of the study, it was not possible to implement, especially in the early 2000s, when LAVI was not included in the standard of echocardiographic assessment. There are numerous and reliable data showing that LAVI correlates with the risk of IS, even if AF was not diagnosed before the event [40]. This is due to AC, which remains in a vicious cycle with AF, predisposing to the development of AF and further exacerbating it after its occurrence [1,41]. However, effective restoration and maintenance of SR can stop or even partially reverse this phenomenon [41,42]. Structural LAR is inevitably accompanied by functional LAR, the main marker of which is impaired contractility of the LA appendage, which is manifested by a decrease in the flow velocity through the LAA and, consequently, the formation of thrombi [43,44]. Finally, structural and functional remodeling goes hand in hand with biochemical remodeling. Its marker is the level of NT-proBNP, which also correlates with the risk of IS [45]. It is probably time to seriously consider developing a parametric scale analogous to the clinical CHA2DS2-VASc (currently from 2024: CHA2DS2-VA) scale, considering objective numerical measures of left LAR: electrophysiological (PWTFV1), structural (LAVI), functional (LA appendage flow velocity), and biochemical (NT-pro-BNP).

An additional parameter considered was the time from first AF diagnosis to hospitalization, and the ratio of this period to the age of the patients (estimated AF% burden and estimated AF burden). The time between first diagnosis of AF and catheter ablation was used by Sessions et al [46]. A longer time between first diagnosis of AF and ablation resulted in increased all-cause mortality in all patients [46]. In the present study, estimated AF burden was significantly correlated with the occurrence of IS. Estimated AF burden was significantly higher (2.33±1.15 years vs 1.18±0.3; W=6892.0, p<0.001) and estimated AF% burden was higher (3.03±1.46% vs 1.70±1.16%; W=6688.0, p<0.001) in the IS group than in the no-IS group. This implies that prolonged AF duration increases IS risk, potentially due to progressive AR or delayed anticoagulation, indicating that the relative duration of AF exposure, adjusted for age, further increases risk. The results of multivariable logistic regression analysis identified longer duration from AF diagnosis to IS (OR: 2.66, 95% CI: 1.54–5.20, p=0.001) as a predictor significantly associated with IS occurrence. This warrants further search for LAR factors, as ongoing arrhythmia favors embolic complications.

A broad array of comorbidities are associated with the recurrence and progression of AF [15]. Managing comorbidities is also central to the success of other aspects of care for patients with AF, with evidence available for hypertension, heart failure, diabetes mellitus, obesity, and sleep apnea, along with lifestyle changes that improve physical activity and reduce alcohol intake. In the present study, only hypertension (OR: 5.30, 95% CI: 1.27–24.34, p=0.025) markedly elevated IS odds, reinforcing its role as a critical modifiable risk factor. Identification and treatment of these comorbidities and risk factor groups are an important part of effective AF-CARE care, recommended in the European Society of Cardiology standards, to improve prognosis, including by reducing the risk of IS [15].

The knowledge gap related to IS prevention is a lively topic of scientific interest [47]. We responded to this need by performing the present retrospective study assessing AR based on simple ECG and echocardiographic parameters, indicating differences in the comparison of the post-stroke group to the non-stroke group and in both sexes. This may provide a starting point for further research to find simple AR screening tools.

Limitations

A limitation of this study is its retrospective nature. The study included 731 patients, and SR was documented in 314 cases, but because of the exclusion criteria, only 256 patients were analyzed (Figure 1). Large randomized controlled trials are needed to assess the possible negative predictive value of all indicators of atrial conduction disturbances simultaneously, as suggested in the present study. Women constituted the majority in both the study and control groups, and patients in the study group were also older. In the control group, patients with AF and without IS were significantly younger than the IS patients, which may have caused this cohort to be slightly under-represented in the study. This may have affected the results of the statistical analysis in relation to the examined parameters to sex and age. The echocardiographic parameter of the size of the LA was the LAD and the surface areas of both atria were calculated in the apical four-chamber view. Volumetric parameters (eg, LAVI) that are currently recommended were not measured, because this retrospective study covered a period of up to 20 years, and at that time these indicators were not widely used. Echocardiographic parameters were not adjusted to BSA, which was impossible due to the retrospective nature of the study. This may result in a slightly distorted estimation of the relationship between atrial parameters and predictors significantly associated with IS occurrence in patients with AF, indicating no association between LAD and the occurrence of IS. However, this does not apply to LVEF, which does not require adjustment to BSA. Electrocardiographic indices were also not adjusted, but this was not performed in most previous studies. Multivariate analysis considers variables selected by the authors, which may be subjective. The selection of variables was based on available data in a retrospective analysis of medical documentation, and this is also likely a limitation of our study.

Conclusions

The main conclusion of the study is that LA enlargement can be found in surface ECG by P wave indices. ECG markers can predict stroke risk. However, the effect is smaller compared to hypertension and estimated AF burden, which appear to be stronger predictors. In patients with IS, higher indices of structural and electrophysiological LAR were observed. P wave indices and LA dimensions on echocardiography reached significantly higher values in the male group than in the female group, which is associated with an earlier occurrence of cardiovascular disease in males. However, sex was not an independent factor in the occurrence of IS. We found that IS was independently associated with the ECG markers PWDV1 and Pmax, and with the echocardiographic index LVEF.

Current research justifies the search for simple and easy-to-use screening tools (eg, useful in the GP’s office). Perhaps simple ECG tracing parameters could become a screening tool to reduce the risk of IS in the future. This study provides reasonable grounds to believe that, after validation, ECG indicators of LA electrophysiological remodeling, similarly to the LAVI as well as LVEF, should also be included in the new, extended CHA2DS2-VASc (currently: CHA2DS2-VA) risk scale.

Footnotes

Conflict of interest: None declared

Patient Permission/Consent Declarations: Informed consent was obtained from all individuals included in the study.

Declaration of Figures’ Authenticity: All figures submitted have been created by the authors who confirm that the images are original with no duplication and have not been previously published in whole or in part.

Financial support: Grant DS 377 from Medical University of Lublin

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