Int J Cardiovasc Imaging (2015) 31:735–742 DOI 10.1007/s10554-015-0613-2
ORIGINAL PAPER
Development of atrial fibrillation in patients with rheumatic mitral valve disease in sinus rhythm Hyun-Jin Kim • Goo-Yeong Cho • Yong-Jin Kim • Hyung-Kwan Kim • Seung-Pyo Lee • Hack-Lyoung Kim • Jin Joo Park • Yeonyee E. Yoon • Joo-Hee Zo • Dae-Won Sohn
Received: 27 November 2014 / Accepted: 4 February 2015 / Published online: 10 February 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract This study evaluated the predictors of atrial fibrillation (AF) and adverse clinical events in patients with rheumatic mitral stenosis (RMS) in sinus rhythm. The patients who diagnosed with RMS in sinus rhythm were evaluated retrospectively between March 2003 and June 2013. The primary outcome was the development of newonset AF with annual event rates and the secondary outcome was the incidence of clinical events including development of new-onset AF, systemic embolism and allcause death during follow-up. Among 293 patients, AF developed in 60 (20.5 %) patients with average annual event rate of 3.5 %/year during mean follow-up period of 68.2 ± 36.6 months (median 72 months). All cause death or systemic embolism occurred in 7.2 % (21 patients; all
cause death 9, embolism 12) with an average annual event rate of 2.1 %. In the multivariate analysis, large left atrium (LA) dimension and severe mitral stenosis (B1.5 cm2) were independent predictors of AF development [HR 1.06, 95 % CI: 1.02–1.10; P = 0.001, HR 1.97, 95 % CI: 1.06–4.14; P = 0.032] after adjustment for confounding factors. Patients with enlarged LA (C47 mm) had an average annual AF development rate of 6.0 %/year. In patients with RMS in sinus rhythm, annual AF development rate was 3.5 %/year and increased according to LA size and mitral stenosis (MS) severity. Because of very high risk embolism, RMS with enlarged LA dimension need focused follow up for early detection of AF development and clinical events. Keywords Mitral valve stenosis Sinus rhythm Embolism Atrial fibrillation
Electronic supplementary material The online version of this article (doi:10.1007/s10554-015-0613-2) contains supplementary material, which is available to authorized users. H.-J. Kim G.-Y. Cho Y.-J. Kim H.-K. Kim S.-P. Lee H.-L. Kim J. J. Park Y. E. Yoon J.-H. Zo D.-W. Sohn Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea H.-J. Kim Y.-J. Kim H.-K. Kim S.-P. Lee D.-W. Sohn Cardiovascular Center, Seoul National University Hospital, Seoul, South Korea G.-Y. Cho (&) J. J. Park Y. E. Yoon Cardiovascular Center, Seoul National University Bundang Hospital, 82 Gumi-ro-173-gil, Bundang, Seongnam, Gyeonggi 463-707, South Korea e-mail: [email protected] H.-L. Kim J.-H. Zo Cardiovascular Center, Seoul National University Boramae Medical Center, Seoul, South Korea
Abbreviations AF Atrial fibrillation CI Confidence interval CT Computed tomographic ECG Electrocardiography EROA Effective regurgitation orifice area GFC Global fibrinolytic capacity GFR Glomerular filtration rate HR Hazard ratio LA Left atrium MR Mitral regurgitation MRI Magnetic resonance imaging MS Mitral stenosis MVA Mitral valve area PISA Proximal isovelocity surface area RMS Rheumatic mitral stenosis TTE Transthoracic echocardiography
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Introduction Atrial fibrillation (AF) develops in half of those patients with rheumatic mitral stenosis (RMS) [1]. Nevertheless, there has been a lack of clarity regarding the medical treatment of mitral stenosis (MS) in sinus rhythm [2]. The current guidelines do not recommend anticoagulation unless there is concomitant AF or prior embolic events, or if there is left atrium (LA) thrombus. Meanwhile in these guidelines, anticoagulation should be considered when echocardiography show dense spontaneous echo contrast or LA enlargement in sinus rhythm [3, 4]. Furthermore, there have been no guidelines regarding electrocardiography (ECG) follow-up in patients with RMS in sinus rhythm. In addition, there have been few reports as to whether anticoagulation therapy could reduce the systemic embolic rate or what percentage of patents developed AF amongst RMS patients with sinus rhythm [1]. However, systemic embolism might be an important complication of rheumatic mitral valve disease even though patients are in sinus rhythm. Chiang et al. [5] showed the occurrence of new systemic embolism during follow-up in patients with MS as being significant, with 11.9 % of patients with MS in AF developing systemic embolism, and 9.1 % with MS in sinus rhythm developing a systemic embolism. Manjunath et al. [6] showed that, in 848 patients with RMS and sinus rhythm who underwent transthoracic echocardiography (TTE), there was a 6.6 % incidence of LA thrombus. Though the risk of an embolic event increases primarily because of the high frequency of AF in patients with rheumatic mitral valve disease [7], several other factors have been correlated with systemic embolic events in rheumatic mitral valve disease [5]. Therefore, rheumatic mitral disease itself might increase the risk of embolism, regardless of cardiac rhythm. The aim of the present study was to evaluate development of AF and adverse events in rheumatic mitral valve disease patients with sinus rhythm.
Materials and methods
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the study: (a) patients who used anticoagulants (including warfarin) for LA thrombus or a history of prior thromboembolism (n = 154), and (b) those who underwent mitral valve replacement within 9 months of diagnosis (n = 125). Finally, 293 patients with rheumatic mitral valve disease and sinus rhythm were included and analyzed in this study. The patient’s demographic and clinical characteristics, laboratory test results and echocardiographic characteristics were reviewed. In addition, we collected dates of the first TTE, first visit, and last visit. Also, we reviewed the dates of the detection of new-onset AF, systemic embolic event, and all-cause death through medical records or from telephone interviews. We identified the RMS by the TTE characteristics of diastolic doming of the MV in the parasternal long-axis window, leaflet thickening, commissural fusion, chordal fusion or a combination of these characteristics [1, 3]. The MVA was calculated from diastolic pressure half-time or 2D planimetry and the MVA B 1.5 cm2 was defined as severe MS according to new guideline [3, 8]. We obtained MVA by 2D planimetry if patients had significant MR or significant aortic valvular disorder, which does not involve any cardiac chamber compliance, flow conditions, or associated valvular lesions. MVA by 2D planimetry was calculated by direct tracing of the mitral orifice on parasternal short-axis view at mid-diastole [3, 9]. The pressure half-time was obtained from the descending slope of the E-wave in apical windows. We calculated the MV mean pressure gradient as recommended, tracing the diastolic mitral flow contours from continuous-wave Doppler in the apical 4-chamber view or long-axis window [9]. Mitral regurgitation (MR) severity was estimated by several methods including proximal isovelocity surface area (PISA) method [PISA radius, regurgitation volume (mL/ beat), effective regurgitation orifice area (EROA) (cm2)], volumetric method [regurgitation fraction (%)], or size of vena contracta width [10]. The study was approved by the Institutional Review Boards of each hospital, and was conducted according to the Declaration of Helsinki. Written informed consent was exempted by the Institutional Review Boards.
Study design and study population Study outcomes Patients diagnosed with rheumatic mitral valve disease who were in sinus rhythm were screened retrospectively between March 2003 and June 2013 in the Seoul National University Bundang Hospital, Seoul National University Hospital, and SMG-SNU Boramae Medical Center. A total of 1019 patients who were more than 18 years of age with rheumatic mitral valve disease were identified regardless of severity. Firstly, of these, 447 patients with past or present AF were excluded. The following patients were also excluded from
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The primary outcome was the development of new-onset AF with annual event rates. For documenting the new-onset AF, all ECG or 24-h Holter monitoring data of patients during follow-up were reviewed by experienced investigators. We adjudicated the new-onset AF that AF was firstly detected by 12-lead ECG or 24-h Holter monitoring during routine check-up after the first TTE in sinus rhythm. The secondary outcomes defined as composite of development of new-onset
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AF, systemic embolism and all-cause death during followup. Systemic embolism included stroke and peripheral embolism. Stroke was defined as the abrupt onset of focal motor, sensory, cranial nerves, visual or speech deficit confirmed by examination by a neurologist and documented by computed tomographic (CT) brain scan or brain magnetic resonance imaging (MRI) [11, 12]. Peripheral embolism was defined as abrupt occlusion of an artery supplying the legs, arms or viscera documented by Doppler image, angiography or CT scan [11]. We also evaluated the predictor of the development of new-onset AF and all clinical events. Statistical analysis All categorical data were summarized as frequencies and percentages, whereas statistics for continuous variables were presented as means and standard deviations. The Pearson’s Chi square test was used for comparison of categorical variables and the Fisher’s exact test was used for comparison of categorical variables with 20 % or more of the expected cell frequencies below 5. The Student’s t test was used for comparison of continuous variables. Univariate followed by Multivariate Cox proportional-hazards regression analyses were performed to evaluate the risk of AF development with adjustment for individual risk factors. Variables that were identified as carrying predictive significance in univariate analysis were included in the regression model. LA dimension was analyzed as continuous variable and MVA was analyzed as dichotomous variable in univariate and multivariate models. We investigated the minimizing value of the Schwarz’s Bayesian criterion in Cox proportional-hazard model to find the proper cut-off value of LA dimension to predict AF development. Also, Kaplan–Meier survival analyses and log-rank tests were used to compare clinical event free-survival rate stratified by the LA dimension. Then, we checked for consistency of result according to cut-off value, LA dimension was analyzed as dichotomous variable in univariate Cox analysis. A P value of \0.05 was considered statistically significant. All analyses were performed with SPSS 18.0 (SPSS Inc., Chicago, IL).
Results Baseline characteristics A total of 293 patients with rheumatic mitral valve disease in sinus rhythm were included. Patient’s baseline characteristics are presented in Table 1. The mean follow-up period was 68.2 ± 36.6 months [median 72 months (1–134 months)]. The mean LA dimension was 46.3 ± 8.0 mm and proportion of severe MS was 32.1 % in all patients. The mean MV pressure gradient was 8.1 ± 5.7 mmHg.
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Development of clinical events Sixty patients (20.5 %) developed AF during the follow-up period with a 3.5 %/year average annual event rate (Table 2). Twenty-one patients (7.2 %) showed composite outcome of systemic embolism (n = 12) and all cause death (n = 9) during the follow-up period with an average annual event rate of 2.1 %. In patients who developed AF, death or systemic embolism occurred more than in patients who did not develop AF (18.3 % vs. 4.3 %, P \ 0.001) (Table 1). In addition, patients with enlarged LA (C47 mm) had an average annual AF development rate of 6.0 %/year, average annual composite of embolism and death rates of 2.4 %/year and average annual all clinical event rates of 6.6 %/year. Predictors of clinical events Table 1 shows the different clinical characteristics, laboratory test results and echocardiographic characteristics between the ‘AF development group’ and ‘no AF development group’. The patients in the AF development group were significantly older than those in no event group (62.2 ± 12.1 years vs. 56.4 ± 15.2 years; P = 0.002) and had significantly lower kidney function by glomerular filtration rate (GFR) (62.0 ± 20.3 mL/min vs. 73.9 ± 30.5 mL/min; P = 0.004). Also, they had larger LA dimension (51.7 ± 7.2 mm vs. 44.8 ± 7.9 mm, P \ 0.001) and had higher rates of severe MS with MVA smaller than 1.5 cm2 (43.3 % vs. 29.2 %, P = 0.036) than patients without new-onset AF. Moreover, embolic event occurred in AF development group with significant higher rates than no AF development group (11.7 % vs. 2.1 %, P = 0.001). However, trans-MV mean pressure gradient and MR grade were not significantly different between the two groups. In univariate analysis, age, lower cholesterol, larger LA dimension, and severe MS (MVA B 1.5 cm2) were associated with AF development (Table 3). In Cox-proportional hazard regression analysis, larger LA dimension [hazard ratio (HR) 1.06, 95 % confidence interval (CI): 1.02–1.10; P = 0.001] and severe MS (MVA B 1.5 cm2) [HR 1.97, 95 % CI: 1.06–4.14; P = 0.032] were independent predictors of AF development after adjustment of confounding factors. MV pressure gradient and MR grade were not associated with AF development. In addition, predictors of secondary outcomes were old age, larger LA dimension, lower kidney function, lower cholesterol and severe MS in univariate analysis (Table 4). Among these predictors, only larger LA dimension had increased risk of all events [HR 1.05, 95 % CI: 1.02–1.09; P = 0.003] in Cox-proportional hazard regression analysis. In Cox proportional-hazard model, LA dimension 47 mm was the best cut-off value predicting development of AF minimizing the Schwarz’s Bayesian criterion (Supplement Fig. 1). Figure 1 shows the cumulative AF development-free
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Table 1 Baseline characteristics All (n = 293)
AF development (n = 60)
No AF development (n = 233)
P value
Age (year)
57.6 ± 14.8
62.2 ± 12.1
56.4 ± 15.2
Male, n (%)
77 (26.3 %)
16 (26.7 %)
61 (26.2 %)
0.002 0.939
BMI (Kg/m2)
23.4 ± 3.7
22.7 ± 3.0
23.6 ± 3.9
0.116
Echocardiography finding LVEDD (mm)
49.9 ± 5.9
50.5 ± 6.0
49.8 ± 5.8
0.390
LVESD (mm)
31.3 ± 5.3
31.2 ± 6.1
31.4 ± 5.1
0.796 \0.001
LA dimension (mm)
46.3 ± 8.0
51.7 ± 7.2
44.8 ± 7.9
E wave velocity (m/s)
1.4 ± 2.4
2.0 ± 4.1
1.3 ± 1.8
0.360
A wave velocity (m/s)
1.4 ± 1.5
1.4 ± 0.9
1.4 ± 1.6
0.772
LV EF (%)
61.8 ± 7.9
61.9 ± 7.7
61.8 ± 8.0
0.969
MVA (cm2) MVA B 1.5 cm2, n (%)
1.4 ± 0.5 94 (32.1 %)
1.4 ± 0.4 26 (43.3 %)
1.5 ± 0.5 68 (29.2 %)
0.161 0.036
MV mean PG (mmHg)
8.1 ± 5.7
8.0 ± 5.4
8.1 ± 5.8
0.911
RVSP (mmHg)
38.1 ± 14.2
41.6 ± 11.8
37.2 ± 14.7
0.053
No or mild MR
199 (67.9 %)
38 (63.3 %)
161 (69.1 %)
Moderate to severe
94 (32.1 %)
22 (36.7 %)
72 (30.9 %)
No or mild AS
270 (92.5 %)
53 (88.3 %)
217 (93.5 %)
Moderate to severe
22 (7.5 %)
7 (11.7 %)
15 (6.5 %)
No or mild AR
238 (81.2 %)
50 (83.3 %)
188 (80.7 %)
Moderate to severe
55 (18.8 %)
10 (16.7 %)
45 (19.3 %)
6588 ± 2380
7015 ± 2341
6472 ± 2383
MR grade
0.394
AS grade
0.174
AR grade
0.640
Laboratory finding WBC (/lL)
0.141
Hemoglobin (g/dL)
13.1 ± 1.9
12.8 ± 1.9
13.2 ± 1.9
0.217
Glucose (mg/dL) GFR (mL/min)
105.8 ± 37.3 70.7 ± 28.6
110.3 ± 39.1 62.0 ± 20.3
104.7 ± 36.8 73.9 ± 30.5
0.337 0.004
Cholesterol (mg/dL)
179.0 ± 41.0
168.5 ± 35.5
181.7 ± 41.9
0.035
Hemoglobin A1C (%)
6.1 ± 1.0
6.6 ± 1.1
5.9 ± 1.0
0.699
Clinical event during follow-up, n (%) Embolic event
12 (4.1 %)
7 (11.7 %)
5 (2.1 %)
0.001
Death
9 (3.4 %)
4 (7.1 %)
5 (2.4 %)
0.099
Embolic event or death
21 (7.2 %)
11 (18.3 %)
10 (4.3 %)
\0.001
AF atrial fibrillation, AS aortic stenosis, AR aortic regurgitation, BMI body mass index, GFR glomerular filtration rate, LA left atrium, LVEDD left ventricle end-diastolic dimension, LVEF left ventricle ejection fraction, LVESD left ventricle end-systolic dimension, MR mitral regurgitation, MV mitral valve, MVA mitral valve area, PG pressure gradient, RVSP right ventricle systolic pressure
survival rates and cumulative clinical event-free survival rates of the two groups. The two groups were stratified by LA dimension of 47 mm. The log-rank test of the survival curves produced a value of P \ 0.001 for differences between the two patient groups. LA dimension C47 mm was a significantly higher predictor for AF development [HR 5.85, 95 % CI: 3.15–10.86; P \ 0.001] (Fig. 1a) and all events [HR 5.04, 95 % CI: 2.90–8.77; P \ 0.001] (Fig. 1b). Additionally, larger LA dimension (C47 mm) had borderline significance for prediction of systemic embolism and/or death [HR 2.45 (95 % CI 0.98–6.15; P = 0.057) in univariate cox regression
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analysis although the data was not shown on the table. After adjusting confounding factors of age, MVA, and GFR, LA dimension was no longer prognosticator. Only age was independent predictor for prediction of systemic embolism and/or death.
Discussion Systemic embolism and AF are important complications of RMS patients in sinus rhythm. Our findings in this study
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Table 2 Cumulative annual event rates of clinical outcome Follow-up (year)
All group AF development (%)
LA dimension C47 All cause death, embolic event (%)
All cause death, embolic event or AF development (%)
AF development (%)
All cause death, embolic event (%)
All cause death, embolic event or AF development (%)
1
2.8
1.4
4.1
5.1
2.1
6.4
2
6.3
1.7
7.6
10.9
2.9
12.9
3
9.3
2.2
11.0
16.6
2.9
18.5
4
12.2
2.2
13.8
23.0
2.9
24.7
5
15.9
3.2
16.9
27.9
5.3
29.5
6
19.5
5.0
21.0
35.8
7.9
37.2
7
25.2
7.2
27.4
47.1
11.4
48.3
8
28.7
8.2
31.7
53.0
13.8
56.3
9
32.5
9.6
38.6
60.0
17.1
65.7
10
34.5
21.2
43.5
60.0
24.0
65.7
3.5
2.1
4.4
6.0
2.4
6.6
Mean annual event rate (%)
AF atrial fibrillation, LA left atrium
Table 3 Univariate and multivariate analysis of AF development
GFR glomerular filtration rate, LAD left atrium dimension, MR mitral regurgitation, MVA mitral valve area
Univariate HR
P value
95 % CI
Age
1.02
0.049
1.00–1.04
Sex (male)
1.07
0.819
0.60–1.90
GFR (mL/min)
0.99
0.091
0.98–1.00
Cholesterol (mg/dL)
0.99
0.024
0.99–0.99
LAD (mm)
1.08 \0.001
1.06–1.11
1.06
0.001
1.02–1.10
MVA B 1.5 cm2
2.01
0.009
1.19–3.37
1.97
0.032
1.06–4.14
No or mild MR versus moderate or severe MR
0.90
0.695
0.53–1.53
Table 4 Univariate and multivariate analysis of systemic embolic event, death or development of AF
AF atrial fibrillation, GFR glomerular filtration rate, LAD left atrium dimension, MR mitral regurgitation, MVA mitral valve area
Multivariate
Univariate
P value
95 % CI
Multivariate
HR
P value
95 % CI
Age
1.02
0.007
1.01–1.04
Sex (male)
1.16
0.585
0.68–1.97
GFR (mL/min)
0.99
0.019
0.98–0.99
Cholesterol (mg/dL)
0.99
0.006
0.99–0.99
LAD (mm)
1.08 \0.001
1.05–1.10
MVA B 1.5 cm2
1.69
0.037
1.03–2.77
No or mild MR versus moderate or severe MR
0.94
0.811
0.57–1.56
indicate that new-onset AF developed frequently with annual rate of 3.5 % in patient with RMS. Larger LA dimension and MVA B 1.5 cm2 were good predictors for detecting new-onset AF. In addition, our findings document that larger LA dimension significantly increases the risk of a composite of all events including systemic
HR
HR
P value
95 % CI
1.05
0.003
1.02–1.09
embolism, death and the development of AF, regardless of MVA, MV pressure gradient and MR. Especially, LA dimension C47 mm was good prognostic factor of a composite of AF development, all-cause death and systemic embolism as well as new-onset AF in RMS patients with sinus rhythm.
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Fig. 1 Event free-survival curves by Kaplan–Meier method. a AF development free survival curve. The cumulative AF developmentfree survival rates of two groups were stratified by LA dimension 47 mm. Patients with LA dimension above 47 mm had a significantly higher rate of AF development. b Systemic embolic event, all cause death and AF development-free survival curve. Patients with LA dimension above 47 mm had significantly higher rates of clinical events. *Event including all-cause death, systemic embolic event or development of AF
About 40–50 % of patients with rheumatic valvular disease developed AF during the course of the disease, and old age and LA diameter were the most important predictors of AF development in patients with rheumatic valvular disease by multivariate analysis [7, 13]. Consistent with previous studies, the present study showed a high incidence
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of newly-developed AF (20.5 % of patients) and the average annual AF development rate was 3.5 %/year during the follow-up period. In addition, larger LA dimension and severe MS were the predictors of newly detected AF during follow-up period in our study. Whether the dilated LA is a cause or a result of AF is still controversial. However, based on our results, we proposed that chronic pressure overload on LA according to degree of MS might be a causative factor of AF. Moreover, systemic embolism is a frequent complication of MS and it has been recognized that about 20 % of patients with RMS suffer a systemic embolism during the course of the disease [14]. Although the incidence of systemic embolism increased in MS with AF rhythm, systemic embolism has also been observed in patients with MS in sinus rhythm, but at lower rates [15]. The previous study showed that about 10 % of patients with MS in sinus rhythm developed systemic embolism [5, 6]. The lower incidence of embolic events in our study, compared to other studies, might be attributable to the different study periods and the strict definition of systemic embolism by image modality. In all, 4.1 % of patients with RMS in sinus rhythm developed systemic embolism including stroke and peripheral embolism during 10 years of follow-up. Several studies have attempted to find the mechanism of thromboembolism development in patients with RMS in sinus rhythm. Thromboembolic events probably occurred in patients with RMS in sinus rhythm because more patients with MS in sinus rhythm had LA appendage contractile dysfunction compared with normal subjects [16, 17]. Decreased global fibrinolytic capacity (GFC) in RMS patients with sinus rhythm could also increase the risk of systemic embolism and thrombus formation. The GFC in RMS patients with sinus rhythm was decreased to the similar levels of GFC of patients with chronic AF [18]. Other study suggested that elevated mean platelet volume in patients with RMS compared with normal subjects could be a possible mechanism of thromboembolism [19]. For patients with RMS in sinus rhythm, therefore, we need regular clinical and ECG follow-up though there is no guidelines regarding electrocardiography (ECG) follow-up. Although systemic embolic events and LA thrombus formation have usually been seen in MS patients with AF, thromboembolisms have often also been seen in previous studies in patients with MS with sinus rhythm [5, 6]. The authors have suggested that older age, enlarged LA, mean elevated MV pressure gradient ([18 mmHg) and dense spontaneous echo contrast were factors that increased the risk of systemic thromboembolism in MS patients with sinus rhythm or AF rhythm [6, 20]. However, these predictors of systemic embolism in MS in previous studies were suggested by univariate analysis. Consistent with these previous studies, new systemic embolism had
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occurred in 11.7 % of RMS patients who developed newonset AF during follow-up compared to in 2.1 % of RMS patients with consistent sinus rhythm in our study. Moreover, LA dimension larger than 47 mm was the best cut-off value predicting all events including systemic embolism, death, and the development of AF. It is worth noting that the 47 mm cut-off value of LA dimension is lower than the 50 mm value reported in current guidelines. Also, renal impairment could induce both hypo- and hypercoagulability [21] and renal impairment (GFR \ 60 mL/min) had twofold higher risk of stroke in patients with AF although on anticoagulation therapy [22]. The results of the present study corresponds with earlier studies that show a lower level of GFR was associated with the risk of systemic embolism and all-cause death in univariate analysis. In addition, it has been known that absence of moderate or severe MR was an independent predictor of systemic embolism in patients with rheumatic mitral valve disease [20]. Wanishsawad et al. [23] showed that none of the patients with predominant rheumatic MR in sinus rhythm had developed LA thrombus, whereas 14.3 % of patients with predominant rheumatic MS had developed LA thrombus. They suggested that significant MR had a protective role for LA thrombus formation in rheumatic mitral valve disease with sinus rhythm, especially in MVA [1 cm2. However, MVA and MR grade were not associated with clinical events including a composite of systemic embolism, all cause death, and AF development in our study. We speculate that the lower event rate rather than the lack of impact of MR on the risk of embolism seems to be reason why MR was not related to the incidence of embolism. A previous study also showed no significant difference of MVA between RMS patients with embolic events and without events [24]. Prophylactic anticoagulant treatment was not established in patients with RMS in sinus rhythm [1, 4]. However, high risk RMS patients with enlarged LA dimensions should be followed more closely for early detection of AF development and clinical events including embolism.
Limitations The main limitation of this study was its design as a retrospective observational study. A limitation is that we might have missed out on the presence or development of AF in patients with asymptomatic paroxysmal AF. Also, we could not get the data about all medical history such as hypertension or diabetes mellitus. Next, we measured only the antero-posterior (AP) diameter for the LA dimension. The AP dimension may not be an accurate representation of LA size than LA volume measurement [25]. We cannot rule out the possibility of generating different results if we
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measured LA volume. Third, we analyzed a relatively small sample size. About 45 % of patients with rheumatic mitral valve disease have already had AF. However, we followed up patients for long periods (median 72 months), which might overcome the limitations of a small sample size to some degree.
Conclusion In patients with RMS in sinus rhythm, annual AF development rate was 3.5 %/year and increased according to LA size and MS severity. Because of very high risk embolism, RMS with enlarged LA dimension need focused follow up for early detection of AF development and clinical events. We need prospective study to determine whether anticoagulation therapy would be beneficial in patients with RMS in sinus rhythm with large LA size or severe MS. Conflict of interest
None declared.
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Int J Cardiovasc Imaging (2015) 31:735–742 mitral stenosis and sinus rhythm: a transesophageal echocardiographic study. Echocardiography 28(4):457–460 Diker E, Aydogdu S, Ozdemir M, Kural T, Polat K, Cehreli S, Erdogan A, Goksel S (1996) Prevalence and predictors of atrial fibrillation in rheumatic valvular heart disease. Am J Cardiol 77(1):96–98 Wunderlich NC, Beigel R, Siegel RJ (2013) Management of mitral stenosis using 2D and 3D echo-Doppler imaging. J Am Coll Cardiol Imaging 6(11):1191–1205 Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP, Iung B, Otto CM, Pellikka PA, Quinones M (2009) Echocardiographic assessment of valve stenosis: eAE/ASE recommendations for clinical practice. Eur J Echocardiogr 10(1):1–25 Chiampan A, Nahum J, Leye M, Oziel J, Cueff C, Brochet E, Iung B, Rossi A, Vahanian A, Messika-Zeitoun D (2012) Determinants of regurgitant volume in mitral regurgitation: contrasting effect of similar effective regurgitant orifice area in functional and organic mitral regurgitation. Eur Heart J Cardiovasc Imaging 13(4):324–329 Stoddard MF, Dawkins PR, Prince CR, Ammash NM (1995) Left atrial appendage thrombus is not uncommon in patients with acute atrial fibrillation and a recent embolic event: a transesophageal echocardiographic study. J Am Coll Cardiol 25(2):452–459 Bakshi R (2000) Diffusion-weighted MRI as an evolving standard of care in acute stroke. Neurology 55(10):1595 Selcuk MT, Selcuk H, Maden O, Temizhan A, Aksu T, Dogan M, Sasmaz A (2007) Relationship between inflammation and atrial fibrillation in patients with isolated rheumatic mitral stenosis. J Heart Valve Dis 16(5):468–474 Perez-Gomez F, Salvador A, Zumalde J, Iriarte JA, Berjon J, Alegria E, Almeria C, Bover R, Herrera D, Fernandez C (2006) Effect of antithrombotic therapy in patients with mitral stenosis and atrial fibrillation: a sub-analysis of NASPEAF randomized trial. Eur Heart J 27(8):960–967 Coulshed N, Epstein EJ, McKendrick CS, Galloway RW, Walker E (1970) Systemic embolism in mitral valve disease. Br Heart J 32(1):26–34 Golbasi Z, Cicek D, Canbay A, Ucar O, Bayol H, Aydogdu S (2002) Left atrial appendage function in patients with mitral stenosis in sinus rhythm. Eur J Echocardiogr 3(1):39–43
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17. Li YH, Hwang JJ, Lin JL, Tseng YZ, Lien WP (1996) Importance of left atrial appendage function as a risk factor for systemic thromboembolism in patients with rheumatic mitral valve disease. Am J Cardiol 78(7):844–847 18. Atalar E, Ozmen F, Haznedaroglu I, Ozer N, Aksoyek S, Ovunc K, Nazli N, Kirazli S, Kes S (2002) Impaired fibrinolytic capacity in rheumatic mitral stenosis with or without atrial fibrillation and nonrheumatic atrial fibrillation. Int J Hematol 76(2):192–195 19. Yavuz B, Ertugrul DT, Yalcin AA, Kucukazman M, Ata N, Dal K (2009) Increased mean platelet volume in rheumatic mitral stenosis: a possible factor for thromboembolic events. J Cardiol 53(2):204–207 20. Kaymaz C, Ozdemir N, Erentug V, Sismanoglu M, Yakut C, Ozkan M (2003) Location, size, and morphologic characteristics of left atrial thrombi as assessed by transesophageal echocardiography in relation to systemic embolism in patients with rheumatic mitral valve disease. Am J Cardiol 91(6):765–769 21. Falga´ C, Capdevila JA, Soler S, Rabun˜al R, Sa´nchez Mun˜ozTorrero JF, Gallego P, Monreal M, Investigators R (2007) Clinical outcome of patients with venous thromboembolism and renal insufficiency. Findings from the RIETE registry. Thromb Haemost 98(4):771–776 22. Apostolakis S, Guo Y, Lane DA, Buller H, Lip GY (2013) Renal function and outcomes in anticoagulated patients with nonvalvular atrial fibrillation: the AMADEUS trial. Eur Heart J 34(46):3572–3579 23. Wanishsawad C, Weathers LB, Puavilai W (1995) Mitral regurgitation and left atrial thrombus in rheumatic mitral valve disease. A clinicopathologic study. Chest 108(3):677–681 24. Nunes MC, Handschumacher MD, Levine RA, Barbosa MM, Carvalho VT, Esteves WA, Zeng X, Guerrero JL, Zheng H, Tan TC, Hung J (2014) Role of LA shape in predicting embolic cerebrovascular events in mitral stenosis: mechanistic insights from 3D echocardiography. J Am Coll Cardiol Imaging 7(5):453– 461 25. Keenan NG, Cueff C, Cimadevilla C, Brochet E, Lepage L, Detaint D, Himbert D, Iung B, Vahanian A, Messika-Zeitoun D (2010) Usefulness of left atrial volume versus diameter to assess thromboembolic risk in mitral stenosis. Am J Cardiol 106(8): 1152–1156
ORIGINAL PAPER
Development of atrial fibrillation in patients with rheumatic mitral valve disease in sinus rhythm Hyun-Jin Kim • Goo-Yeong Cho • Yong-Jin Kim • Hyung-Kwan Kim • Seung-Pyo Lee • Hack-Lyoung Kim • Jin Joo Park • Yeonyee E. Yoon • Joo-Hee Zo • Dae-Won Sohn
Received: 27 November 2014 / Accepted: 4 February 2015 / Published online: 10 February 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract This study evaluated the predictors of atrial fibrillation (AF) and adverse clinical events in patients with rheumatic mitral stenosis (RMS) in sinus rhythm. The patients who diagnosed with RMS in sinus rhythm were evaluated retrospectively between March 2003 and June 2013. The primary outcome was the development of newonset AF with annual event rates and the secondary outcome was the incidence of clinical events including development of new-onset AF, systemic embolism and allcause death during follow-up. Among 293 patients, AF developed in 60 (20.5 %) patients with average annual event rate of 3.5 %/year during mean follow-up period of 68.2 ± 36.6 months (median 72 months). All cause death or systemic embolism occurred in 7.2 % (21 patients; all
cause death 9, embolism 12) with an average annual event rate of 2.1 %. In the multivariate analysis, large left atrium (LA) dimension and severe mitral stenosis (B1.5 cm2) were independent predictors of AF development [HR 1.06, 95 % CI: 1.02–1.10; P = 0.001, HR 1.97, 95 % CI: 1.06–4.14; P = 0.032] after adjustment for confounding factors. Patients with enlarged LA (C47 mm) had an average annual AF development rate of 6.0 %/year. In patients with RMS in sinus rhythm, annual AF development rate was 3.5 %/year and increased according to LA size and mitral stenosis (MS) severity. Because of very high risk embolism, RMS with enlarged LA dimension need focused follow up for early detection of AF development and clinical events. Keywords Mitral valve stenosis Sinus rhythm Embolism Atrial fibrillation
Electronic supplementary material The online version of this article (doi:10.1007/s10554-015-0613-2) contains supplementary material, which is available to authorized users. H.-J. Kim G.-Y. Cho Y.-J. Kim H.-K. Kim S.-P. Lee H.-L. Kim J. J. Park Y. E. Yoon J.-H. Zo D.-W. Sohn Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea H.-J. Kim Y.-J. Kim H.-K. Kim S.-P. Lee D.-W. Sohn Cardiovascular Center, Seoul National University Hospital, Seoul, South Korea G.-Y. Cho (&) J. J. Park Y. E. Yoon Cardiovascular Center, Seoul National University Bundang Hospital, 82 Gumi-ro-173-gil, Bundang, Seongnam, Gyeonggi 463-707, South Korea e-mail: [email protected] H.-L. Kim J.-H. Zo Cardiovascular Center, Seoul National University Boramae Medical Center, Seoul, South Korea
Abbreviations AF Atrial fibrillation CI Confidence interval CT Computed tomographic ECG Electrocardiography EROA Effective regurgitation orifice area GFC Global fibrinolytic capacity GFR Glomerular filtration rate HR Hazard ratio LA Left atrium MR Mitral regurgitation MRI Magnetic resonance imaging MS Mitral stenosis MVA Mitral valve area PISA Proximal isovelocity surface area RMS Rheumatic mitral stenosis TTE Transthoracic echocardiography
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Introduction Atrial fibrillation (AF) develops in half of those patients with rheumatic mitral stenosis (RMS) [1]. Nevertheless, there has been a lack of clarity regarding the medical treatment of mitral stenosis (MS) in sinus rhythm [2]. The current guidelines do not recommend anticoagulation unless there is concomitant AF or prior embolic events, or if there is left atrium (LA) thrombus. Meanwhile in these guidelines, anticoagulation should be considered when echocardiography show dense spontaneous echo contrast or LA enlargement in sinus rhythm [3, 4]. Furthermore, there have been no guidelines regarding electrocardiography (ECG) follow-up in patients with RMS in sinus rhythm. In addition, there have been few reports as to whether anticoagulation therapy could reduce the systemic embolic rate or what percentage of patents developed AF amongst RMS patients with sinus rhythm [1]. However, systemic embolism might be an important complication of rheumatic mitral valve disease even though patients are in sinus rhythm. Chiang et al. [5] showed the occurrence of new systemic embolism during follow-up in patients with MS as being significant, with 11.9 % of patients with MS in AF developing systemic embolism, and 9.1 % with MS in sinus rhythm developing a systemic embolism. Manjunath et al. [6] showed that, in 848 patients with RMS and sinus rhythm who underwent transthoracic echocardiography (TTE), there was a 6.6 % incidence of LA thrombus. Though the risk of an embolic event increases primarily because of the high frequency of AF in patients with rheumatic mitral valve disease [7], several other factors have been correlated with systemic embolic events in rheumatic mitral valve disease [5]. Therefore, rheumatic mitral disease itself might increase the risk of embolism, regardless of cardiac rhythm. The aim of the present study was to evaluate development of AF and adverse events in rheumatic mitral valve disease patients with sinus rhythm.
Materials and methods
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the study: (a) patients who used anticoagulants (including warfarin) for LA thrombus or a history of prior thromboembolism (n = 154), and (b) those who underwent mitral valve replacement within 9 months of diagnosis (n = 125). Finally, 293 patients with rheumatic mitral valve disease and sinus rhythm were included and analyzed in this study. The patient’s demographic and clinical characteristics, laboratory test results and echocardiographic characteristics were reviewed. In addition, we collected dates of the first TTE, first visit, and last visit. Also, we reviewed the dates of the detection of new-onset AF, systemic embolic event, and all-cause death through medical records or from telephone interviews. We identified the RMS by the TTE characteristics of diastolic doming of the MV in the parasternal long-axis window, leaflet thickening, commissural fusion, chordal fusion or a combination of these characteristics [1, 3]. The MVA was calculated from diastolic pressure half-time or 2D planimetry and the MVA B 1.5 cm2 was defined as severe MS according to new guideline [3, 8]. We obtained MVA by 2D planimetry if patients had significant MR or significant aortic valvular disorder, which does not involve any cardiac chamber compliance, flow conditions, or associated valvular lesions. MVA by 2D planimetry was calculated by direct tracing of the mitral orifice on parasternal short-axis view at mid-diastole [3, 9]. The pressure half-time was obtained from the descending slope of the E-wave in apical windows. We calculated the MV mean pressure gradient as recommended, tracing the diastolic mitral flow contours from continuous-wave Doppler in the apical 4-chamber view or long-axis window [9]. Mitral regurgitation (MR) severity was estimated by several methods including proximal isovelocity surface area (PISA) method [PISA radius, regurgitation volume (mL/ beat), effective regurgitation orifice area (EROA) (cm2)], volumetric method [regurgitation fraction (%)], or size of vena contracta width [10]. The study was approved by the Institutional Review Boards of each hospital, and was conducted according to the Declaration of Helsinki. Written informed consent was exempted by the Institutional Review Boards.
Study design and study population Study outcomes Patients diagnosed with rheumatic mitral valve disease who were in sinus rhythm were screened retrospectively between March 2003 and June 2013 in the Seoul National University Bundang Hospital, Seoul National University Hospital, and SMG-SNU Boramae Medical Center. A total of 1019 patients who were more than 18 years of age with rheumatic mitral valve disease were identified regardless of severity. Firstly, of these, 447 patients with past or present AF were excluded. The following patients were also excluded from
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The primary outcome was the development of new-onset AF with annual event rates. For documenting the new-onset AF, all ECG or 24-h Holter monitoring data of patients during follow-up were reviewed by experienced investigators. We adjudicated the new-onset AF that AF was firstly detected by 12-lead ECG or 24-h Holter monitoring during routine check-up after the first TTE in sinus rhythm. The secondary outcomes defined as composite of development of new-onset
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AF, systemic embolism and all-cause death during followup. Systemic embolism included stroke and peripheral embolism. Stroke was defined as the abrupt onset of focal motor, sensory, cranial nerves, visual or speech deficit confirmed by examination by a neurologist and documented by computed tomographic (CT) brain scan or brain magnetic resonance imaging (MRI) [11, 12]. Peripheral embolism was defined as abrupt occlusion of an artery supplying the legs, arms or viscera documented by Doppler image, angiography or CT scan [11]. We also evaluated the predictor of the development of new-onset AF and all clinical events. Statistical analysis All categorical data were summarized as frequencies and percentages, whereas statistics for continuous variables were presented as means and standard deviations. The Pearson’s Chi square test was used for comparison of categorical variables and the Fisher’s exact test was used for comparison of categorical variables with 20 % or more of the expected cell frequencies below 5. The Student’s t test was used for comparison of continuous variables. Univariate followed by Multivariate Cox proportional-hazards regression analyses were performed to evaluate the risk of AF development with adjustment for individual risk factors. Variables that were identified as carrying predictive significance in univariate analysis were included in the regression model. LA dimension was analyzed as continuous variable and MVA was analyzed as dichotomous variable in univariate and multivariate models. We investigated the minimizing value of the Schwarz’s Bayesian criterion in Cox proportional-hazard model to find the proper cut-off value of LA dimension to predict AF development. Also, Kaplan–Meier survival analyses and log-rank tests were used to compare clinical event free-survival rate stratified by the LA dimension. Then, we checked for consistency of result according to cut-off value, LA dimension was analyzed as dichotomous variable in univariate Cox analysis. A P value of \0.05 was considered statistically significant. All analyses were performed with SPSS 18.0 (SPSS Inc., Chicago, IL).
Results Baseline characteristics A total of 293 patients with rheumatic mitral valve disease in sinus rhythm were included. Patient’s baseline characteristics are presented in Table 1. The mean follow-up period was 68.2 ± 36.6 months [median 72 months (1–134 months)]. The mean LA dimension was 46.3 ± 8.0 mm and proportion of severe MS was 32.1 % in all patients. The mean MV pressure gradient was 8.1 ± 5.7 mmHg.
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Development of clinical events Sixty patients (20.5 %) developed AF during the follow-up period with a 3.5 %/year average annual event rate (Table 2). Twenty-one patients (7.2 %) showed composite outcome of systemic embolism (n = 12) and all cause death (n = 9) during the follow-up period with an average annual event rate of 2.1 %. In patients who developed AF, death or systemic embolism occurred more than in patients who did not develop AF (18.3 % vs. 4.3 %, P \ 0.001) (Table 1). In addition, patients with enlarged LA (C47 mm) had an average annual AF development rate of 6.0 %/year, average annual composite of embolism and death rates of 2.4 %/year and average annual all clinical event rates of 6.6 %/year. Predictors of clinical events Table 1 shows the different clinical characteristics, laboratory test results and echocardiographic characteristics between the ‘AF development group’ and ‘no AF development group’. The patients in the AF development group were significantly older than those in no event group (62.2 ± 12.1 years vs. 56.4 ± 15.2 years; P = 0.002) and had significantly lower kidney function by glomerular filtration rate (GFR) (62.0 ± 20.3 mL/min vs. 73.9 ± 30.5 mL/min; P = 0.004). Also, they had larger LA dimension (51.7 ± 7.2 mm vs. 44.8 ± 7.9 mm, P \ 0.001) and had higher rates of severe MS with MVA smaller than 1.5 cm2 (43.3 % vs. 29.2 %, P = 0.036) than patients without new-onset AF. Moreover, embolic event occurred in AF development group with significant higher rates than no AF development group (11.7 % vs. 2.1 %, P = 0.001). However, trans-MV mean pressure gradient and MR grade were not significantly different between the two groups. In univariate analysis, age, lower cholesterol, larger LA dimension, and severe MS (MVA B 1.5 cm2) were associated with AF development (Table 3). In Cox-proportional hazard regression analysis, larger LA dimension [hazard ratio (HR) 1.06, 95 % confidence interval (CI): 1.02–1.10; P = 0.001] and severe MS (MVA B 1.5 cm2) [HR 1.97, 95 % CI: 1.06–4.14; P = 0.032] were independent predictors of AF development after adjustment of confounding factors. MV pressure gradient and MR grade were not associated with AF development. In addition, predictors of secondary outcomes were old age, larger LA dimension, lower kidney function, lower cholesterol and severe MS in univariate analysis (Table 4). Among these predictors, only larger LA dimension had increased risk of all events [HR 1.05, 95 % CI: 1.02–1.09; P = 0.003] in Cox-proportional hazard regression analysis. In Cox proportional-hazard model, LA dimension 47 mm was the best cut-off value predicting development of AF minimizing the Schwarz’s Bayesian criterion (Supplement Fig. 1). Figure 1 shows the cumulative AF development-free
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Table 1 Baseline characteristics All (n = 293)
AF development (n = 60)
No AF development (n = 233)
P value
Age (year)
57.6 ± 14.8
62.2 ± 12.1
56.4 ± 15.2
Male, n (%)
77 (26.3 %)
16 (26.7 %)
61 (26.2 %)
0.002 0.939
BMI (Kg/m2)
23.4 ± 3.7
22.7 ± 3.0
23.6 ± 3.9
0.116
Echocardiography finding LVEDD (mm)
49.9 ± 5.9
50.5 ± 6.0
49.8 ± 5.8
0.390
LVESD (mm)
31.3 ± 5.3
31.2 ± 6.1
31.4 ± 5.1
0.796 \0.001
LA dimension (mm)
46.3 ± 8.0
51.7 ± 7.2
44.8 ± 7.9
E wave velocity (m/s)
1.4 ± 2.4
2.0 ± 4.1
1.3 ± 1.8
0.360
A wave velocity (m/s)
1.4 ± 1.5
1.4 ± 0.9
1.4 ± 1.6
0.772
LV EF (%)
61.8 ± 7.9
61.9 ± 7.7
61.8 ± 8.0
0.969
MVA (cm2) MVA B 1.5 cm2, n (%)
1.4 ± 0.5 94 (32.1 %)
1.4 ± 0.4 26 (43.3 %)
1.5 ± 0.5 68 (29.2 %)
0.161 0.036
MV mean PG (mmHg)
8.1 ± 5.7
8.0 ± 5.4
8.1 ± 5.8
0.911
RVSP (mmHg)
38.1 ± 14.2
41.6 ± 11.8
37.2 ± 14.7
0.053
No or mild MR
199 (67.9 %)
38 (63.3 %)
161 (69.1 %)
Moderate to severe
94 (32.1 %)
22 (36.7 %)
72 (30.9 %)
No or mild AS
270 (92.5 %)
53 (88.3 %)
217 (93.5 %)
Moderate to severe
22 (7.5 %)
7 (11.7 %)
15 (6.5 %)
No or mild AR
238 (81.2 %)
50 (83.3 %)
188 (80.7 %)
Moderate to severe
55 (18.8 %)
10 (16.7 %)
45 (19.3 %)
6588 ± 2380
7015 ± 2341
6472 ± 2383
MR grade
0.394
AS grade
0.174
AR grade
0.640
Laboratory finding WBC (/lL)
0.141
Hemoglobin (g/dL)
13.1 ± 1.9
12.8 ± 1.9
13.2 ± 1.9
0.217
Glucose (mg/dL) GFR (mL/min)
105.8 ± 37.3 70.7 ± 28.6
110.3 ± 39.1 62.0 ± 20.3
104.7 ± 36.8 73.9 ± 30.5
0.337 0.004
Cholesterol (mg/dL)
179.0 ± 41.0
168.5 ± 35.5
181.7 ± 41.9
0.035
Hemoglobin A1C (%)
6.1 ± 1.0
6.6 ± 1.1
5.9 ± 1.0
0.699
Clinical event during follow-up, n (%) Embolic event
12 (4.1 %)
7 (11.7 %)
5 (2.1 %)
0.001
Death
9 (3.4 %)
4 (7.1 %)
5 (2.4 %)
0.099
Embolic event or death
21 (7.2 %)
11 (18.3 %)
10 (4.3 %)
\0.001
AF atrial fibrillation, AS aortic stenosis, AR aortic regurgitation, BMI body mass index, GFR glomerular filtration rate, LA left atrium, LVEDD left ventricle end-diastolic dimension, LVEF left ventricle ejection fraction, LVESD left ventricle end-systolic dimension, MR mitral regurgitation, MV mitral valve, MVA mitral valve area, PG pressure gradient, RVSP right ventricle systolic pressure
survival rates and cumulative clinical event-free survival rates of the two groups. The two groups were stratified by LA dimension of 47 mm. The log-rank test of the survival curves produced a value of P \ 0.001 for differences between the two patient groups. LA dimension C47 mm was a significantly higher predictor for AF development [HR 5.85, 95 % CI: 3.15–10.86; P \ 0.001] (Fig. 1a) and all events [HR 5.04, 95 % CI: 2.90–8.77; P \ 0.001] (Fig. 1b). Additionally, larger LA dimension (C47 mm) had borderline significance for prediction of systemic embolism and/or death [HR 2.45 (95 % CI 0.98–6.15; P = 0.057) in univariate cox regression
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analysis although the data was not shown on the table. After adjusting confounding factors of age, MVA, and GFR, LA dimension was no longer prognosticator. Only age was independent predictor for prediction of systemic embolism and/or death.
Discussion Systemic embolism and AF are important complications of RMS patients in sinus rhythm. Our findings in this study
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Table 2 Cumulative annual event rates of clinical outcome Follow-up (year)
All group AF development (%)
LA dimension C47 All cause death, embolic event (%)
All cause death, embolic event or AF development (%)
AF development (%)
All cause death, embolic event (%)
All cause death, embolic event or AF development (%)
1
2.8
1.4
4.1
5.1
2.1
6.4
2
6.3
1.7
7.6
10.9
2.9
12.9
3
9.3
2.2
11.0
16.6
2.9
18.5
4
12.2
2.2
13.8
23.0
2.9
24.7
5
15.9
3.2
16.9
27.9
5.3
29.5
6
19.5
5.0
21.0
35.8
7.9
37.2
7
25.2
7.2
27.4
47.1
11.4
48.3
8
28.7
8.2
31.7
53.0
13.8
56.3
9
32.5
9.6
38.6
60.0
17.1
65.7
10
34.5
21.2
43.5
60.0
24.0
65.7
3.5
2.1
4.4
6.0
2.4
6.6
Mean annual event rate (%)
AF atrial fibrillation, LA left atrium
Table 3 Univariate and multivariate analysis of AF development
GFR glomerular filtration rate, LAD left atrium dimension, MR mitral regurgitation, MVA mitral valve area
Univariate HR
P value
95 % CI
Age
1.02
0.049
1.00–1.04
Sex (male)
1.07
0.819
0.60–1.90
GFR (mL/min)
0.99
0.091
0.98–1.00
Cholesterol (mg/dL)
0.99
0.024
0.99–0.99
LAD (mm)
1.08 \0.001
1.06–1.11
1.06
0.001
1.02–1.10
MVA B 1.5 cm2
2.01
0.009
1.19–3.37
1.97
0.032
1.06–4.14
No or mild MR versus moderate or severe MR
0.90
0.695
0.53–1.53
Table 4 Univariate and multivariate analysis of systemic embolic event, death or development of AF
AF atrial fibrillation, GFR glomerular filtration rate, LAD left atrium dimension, MR mitral regurgitation, MVA mitral valve area
Multivariate
Univariate
P value
95 % CI
Multivariate
HR
P value
95 % CI
Age
1.02
0.007
1.01–1.04
Sex (male)
1.16
0.585
0.68–1.97
GFR (mL/min)
0.99
0.019
0.98–0.99
Cholesterol (mg/dL)
0.99
0.006
0.99–0.99
LAD (mm)
1.08 \0.001
1.05–1.10
MVA B 1.5 cm2
1.69
0.037
1.03–2.77
No or mild MR versus moderate or severe MR
0.94
0.811
0.57–1.56
indicate that new-onset AF developed frequently with annual rate of 3.5 % in patient with RMS. Larger LA dimension and MVA B 1.5 cm2 were good predictors for detecting new-onset AF. In addition, our findings document that larger LA dimension significantly increases the risk of a composite of all events including systemic
HR
HR
P value
95 % CI
1.05
0.003
1.02–1.09
embolism, death and the development of AF, regardless of MVA, MV pressure gradient and MR. Especially, LA dimension C47 mm was good prognostic factor of a composite of AF development, all-cause death and systemic embolism as well as new-onset AF in RMS patients with sinus rhythm.
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Fig. 1 Event free-survival curves by Kaplan–Meier method. a AF development free survival curve. The cumulative AF developmentfree survival rates of two groups were stratified by LA dimension 47 mm. Patients with LA dimension above 47 mm had a significantly higher rate of AF development. b Systemic embolic event, all cause death and AF development-free survival curve. Patients with LA dimension above 47 mm had significantly higher rates of clinical events. *Event including all-cause death, systemic embolic event or development of AF
About 40–50 % of patients with rheumatic valvular disease developed AF during the course of the disease, and old age and LA diameter were the most important predictors of AF development in patients with rheumatic valvular disease by multivariate analysis [7, 13]. Consistent with previous studies, the present study showed a high incidence
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of newly-developed AF (20.5 % of patients) and the average annual AF development rate was 3.5 %/year during the follow-up period. In addition, larger LA dimension and severe MS were the predictors of newly detected AF during follow-up period in our study. Whether the dilated LA is a cause or a result of AF is still controversial. However, based on our results, we proposed that chronic pressure overload on LA according to degree of MS might be a causative factor of AF. Moreover, systemic embolism is a frequent complication of MS and it has been recognized that about 20 % of patients with RMS suffer a systemic embolism during the course of the disease [14]. Although the incidence of systemic embolism increased in MS with AF rhythm, systemic embolism has also been observed in patients with MS in sinus rhythm, but at lower rates [15]. The previous study showed that about 10 % of patients with MS in sinus rhythm developed systemic embolism [5, 6]. The lower incidence of embolic events in our study, compared to other studies, might be attributable to the different study periods and the strict definition of systemic embolism by image modality. In all, 4.1 % of patients with RMS in sinus rhythm developed systemic embolism including stroke and peripheral embolism during 10 years of follow-up. Several studies have attempted to find the mechanism of thromboembolism development in patients with RMS in sinus rhythm. Thromboembolic events probably occurred in patients with RMS in sinus rhythm because more patients with MS in sinus rhythm had LA appendage contractile dysfunction compared with normal subjects [16, 17]. Decreased global fibrinolytic capacity (GFC) in RMS patients with sinus rhythm could also increase the risk of systemic embolism and thrombus formation. The GFC in RMS patients with sinus rhythm was decreased to the similar levels of GFC of patients with chronic AF [18]. Other study suggested that elevated mean platelet volume in patients with RMS compared with normal subjects could be a possible mechanism of thromboembolism [19]. For patients with RMS in sinus rhythm, therefore, we need regular clinical and ECG follow-up though there is no guidelines regarding electrocardiography (ECG) follow-up. Although systemic embolic events and LA thrombus formation have usually been seen in MS patients with AF, thromboembolisms have often also been seen in previous studies in patients with MS with sinus rhythm [5, 6]. The authors have suggested that older age, enlarged LA, mean elevated MV pressure gradient ([18 mmHg) and dense spontaneous echo contrast were factors that increased the risk of systemic thromboembolism in MS patients with sinus rhythm or AF rhythm [6, 20]. However, these predictors of systemic embolism in MS in previous studies were suggested by univariate analysis. Consistent with these previous studies, new systemic embolism had
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occurred in 11.7 % of RMS patients who developed newonset AF during follow-up compared to in 2.1 % of RMS patients with consistent sinus rhythm in our study. Moreover, LA dimension larger than 47 mm was the best cut-off value predicting all events including systemic embolism, death, and the development of AF. It is worth noting that the 47 mm cut-off value of LA dimension is lower than the 50 mm value reported in current guidelines. Also, renal impairment could induce both hypo- and hypercoagulability [21] and renal impairment (GFR \ 60 mL/min) had twofold higher risk of stroke in patients with AF although on anticoagulation therapy [22]. The results of the present study corresponds with earlier studies that show a lower level of GFR was associated with the risk of systemic embolism and all-cause death in univariate analysis. In addition, it has been known that absence of moderate or severe MR was an independent predictor of systemic embolism in patients with rheumatic mitral valve disease [20]. Wanishsawad et al. [23] showed that none of the patients with predominant rheumatic MR in sinus rhythm had developed LA thrombus, whereas 14.3 % of patients with predominant rheumatic MS had developed LA thrombus. They suggested that significant MR had a protective role for LA thrombus formation in rheumatic mitral valve disease with sinus rhythm, especially in MVA [1 cm2. However, MVA and MR grade were not associated with clinical events including a composite of systemic embolism, all cause death, and AF development in our study. We speculate that the lower event rate rather than the lack of impact of MR on the risk of embolism seems to be reason why MR was not related to the incidence of embolism. A previous study also showed no significant difference of MVA between RMS patients with embolic events and without events [24]. Prophylactic anticoagulant treatment was not established in patients with RMS in sinus rhythm [1, 4]. However, high risk RMS patients with enlarged LA dimensions should be followed more closely for early detection of AF development and clinical events including embolism.
Limitations The main limitation of this study was its design as a retrospective observational study. A limitation is that we might have missed out on the presence or development of AF in patients with asymptomatic paroxysmal AF. Also, we could not get the data about all medical history such as hypertension or diabetes mellitus. Next, we measured only the antero-posterior (AP) diameter for the LA dimension. The AP dimension may not be an accurate representation of LA size than LA volume measurement [25]. We cannot rule out the possibility of generating different results if we
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measured LA volume. Third, we analyzed a relatively small sample size. About 45 % of patients with rheumatic mitral valve disease have already had AF. However, we followed up patients for long periods (median 72 months), which might overcome the limitations of a small sample size to some degree.
Conclusion In patients with RMS in sinus rhythm, annual AF development rate was 3.5 %/year and increased according to LA size and MS severity. Because of very high risk embolism, RMS with enlarged LA dimension need focused follow up for early detection of AF development and clinical events. We need prospective study to determine whether anticoagulation therapy would be beneficial in patients with RMS in sinus rhythm with large LA size or severe MS. Conflict of interest
None declared.
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