Introduction

Atrial cardiopathy is characterized by changes in atrial structure or function, such as atrial fibrosis, impaired cardiac cell function, and atrial enlargement, which may precede and promote atrial fibrillation1,2,3. Although currently there is no golden standard to define atrial cardiopathy, established biomarkers of atrial cardiopathy include increased P-wave terminal force in lead V1 (PTFV1) on electrocardiogram, left atrial enlargement (LAE) on echocardiogram, and elevated serum N-terminal pro-brain natriuretic peptide (NT-proBNP)4. In stroke free individuals, increased PTFV1 was associated with incident stroke risk5,6 in the absence of clinically apparent atrial fibrillation7. Observational evidence showed that LAE on echocardiogram was independently associated with an increased risk of ischemic stroke in the absence of atrial fibrillation8,9,10. Moreover, increased serum level of NT-proBNP, a biomarker of ventricular and atrial dysfunction, is also associated with ischemic stroke11,12.

Previous studies have shown that atrial cardiopathy might be useful to assess the probability of cardioembolism in patients with cryptogenic stroke13. However, whether atrial cardiopathy relates to stroke severity has been scarcely reported. The influence of initial stroke severity on stroke recovery has been increasingly recognized. For example, moderate to severe stroke has been shown to be associated with mortality, increasing the likelihood of in-hospital mortality by more than nine-fold14,15. Several previous studies assessed the association between atrial cardiopathy and stroke severity in acute ischemic stroke (AIS) patients, yielding inconsistent findings. A small cohort of the Stepwise screening for silent atrial fibrillation after stroke (SAFAS) study showed a significant difference in the National Institutes of Health Stroke Scale (NIHSS) score in patients with and without atrial cardiopathy, suggesting a potential link between atrial cardiopathy and stroke severity16. However, a small prospective cohort study showed that the proportion of a higher NIHSS score (NIHSS of 9 or above) was similar in participants with and without atrial cardiopathy (10 [14%] vs. 6 [13%], p = 0.91)17. To our knowledge, the association between atrial cardiopathy and stroke severity in AIS patients remains not fully understood. We therefore aimed to investigate whether the presence of atrial cardiopathy is associated with stroke severity in AIS population.

Methods

Participants

In this hospital-based cross-sectional analytic study, we retrospectively reviewed clinical data of adult patients with AIS between January 2017 and April 2023 in a university teaching hospital. The exclusion criteria were as follows: (1) Recorded rheumatic heart valve disease or artificial heart valve; (2) Without adequate electrocardiogram parameters to assess PTFV1; (3) Without transthoracic echocardiogram assessment of left atrial diameter; (4) Without NT-proBNP data. We collected the demographic and clinical characteristics including age, sex, body mass index, alcohol and cigarette consumption, history of hypertension, hyperlipidemia, diabetes, atrial fibrillation, and coronary heart disease from patients’ medical notes. Atrial fibrillation included paroxysmal, persistent, and permanent atrial fibrillation, which was either previously known or diagnosed during index hospitalization18. Etiologic subtypes of ischemic stroke were classified according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria19. Laboratory findings (fasting blood glucose, triglyceride, total cholesterol, low-density lipoprotein, and high-density lipoprotein) were collected from a digital medical database. The study protocol was reviewed and approved by the Fujian Medical University Union Hospital Ethics Committees (2023KY030). Informed consent was waived, due to the nature of the retrospective study with routine anonymous and de-identified information. This study was conducted in accordance with the Declaration of Helsinki and relevant guidelines and regulations. The datasets of the current study are available from the corresponding author on reasonable request.

Atrial cardiopathy assessment

Biomarkers of atrial cardiopathy were routinely assessed within 48 h after admission. PTFV1 in electrocardiogram was calculated by multiplying the duration (ms) of the terminal negative component of P-wave by its amplitude (µV) in lead V1 recorded by manual calculation20. Left atrium size was calculated as the antero-posterior maximal diameter of the left atrium in systole on B-mode transthoracic echocardiogram. Severe left atrial enlargement was defined as left atrial diameter ≥ 52 mm (males) or ≥ 47 mm (females)21. NT-proBNP was measured by an automated electrochemiluminescence immunoassay (Elecsys proBNP II assay). The coefficient of variation for the NT-proBNP assay was 2–5% during the testing period, and the analytical measurement range for NT-proBNP was 5–35,000 pg/ml. In the present study, atrial cardiopathy was defined as any of the following: severe LAE, PTFV1 > 5000 μV ms, or increased serum levels of NT-proBNP > 250 pg/ml22.

Stroke severity assessment

Initial stroke severity was assessed using the NIHSS on admission. Moderate-to-severe stroke was defined as a NIHSS scored of 5 or higher, and severe stroke as a NIHSS score of 15 or higher23.

Statistical analysis

Continuous variables were presented as means (standard deviation) if normally distributed, or medians (interquartile range, IQR) if not normally distributed. Categorical variables were expressed as frequencies with proportions. Between group differences were compared using the t-test, the Mann–Whitney test, the Chi-square test, or the Fisher’s exact test as appropriate. Logistic regression models were used to calculate the unadjusted and adjusted odds ratios (ORs) of outcomes with atrial cardiopathy. Two models were used: Model 1, Age- and sex- adjusted; and Model 2, adjusted for variables with a p < 0.1 in the univariate analysis for outcomes. We conducted several subgroup analyses of outcomes stratified by age group (< 65 vs. ≥ 65 years), sex (male vs. female), smoking status (current smoker vs. not), alcohol consumption (regular vs. not), hypertension (yes vs. no), dyslipidemia (yes vs. no), coronary artery disease (yes vs. no), and atrial fibrillation (yes vs. no), with the interaction terms as covariates. We conducted a sensitivity analysis by including patients without atrial fibrillation or coronary artery disease. We additionally assessed the linear relationship between atrial cardiopathy and continuous NIHSS score. A p-value < 0.05 was considered statistically significant. All statistical analyses were done using SPSS version 26.0 (IBM Corp., Armonk, NY, USA).

Ethical approval

This study protocol was reviewed and approved by Fujian Medical University Union Hospital Ethics Committees (2023KY030). Written informed consent was waived by the Fujian Medical University Union Hospital Ethics Committees due to the nature of our retrospective study based on routine clinical data.

Results

Baseline characteristics

A total of 662 AIS patients (mean age 70 years [IQR 61–78], 31.3% women) who met the inclusion criteria were finally analyzed (Fig. S1). A total of 303 (45.8%) patients had atrial cardiopathy. Table 1 shows the baseline characteristics between participants in the acute ischemic stroke with and without atrial cardiopathy. Patients with atrial cardiopathy were older (74 years [IQR 65–81] vs. 66 [IQR 58–73], p < 0.001), more likely to be female (35.3% vs. 27.9%, p = 0.039), and less likely to be current smoker (23.1% vs. 34.3%, p = 0.002) and regular alcohol user (9.0% vs. 17.0%, p = 0.008). The prevalence of hypertension (74.3% vs. 60.4%, p < 0.001), atrial fibrillation (48.2% vs. 5.0%, p < 0.001), coronary artery disease (22.8% vs. 8.1%, p < 0.001), pre-stroke anticoagulation (7.6% vs. 0.6%, p < 0.001), and the level of high-density lipoprotein (1.14 ± 0.31 vs. 1.07 ± 0.25 mmol/L, p = 0.004) were higher, while the proportion of dyslipidemia and serum levels of triglyceride were lower among patients with atrial cardiopathy compared to those without atrial cardiopathy. Stroke subtypes in patients with and without atrial cardiopathy were significantly different (p < 0.001).

Table 1 Baseline characteristics between patients with and without atrial cardiopathy.
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Atrial cardiopathy and stroke severity

Patients with atrial cardiopathy had a higher NIHSS score (5 [IQR 2–12] vs. 3 [IQR 1–5], p < 0.001). A total of 261 (39.4%) patients had a moderate-to-severe stroke, and 70 (10.6%) had a severe stroke. Table 2 summarizes the differences in characteristics in patients with and without moderate-to-severe stroke. Compared to those with mild stroke (NIHSS < 5), those with moderate-to-severe stroke (NIHSS ≥ 5) were more likely to be female (36.8% vs. 27.7%, p = 0.014) and had a higher proportion of atrial fibrillation (29.9% vs. 21.4%, p = 0.014), coronary artery disease (18.8% vs. 12.2%, p = 0.020), a higher serum level of fasting blood glucose (6.53 [5.38–8.09] vs. 5.83 [5.05–7.56] mmol/L, p < 0.001), and a lower triglyceride level (1.16 [0.92–1.48] vs. 1.25 [0.96–1.75] mmol/L, p = 0.016). Stroke subtypes in patients with and without moderate-to-severe stroke were significantly different (p < 0.001). Of the individual atrial cardiopathy biomarkers, patients with moderate-to-severe stroke were more likely to have an NT-proBNP > 250 pg/mL (55.9% vs. 35.4%, p < 0.001). Similar findings were detected in patients with severe stroke (NIHSS ≥ 15) compared to those with non-severe stroke (NIHSS < 15) (Table 3).

Table 2 Baseline characteristics in patients with and without moderate-to-severe stroke.
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Table 3 Baseline characteristics in patients with and without severe stroke.
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Table 4 shows the association between atrial cardiopathy and stroke severity. Patients with atrial cardiopathy were at a higher odd of moderate-to-severe stoke (unadjusted OR 2.31, 95%CI 1.68–3.17, p < 0.001) and severe stroke (unadjusted OR 5.58, 95%CI 3.04–10.26, p = 0.001). The associations remained after adjustment for age and sex. After further adjustment for those variables with a p < 0.1 in the univariable analysis, atrial cardiopathy remained significantly associated with a higher odd of moderate-to-severe stoke (adjusted OR 2.16, 95%CI 1.46–3.20, p < 0.001) and severe stroke (adjusted OR 4.89, 95%CI 2.45–9.76, p < 0.001). This association remained significant when considering the NIHSS score as a continuous variable (unadjusted Beta 0.292, adjusted Beta 0.280, p < 0.001, respectively; Table 4).

Table 4 Association between atrial cardiopathy and stroke severity.
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Subgroup analysis and sensitivity analysis

We detected no significant interactions between atrial cardiopathy and variables including age (< 65 vs. ≥ 65 years), sex (male vs. female), smoking status (current smoker vs. not), alcohol consumption (regular vs. not), hypertension (yes vs. no), dyslipidemia (yes vs. no), coronary artery disease (yes vs. no), and atrial fibrillation (yes vs. no) for stroke severity (Fig. 1a,b). We observed a significant association of atrial cardiopathy with moderate to severe stroke (OR 2.31, 95%CI 1.57–3.40, p < 0.001) and severe stroke (OR 4.64, 95%CI 2.35–9.16, p < 0.001) in patients without atrial fibrillation. In the presence of atrial fibrillation, there was trend for a higher odd of moderate to severe stroke with atrial cardiopathy, although this did not reach statistical significance (OR 2.60, 95%CI 0.88–7.67, p = 0.083; Fig. 1a).

Figure 1
figure 1

The association between atrial cardiopathy and stroke severity in different subgroups. (a) The association between atrial cardiopathy and moderate-to-severe stroke (NIHSS ≥ 5) in different subgroups. (b) The association between atrial cardiopathy and severe stroke (NIHSS ≥ 15) in different subgroups. Abbreviations: OR, odds ratio; CI, confidence interval.

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A sensitivity analysis after excluding patients with atrial fibrillation or coronary artery disease showed that atrial cardiopathy remained associated with moderate-to-severe stroke as well as severe stroke (Table 4).

Discussion

The current study showed that atrial cardiopathy was associated with initial stroke severity, suggesting that atrial cardiopathy may serve as a clinical indicator of stroke severity in AIS population. Our findings underscore the importance of increasing awareness and attention to this relationship.

Atrial cardiopathy is independently associated with incident ischemic stroke. A recent meta-analysis of observational cohort data showed that the biomarkers of atrial cardiopathy were significantly associated with the risk of ischemic stroke (increased PTFV1, hazards ratio [HR] 1.29, 95%CI 1.06–1.57; LAE, HR 1.39, 95% CI 1.06–1.82; and increased NT-proBNP, HR 2.37, 95%CI 1.61–3.50)4. In a retrospective longitudinal cohort of 32,454 community-dwelling old participants, atrial cardiopathy was independently associated with an increased risk of ischemic stroke in the absence of atrial fibrillation8. Data from the Third China National Stroke Registry (CNSR-III) also showed an association of poor prognosis with atrial cardiopathy in patients with ischemic stroke, even when patients with atrial fibrillation were excluded24. The Cardiovascular Health Study of community-dwelling elderly adults who were free of stroke and atrial fibrillation at baseline showed that atrial cardiopathy was independently associated with incident ischemic stroke25. Our results build on the above-mentioned studies by showing an independent association between atrial cardiopathy and index stroke severity, suggesting the potential prognostic role of atrial cardiopathy in AIS population. In line with our findings, an observational study of 1271 AIS patients showed that LAE was associated with more severe initial neurologic deficits of embolic subtypes (cardioembolic and cryptogenic stroke)26. However, the small number of patients with cryptogenic stroke (n = 11) in our cohort does not allow us to assess the relationship between stroke severity and atrial cardiopathy in this subgroup. On the contrary, a retrospective analysis of the Henry Ford Health System did not detect the association between atrial cardiopathy and stroke risk27. Possible explanations for the disparities in the above-mentioned studies may include the different study population and different definition for atrial cardiopathy.

The association between atrial cardiopathy and stroke severity might be partly explained by the relationship between atrial cardiopathy and atrial fibrillation, a well-established condition that increases the risk of severe stroke28. This hypothesis is supported by our data showing that patients with atrial cardiopathy were more likely to have atrial fibrillation than those without atrial cardiopathy (48.2% vs. 5.0%, p < 0.001). Interestingly, our subgroup analysis showed only a trend for a higher odd of moderate to severe stroke with atrial cardiopathy in those with atrial fibrillation, while this association was quite significant in patients without atrial fibrillation. This is probably attributable to the fact that most patients with atrial fibrillation have atrial cardiopathy as defined in our participants, independent of the severity of their stroke. In line with our findings, a small observational study showed that LAE, a biomarker for atrial cardiopathy, was associated with severe ischemic stroke in men with nonvalvular atrial fibrillation, suggesting that atrial cardiopathy may play a crucial role for thrombogenesis in atrial fibrillation29. Moreover, several recent studies have shown that atrial cardiopathy may be a cause of cardioembolic stroke even in the absence of atrial fibrillation5,6,30. In agreement of the aforementioned studies, our data also showed that patients with atrial cardiopathy were more likely to have a cardioembolic stroke (46.2% vs. 10.3%). Our findings need to be validated in future large prospective studies.

Our study has several limitations. First, our study is a single-center retrospective observational study with inevitable selection bias. Second, our study lacked the data of LA volume, which is a more reliable estimator of LA size31. However, LA diameter is more readily available and more widely used in clinical practice. Third, we only analyzed Chinese stroke patients; our findings may therefore not be generalizable to other populations. Moreover, our findings should be interpreted with caution due to unmeasured potential confounding effects of volume expansion for stroke management and stress-induced cardiomyopathy. Finally, we only assess the association of atrial cardiopathy with stroke severity cross-sectionally, studies with a long-term follow-up will better evaluate the relationship between atrial cardiopathy and long-term prognosis of acute ischemic stroke.

Conclusion

This study showed that atrial cardiopathy was significantly associated with stroke severity, suggesting that atrial cardiopathy may help in predicting stroke prognosis. Future studies are needed to explore improved stroke prevention strategies for patients with atrial cardiopathy.