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J Stroke > Volume 25(3); 2023 > Article
Ha, Jeong, Park, Yang, Cha, Cho, Chang, Kang, Kwon, and Kim: Association Between Slow Ventricular Response and Severe Stroke in Atrial Fibrillation-Related Cardioembolic Stroke
Dear Sir:
Atrial fibrillation (AF)-related strokes usually have a higher initial stroke severity and frequently lead to severe disability and mortality [1,2]. Stroke recurrence was not found to be linked to heart rate (HR); however, there was an association between HR and mortality in patients with AF-related stroke [3]. While AF typically presents with tachycardia, a slow ventricular response (SVR) is also observed, albeit less frequently.
Hemodynamic changes associated with AF have been studied, and AF with SVR may lead to intracardiac hemodynamic alterations, thrombus formation, and hypoperfusion in the ischemic area [4]. However, the association between SVR and initial stroke severity, early neurological deterioration, and functional outcome in patients with AF-related stroke is not known.
We retrospectively reviewed the data of patients who had acute AF-related stroke (within 7 days of stroke onset) and were admitted to Asan Medical Center between January 2017 and March 2022. We included patients who fulfilled the following criteria: (1) cardioembolic stroke, (2) known or newly diagnosed AF, and (3) relevant acute ischemic lesions on diffusion-weighted imaging (DWI). We excluded patients who had (1) AF with rapid ventricular rate in the initial twelve-lead electrocardiogram (ECG), (2) poor initial magnetic resonance imaging (MRI) quality, (3) incomplete clinical data, (4) presence of stroke mechanisms other than cardioembolism, and (5) presence of low temperature or electrolyte abnormalities that may systematically reduce the HR. The study protocol was approved by the Institutional Review Board Committee of Asan Medical Center (IRB number: 2022-1178) and informed consent was waived because of the retrospective nature of the study. Demographic data and risk factors were obtained by reviewing the medical records. Neurological deficits at admission were evaluated using the National Institutes of Health Stroke Scale (NIHSS) score, and severe stroke was defined as patients whose NIHSS score at admission was >15 points [5]. All patients underwent neurovascular MRI with a 3.0T Philips scanner (Philips Healthcare, Eindhoven, The Netherlands) within 24 hours of admission. We also used the Olea Sphere® imaging system (Olea Medical SAS, La Ciotat, France) for automatic post-processing and measurement of the DWI lesion volumes.
ECGs were obtained from the emergency department after >5 minutes of rest in the supine position. Paroxysmal AF was defined as the spontaneous restoration of normal sinus rhythm within 7 days, and persistent AF was defined as AF lasting >7 days. In terms of ventricular response, patients with an HR <60 beats per minute on an initial ECG were considered to have SVR [6]. Diagnosis of AF and transthoracic echocardiography were performed during admission by an experienced cardiologist and ejection fraction (EF) and left atrium (LA) diameters were measured.
The baseline characteristics were compared according to the presence of SVR. The chi-square test, Fisher’s exact test, Student’s t-test, or Mann-Whitney U test were used as indicated. Univariate and multivariate analyses were performed to identify the factors associated with severe stroke. According to the results of the univariate analyses, age, male sex, and variables yielding P values <0.10 were included in the multivariate analysis. IBM SPSS Statistics for Windows, version 21.0 (IBM Corp., Armonk, NY, USA) was used for all analyses, and P<0.05 was considered statistically significant.
A total of 496 patients (mean age, 73±11 years; male, 53.7%) were included in this study; 31 (6.2%) had SVR, and 109 (22.0%) had severe stroke. There were no significant differences in the demographics or vascular risk factors according to the presence of SVR. However, patients with SVR had higher initial NIHSS scores and larger DWI lesion volumes than those without SVR. Patients with SVR had larger LA diameters and were more likely to have persistent AF and severe stroke than those without SVR (Table 1).
Univariate analysis showed that older age, diabetes mellitus, lack of prestroke antiplatelet use, newly diagnosed AF, and SVR were associated with severe stroke. In the multivariate analysis, older age (adjusted odds ratio [aOR]=1.03, 95% confidence interval [CI] 1.01-1.05; P=0.008), diabetes mellitus (aOR=1.66, 95% CI 1.04-2.64; P=0.034), no prestroke antiplatelet use (reference= none; aOR=0.50, 95% CI 0.28-0.90; P=0.020), and SVR (aOR=2.30, 95% CI 1.05-5.04; P=0.038) were independently associated with severe stroke (Table 2).
In this study, 6.2% of patients with AF-related cardioembolic stroke had SVR at presentation. We found that SVR was associated with severe stroke. The mechanisms underlying our findings remain unclear. One possible mechanism is that SVR leads to prolonged left ventricular diastolic filling, elevated LA pressure, and deterioration of left atrial appendage contractility, which, in turn, leads to blood stasis and large thrombus formation [7]. We also found that LA size was significantly larger in patients with SVR than in those without SVR. An enlarged LA is an independent risk factor for thromboembolism in patients with AF [8]. Furthermore, most patients with SVR have persistent AF, which can lead to decreased flow velocity in the LA through structural remodeling and endocardial fibroelastosis, thereby increasing the risk of large thrombus development [8].
In patients with AF-related cardioembolic stroke, both low and high HRs during the acute stage were associated with an increased risk of mortality. The potential reason for this association is decreased heart function, which could result from either a low or high HR [3,9]. However, our results showed that the EF was similar between those with and without SVR. Instead, the high proportion of patients with severe stroke may at least partially explain the association between high mortality and low HR in patients with AF-related stroke. Nevertheless, data on the optimal HR for patients with acute AF-related stroke are insufficient. This study focused on the association between SVR and severe stroke. Thus, future studies focusing on the effect of rate control on stroke severity are needed.
This study had several limitations. First, this study was performed at a single center and included a small number of patients. Second, due to the retrospective study design, we were unable to obtain information on the sustained presence of SVR prior to stroke onset. Despite these limitations, we found that SVR was strongly associated with initial stroke severity in patients with AF-related cardioembolic stroke.


Funding statement
This research was supported by the Brain Convergence Research Program of the National Research Foundation (NRF), funded by the Korean government (MSIT) (No. 2020M3E5D2A01084576), and the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2020R1A2C2100077).
Conflicts of interest
The authors have no financial conflicts of interest.
Author contribution
Conceptualization: SHH, BJK. Study design: SHH, BJK, MJC, MSC. Methodology: SJ, JYP, SYY, JYC, DWK, SUK. Data collection: SHH. Investigation: SJ, JYP, SYY, MJC, MSC, JYC, DWK, SUK. Statistical analysis: SHH. Writing—original draft: SHH, BJK. Writing—review & editing: all authors. Funding acquisition: BJK. Approval of final manuscript: all authors.

Table 1.
Baseline characteristics
Without SVR (n=465) With SVR (n=31) P
Age (yr) 73±11 75±8 0.264
Male sex 246 (52.9) 21 (67.7) 0.109
Hypertension 317 (68.2) 24 (77.4) 0.282
Diabetes mellitus 129 (27.7) 12 (38.7) 0.190
Hyperlipidemia 153 (32.9) 10 (32.3) 0.941
Smoking 91 (19.6) 10 (32.3) 0.089
Coronary artery disease 94 (20.2) 5 (16.1) 0.582
CHA2DS2VASc 3 (2-4) 3 (2-4) 0.189
Previous stroke 129 (27.7) 12 (38.7) 0.190
Medication history
None 179 (38.5) 8 (25.8)
Antiplatelet 122 (26.2) 6 (19.4) 0.183
NOAC 113 (24.3) 12 (38.7)
Warfarin 51 (11.0) 5 (16.1)
Digoxin 46 (9.9) 2 (6.5) 0.530
Beta-blocker 150 (32.3) 6 (19.4) 0.134
Anti-arrhythmic drugs* 28 (6.0) 1 (3.2) 0.519
Initial NIHSS score 6 (2-13) 11 (3-17) 0.035
Severe stroke (NIHSS score >15) 97 (20.9) 12 (38.7) 0.020
Endovascular treatment 99 (21.4) 9 (30.0) 0.272
Intravenous thrombolysis 71 (15.3) 7 (22.6) 0.282
DWI lesion volume (mL) 23±39 37±35 0.028
Newly diagnosed AF 173 (37.3) 9 (29.0) 0.356
Persistent AF 275 (59.1) 31 (100) <0.001
Valvular AF 36 (7.7) 3 (9.7) 0.698
Ejection fraction (%) 59±8 59±9 0.462
Left atrium diameter (mm) 46±8 50±7 0.006
Valve operation 28 (6.0) 2 (6.5) 0.923
Results are presented as number (%), mean±standard deviation, or median (interquartile range).
SVR, slow ventricular response; NOAC, non-vitamin-K antagonist oral anticoagulant; NIHSS, National Institutes of Health Stroke Scale; DWI, diffusion-weighted imaging; AF, atrial fibrillation.
* Include flecainide, propafenone, amiodarone, etc.
Table 2.
Factors associated with severe stroke
Crude OR (95% CI) P Adjusted OR (95% CI)* P
Age 1.03 (1.01-1.06) 0.002 1.03 (1.01-1.05) 0.008
Male sex 0.70 (0.45-1.07) 0.096 -
Hypertension 1.00 (0.63-1.59) 0.988
Diabetes mellitus 1.82 (1.17-2.86) 0.009 1.66 (1.04-2.64) 0.034
Hyperlipidemia 0.73 (0.45-1.16) 0.180
Smoking 1.22 (0.73-2.03) 0.451
Coronary artery disease 0.69 (0.39-1.22) 0.199
CHA2DS2VASc score 1.25 (1.07-1.44) 0.004 -
Previous stroke history 1.00 (0.63-1.60) 0.997
History of medication
None 1 (reference) 1 (reference)
Antiplatelet 0.54 (0.30-0.95) 0.033 0.50 (0.28-0.90) 0.020
NOAC 0.76 (0.44-1.29) 0.303 0.64 (0.37-1.12) 0.121
Warfarin 0.54 (0.30-0.95) 0.285 1.07 (0.47-2.45) 0.874
Digoxin 0.69 (0.31-1.52) 0.352
Beta-blocker 0.74 (0.46-1.19) 0.218
Anti-arrhythmic drugs 0.56 (0.19-1.64) 0.287
Newly diagnosed AF 1.59 (1.03-2.45) 0.037 -
Persistent AF 1.41 (0.90-2.22) 0.133
Ejection fraction 1.01 (0.98-1.03) 0.694
Left atrium diameter 1.00 (0.97-1.03) 0.958
SVR 2.40 (1.12-5.11) 0.024 2.30 (1.05-5.04) 0.038
Valve operation 0.24 (0.06-1.02) 0.054 0.24 (0.05-1.17) 0.077
OR, odds ratio; CI, confidence interval; NOAC, non-vitamin-K antagonist oral anticoagulant; AF, atrial fibrillation; SVR, slow ventricular response.
* Multivariate analysis adjusted for age, male sex, diabetes mellitus, newly diagnosed AF, history of medication, history of valve operation, CHA2DS2VASc, and SVR;
Include flecainide, propafenone, amiodarone, etc.


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