Relation of left atrial blood stasis to clinical risk factors in atrial fibrillation

International Journal of Cardiology 132 (2009) 210 – 215 www.elsevier.com/locate/ijcard

Relation of left atrial blood stasis to clinical risk factors in atrial fibrillation ☆ Kazumasa Ohara, Tadakazu Hirai ⁎, Nobuyuki Fukuda, Kenji Sakurai, Keiko Nakagawa, Takashi Nozawa, Hiroshi Inoue The Second Department of Internal Medicine University of Toyama, Toyama, 2630 Sugitani, Toyama 930-0194, Japan Received 27 June 2007; received in revised form 24 October 2007; accepted 17 November 2007 Available online 10 January 2008

Abstract Background: The present study was conducted to investigate whether an accumulation of clinical risk factors for thromboembolism would correlate with severity of blood stasis in the left atrium (LA) and aortic atherosclerosis in patients with nonvalvular atrial fibrillation (NVAF). Methods: Risk levels of thromboembolism were assessed in 515 (mean age 67.5 years) NVAF patients using CHADS2 score (an acronym for Congestive heart failure, Hypertension, Age ≥ 75, Diabetes mellitus, and prior Stroke or transient ischemic attack) to estimate the thromboembolic risk. Spontaneous echocardiographic contrast in the LA (LASEC), left atrial appendage (LAA) peak flow velocity, and severity of atherosclerosis in the descending aorta were determined with transesophageal echocardiography. Results: LASEC was significantly increased, and LAA flow velocity significantly decreased in correlation with an increase in the risk levels, as evaluated by CHADS2 score (p b 0.001). Severity of aortic atherosclerosis also increased in correlation with an increase in the risk levels (p b 0.001). Even at the comparable risk level, patients with chronic atrial fibrillation (AF) (n = 268) had higher LASEC (p b 0.001) and lower LAA flow velocity (p b 0.001) than those with paroxysmal AF (n = 52) who were in AF rhythm at the time of echocardiographic investigation. Conclusion: Severity of blood stasis in the LA and aortic atherosclerosis correlates with an accumulation of clinical risk factors for thromboembolism in NVAF patients. Additionally, the severity of blood stasis in the LA was greater in chronic AF patients than in paroxysmal AF patients at the comparable risk level. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Atrial fibrillation; Thromboembolism; Transesophageal echocardiography

1. Introduction It is well known that patients with nonvalvular atrial fibrillation (NVAF) can be at an increased risk for thromboembolism, especially when complicated with the well-known clinical risk factors for thromboembolism [1,2]. Transesophageal echocardiography (TEE) offers highresolution images of the left atrium (LA) and the thoracic aorta for evaluation of blood stasis in the LA and aortic ☆

This study was supported by a Grant from the Vehicle Racing Commemorative Foundation. ⁎ Corresponding author. Tel.: +81 76 434 7297; fax: +81 76 434 5026. E-mail address: [email protected] (T. Hirai). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.11.012

atherosclerosis, respectively. Doppler echocardiographic measurement of blood flow velocity in the left atrial appendage (LAA), and findings of spontaneous echocardiographic contrast in the left atrium (LASEC) have been used to assess the severity of blood stasis in the LAA, and consequently, the risk of thromboembolism [3,4]. In addition, aortic atheroma is a significant predictor of stroke and mortality [5,6], suggesting that aortic atherosclerosis seen on TEE could be a marker of generalized atherosclerosis. Previous reports have shown that dense LASEC, reduced LAA flow velocity, and complex aortic plaque on TEE are independent risk factors for subsequent thromboembolic events [4,7–9], and are seen frequently in NVAF patients with clinical thromboembolic risk factors [8,10]. Although

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an accumulation of risk factors quantified by the CHADS2 score (an acronym for Congestive heart failure (CHF), Hypertension, Age ≥ 75, Diabetes mellitus, and prior Stroke or transient ischemic attack) has been shown to be associated with an increase in thromboembolic events [2,11], it remains unknown whether an accumulation of risk factors would be related to TEE findings. Therefore, the present study was conducted to investigate the relationship, in patients with NVAF, between an accumulation of the clinical risk factors for thromboembolism and the TEE findings. In addition, TEE findings and CHADS2 score were also compared between paroxysmal and chronic AF patients. 2. Methods 2.1. Study subjects Five hundred and fifteen consecutive patients with NVAF (361 men and 154 women; mean age ± standard deviation [SD], 67.5 ± 11.1 years), who underwent transthoracic echocardiography (TTE) and TEE, were studied. Two hundred sixty-eight patients had chronic atrial fibrillation (AF) and 247 had paroxysmal AF. Patients with mitral stenosis or mechanical heart valves were excluded. Chronic AF was confirmed electrocardiographically on at least two separate occasions (4 weeks apart). Paroxysmal AF was defined as AF documented electrocardiographically at least once in the preceding 12 months and lasting at least 1 h. The study was approved by the institutional ethics committee and informed consent was given by all patients. The indication for TEE was based on either an evaluation of the potential thromboembolic risk, or the identification of cardiogenic source of recent embolism. Two hundred forty patients, with a mean international normalized ratio (INR) of 2.14 at the time of the study, received oral anticoagulation, and 124 received antiplatelet therapy with aspirin or ticlopidine; the remaining 210 patients were not receiving antithrombotic therapy. 2.2. Echocardiography TTE was performed with a 2.5- or 3.5-MHz phased-array transducer connected to an ultrasound system (SSH-140A; Toshiba, Tokyo, Japan). The left atrial dimension (LAD) and left ventricular ejection fraction (LVEF) were determined from the M-mode images [12]. TEE was performed with a 5-MHz multiplane transducer. Each patient was studied in the fasting state, and without premedication except for topical anesthesia of the hypopharynx with lidocaine spray. Multiple standard tomographic planes were imaged. Subsequently, the severity of LASEC and LAA peak flow velocity were both determined. LASEC was diagnosed in the presence of dynamic smoke-like echoes within the LA or LAA with a characteristic swirling motion that was distinct from the white noise artifact. The severity of LASEC was defined by the criteria of Fatkin et al. [4]; 0 = none (absence of echogenicity); 1+ = mild (minimal echogenicity

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detectable only transiently during the cardiac cycle with optimal gain settings); 2+ = mild to moderate (transient spontaneous echocardiographic contrast without increased gain settings and more dense pattern than 1+); 3+ = moderate (dense swirling pattern during the entire cardiac cycle); and 4+ = severe (intense echodensity and very slow swirling patterns in the LAA, usually with a similar density in the main left atrial cavity). LAA flow velocity profiles were obtained by pulsewave Doppler echocardiographic interrogation at the orifice of the appendage. Peak outflow velocity signals within each R–R interval were averaged over a minimum of six cardiac cycles. Severity of aortic atherosclerosis was evaluated using the grading system of Montgomery et al. [6]: grade I = no disease or intimal thickening; grade II = intimal thickening; grade III = atheroma b 5 mm; grade IV = atheroma ≥5 mm; and grade V = any mobile atheroma. The severity of LASEC and aortic atherosclerosis were determined by two independent observers. Any difference in the determination was resolved by a third independent observer. 2.3. Estimation of the risk for thromboembolism Accumulation of clinical risk factors for thromboembolism was scored according to the CHADS2 index [2]. That is, 1 point each was added for the presence of: recent CHF, hypertension, age 75 years or older and diabetes mellitus; 2 points were added for a history of stroke or transient ischemic attack (TIA). For instance, a patient with all 5 risk factors would have a CHADS2 score of 6. 2.4. Analyses of data The data are presented as mean ± SD. Comparison of continuous variables was performed with a one-way analysis of variance, and a two-way analysis of variance followed by Bonferroni t-test for multiple comparisons. Categoric variables were compared with a chi-square test. A p value of less than 0.05 was defined as statistically significant. Statistical analyses were performed with SigmaStat (SigmaStat version 3.11, Richmond, California, USA) and SPSS (SPSS version 14.0, Chicago, IL, USA). 3. Results The baseline clinical characteristics and TTE variables are summarized in Table 1. Increased age, the frequency of patients with paroxysmal AF and LA dilatation were associated with an increase in the risk levels (p b 0.01, for all). LVEF did not differ between the risk levels. In the present study, there were no patients with a CHADS2 score of 6. 3.2. Blood stasis in the LA and LAA There was a significant association between increased LASEC and increased risk level (pb 0.001, Fig. 1). Furthermore,

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Table 1 Baseline clinical characteristics and transthoratic echocardiographic variables of patients with nonvalvular AF at different levels of thromboembolic risk based on the CHADS2 score a CHADS2 score

Men Age (years) ⁎ NYHA ≧ 2 ⁎ Hypertension ⁎ Age ≥ 75years ⁎ Diabetes mellitus ⁎ Prior stroke or TIA ⁎ Hyperlipidemia Smoking Paroxysmal AF ⁎ Warfarin ⁎ LAD (mm) ⁎ LVEF (%)

0

1

2

3

4

5

(n = 118)

(n = 139)

(n = 98)

(n = 101)

(n = 45)

(n = 14)

92(78.0) 59.9 ± 10.3 0 0 0 0 0 12(10.2) 44(37.3) 73(61.9) 30(25.4) 38.6 ± 7.6 59.8 ± 13.5

94(67.6) 66.2 ± 10.6 34(24.5) 63(45.3) 28(20.1) 14(10.1) 0(0) 26(18.7) 54(38.8) 70(50.4) 69(49.6) 41.3 ± 7.8 58.1 ± 14.4

70(71.4) 70.0 ± 9.9 35(35.7) 52(53.1) 34(34.7) 25(25.5) 25(25.5) 21(21.4) 43(43.9) 38(38.8) 51(52.0) 42.5 ± 8.4 57.3 ± 15.9

69(68.3) 72.0 ± 9.2 31(30.7) 64(63.4) 42(41.6) 32(32.7) 67(66.3) 22(21.8) 48(47.5) 47(46.5) 57(56.4) 41.6 ± 8.5 57.5 ± 13.5

25(55.6) 73.2 ± 10.6 16(35.6) 36(80.0) 26(57.8) 14(31.8) 44(97.8) 7(15.6) 19(42.2) 16(35.6) 23(51.1) 44.5 ± 9.9 54.5 ± 16.6

11(78.6) 76.9 ± 5.7 9(64.3) 13(92.9) 11(78.6) 9(64.3) 14(100.0) 4(28.6) 7(50.0) 3(21.4) 10(71.4) 46.2 ± 7.2 50.7 ± 16.7

Values are number of patients (%) or mean ± SD. AF = atrial fibrillation, NYHA = New York Heart Association functional class, TIA = transient ischemic attack, LAD = left atrial dimension, LVEF = left ventricular ejection fraction. a See the text for details. ⁎ p b 0.01 among groups.

the severity of LASEC was lower in patients with a CHADS2 score of 0 than in those with scores of 2 to 5 (p b 0.05 for all), while those with a score of 1 had less severe LASEC than those with scores of 4 and 5 (p b 0.05 for both). There was also a significant association between decreased LAA flow velocity and increased risk level (pb 0.001, Fig. 2). Patients with a score of 0 had significantly higher LAA flow velocities than those with scores of 2 to 5 (p b 0.05 for all), while those with a score of 1 had higher LAA flow velocities than those with score of 4 (pb 0.05). The clinical backgrounds of 268 chronic AF patients and 52 paroxysmal AF patients, who were in AF rhythm at the time of TEE analysis, are summarized in Table 2. There was a significant difference in the mean CHADS2 score between the two groups (1.9 ± 1.4 vs 1.5 ± 1.4, p = 0.03). Patients with chronic AF had larger LAD than those with paroxysmal AF.

To determine difference between TEE findings of the two groups at the comparable risk levels, patients with CHADS2 scores of 0–4 were classified into three groups based on their score; 0, 1 or 2–4. These groupings were chosen due to the smaller number of patients with a score of 3 or 4. Those with a score of 5 were excluded from the analysis, since no patients in the paroxysmal AF group had a score of 5 (Table 3). LASEC and LAA flow velocity worsened with an increase in the risk level in chronic AF patients, but LAA flow velocity did not worsen in paroxysmal AF patients (Table 3). Taken together, for patients with CHADS2 scores of 0–4 and in AF rhythm at the time of TEE analysis, the grade of LASEC was significantly higher (2.0 ± 1.3 vs 1.2 ± 1.0, p b 0.001), while LAA flow velocity was significantly lower (26.9 ± 14.4 vs 47.6 ± 27.2 cm/s, p b 0.001) in patients with chronic AF than in those with paroxysmal AF.

Fig. 1. Relation between CHADS2 score and spontaneous echocardiographic contrast in left atrium (LASEC). LASEC increased in correlation with an increase in CHADS2 score (p b 0.001). There was no patient with CHADS2 score of 6. Mean + SD. ⁎p b 0.05 vs CHADS2 score of 0, †p b 0.05 vs CHADS2 score of 1.

Fig. 2. Relation between CHADS2 score and left atrial appendage (LAA) flow velocity. LAA flow velocity decreased significantly but not proportionally along with an increase in CHADS2 score (p b 0.001). Mean + SD. ⁎p b 0.05 vs CHADS2 score of 0, †p b 0.05 vs CHADS2 score of 1.

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Table 2 Clinical characteristics of patients with chronic and paroxysmal AF a Chronic AF

Paroxysmal AF

(n = 268)

(n = 52)

Men Age (years) NYHA ≧ 2 Hypertension Age ≥ 75 years Diabetes mellitus Prior stroke or TIA Hyperlipidemia Smoking LAD (mm) LVEF (%)

191(71.3) 68.7 ± 11.3 86(32.1) 132(49.3) 88(32.8) 54(20.1) 81(30.2) 53(19.8) 121(44.8) 44.3 ± 8.2 55.8 ± 15.4

35(67.3) 65.9 ± 11.6 10(19.2) 20(38.5) 11(21.2) 10(19.2) 13(25.0) 7(13.5) 21(38.5) 39.7 ± 7.8 ⁎ 54.4 ± 15.2

CHADS2 score 0 1 2 3 4 5 6

45(16.8) 69(25.7) 60(22.4) 54(20.2) 29(10.8) 11(4.1) 0

17(32.7) 12(23.1) 8(15.4) 11(21.1) 4(7.7) 0 0

Values are number of patients (%) or mean ± SD. AF = atrial fibrillation, NYHA = New York Heart Association functional class, TIA = transient ischemic attack, LAD = left atrial dimension, LVEF = left ventricular ejection fraction. a Paroxysmal AF patients were in AF rhythm at the time of the transesophageal echocardiographic investigations. ⁎ p b 0.01 vs chronic AF.

3.3. LA thrombi Seventy-eight (15.1%) patients had thrombi in LAA. Patients with LA thrombi had higher LASEC (2.0 ± 1.4 vs Table 3 Comparison of echocardiographic indices between chronic and paroxysmal AF groups CHADS2 score 0 LASEC Chronic AF (grade) group Paroxysmal AF group LAAFV Chronic AF (cm/sec) group Paroxysmal AF group Ao-grade Chronic AF (grade) group Paroxysmal AF group

1

2–4

1.3 ± 1.3 ⁎

1.8 ± 1.2 ⁎

2.3 ± 1.1

0.7 ± 0.7 ⁎

0.7 ± 1.0 ⁎

1.8 ± 1.0

p value a b0.001

34.2 ± 16.6 ⁎ 29.7 ± 15.7 ⁎ 23.2 ± 11.6 b0.001 52.2 ± 27.1

53.7 ± 27.7

40.9 ± 26.7

2.6 ± 1.1 ⁎

3.0 ± 0.9

3.4 ± 1.0

2.1 ± 0.9 ⁎

2.4 ± 0.7 ⁎

3.5 ± 0.9

0.026

Values are mean ± SD. AF = atrial fibrillation, LASEC = spontaneous echocardiographic contrast in the left atrium, LAAFV = left atrial appendage flow velocity, Ao-grade = grade of aortic atherosclerosis. Patients were in AF rhythm at the time of transesophageal echocardiographic investigations. a For intergroup comparisons between chronic and paroxysmal AF groups. ⁎ p b 0.05 vs score 2–4.

Fig. 3. Relation between CHADS2 score and severity of aortic atherosclerosis (Ao-grade). Ao-grade increased along with an increase in CHADS2 score (p b 0.001). Mean + SD. ⁎p b 0.05 vs CHADS2 score of 0, †p b 0.05 vs CHADS2 score of 1.

1.4 ± 1.2, p b 0.01) and lower LAA flow velocity (29.5 ± 17.4 vs 41.9 ± 26.3 cm/s, p b 0.01) than those without thrombi did. In addition, CHADS2 score was higher in those with thrombi than in those without thrombi (2.03 ± 1.43 vs 1.67 ± 1.37, p b 0.05). 3.4. Grade of atherosclerosis in the descending aorta Severity of aortic atherosclerosis increased with an increase in risk level (p b 0.001, Fig. 3). Patients with a CHADS2 score of 0 had significantly less severe aortic atherosclerosis than those with scores of 1–5 (p b 0.01 for all). In addition, patients with a score of 1 had significantly less severe atherosclerosis than those with a score of 3 (p b 0.05). The severity of aortic atherosclerosis was significantly higher in patients with chronic AF than in those with paroxysmal AF in AF rhythm (3.1 ± 1.0 vs 2.8 ±1.1, p b 0.05). 4. Discussion The major findings of the present study were as follows. First, LASEC was significantly increased, and LAA flow velocity was significantly decreased along with an increase in the clinically-determined thromboembolic risk level. Additionally, the severity of blood stasis of the LA was greater in chronic AF patients than in paroxysmal AF patients. Second, patients with thrombi in LAA had higher CHADS2 scores than those without thrombi. Third, severity of aortic atherosclerosis increased along with an increase in the risk level. 4.1. Blood stasis in the LA TEE measurement of blood flow velocity in the LAA and evaluation of LASEC have been used to assess the severity of blood stasis in the LA and LAA [3,4]. SPAF III investigators showed that dense LASEC and low LAA flow velocity occurred more frequently in NVAF patients with at least one thromboembolic risk factor than in those without any risk factors [8]. However, it remains uncertain whether blood stasis in the LA is affected by an accumulation of thromboembolic

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risk factors. The present study indicated that the severity of left atrial blood stasis was increased along with an increase in the thromboembolic risk levels. Both hypertension and CHF burden the LA with pressure overload, thereby leading to dilatation and fibrosis. Diabetes mellitus might induce ventricular fibrosis [13], suggesting that fibrosis might also develop in the LA. Furthermore, patients with a history of stroke might have a predisposition that primarily affects blood stasis. All these factors could contribute to blood stasis in the LA, resulting in increased thromboembolic risk levels. 4.2. LA thrombi The LA thrombi were found in 78 patients (15.1%) with NVAF. This prevalence was relatively high, since TEE was indicated for either evaluation of the potential thromboembolic risk or identification of cardiogenic source of recent embolism, suggesting that most of patients were at high risk for thromboembolism. Indeed, the prevalence of patients with LA thrombi in this study was almost similar to that in other studies [3,4,9], in which patients with clinically determined risk for ischemic stroke had been included. 4.3. Atherosclerosis of descending aorta Prior stroke, hypertension and diabetes mellitus employed in CHADS2 scoring system were risk factors for atherosclerosis and ischemic stroke. Complex aortic plaque is more likely to be present in NVAF patients with at least one clinical thromboembolic risk factor compared with those without any risk factors, and will also be associated with subsequent thromboembolic events [8,9]. Blackshear et al showed that aortic plaque was related to atherosclerotic risk factors and left atrial blood stasis [14]. Indeed, we have shown in the present study that the severity of aortic atherosclerosis was associated with an increase in the risk level. Aortic atherosclerosis might be associated with a hypercoagulable state in patients with AF, resulting in a high prevalence of cerebral infarction [15]. 4.4. Difference between chronic and paroxysmal AF patients Even at the comparable risk level, patients with chronic AF had higher LASEC and lower LAA flow velocity than those with paroxysmal AF. AF rhythm is essential to blood stasis in the LA, and structural remodeling of the LA may be an additional cumulative risk factor. Sustained AF can lead to a further increase in the left atrial size [16], thereby leading to blood stasis in the LA [17–19]. In the present study, we found that LAD was larger in patients with chronic AF than in those with paroxysmal AF, a finding consistent with previous reports [20,21]. This could lead to a worsening of blood stasis in patients with chronic AF. Based on TEE findings, it appears that left ventricular dysfunction correlates with dense LASEC and low LAA

flow velocity [10]. In the present study, however, LVEF was preserved in patients with both chronic and paroxysmal AF. Therefore, in this present study, LVEF did not contribute to the difference in the TEE findings between chronic and paroxysmal AF patients. 4.5. Study limitation The present study had several limitations. First, the duration of AF was not determined in our patient group. Previously an association has been shown between duration of AF rhythm and worsening of blood stasis [16,19,22]. Second, 47% of patients in our study were taking warfarin. However, since warfarin does not affect the severity of LASEC [3,23], patients were pooled and analyzed as a single group, irrespective of whether they were taking warfarin. Third, we used the CHADS2 score to stratify thromboembolic risk. Using Japanese patients with NVAF, we have been able to easily stratify risk level with the CHADS2 score [11]. However, the number of subjects in the present study was small and the number of patients with a score of 4 or more was very limited, particularly amongst the patients with paroxysmal AF, and there were no patients with a score of 6. Therefore, we could not compare the TEE findings between chronic AF and paroxysmal AF patients with CHADS2 scores of 4 and 5, nor with a CHADS2 score of 6. 5. Conclusions Although we recognize there were limitations to our study as outlined above, we were able to show that blood stasis of LA clearly increased along with an accumulation of clinical thromboembolic risk factors in NVAF patients. NVAF patients, judged to be at an increased risk for thromboembolism based on their individual CHADS2 score, should require more intensive anticoagulation therapy. References [1] Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154: 1449–57. [2] Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–70. [3] Black IW, Hopkins AP, Lee LC, et al. Left atrial spontaneous echo contrast: a clinical and echocardiographic analysis. J Am Coll Cardiol 1991;18:398–404. [4] Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. J Am Coll Cardiol 1994;23: 961–9. [5] Tunick PA, Kronzon I. Protruding atherosclerotic plaque in the aortic arch of patients with systemic embolization: a new finding seen by transesophageal echocardiography. Am Heart J 1990;120:658–60. [6] Montgomery DH, Ververis JJ, McGorisk G, et al. Natural history of severe atheromatous disease of the thoracic aorta: a transoesophageal echocardiographic study. J Am Coll Cardiol 1996;27:95–101.

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