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Excessive atrial ectopic activity as an independent risk factor for ischemic stroke
International Journal of Cardiology 249 (2017) 226–230
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Excessive atrial ectopic activity as an independent risk factor for ischemic stroke Rita Marinheiro ⁎,1, Leonor Parreira 1, Pedro Amador 1, Catarina Sá 1, Tatiana Duarte 1, Rui Caria 1 Centro Hospitalar de Setubal, Cardiology Department, Setubal, Portugal
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Article history: Received 16 May 2017 Received in revised form 8 August 2017 Accepted 21 August 2017 Available online 26 August 2017 Keywords: Excessive atrial ectopy Ischemic stroke Atrial fibrillation
a b s t r a c t Background: Excessive atrial ectopic activity (EAEA) has been related with an increased risk of atrial fibrillation (AF) and stroke but different cutoff values have been used. We aimed to determine the association between EAEA and stroke, AF and overall death. Methods: Consecutive 24-hour Holter monitoring performed between 2005 and 2010 in a single center was evaluated. Patients with a previous diagnosis of stroke or AF were excluded. The number of premature atrial contractions (PACs) during 24 h was analyzed in 2480 subjects and according to that 3 sub-groups were defined: N 97 PACs/h (above the top 5th percentile of the population) (EAEA+); intermediate value of PACs/h (below the top 5th percentile but above 30 PACs/h) (EAEA+/−) and b30 PACs/h (EAEA−). Results: After adjusting for risk factors, laboratory findings and medication, EAEA+ was associated with ischemic stroke (hazard ratio [HR] 2.83; 95% confidence interval [CI], 1.65–4.84, p b 0.001). Both EAEA+ and EAEA+/− were independently associated with AF (HR 2.05; 95% CI 1.31–3.23, p = 0.010 for EAEA+ and HR 1.90; 95% CI 1.10–2.78, p = 0.020 for EAEA+/−) and overall death (HR 2.17; 95% CI 1.48–3.28, p = 0.031 for EAEA+; HR 2.01; 95% CI 1.06–2.52, p = 0.029 for EAEA+/−). Conclusion: In this population, having N 30 PACs/h was independently associated with a higher risk of AF and overall death but only subjects with N 97 PACs/h had a higher risk of ischemic stroke. In the majority of subjects with stroke and EAEA+, AF has not been detected before stroke event. © 2017 Elsevier B.V. All rights reserved.
1. Introduction The role of atrial ectopic activity in the initiation of atrial fibrillation (AF) is well established. In 1998, Haissaguerre et al. demonstrated that the pulmonary veins are an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation [1]. Premature atrial contractions (PACs) may be a marker for foci that are or will be capable of firing rapidly to initiate AF [2] through a reentry-maintaining substrate. Rapid and repetitive stimulation of the atrial muscle is known to alter its electrophysiological properties by shortening atrial refractoriness, leading to the development and maintenance of AF. Alternatively, PACs may be a marker of developing atrial electrophysiological changes that promote AF, such as interstitial fibrosis and abnormal intracellular calcium handling [3]. Recent studies suggested that excessive atrial ectopic activity (EAEA) not only increases risk of AF but it is also associated with an increased risk Abbreviations: AF, atrial fibrillation; CI, confidence interval; CV, cardiovascular; EAEA, excessive atrial ectopic activity; ECG, electrocardiogram; h, hour; HR, hazard ratio; LDL, low-density lipoprotein; PACs, premature atrial contractions. ⁎ Corresponding author. E-mail addresses: [email protected] (R. Marinheiro), [email protected] (L. Parreira). 1 “This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation”.
http://dx.doi.org/10.1016/j.ijcard.2017.08.054 0167-5273/© 2017 Elsevier B.V. All rights reserved.
of stroke, adverse cardiovascular events and death [4–8]. The lack of precise definition for “excessive” atrial ectopy leads investigators to use arbitrary cut-off values according to top percentiles for frequency of PACs [6–8]. However, considering the number of PACs as a continuous variable, the risk of adverse events is related to the number of PACs. The aim of this study was to use a higher cutoff value in order to identify high risk patients that would benefit from therapeutic intervention. 2. Methods 2.1. Patients Between January 2005 and December 2010, 3589 consecutive patients were referred to our non-invasive cardiology laboratory for elective 24-hour (h) Holter monitoring. Patients were excluded if they had previously documented AF (n = 396), AF diagnosed during the exam (n = 206), history of stroke or transient ischemic attack (n = 409) or if they were under medication with anticoagulants (n = 98). The final analysis thus involved 2480 subjects. 2.2. Study design Demographic data, cardiovascular risk factors, indications for 24 h Holter monitoring, transthoracic echocardiograms and medications were recorded. Hypertension was defined as resting systolic or diastolic blood pressure ≥140/90 mm Hg on two occasions or prescription of anti-hypertensive drugs. Diabetes mellitus was defined as a serum fasting glucose ≥7.0 mmol/L or prescription of anti-diabetic medication. Smoking status was recorded as
R. Marinheiro et al. / International Journal of Cardiology 249 (2017) 226–230 current smoker or non-smoker. The CHA2DS2VASc (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female) score was calculated [9]. All transthoracic echocardiograms were retrospectively collected and reviewed by study personnel. Holter recording was performed with the use of 3-channel tape recorders (GE SEER LIGHT®). Recordings had to exceed 20 h and be of good quality to be analyzed and all of them were reviewed and edited manually. Subjects were asked about PACs-related symptoms, namely palpitations during the exam. Premature atrial complexes were quantified using the number of PACs/h (PACs/h). Patients with PACs/h at the top 5th percentile in the present cohort were considered to have EAEA (n = 124) (EAEA+). Subjects with less than the commonly accepted cutoff value for frequent PACs (30 PACs/h) were assumed to have no EAEA (EAEA−). Patients with N30 PACs/h but b97 PACs/h were considered as an intermediate group with frequent but not excessive PACs/h (EAEA+/−). According to gender and age, propensity score matching method was used to obtain pairs of matched subjects: 124 for EAEA– group and 114 for EAEA+/− group, in order to exclude bias in recruitment. The selection of patients for analysis is shown in the study flow diagram (Fig. 1). Events of stroke, AF and overall death were retrieved from the national patient registry and from medical records or discharge letters and were validated by reviewing patients' files. Patients who failed to have recent clinical records were contacted by phone. Ischemic stroke was defined as a neurological deficit of sudden onset that persisted for N24 h, corresponded to a vascular territory in the absence of primary hemorrhage and that could not be explained by other causes (trauma, infection, vasculitis). It was confirmed by computerized axial tomography or magnetic resonance imaging of the brain. New occurrence of AF was defined as AF documented by a standard 12 lead electrocardiogram (ECG) or a new 24-h Holter monitoring.
2.3. Ethics All participants provided written informed consent. The Ethical Committee of Centro Hospitalar de Setubal approved the study. The study is in compliance with the Helsinki Declaration.
2.4. Statistics analysis SPSS version 23 software (SPSS Inc., Chicago, Illinois) was used for statistical analysis. Data is expressed as means ± standard deviation for continuous variables and as frequencies and percentages for categorical variables. Baseline characteristics and outcomes were compared using the chi-square test for categorical variables and the ANOVA test for continuous variables. Univariate and multivariate Coxproportional-hazards regression analysis was used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of ischemic stroke, new-onset AF and overall death between patients in the studied groups. Kaplan–Meier survival function and the log-rank test were used to compare the survival distributions. A value of p b 0.05 was considered statistically significant.
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3. Results 3.1. Study population Clinical characteristics are shown in Table 1. Median follow-up was 7.1 years and it was similar between the groups. No patients were lost to follow-up. 3.2. Follow-up Events per 1.000 person-years observed in up to 11 years of followup in the three studied groups are shown in Table 2. Supplementary Fig. 1 represents the percentage of events that occurred during the followup in the three groups. 3.2.1. Stroke Stroke occurred in 54 of all patients. Subjects who experienced a stroke were older (74 ± 6 years versus 70 ± 9 years; p b 0.001), had more hypertension (76% versus 89%, p = 0.02) and had a higher CHA2DS2VASc score (CHA2DS2VASc ≥ 3 in 78% versus 61%; p = 0.03). Other baseline variables and risk factors were not significantly different between the groups (Supplementary Table 2). Subjects with EAEA + had 34.9 strokes/1.000 person-years; those with EAEA +/− had 15.1 strokes/1.000 person-years and those with EAEA− 11.5 strokes/1.000 person-years (p b 0.001 for EAEA+). In univariate analysis, EAEA+ was associated with ischemic stroke (HR 2.71; 95% CI 1.60–4.61, p = 0.002 for EAEA+ group). This remained significant after adjustment for conventional risk factors (sex, age, body mass index, current smoking, hypertension, diabetes mellitus) (HR 2.87; 95% CI 1.68–4.91, p b 0.001). Further adjustment for blood glucose, creatinine, low-density lipoprotein (LDL) cholesterol, coronary or peripheral arterial disease and heart failure did not affect the results (HR 2.83; 95% CI 1.65– 4.84, p b 0.001). If use of medication is considered, including aspirin, the results will remain almost unchanged. Of note, EAEA+/− were not included in the model, regardless of adjustments. Fig. 2A shows KaplanMeier curve for stroke-free survival in patients with and without EAEA. In patients with stroke, AF was detected in 18 (60%) of patients with EAEA+ and in 8 (62%) of patients with EAEA+/− comparing to 4
Fig. 1. Flow diagram of the study selection process. Flow diagram of patients included in analysis: 124 patients with EAEA, 114 age- and gender-matched subjects with intermediate EAEA and 124 age- and gender-matched subjects with no EAEA. EAEA: excessive atrial ectopic activity. ECG: electrocardiogram. h: hour. PACs: premature atrial contractions.
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R. Marinheiro et al. / International Journal of Cardiology 249 (2017) 226–230 Table 1 Baseline characteristics of the studied groups. EAEA+ (n = 124)
EAEA+/− (n = 114)
EAEA− (n = 124)
p-Value
Demographic data Male gender, n (%) Age (years), mean ± SD Body mass index, kg/m2, mean ± SD
63 (51) 70.6 ± 5.6 28.1 ± 10.1
66 (58) 71.9 ± 9.3 27.1 ± 6.1
75 (60) 71.4 ± 8.6 26.8 ± 5.6
0.25 0.58 0.28
Risk factors and history Hypertension, n (%) Diabetes mellitus, n (%) Current smoking, n (%) Alcohol consumption N 101 g/wk, n (%) Coronary or peripheral arterial disease, n (%) Heart failure, n (%) Obstructive sleep apnea, n (%) Chronic obstructive pulmonary disease or asthma, n (%) Thyroid dysfunction, n (%)
97 (78) 32 (26) 30 (24) 5 (4) 25 (20) 9 (7) 11 (9) 16 (13) 4 (3)
87 (76) 31 (27) 17 (15) 4 (3) 23 (20) 12 (10) 7 (6) 8 (7) 5 (4)
97 (78) 28 (23) 22 (18) 3 (2) 26 (21) 16 (13) 11 (9) 18 (15) 1 (1)
0.51 0.70 0.17 0.77 0.98 0.14 034 0.17 0.22
Laboratory Glucose (mg/dL), mean ± SD Creatinine (mg/dL), mean ± SD LDL cholesterol (mg/dL), mean ± SD
111 ± 23 1.17 ± 0.72 129 ± 57
118 ± 25 1.15 ± 0.51 124 ± 45
114 ± 33 1.09 ± 0.50 128 ± 40
0.28 0.41 0.76
Echocardiographic parameters Left atrial volume/BSA, mL/m2, mean ± SD
37 ± 11
36 ± 12
35 ± 10
0.31
0.03 0.70
Symptoms Palpitations, n (%) CHA2DS2VASc scorea 0–1, n (%) 2, n (%) ≥3, n (%)
25 (20)
14 (12)
11(9)
20 (16) 32 (26) 72 (58)
18 (16) 21 (18) 75 (60)
18 (14) 27 (22) 79 (64)
Medication Beta-blocker, n (%) Ivabradine, n (%) Diuretic, n (%) ACEI/ARB, n (%) Aspirin/clopidogrel, n (%) Beta2-agonist, n (%)
25 (20) 2 (2) 19 (15) 79 (64) 54 (43) 10 (8)
18 (16) 1 (1) 21 (18) 69 (60) 46 (40) 6 (5)
25 (20) 0 (0) 17 (14) 79 (64) 44 (35) 6 (5)
0.59 0.37 0.96 0.89 0.25 0.48
24-h ECG monitoring PACs/h, mean ± SD Runs of ≥5 PACs Follow-up (years)
344 ± 276 66 (53) 6.8 ± 2.3
56 ± 19 59 (52) 7.0 ± 2.4
5±5 43 (35) 7.3 ± 2.6
b0.001 0.005 0.08
Values are presented as mean ± standard deviation (SD) and number (%). BSA: body surface área. EAEA: excessive atrial ectopic activity. PACs: premature atrial contractions. wk: week. EAEA+: N97 PACs/h; EAEA+/−: PACs/h = 30–97; EAEA−: PACS/h b 30. a The CHA2DS2VASc score was calculated according to the presence of congestive heart failure/left ventricular dysfunction (1 point); hypertension (1 point); age ≥ 75 years (2 points); diabetes mellitus (1 point); history of stroke, TIA or thromboembolism (2 points); vascular disease (history of MI, PVD or aortic atherosclerosis) (1 point); age 65–74 years (1 point) and female gender (1 point).
(36%) of patients with EAEA−. However, AF was detected before the stroke event in 9 patients and only 3 of this patients initiated oral anticoagulation (for reasons unrelated with investigators) (Supplementary Table 1). 3.2.2. Atrial fibrillation Table 2 shows AF/1.000 person-years in participants. Subjects who developed AF during the follow-up period were older (74 ± 6 years versus 70 ± 7 years, p = 0.009) and had more frequently hypertension (91% Table 2 Events per 1.000 person-years in subjects with EAEA+, EAEA+/− and no EAEA−.
Stroke AF Overall death
EAEA+ (n = 124)
EAEA+/− (n = 114)
EAEA– (n = 124)
p-Value
34.9 67.2 77.8
15.1 55.8 56.8
11.5 33.3 33.3
b0.001⁎ 0.014⁎⁎ b0.001⁎⁎
AF: Atrial fibrillation. EAEA: excessive atrial ectopic activity. EAEA+: N97 PACs/h; EAEA+/−: PACs/h = 30–97; EAEA−: PACS/h b 30. ⁎ For EAEA+. ⁎⁎ For EAEA+ and EAEA+/−.
versus 69%, p b 0.001) and diabetes mellitus (35% versus 23%, p = 0.004). In Cox regression models, EAEA+ and EAEA+/− were both associated with an increased risk of AF in both univariate (HR 2.05; 95% CI 1.31– 3.20, p = 0.002 and HR 1.68; 95% CI 1.05–2.69, p = 0.03, respectively) and adjusted models for conventional risk factors (HR 2.00; 95% CI 1.27–3.15, p = 0.003; HR 1.66; 95% CI 1.04–2.67, p = 0.035; respectively). Adjusted model for blood glucose, creatinine, low-density lipoprotein (LDL) cholesterol, coronary or peripheral arterial disease, heart failure and medication use showed similar results (HR 2.05; 95% CI 1.31–3.23, p = 0.01 for EAEA + and HR 1.90; 95% CI 1.10–2.78, p = 0.02 for EAEA+/−). Fig. 2B shows AF-free survival in patients with EAEA +, EAEA+/− and EAEA−. In addition to EAEA+ and EAEA+/−, hypertension (HR 2.78; 95% CI 1.31–3.82, p = 0.006) was associated with an increased risk of AF during follow-up. 3.2.3. Overall death Fifty-eight patients with EAEA+ (47%), 42 (37%) with EAEA+/− and 29 patients (23%) with EAEA− died during the follow-up (Supplementary Fig. 1) (HR 2.40; 95% CI 1.54–3.73, p b 0.001 for EAEA+; HR 1.69; 95% CI 1.06–2.72, p = 0.029 for EAEA +/−, in univariate analysis). This
R. Marinheiro et al. / International Journal of Cardiology 249 (2017) 226–230
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Fig. 2. Kaplan-Meier survival estimate of stroke-free survival (A), AF-free survival (B) and overall survival (C) in subjects with EAEA+, EAEA+/− and EAEA−.
remained significant after adjustment for conventional risk factors (HR 2.02; 95% CI 1.35–3.24, p = 0.028 for EAEA +; HR 1.78; 95% CI 1.02–2.46, p = 0.034 for EAEA+/−) and for blood glucose, creatinine, LDL cholesterol, coronary or peripheral arterial disease, heart failure and medication (HR 2.17; 95% CI 1.48–3.28, p = 0.031 for EAEA+; HR 2.01; 95% CI 1.06–2.52, p = 0.029 for EAEA+/−). Fig. 2C shows overall survival in the three groups. Besides EAEA, age (in years) was associated with an increased risk of death (HR = 1.1 per year; 95% CI 1.07–1.13, p b 0.001). Other risk factors were not significantly associated to death. 4. Discussion There is no clear and accepted cutoff value for the frequency of PACs to be considered pathological. Assuming that PACs had to be excessive to increase the adverse events substantially, we set the cutoff at the top 5th percentile of the present cohort: patients with N97 PACs/h were considered to have EAEA. An intermediate group defined as having more than the general accepted cut-off value (30 PACs/h) but less than 97 PACs/h was also studied in order to better define if having “excessive” PACs/h is distinct from having “frequent” PACs/h. Previous studies considered lower cutoff values [4–8]. Bicini et al. [7] and Larsen et al. [5] used the higher cutoff value and even thought it was 30 PACs/h, which corresponded to top 10th percentile in Bicini's study. In our study, having more than 97 PACs/h was independently associated with almost a 3-fold increased in the rate of ischemic stroke, after adjustment for other risk factors. Interesting, subjects who had 30– 97 PACs/h do not have an increased risk of ischemic stroke, demonstrating that a higher burden of EAEA is necessary. Two possible pathophysiological mechanisms could be involved: EAEA precedes undiagnosed
incident AF or EAEA may lead to the dilatation of left atrium and stasis in the left atrial appendage, fibrosis and endothelial dysfunction resulting in a hypercoagulable state similar to that seen in AF [10–11]. Some authors proposed that EAEA could be a marker of a higher prevalence of cardiovascular (CV) risk factors such as hypertension, diabetes, dyslipidemia and smoking status [5–6]. Although underpowered for such findings, our results did not corroborate such hypothesis since there were no significant differences regarding CV risk factors between patients in the EAEA+ group comparing to EAEA+/− or EAEA− group. Although still arbitrary, a fairly stringent cutoff value suggests that defining a higher cutoff (e.g. N100 PACs/h) can identify more accurately patients at a higher risk of stroke. As in others studies [5–8], EAEA was associated with new-onset AF, demonstrating that a close follow-up of these patients is needed. Both EAEA + and EAEA +/− patients had an increased risk of developing AF, although EAEA+ group had a higher risk. These results are in accordance with Alhede et al. [12], who demonstrated that lower PACs burden after catheter ablation or medical therapy in patients with known AF were associated with lower long-term AF burden. These findings may raise the question of treating EAEA in order to decrease this risk. Other main question is the importance of an early detection of AF in order to prevent embolic events since it is a well-known risk factor for ischemic stroke. In recent years, more efforts have been done to detect possible AF in patients with cryptogenic stroke [13–17]. Identifying patient populations at high risk for occult AF may provide a more targeted and higher yield AF screening approach [18], since it is time consuming and expensive. Using EAEA as a method to predict AF [19] is very useful since EAEA is more frequent than AF episodes. Patients with EAEA also had an increased risk of overall death, which was in accordance with other studies. While it is conceivable that the
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EAEA predicts the development of new AF, the mechanism by which EAEA results in an increased risk of death is not as clear. The increased risk of death may be attributable to AF and/or stroke but also to underlying cardiac conditions in which EAEA is more frequent (e.g. coronary heart disease, left ventricular dysfunction) or more severe/uncontrolled CV risk factors. However our study did not analyzed specific causes of death, namely cardiovascular deaths to draw this conclusion. According to Conen et al. [19], PACs frequency is independently associated with age, height, history of cardiovascular disease, natriuretic peptide levels, physical activity and high-density lipoprotein cholesterol. Although in our study there were no differences in these risk factors between the three groups and death was more frequent in EAEA+ and EAEA+/− groups, the study may be underpowered to find such differences. Of note, PACs-related symptoms were uncommon in our study; only 20% of subjects with N97 PACs/h and 12% of those with more than 30 PACs/h complained of palpitations. While no differences were found in the number of patients with beta-blockers at the time of the Holter recording, beta-blockers dosage or titration during follow-up were not analyzed. No differences in endpoints were found between symptomatic and asymptomatic subjects. Conventionally, only AF and atrial flutter are considered to cause ischemic stroke. Our study suggests that other atrial electric instabilities as EAEA can contribute to some cryptogenic strokes. However, it remains to clarify if EAEA is associated with an increased risk of ischemic stroke by itself or through the appearance of paroxysmal AF (detected or not). Larsen et al. (2015) found a correlation between EAEA and ischemic stroke beyond AF when censoring analysis and modeling AF as a timevarying exposure. However in a competing risk analysis with death and AF as competing events, the association between EAEA and ischemic stroke attenuated to insignificantly [5]. In our study, 40% of patients with EAEA and stroke had no AF detected suggesting that EAEA could have been the responsible for the stroke event. Even in those with AF detected after acute stroke (37%), there is no certainty about the mechanism for stroke: EAEA that increased the risk for AF after acute stroke or occult AF not detected before acute stroke. Given these results, it is possible that patients with EAEA (in particular those with more than 100 PACs/h) can benefit from therapeutic intervention (oral anticoagulation) if CHA2DS2VASc score was high, even in the absence of AF diagnosis. Further studies are needed to answer these questions. Until then, the best manner to treat patients with EAEA in order to reduce the risk of AF, stroke and death is appropriate risk factor modification. 4.1. Study limitations It was an observational and retrospective study. The diagnosis of atrial fibrillation in our study is probably underestimated because it was based on admission for AF or occasional ECG or 24 h Holter monitoring during follow-up. Indeed the number of cases of asymptomatic AF is not known. 5. Conclusions EAEA is associated with an increased risk of stroke, AF and death. Subjects with N100 PACs per hour are at higher risk and need strict close follow-up, risk factor modification and may benefit from therapeutic intervention. More investigation in this field is needed.
Grant support None. Conflicts of interest None Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2017.08.054. References [1] M. Haïssaguerre, P. Jaïs, D. Shah, et al., Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins, N. Engl. J. Med. 339 (1998) 659–666. [2] C. Kolb, S. Nurnberger, G. Ndrepepa, B. Zrenner, A. Schomig, C. Schmitt, Modes of initiation of paroxysmal atrial fibrillation from analysis of spontaneously occurring episodes using a 12-lead Holter monitoring system, Am. J. Cardiol. 88 (2001) 853–857. [3] S. Nattel, M. Harada, Atrial remodeling and atrial fibrillation: recent advances and translational perspectives, J. Am. Coll. Cardiol. 63 (2014) 2335–2345. [4] N. Murakoshi, D. Xu, T. Sairenchi, et al., Prognostic impact of supraventricular premature complexes in community-based health checkups: the Ibaraki Prefectural Health Study, Eur. Heart J. 36 (2015) 170–178. [5] B.S. Larsen, P. Kumarathurai, J. Falkenberg, O.W. Nielsen, A. Sajadieh, Excessive atrial ectopy and short atrial runs increase the risk of stroke beyond incident atrial fibrillation, J. Am. Coll. Cardiol. 66 (3) (2015) 232–241. [6] B. Chong, V. Pong, K. Lam, et al., Frequent premature atrial complexes predict new occurrence of atrial fibrillation and adverse cardiovascular events, Europace 14 (2012) 942–947. [7] Z. Binici, T. Intzilakis, O.W. Nielsen, L. Køber, A. Sajadieh, Excessive supraventricular ectopic activity and increased risk of atrial fibrillation and stroke, Circulation 121 (2010) 1904–1911. [8] G. Engström, B. Hedblad, S. Juul-Möller, P. Tydén, L. Janzon, Cardiac arrhythmias and stroke: increased risk in men with high frequency of atrial ectopic beats, Stroke 31 (12) (2000) 2925–2929. [9] G.Y. Lip, R. Nieuwlaat, R. Pisters, D. Lane, H. Crijns, Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation, Chest 137 (2010) 263–272. [10] M. Goldman, L. Pearce, R. Hart, et al., Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (the stroke prevention in atrial fibrillation [SPAF-III] study), J. Am. Soc. Echocardiogr. 12 (1999) 1080–1087. [11] T. Watson, E. Shantsila, G. Lip, Mechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited, Lancet 373 (2009) 155–166. [12] C. Alhede, T. Lauridsen, A. Johannessen, et al., Antiarrhythmic medication is superior to catheter ablation in suppressing supraventricular ectopic complexes in patients with atrial fibrillation, Int. J. Cardiol. 244 (2017) 186–191. [13] S. Kochhäuser, D.G. Dechering, R. Dittrich, et al., Supraventricular premature beats and short atrial runs predict atrial fibrillation in continuously monitored patients with cryptogenic stroke, Stroke 45 (2014) 884–886. [14] T.A. Dewland, E. Vittinghoff, M.C. Mandyam, et al., Atrial ectopy as a predictor of incident atrial fibrillation: a cohort study, Ann. Intern. Med. 159 (2013) 721–728. [15] W.N. Kernan, B. Ovbiagele, H.R. Black, et al., Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association, Stroke 45 (2014) 2160–2236. [16] D. Wallmann, D. Tüller, K. Wustmann, et al., Frequent atrial premature beats predict paroxysmal atrial fibrillation in stroke patients: an opportunity for a new diagnostic strategy, Stroke 38 (2007) 2292–2294. [17] D. Wallmann, D. Tüller, N. Kucher, et al., Frequent atrial premature contractions as a surrogate marker for paroxysmal atrial fibrillation in patients with acute ischaemic stroke, Heart 89 (2003) 1247–1248. [18] J.W. Keach, S. Bradley, M. Turakhia, et al., Early detection of occult atrial fibrillation and stroke prevention, Heart 101 (14) (2015) 1097–1102. [19] D. Conen, M. Adam, F. Roche, et al., Premature atrial contractions in the general population: frequency and risk factors, Circulation 126 (2012) 2302–2308.
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Excessive atrial ectopic activity as an independent risk factor for ischemic stroke Rita Marinheiro ⁎,1, Leonor Parreira 1, Pedro Amador 1, Catarina Sá 1, Tatiana Duarte 1, Rui Caria 1 Centro Hospitalar de Setubal, Cardiology Department, Setubal, Portugal
a r t i c l e
i n f o
Article history: Received 16 May 2017 Received in revised form 8 August 2017 Accepted 21 August 2017 Available online 26 August 2017 Keywords: Excessive atrial ectopy Ischemic stroke Atrial fibrillation
a b s t r a c t Background: Excessive atrial ectopic activity (EAEA) has been related with an increased risk of atrial fibrillation (AF) and stroke but different cutoff values have been used. We aimed to determine the association between EAEA and stroke, AF and overall death. Methods: Consecutive 24-hour Holter monitoring performed between 2005 and 2010 in a single center was evaluated. Patients with a previous diagnosis of stroke or AF were excluded. The number of premature atrial contractions (PACs) during 24 h was analyzed in 2480 subjects and according to that 3 sub-groups were defined: N 97 PACs/h (above the top 5th percentile of the population) (EAEA+); intermediate value of PACs/h (below the top 5th percentile but above 30 PACs/h) (EAEA+/−) and b30 PACs/h (EAEA−). Results: After adjusting for risk factors, laboratory findings and medication, EAEA+ was associated with ischemic stroke (hazard ratio [HR] 2.83; 95% confidence interval [CI], 1.65–4.84, p b 0.001). Both EAEA+ and EAEA+/− were independently associated with AF (HR 2.05; 95% CI 1.31–3.23, p = 0.010 for EAEA+ and HR 1.90; 95% CI 1.10–2.78, p = 0.020 for EAEA+/−) and overall death (HR 2.17; 95% CI 1.48–3.28, p = 0.031 for EAEA+; HR 2.01; 95% CI 1.06–2.52, p = 0.029 for EAEA+/−). Conclusion: In this population, having N 30 PACs/h was independently associated with a higher risk of AF and overall death but only subjects with N 97 PACs/h had a higher risk of ischemic stroke. In the majority of subjects with stroke and EAEA+, AF has not been detected before stroke event. © 2017 Elsevier B.V. All rights reserved.
1. Introduction The role of atrial ectopic activity in the initiation of atrial fibrillation (AF) is well established. In 1998, Haissaguerre et al. demonstrated that the pulmonary veins are an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation [1]. Premature atrial contractions (PACs) may be a marker for foci that are or will be capable of firing rapidly to initiate AF [2] through a reentry-maintaining substrate. Rapid and repetitive stimulation of the atrial muscle is known to alter its electrophysiological properties by shortening atrial refractoriness, leading to the development and maintenance of AF. Alternatively, PACs may be a marker of developing atrial electrophysiological changes that promote AF, such as interstitial fibrosis and abnormal intracellular calcium handling [3]. Recent studies suggested that excessive atrial ectopic activity (EAEA) not only increases risk of AF but it is also associated with an increased risk Abbreviations: AF, atrial fibrillation; CI, confidence interval; CV, cardiovascular; EAEA, excessive atrial ectopic activity; ECG, electrocardiogram; h, hour; HR, hazard ratio; LDL, low-density lipoprotein; PACs, premature atrial contractions. ⁎ Corresponding author. E-mail addresses: [email protected] (R. Marinheiro), [email protected] (L. Parreira). 1 “This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation”.
http://dx.doi.org/10.1016/j.ijcard.2017.08.054 0167-5273/© 2017 Elsevier B.V. All rights reserved.
of stroke, adverse cardiovascular events and death [4–8]. The lack of precise definition for “excessive” atrial ectopy leads investigators to use arbitrary cut-off values according to top percentiles for frequency of PACs [6–8]. However, considering the number of PACs as a continuous variable, the risk of adverse events is related to the number of PACs. The aim of this study was to use a higher cutoff value in order to identify high risk patients that would benefit from therapeutic intervention. 2. Methods 2.1. Patients Between January 2005 and December 2010, 3589 consecutive patients were referred to our non-invasive cardiology laboratory for elective 24-hour (h) Holter monitoring. Patients were excluded if they had previously documented AF (n = 396), AF diagnosed during the exam (n = 206), history of stroke or transient ischemic attack (n = 409) or if they were under medication with anticoagulants (n = 98). The final analysis thus involved 2480 subjects. 2.2. Study design Demographic data, cardiovascular risk factors, indications for 24 h Holter monitoring, transthoracic echocardiograms and medications were recorded. Hypertension was defined as resting systolic or diastolic blood pressure ≥140/90 mm Hg on two occasions or prescription of anti-hypertensive drugs. Diabetes mellitus was defined as a serum fasting glucose ≥7.0 mmol/L or prescription of anti-diabetic medication. Smoking status was recorded as
R. Marinheiro et al. / International Journal of Cardiology 249 (2017) 226–230 current smoker or non-smoker. The CHA2DS2VASc (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female) score was calculated [9]. All transthoracic echocardiograms were retrospectively collected and reviewed by study personnel. Holter recording was performed with the use of 3-channel tape recorders (GE SEER LIGHT®). Recordings had to exceed 20 h and be of good quality to be analyzed and all of them were reviewed and edited manually. Subjects were asked about PACs-related symptoms, namely palpitations during the exam. Premature atrial complexes were quantified using the number of PACs/h (PACs/h). Patients with PACs/h at the top 5th percentile in the present cohort were considered to have EAEA (n = 124) (EAEA+). Subjects with less than the commonly accepted cutoff value for frequent PACs (30 PACs/h) were assumed to have no EAEA (EAEA−). Patients with N30 PACs/h but b97 PACs/h were considered as an intermediate group with frequent but not excessive PACs/h (EAEA+/−). According to gender and age, propensity score matching method was used to obtain pairs of matched subjects: 124 for EAEA– group and 114 for EAEA+/− group, in order to exclude bias in recruitment. The selection of patients for analysis is shown in the study flow diagram (Fig. 1). Events of stroke, AF and overall death were retrieved from the national patient registry and from medical records or discharge letters and were validated by reviewing patients' files. Patients who failed to have recent clinical records were contacted by phone. Ischemic stroke was defined as a neurological deficit of sudden onset that persisted for N24 h, corresponded to a vascular territory in the absence of primary hemorrhage and that could not be explained by other causes (trauma, infection, vasculitis). It was confirmed by computerized axial tomography or magnetic resonance imaging of the brain. New occurrence of AF was defined as AF documented by a standard 12 lead electrocardiogram (ECG) or a new 24-h Holter monitoring.
2.3. Ethics All participants provided written informed consent. The Ethical Committee of Centro Hospitalar de Setubal approved the study. The study is in compliance with the Helsinki Declaration.
2.4. Statistics analysis SPSS version 23 software (SPSS Inc., Chicago, Illinois) was used for statistical analysis. Data is expressed as means ± standard deviation for continuous variables and as frequencies and percentages for categorical variables. Baseline characteristics and outcomes were compared using the chi-square test for categorical variables and the ANOVA test for continuous variables. Univariate and multivariate Coxproportional-hazards regression analysis was used to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of ischemic stroke, new-onset AF and overall death between patients in the studied groups. Kaplan–Meier survival function and the log-rank test were used to compare the survival distributions. A value of p b 0.05 was considered statistically significant.
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3. Results 3.1. Study population Clinical characteristics are shown in Table 1. Median follow-up was 7.1 years and it was similar between the groups. No patients were lost to follow-up. 3.2. Follow-up Events per 1.000 person-years observed in up to 11 years of followup in the three studied groups are shown in Table 2. Supplementary Fig. 1 represents the percentage of events that occurred during the followup in the three groups. 3.2.1. Stroke Stroke occurred in 54 of all patients. Subjects who experienced a stroke were older (74 ± 6 years versus 70 ± 9 years; p b 0.001), had more hypertension (76% versus 89%, p = 0.02) and had a higher CHA2DS2VASc score (CHA2DS2VASc ≥ 3 in 78% versus 61%; p = 0.03). Other baseline variables and risk factors were not significantly different between the groups (Supplementary Table 2). Subjects with EAEA + had 34.9 strokes/1.000 person-years; those with EAEA +/− had 15.1 strokes/1.000 person-years and those with EAEA− 11.5 strokes/1.000 person-years (p b 0.001 for EAEA+). In univariate analysis, EAEA+ was associated with ischemic stroke (HR 2.71; 95% CI 1.60–4.61, p = 0.002 for EAEA+ group). This remained significant after adjustment for conventional risk factors (sex, age, body mass index, current smoking, hypertension, diabetes mellitus) (HR 2.87; 95% CI 1.68–4.91, p b 0.001). Further adjustment for blood glucose, creatinine, low-density lipoprotein (LDL) cholesterol, coronary or peripheral arterial disease and heart failure did not affect the results (HR 2.83; 95% CI 1.65– 4.84, p b 0.001). If use of medication is considered, including aspirin, the results will remain almost unchanged. Of note, EAEA+/− were not included in the model, regardless of adjustments. Fig. 2A shows KaplanMeier curve for stroke-free survival in patients with and without EAEA. In patients with stroke, AF was detected in 18 (60%) of patients with EAEA+ and in 8 (62%) of patients with EAEA+/− comparing to 4
Fig. 1. Flow diagram of the study selection process. Flow diagram of patients included in analysis: 124 patients with EAEA, 114 age- and gender-matched subjects with intermediate EAEA and 124 age- and gender-matched subjects with no EAEA. EAEA: excessive atrial ectopic activity. ECG: electrocardiogram. h: hour. PACs: premature atrial contractions.
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R. Marinheiro et al. / International Journal of Cardiology 249 (2017) 226–230 Table 1 Baseline characteristics of the studied groups. EAEA+ (n = 124)
EAEA+/− (n = 114)
EAEA− (n = 124)
p-Value
Demographic data Male gender, n (%) Age (years), mean ± SD Body mass index, kg/m2, mean ± SD
63 (51) 70.6 ± 5.6 28.1 ± 10.1
66 (58) 71.9 ± 9.3 27.1 ± 6.1
75 (60) 71.4 ± 8.6 26.8 ± 5.6
0.25 0.58 0.28
Risk factors and history Hypertension, n (%) Diabetes mellitus, n (%) Current smoking, n (%) Alcohol consumption N 101 g/wk, n (%) Coronary or peripheral arterial disease, n (%) Heart failure, n (%) Obstructive sleep apnea, n (%) Chronic obstructive pulmonary disease or asthma, n (%) Thyroid dysfunction, n (%)
97 (78) 32 (26) 30 (24) 5 (4) 25 (20) 9 (7) 11 (9) 16 (13) 4 (3)
87 (76) 31 (27) 17 (15) 4 (3) 23 (20) 12 (10) 7 (6) 8 (7) 5 (4)
97 (78) 28 (23) 22 (18) 3 (2) 26 (21) 16 (13) 11 (9) 18 (15) 1 (1)
0.51 0.70 0.17 0.77 0.98 0.14 034 0.17 0.22
Laboratory Glucose (mg/dL), mean ± SD Creatinine (mg/dL), mean ± SD LDL cholesterol (mg/dL), mean ± SD
111 ± 23 1.17 ± 0.72 129 ± 57
118 ± 25 1.15 ± 0.51 124 ± 45
114 ± 33 1.09 ± 0.50 128 ± 40
0.28 0.41 0.76
Echocardiographic parameters Left atrial volume/BSA, mL/m2, mean ± SD
37 ± 11
36 ± 12
35 ± 10
0.31
0.03 0.70
Symptoms Palpitations, n (%) CHA2DS2VASc scorea 0–1, n (%) 2, n (%) ≥3, n (%)
25 (20)
14 (12)
11(9)
20 (16) 32 (26) 72 (58)
18 (16) 21 (18) 75 (60)
18 (14) 27 (22) 79 (64)
Medication Beta-blocker, n (%) Ivabradine, n (%) Diuretic, n (%) ACEI/ARB, n (%) Aspirin/clopidogrel, n (%) Beta2-agonist, n (%)
25 (20) 2 (2) 19 (15) 79 (64) 54 (43) 10 (8)
18 (16) 1 (1) 21 (18) 69 (60) 46 (40) 6 (5)
25 (20) 0 (0) 17 (14) 79 (64) 44 (35) 6 (5)
0.59 0.37 0.96 0.89 0.25 0.48
24-h ECG monitoring PACs/h, mean ± SD Runs of ≥5 PACs Follow-up (years)
344 ± 276 66 (53) 6.8 ± 2.3
56 ± 19 59 (52) 7.0 ± 2.4
5±5 43 (35) 7.3 ± 2.6
b0.001 0.005 0.08
Values are presented as mean ± standard deviation (SD) and number (%). BSA: body surface área. EAEA: excessive atrial ectopic activity. PACs: premature atrial contractions. wk: week. EAEA+: N97 PACs/h; EAEA+/−: PACs/h = 30–97; EAEA−: PACS/h b 30. a The CHA2DS2VASc score was calculated according to the presence of congestive heart failure/left ventricular dysfunction (1 point); hypertension (1 point); age ≥ 75 years (2 points); diabetes mellitus (1 point); history of stroke, TIA or thromboembolism (2 points); vascular disease (history of MI, PVD or aortic atherosclerosis) (1 point); age 65–74 years (1 point) and female gender (1 point).
(36%) of patients with EAEA−. However, AF was detected before the stroke event in 9 patients and only 3 of this patients initiated oral anticoagulation (for reasons unrelated with investigators) (Supplementary Table 1). 3.2.2. Atrial fibrillation Table 2 shows AF/1.000 person-years in participants. Subjects who developed AF during the follow-up period were older (74 ± 6 years versus 70 ± 7 years, p = 0.009) and had more frequently hypertension (91% Table 2 Events per 1.000 person-years in subjects with EAEA+, EAEA+/− and no EAEA−.
Stroke AF Overall death
EAEA+ (n = 124)
EAEA+/− (n = 114)
EAEA– (n = 124)
p-Value
34.9 67.2 77.8
15.1 55.8 56.8
11.5 33.3 33.3
b0.001⁎ 0.014⁎⁎ b0.001⁎⁎
AF: Atrial fibrillation. EAEA: excessive atrial ectopic activity. EAEA+: N97 PACs/h; EAEA+/−: PACs/h = 30–97; EAEA−: PACS/h b 30. ⁎ For EAEA+. ⁎⁎ For EAEA+ and EAEA+/−.
versus 69%, p b 0.001) and diabetes mellitus (35% versus 23%, p = 0.004). In Cox regression models, EAEA+ and EAEA+/− were both associated with an increased risk of AF in both univariate (HR 2.05; 95% CI 1.31– 3.20, p = 0.002 and HR 1.68; 95% CI 1.05–2.69, p = 0.03, respectively) and adjusted models for conventional risk factors (HR 2.00; 95% CI 1.27–3.15, p = 0.003; HR 1.66; 95% CI 1.04–2.67, p = 0.035; respectively). Adjusted model for blood glucose, creatinine, low-density lipoprotein (LDL) cholesterol, coronary or peripheral arterial disease, heart failure and medication use showed similar results (HR 2.05; 95% CI 1.31–3.23, p = 0.01 for EAEA + and HR 1.90; 95% CI 1.10–2.78, p = 0.02 for EAEA+/−). Fig. 2B shows AF-free survival in patients with EAEA +, EAEA+/− and EAEA−. In addition to EAEA+ and EAEA+/−, hypertension (HR 2.78; 95% CI 1.31–3.82, p = 0.006) was associated with an increased risk of AF during follow-up. 3.2.3. Overall death Fifty-eight patients with EAEA+ (47%), 42 (37%) with EAEA+/− and 29 patients (23%) with EAEA− died during the follow-up (Supplementary Fig. 1) (HR 2.40; 95% CI 1.54–3.73, p b 0.001 for EAEA+; HR 1.69; 95% CI 1.06–2.72, p = 0.029 for EAEA +/−, in univariate analysis). This
R. Marinheiro et al. / International Journal of Cardiology 249 (2017) 226–230
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Fig. 2. Kaplan-Meier survival estimate of stroke-free survival (A), AF-free survival (B) and overall survival (C) in subjects with EAEA+, EAEA+/− and EAEA−.
remained significant after adjustment for conventional risk factors (HR 2.02; 95% CI 1.35–3.24, p = 0.028 for EAEA +; HR 1.78; 95% CI 1.02–2.46, p = 0.034 for EAEA+/−) and for blood glucose, creatinine, LDL cholesterol, coronary or peripheral arterial disease, heart failure and medication (HR 2.17; 95% CI 1.48–3.28, p = 0.031 for EAEA+; HR 2.01; 95% CI 1.06–2.52, p = 0.029 for EAEA+/−). Fig. 2C shows overall survival in the three groups. Besides EAEA, age (in years) was associated with an increased risk of death (HR = 1.1 per year; 95% CI 1.07–1.13, p b 0.001). Other risk factors were not significantly associated to death. 4. Discussion There is no clear and accepted cutoff value for the frequency of PACs to be considered pathological. Assuming that PACs had to be excessive to increase the adverse events substantially, we set the cutoff at the top 5th percentile of the present cohort: patients with N97 PACs/h were considered to have EAEA. An intermediate group defined as having more than the general accepted cut-off value (30 PACs/h) but less than 97 PACs/h was also studied in order to better define if having “excessive” PACs/h is distinct from having “frequent” PACs/h. Previous studies considered lower cutoff values [4–8]. Bicini et al. [7] and Larsen et al. [5] used the higher cutoff value and even thought it was 30 PACs/h, which corresponded to top 10th percentile in Bicini's study. In our study, having more than 97 PACs/h was independently associated with almost a 3-fold increased in the rate of ischemic stroke, after adjustment for other risk factors. Interesting, subjects who had 30– 97 PACs/h do not have an increased risk of ischemic stroke, demonstrating that a higher burden of EAEA is necessary. Two possible pathophysiological mechanisms could be involved: EAEA precedes undiagnosed
incident AF or EAEA may lead to the dilatation of left atrium and stasis in the left atrial appendage, fibrosis and endothelial dysfunction resulting in a hypercoagulable state similar to that seen in AF [10–11]. Some authors proposed that EAEA could be a marker of a higher prevalence of cardiovascular (CV) risk factors such as hypertension, diabetes, dyslipidemia and smoking status [5–6]. Although underpowered for such findings, our results did not corroborate such hypothesis since there were no significant differences regarding CV risk factors between patients in the EAEA+ group comparing to EAEA+/− or EAEA− group. Although still arbitrary, a fairly stringent cutoff value suggests that defining a higher cutoff (e.g. N100 PACs/h) can identify more accurately patients at a higher risk of stroke. As in others studies [5–8], EAEA was associated with new-onset AF, demonstrating that a close follow-up of these patients is needed. Both EAEA + and EAEA +/− patients had an increased risk of developing AF, although EAEA+ group had a higher risk. These results are in accordance with Alhede et al. [12], who demonstrated that lower PACs burden after catheter ablation or medical therapy in patients with known AF were associated with lower long-term AF burden. These findings may raise the question of treating EAEA in order to decrease this risk. Other main question is the importance of an early detection of AF in order to prevent embolic events since it is a well-known risk factor for ischemic stroke. In recent years, more efforts have been done to detect possible AF in patients with cryptogenic stroke [13–17]. Identifying patient populations at high risk for occult AF may provide a more targeted and higher yield AF screening approach [18], since it is time consuming and expensive. Using EAEA as a method to predict AF [19] is very useful since EAEA is more frequent than AF episodes. Patients with EAEA also had an increased risk of overall death, which was in accordance with other studies. While it is conceivable that the
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EAEA predicts the development of new AF, the mechanism by which EAEA results in an increased risk of death is not as clear. The increased risk of death may be attributable to AF and/or stroke but also to underlying cardiac conditions in which EAEA is more frequent (e.g. coronary heart disease, left ventricular dysfunction) or more severe/uncontrolled CV risk factors. However our study did not analyzed specific causes of death, namely cardiovascular deaths to draw this conclusion. According to Conen et al. [19], PACs frequency is independently associated with age, height, history of cardiovascular disease, natriuretic peptide levels, physical activity and high-density lipoprotein cholesterol. Although in our study there were no differences in these risk factors between the three groups and death was more frequent in EAEA+ and EAEA+/− groups, the study may be underpowered to find such differences. Of note, PACs-related symptoms were uncommon in our study; only 20% of subjects with N97 PACs/h and 12% of those with more than 30 PACs/h complained of palpitations. While no differences were found in the number of patients with beta-blockers at the time of the Holter recording, beta-blockers dosage or titration during follow-up were not analyzed. No differences in endpoints were found between symptomatic and asymptomatic subjects. Conventionally, only AF and atrial flutter are considered to cause ischemic stroke. Our study suggests that other atrial electric instabilities as EAEA can contribute to some cryptogenic strokes. However, it remains to clarify if EAEA is associated with an increased risk of ischemic stroke by itself or through the appearance of paroxysmal AF (detected or not). Larsen et al. (2015) found a correlation between EAEA and ischemic stroke beyond AF when censoring analysis and modeling AF as a timevarying exposure. However in a competing risk analysis with death and AF as competing events, the association between EAEA and ischemic stroke attenuated to insignificantly [5]. In our study, 40% of patients with EAEA and stroke had no AF detected suggesting that EAEA could have been the responsible for the stroke event. Even in those with AF detected after acute stroke (37%), there is no certainty about the mechanism for stroke: EAEA that increased the risk for AF after acute stroke or occult AF not detected before acute stroke. Given these results, it is possible that patients with EAEA (in particular those with more than 100 PACs/h) can benefit from therapeutic intervention (oral anticoagulation) if CHA2DS2VASc score was high, even in the absence of AF diagnosis. Further studies are needed to answer these questions. Until then, the best manner to treat patients with EAEA in order to reduce the risk of AF, stroke and death is appropriate risk factor modification. 4.1. Study limitations It was an observational and retrospective study. The diagnosis of atrial fibrillation in our study is probably underestimated because it was based on admission for AF or occasional ECG or 24 h Holter monitoring during follow-up. Indeed the number of cases of asymptomatic AF is not known. 5. Conclusions EAEA is associated with an increased risk of stroke, AF and death. Subjects with N100 PACs per hour are at higher risk and need strict close follow-up, risk factor modification and may benefit from therapeutic intervention. More investigation in this field is needed.
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