General C ardiology
Cardiology 1992;81:189-195
Departments of Medicine, Mariestad Hospital, St Goran Hospital, Sabbatsberg Hospital, and Danderyd Hospital, Sweden
Keyw ords
Stroke Atrial fibrillation Echocardiography
Echocardiographie Findings and the Increased Risk of Stroke in Nonvalvular Atrial Fibrillation
Abstract
We studied whether cardiac abnormalities contribute to the increased risk of stroke in patients with nonvalvular atrial fibrillation (NVAF). M-mode and 2D echocardiography were performed in four age- and gender-matched groups: 20 stroke patients with NVAF, 20 patients with NVAF who had not suf fered a previous stroke, 20 stroke patients with sinus rhythm, and 40 healthy controls. Their mean age was 77 years. The two groups with atrial fibrillation differed from healthy controls in that they had more 2D-echocardiographic findings of severe left-ventricular-wall-motion abnormalities (p < 0.05) and tended more often to have enlarged left ventricles, and hyper trophic and congestive cardiomyopathy. Left atrial diameter was 47 mm compared to 41 and 39 mm in the two groups with sinus rhythm (p < 0.001). Intracardiac thrombi were only found in the two atrial-fibrillation groups (with stroke: 15% without stroke: 5%). Aortic sclerosis was common in all groups (30-60%), as was mitral annulus calcification (1020%). The only significant difference between the two atrialfibrillation groups was a higher frequency of earlier ischemic heart disease in the stroke group. Both atrial-fibrillation groups had cardiac abnormalities predisposing for embolic as well as thrombotic stroke.
Introduction
Chronic atrial fibrillation is one of the main risk factors for stroke [ 1]. The etiology is thought to be embolic from left atrial throm
The study was conducted at the Department of Medicine, Danderyd Hospital. Karolinska Institute. Stockholm. Sweden.
Received: May 26. 1992 Accepted: May 28,1992
bi. Clinical evidence supports an atherothrombotic mechanism in 25-67% of strokes in the aged nonvalvular atrial fibrillation (NVAF) population [2, 3]. NVAF patients also have multiple coagulation disturbances
Clacs Gustafsson. MD Department of Mcdicinc Mariestad Hospital Box 4 11 S-542 24 Mariestad (Swcden)
© 1992 S. Karger AG. Basel 0008-6312/92/ 0815-0189Î2.75/0
Downloaded by: Stockholm University Library 130.237.165.40 - 12/18/2018 10:41:54 AM
Claes Gu.stafs.sona Mona Britton b Fredrik Brolundc Sven VEriksson6 Kaj LindvalF
Materials and Methods Group 1 consisted of 20 consecutive patients with electrocardiographically verified chronic (> 1 year) atrial fibrillation, no mitral stenosis on echocardiogra phy. and a previous stroke. Group 2 comprised 20 patients matched for gender, age (± 2 years) and dura tion (± 2 years) of NVAF but who had not suffered a previous stroke. They were randomly selected outpa tients from a data register of patients with NVAF. Mean duration of NVAF in the two groups was 7.1 and 6.3 years, respectively (NS). Group 3 was made up of 20 patients with SR who had had a previous stroke, matched to group 1 for gender and age. No patient had malignant disease or overconsumed alcohol. Group 4. the control group, consisted of 40 gender- and agematched healthy subjects randomly selected from the population register. None of the control patients had a
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history, physical signs, or electrocardiographic find ings indicating previous thromboembolic events, isch emic heart disease, hypertension, atrial fibrillation, diabetes mellitus. malignancy, current infection, or inflammatory disease. Mean age in all groups was 77 (range: 62-84) years. Electrocardiograms were classi fied according to the Minnesota code [9]. Echocardio grams were obtained with an Irex III phased array sec tor scanner with a 2.25-MHz transducer. The M-mode registrations were guided by a cross-sectional image of the left ventricle and atrium. The conventional Mmode echocardiographic-registration technique was standardized according to American Society of Echo cardiography criteria [ 10]. Each patient was examined lying in the left lateral supine position. 2D echocardio grams were obtained for all patients in three standard views: parasternal (short and long axes), apical (two and four chamber), and subxiphoid. The 2D echocar diograms were recorded on a video recorder and ana lyzed by two independent observers unaware of the patient history'. The criterion for mitral annulus calci fication (MAC) was a bright dense linear echo behind the mitral valve with a motion similar to that of the posterior left ventricular wall. Mitral valve prolapse was diagnosed from 2D echocardiography if the ante rior or posterior mitral leaflet bulged through a line extending from the base of the aortic valve to the athcroventricular junction [II]. Aortic sclerosis was de fined as dense echogenic structure presumed to be caused by fibrous or calcification changes in the aortic valves. In aortic stenosis the commissures are more or less fused, while in aortic sclerosis they can open to the aortic ring. Left ventricular ejection time (LVET) was defined as the time elapsed from opening to closure of the aortic valve [ 12], Left ventricular preejection time (LPET) was defined as the time elapsed from the beginning of the complex of the electrocardiogram (QRS) to the opening of the aortic valve. Systolic-timcinterval index (STI) was calculated as follows: STI = LPET/LVET [12]. Percent left ventricular fractional shortening was computed [100(LVDD - LVSD)/ LVDD] where LVDD = left-ventricular diastolic di ameter and LVSD = left-ventricular systolic diameter and together with STI was used as an indicator of left ventricular systolic function. Left ventricular muscular mass was calculated according to Troy et al. [13]. Informed consent was obtained from all partici pants. and the study protocol was approved by the regional ethics committee.
Gustafsson/Britton/Brolund/Eriksson/ Lindvall
Echocardiography in NVAF Stroke
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that may contribute to their increased risk of stroke [4], Patients with atrial fibrillation without any concomitant risk factors, termed 'lone atrial fibrillation', have been shown to carry a low risk of thromboembolism [5. 6], Left atrial diameter > 4 0 mm. female gender and underlying heart disease have been found to be independent risk factors for systemic embolization in referred patients with atrial fibrillation [7], Left ventricular dysfunction and the size of the left atrium were indepen dent predictors of later thromboembolism in the Stroke Prevention in Atrial Fibrillation (SPAF) study [8], The role and prevalence of possible cardiogenic embolic sources in the NVAF group need to be investigated further. We therefore studied embolic sources and cardiac function in NVAF patients with and without previous stroke, in stroke patients with sinus rhythm (SR), and in healthy con trols to look for possible disturbances that might explain the increased risk of stroke among the NVAF patients. The second aim of our study was to investigate whether NVAF patients with stroke differed from NVAF pa tients without a previous stroke and if em bolic-prone group could be identified.
Table 1. Prevalence o f risk factors in patients with N V A F with and w ithout stroke, stroke p atients with SR and age-matched controls Risk factors
Mean age. years Congestive heart failure Hypertension Ischemic heart disease Diabetes mellitus Hyperlipidemia Smoking
NVAF
SR
with previous stroke withouth stroke (n = 20) (n = 20)
with previous stroke comtois (n = 40) (n - 20)
77 13(65)*** 7(35) 8 (40)* 3(15) 2 ( 10) 7(35)
77
77 13(65)*** 4 (20)
2(101 2 ( 10) 2 ( 10) 5 (25)
2 ( 10) 6(30) 4 (20) 2 ( 10) 2 ( 10) 5(25)
77
0 0 0 0 0 4(10)
Statistics Difference of proportions was tested with the x: test including Yate’s correction. Continuous data are expressed as means and as interquartile intervals. The significance of differences in échocardiographie vari ables between groups was tested using one-way analy sis of variance and a two-tailed t test. Coefficients of skewness and kurtosis were used to test deviations from a normal distribution and logarithmic transfor mation of the individual values of skewed variables was performed before statistical computations and sig nificance testing. The levels of significance considered were 0.1, 1. and 5 %. and not significant (NS).
Results
Cardiovascular risk factors in the four groups are presented in table 1. As expected, congestive heart failure was significantly more common in the two groups of NVAF patients. Ischemic heart disease was signifi cantly more common in the NVAF stroke group than in the NVAF group without stroke. Definite or suspected left atrial or ven tricular thrombosis was detected in 15% of NVAF patients with stroke and 5% (NS) of NVAF patients without stroke on 2D echo
cardiography (table 2). No patient with SR had thrombosis. Left atrial diameter, mea sured by M-mode echocardiography, was 47 mm in both NVAF groups and signifi cantly larger than in the groups with SR (ta ble 3). Atria were larger than 40 mm in 85 and 90% in the two NVAF groups as compared to 60% in the SR stroke group and 50% in the control group (p < 0.01). No correlation be tween duration of NVAF and left atrial diam eter could be found (r2 = 0.045). The M-mode and 2D echocardiography re sults in the NVAF groups indicated that more patients had markedly dilated hearts with thinner walls and severer disturbances of left ventricular wall motion (tables 2. 3). 2D echocardiography showed alterations from normal findings in 65-75% in all groups. A high proportion of patients in all groups (30-60%) had aortic sclerosis. Mild to moderate aortic stenosis was found in 0-15%. M-mode and 2-D echocardiography have lower specificity than Doppler investigation for the diagnosis of aortic stenosis and some cases might have been overdiagnosed. MAC was found in 10-20% in all groups.
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Values in parentheses are percentages. * p < 0.05 vs. NVAF without stroke: *** p < 0.001 vs. SR patients with previous stroke.
Table 2 . 2-D échocardiographie findings in patients with NVAF with and w ithout stroke, stroke patients with SR and age-matched controls NVAF
SR
with previous stroke without stroke (n = 20) (n = 20)
with previous stroke controls (n « 20) (n = 40)
2-D findings
Left atrial thrombus Left ventricular thrombus Severe wall motion abnormalities Congestive cardiomyopathy Left ventricular dilatation Hypertrophic cardiomyopathy None of the above findings Mitral annulus calcification Mitral valve prolapse Mitral sclerosis Aortic sclerosis Aortic stenosis
1(5)
1 (5)
2 ( 10)
0 6 (30)* 0
5(25)* 3(15) 3(15) 3(15) 14(70) 4(20) K5) 1 (5) 8(40) 2 ( 10)
0 0
0 0
1(5) 1(5)
2(5)
0
0 0
3(15) 1(5) 13(65) 4(20) 1(5) 1(5) 6(30)
1(3)
0
16(80) 2 ( 10)
0 2 ( 10) 12(60) 3(15)
0
37 (92) 7(18) 1(3) 4(10) 20(50) 4(10)
Values within parentheses are percentages. * p < 0.05 vs. controls, by y}.
Table 3. M-mode échocardiographie variables in patients with NVAF with and without stroke, stroke patients with SR and age-matched controls M-mode findings
NVAF
Left atrial diameter, mm Left ventricular diastolic diameter, mm Right ventricular diastolic diameter, mm Septal will thickness, mm Posterior wall thickness, mm Left ventricular muscular mass, g STI Left ventricular fractional shortening, %
with previous stroke (n = 20)
without stroke (n = 20)
mean
mean
47***. o 53
20 10**°°
9» 327° 0.48 32
1st—3rd quartiles
^•y***, o
40-55 47-57 10-23
51 2 s***. o°° 10°
8-12 8-10
10
229-309 0.31-0.36 27-37
327° 0.38 32
1st—3rd quartiles
44-52 44-57 20-29
8-12 9-10 218-361 0.36-0.41 24-36
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*■**• *** p < 0.05.0.01,0.001. respectively, vs. controls by two-tailed t test: o. °°.°°° p < o.05,0.01,0.001, respectively, vs. stroke patients with SR.
Our aim was to study cardiac disturbances that could explain the high risk of stroke in NVAF patients. All four groups were well matched with respect to age and gender. Congestive heart failure was more frequent in the two NVAF groups, and ischemic heart disease in the NVAF stroke group. Both are well-known risk factors for stroke in the popu lation [14]. The AFASAK study [15] and the Boston Area Anticoagulant Study [16] found previous myocardial infarction and angina pectoris, respectively, to be predictors of stroke. Severe left-ventricular-wall-motion abnormalities were more common in both our NVAF groups. Data from the SPAF study showed such abnormalities to be a risk factor for stroke, as were hypertension, recent con
SR with previous stroke (n = 20) mean
1st—3rd
controls (n = 40) mean
1st—3rd quartiles
39 51 15
34-44 47-55 11-18
11 10
10-12
10-12 298-440 0.33-0.41 28-42
336 0.37 36
quartilcs 41 52 16
12 11* 398* 0.40 37
38-45 48-58 10-19 10-13
9-10 276-381 0.29-0.41 33-40
gestive heart failure, and earlier stroke or transient ischemic attack (TI A) [6,8]. It seems that in the NVAF population the same risk factors for stroke operate as in the population in general. Some of the conditions might pre dispose to thrombus formation in the left ven tricle but they could also be independent markers of an atherosclerotic process in which atrial fibrillation and stroke arc others. Stroke is common in patients with conges tive cardiomyopathy and thought to be re lated to intracardiac thrombi [ 17], Two thirds of NVAF stroke patients with echocardiographic signs of congestive cardiomyopathy had left ventricular thrombi. One stroke pa tient with SR had congestive cardiomyopathy without a ventricular thrombus. Hypertro phic cardiomyopathy associated with a 510% yearly risk of embolism in patients with atrial fibrillation was only found in the NVAF groups [18]. The only left atrial thrombus found was in a patient in the NVAF stroke group. This finding supports those in other transthoracic echocardiographic studies and is an underestimation, as shown by trans esophageal echocardiography [19, 20], Left atrial diameter has been shown to increase with increased duration of NVAF [21], The fact that the NVAF patients in our study had had NVAF for a minimum duration of 1 year could explain why we found no association with duration. Left atrial diameter was in creased in both NVAF groups. This has been confirmed by some authors [19, 22] but not by others, who found larger atria in the stroke group of NVAF patients [23. 24]. Atrial diam eter > 4 0 mm has been shown to be the stron gest predictor of increased risk of emboliza tion [7], Left atrial size was also an indepen dent predictor of later thromboembolism in the SPAF study but not in the other two large primary-prevention studies [8, 15. 16]. MAC is associated with an increased risk of retinal emboli and TIA but is more often a
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Discussion
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atria were significantly larger in both NVAF groups. These results in the two NVAF groups indicate that cardiac function is impaired with a poorer cardiac output. This predis poses for intracardiac thrombus formation and this was verified by the greater prevalence of thrombi found in the NVAF groups. A lower cardiac output also decreases cerebral blood flow [31] and this, in combination with atherosclerosis, may predispose for thrombus formation. This risk is further increased by the blood hypercoagulability that also accom panies NVAF [4], Thus the NVAF patients are at a high risk for both embolic and thrombotic stroke.
Acknowledgements This study was supported by grants from the Foun dations of Serafimerlasarettet. Clas Groschinskv. Loo and Hans Osterman. Fredrik and Ingrid Thuring. Eirs 50-years Foundation. 1987 years Foundation for Stroke Research and Fonus.
Gustafsson/Britton/Brolund/Eriksson/ Lindvall
Echocardiography in NVAF Stroke
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marker of generalized atherosclerosis [25]. About half of the patients with MAC and cerebral ischemia have coexistent atrial fibril lation [26]. MAC was an obvious risk factor for stroke in the Boston study, but not in the SPAF or AFASAK studies [8, 15, 16]. In our study, no difference in the frequency of MAC was found between the groups. The association between mitral valve pro lapse and stroke has only been established for young adults and therefore our low frequency was not surprising. Aortic sclerosis might be a rare source of small calcified emboli [27]. The prevalence increases with age [29], Angiography has shown the aortic valve area to contract by 0.1cm 2/ycar [30], The higher frequency of these age-related changes in echogenicity on the aortic valves in our study compared to other echocardiographic studies is probably due to the higher mean age of our patients. We found no patients with left ventricular aneurysm or myxoma. Left ventricular hypertrophy is a wellknown risk factor for stroke [23, 30], and stroke has been found to be associated with left ventricular hypertrophy in patients with chronic atrial fibrillation [23], In our study, the stroke group with SR. but not the NVAF stroke group, had significantly higher left ven tricular muscular mass. We found at least one aberrant echocardio graphic finding in 65-75% of subjects in all four groups. This high frequency was presum ably due to the high age of the subjects, show ing that age has to be considered when defin ing ‘normality’. Patients in both NVAF groups differed from those in the groups with SR in that more of them had a history of congestive heart fail ure. The patients in the NVAF stroke group had ischemic heart disease significantly more often. Severe abnormalities of left-ventricuiar-wali motion were more frequent and left
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1 Wolf PA. Dawbcr TR. Thomas E Jr, 11 Nishide M. Tadayoshi I, Gotoh M. 21 Petersen P. Kastrup J. Brinch K. Godtfredsen J, Boysen G: Relation Naka M. Tsuji K: Cardiac abnor Kännel WB: Epidemiologic assess ment of chronic atrial fibrillation between left atrial dimension and malities in ischemic cerebrovascular duration of atrial fibrillation. Am J disease studied by two-dimensional and risk of stroke: The Framingham Cardiol 1987;60:382-384. echocardiography. Stroke 1983; 14: study. Neurology 1978:28:973-977. 541-545. 22 Tegeler CH, Hart RG: Atrial size, 2 Hart RO. Coull BM. Hart D: Early atrial fibrillation, and stroke. Ann 12 Spodick DH. Doi YL. Bishop RL. recurrent embolism associated with Neurol 1987;21:315-316. Hashimoto T: Systolic time inter nonvalvular atrial fibrillation: A ret vals reconsidered. Réévaluation of 23 Aronow WS. Gutstein H, Hsieh FY: rospective study. 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Clinical features of patients tern Med 1987:106:292-298. at risk. Ann Intern Med 1992; 116: cet 1989;i: 175—179. 16 The Boston area anticoagulation 28 Pomcrance A: Pathogenesis of aor 1-5. tic stenosis and its relation to age. Br trial for atrial fibrillation investiga 7 Cabin IIS, Hall C. Perlmutter RA. Heart J 1972:34:569-574. tors: The effect of low-dose warfarin Feinstein AR: Risk for systemic em on the risk of stroke in patients with 29 Jonasson R. Jonsson B. Nordländer bolization of atrial fibrillation with R. Orinius E. Szamosi A: Rate of out mitral stenosis. Am J Cardiol nonrheumatic atrial fibrillation. N progression of severity of valvular Engl J Med 1990:323:1505-1511. 1990:65:1112-1116. aortic stenosis. Acta Med Scand 17 Segal JP, Harvey P. Gurel T: Diag 8 The Stroke Prevention in Atrial Fi 1983:213:51-54. brillation Investigators: Predictors nosis and treatment of primary myocardial disease. Circulation 30 Levy D. Plehn JF. Wolf PA, Garri of thromboembolism in atrial fibril son RJ. Käse CS. Abbott RD. Kan1965;27:837-845. lation. II. Echocardiographie fea ncl WB. Castelli WP: Left ventricu 18 Koga Y. Itaya K. Toshima H: Prog tures of patients at risk. Ann Intern lar mass and risk of stroke in men. nosis in hypertrophic cardiomyopa Med 1992;116:6-12. Circulation 1987;76(suppl IV): 143. thy. Am Heart J 1984:108:351-355. 9 The Scandinavian Committee on 19 Wiener I. Hafner R. Nicolai M, 31 Petersen P. Kastrup J. Videbaek R. ECG Classification: The Minnesota Boysen G: Cerebral blood flow be Lyons H: Clinical and échocardio Code for ECG Classification. fore and after cardioversion of atrial graphie correlates of systemic em Adaption to Cr leads and modifica fibrillation. J Ccreb Blood Flow Me bolization in nonrheumatic atrial fi tion of the code for ECGs recorded tab 1989:9:422-425. brillation. Am J Cardiol 1987:59: during and after exercise. Acta Med 177. Scand 1967(suppl):481. 20 Hofmann T. Kasper W, Meinertz 10 Sahn DG, DeMaria A. Kisslo J, AG, Just H: Echocardiographie Wevman AE: Recommendations re evaluation of patients with clinically garding quantification in M-mode suspected arterial emboli. Lancet echocardiography: Results of a sur 1990:336:1421-1424. vey of échocardiographie measure ments. Circulation 1978:58:1072— 1083.
Cardiology 1992;81:189-195
Departments of Medicine, Mariestad Hospital, St Goran Hospital, Sabbatsberg Hospital, and Danderyd Hospital, Sweden
Keyw ords
Stroke Atrial fibrillation Echocardiography
Echocardiographie Findings and the Increased Risk of Stroke in Nonvalvular Atrial Fibrillation
Abstract
We studied whether cardiac abnormalities contribute to the increased risk of stroke in patients with nonvalvular atrial fibrillation (NVAF). M-mode and 2D echocardiography were performed in four age- and gender-matched groups: 20 stroke patients with NVAF, 20 patients with NVAF who had not suf fered a previous stroke, 20 stroke patients with sinus rhythm, and 40 healthy controls. Their mean age was 77 years. The two groups with atrial fibrillation differed from healthy controls in that they had more 2D-echocardiographic findings of severe left-ventricular-wall-motion abnormalities (p < 0.05) and tended more often to have enlarged left ventricles, and hyper trophic and congestive cardiomyopathy. Left atrial diameter was 47 mm compared to 41 and 39 mm in the two groups with sinus rhythm (p < 0.001). Intracardiac thrombi were only found in the two atrial-fibrillation groups (with stroke: 15% without stroke: 5%). Aortic sclerosis was common in all groups (30-60%), as was mitral annulus calcification (1020%). The only significant difference between the two atrialfibrillation groups was a higher frequency of earlier ischemic heart disease in the stroke group. Both atrial-fibrillation groups had cardiac abnormalities predisposing for embolic as well as thrombotic stroke.
Introduction
Chronic atrial fibrillation is one of the main risk factors for stroke [ 1]. The etiology is thought to be embolic from left atrial throm
The study was conducted at the Department of Medicine, Danderyd Hospital. Karolinska Institute. Stockholm. Sweden.
Received: May 26. 1992 Accepted: May 28,1992
bi. Clinical evidence supports an atherothrombotic mechanism in 25-67% of strokes in the aged nonvalvular atrial fibrillation (NVAF) population [2, 3]. NVAF patients also have multiple coagulation disturbances
Clacs Gustafsson. MD Department of Mcdicinc Mariestad Hospital Box 4 11 S-542 24 Mariestad (Swcden)
© 1992 S. Karger AG. Basel 0008-6312/92/ 0815-0189Î2.75/0
Downloaded by: Stockholm University Library 130.237.165.40 - 12/18/2018 10:41:54 AM
Claes Gu.stafs.sona Mona Britton b Fredrik Brolundc Sven VEriksson6 Kaj LindvalF
Materials and Methods Group 1 consisted of 20 consecutive patients with electrocardiographically verified chronic (> 1 year) atrial fibrillation, no mitral stenosis on echocardiogra phy. and a previous stroke. Group 2 comprised 20 patients matched for gender, age (± 2 years) and dura tion (± 2 years) of NVAF but who had not suffered a previous stroke. They were randomly selected outpa tients from a data register of patients with NVAF. Mean duration of NVAF in the two groups was 7.1 and 6.3 years, respectively (NS). Group 3 was made up of 20 patients with SR who had had a previous stroke, matched to group 1 for gender and age. No patient had malignant disease or overconsumed alcohol. Group 4. the control group, consisted of 40 gender- and agematched healthy subjects randomly selected from the population register. None of the control patients had a
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history, physical signs, or electrocardiographic find ings indicating previous thromboembolic events, isch emic heart disease, hypertension, atrial fibrillation, diabetes mellitus. malignancy, current infection, or inflammatory disease. Mean age in all groups was 77 (range: 62-84) years. Electrocardiograms were classi fied according to the Minnesota code [9]. Echocardio grams were obtained with an Irex III phased array sec tor scanner with a 2.25-MHz transducer. The M-mode registrations were guided by a cross-sectional image of the left ventricle and atrium. The conventional Mmode echocardiographic-registration technique was standardized according to American Society of Echo cardiography criteria [ 10]. Each patient was examined lying in the left lateral supine position. 2D echocardio grams were obtained for all patients in three standard views: parasternal (short and long axes), apical (two and four chamber), and subxiphoid. The 2D echocar diograms were recorded on a video recorder and ana lyzed by two independent observers unaware of the patient history'. The criterion for mitral annulus calci fication (MAC) was a bright dense linear echo behind the mitral valve with a motion similar to that of the posterior left ventricular wall. Mitral valve prolapse was diagnosed from 2D echocardiography if the ante rior or posterior mitral leaflet bulged through a line extending from the base of the aortic valve to the athcroventricular junction [II]. Aortic sclerosis was de fined as dense echogenic structure presumed to be caused by fibrous or calcification changes in the aortic valves. In aortic stenosis the commissures are more or less fused, while in aortic sclerosis they can open to the aortic ring. Left ventricular ejection time (LVET) was defined as the time elapsed from opening to closure of the aortic valve [ 12], Left ventricular preejection time (LPET) was defined as the time elapsed from the beginning of the complex of the electrocardiogram (QRS) to the opening of the aortic valve. Systolic-timcinterval index (STI) was calculated as follows: STI = LPET/LVET [12]. Percent left ventricular fractional shortening was computed [100(LVDD - LVSD)/ LVDD] where LVDD = left-ventricular diastolic di ameter and LVSD = left-ventricular systolic diameter and together with STI was used as an indicator of left ventricular systolic function. Left ventricular muscular mass was calculated according to Troy et al. [13]. Informed consent was obtained from all partici pants. and the study protocol was approved by the regional ethics committee.
Gustafsson/Britton/Brolund/Eriksson/ Lindvall
Echocardiography in NVAF Stroke
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that may contribute to their increased risk of stroke [4], Patients with atrial fibrillation without any concomitant risk factors, termed 'lone atrial fibrillation', have been shown to carry a low risk of thromboembolism [5. 6], Left atrial diameter > 4 0 mm. female gender and underlying heart disease have been found to be independent risk factors for systemic embolization in referred patients with atrial fibrillation [7], Left ventricular dysfunction and the size of the left atrium were indepen dent predictors of later thromboembolism in the Stroke Prevention in Atrial Fibrillation (SPAF) study [8], The role and prevalence of possible cardiogenic embolic sources in the NVAF group need to be investigated further. We therefore studied embolic sources and cardiac function in NVAF patients with and without previous stroke, in stroke patients with sinus rhythm (SR), and in healthy con trols to look for possible disturbances that might explain the increased risk of stroke among the NVAF patients. The second aim of our study was to investigate whether NVAF patients with stroke differed from NVAF pa tients without a previous stroke and if em bolic-prone group could be identified.
Table 1. Prevalence o f risk factors in patients with N V A F with and w ithout stroke, stroke p atients with SR and age-matched controls Risk factors
Mean age. years Congestive heart failure Hypertension Ischemic heart disease Diabetes mellitus Hyperlipidemia Smoking
NVAF
SR
with previous stroke withouth stroke (n = 20) (n = 20)
with previous stroke comtois (n = 40) (n - 20)
77 13(65)*** 7(35) 8 (40)* 3(15) 2 ( 10) 7(35)
77
77 13(65)*** 4 (20)
2(101 2 ( 10) 2 ( 10) 5 (25)
2 ( 10) 6(30) 4 (20) 2 ( 10) 2 ( 10) 5(25)
77
0 0 0 0 0 4(10)
Statistics Difference of proportions was tested with the x: test including Yate’s correction. Continuous data are expressed as means and as interquartile intervals. The significance of differences in échocardiographie vari ables between groups was tested using one-way analy sis of variance and a two-tailed t test. Coefficients of skewness and kurtosis were used to test deviations from a normal distribution and logarithmic transfor mation of the individual values of skewed variables was performed before statistical computations and sig nificance testing. The levels of significance considered were 0.1, 1. and 5 %. and not significant (NS).
Results
Cardiovascular risk factors in the four groups are presented in table 1. As expected, congestive heart failure was significantly more common in the two groups of NVAF patients. Ischemic heart disease was signifi cantly more common in the NVAF stroke group than in the NVAF group without stroke. Definite or suspected left atrial or ven tricular thrombosis was detected in 15% of NVAF patients with stroke and 5% (NS) of NVAF patients without stroke on 2D echo
cardiography (table 2). No patient with SR had thrombosis. Left atrial diameter, mea sured by M-mode echocardiography, was 47 mm in both NVAF groups and signifi cantly larger than in the groups with SR (ta ble 3). Atria were larger than 40 mm in 85 and 90% in the two NVAF groups as compared to 60% in the SR stroke group and 50% in the control group (p < 0.01). No correlation be tween duration of NVAF and left atrial diam eter could be found (r2 = 0.045). The M-mode and 2D echocardiography re sults in the NVAF groups indicated that more patients had markedly dilated hearts with thinner walls and severer disturbances of left ventricular wall motion (tables 2. 3). 2D echocardiography showed alterations from normal findings in 65-75% in all groups. A high proportion of patients in all groups (30-60%) had aortic sclerosis. Mild to moderate aortic stenosis was found in 0-15%. M-mode and 2-D echocardiography have lower specificity than Doppler investigation for the diagnosis of aortic stenosis and some cases might have been overdiagnosed. MAC was found in 10-20% in all groups.
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Values in parentheses are percentages. * p < 0.05 vs. NVAF without stroke: *** p < 0.001 vs. SR patients with previous stroke.
Table 2 . 2-D échocardiographie findings in patients with NVAF with and w ithout stroke, stroke patients with SR and age-matched controls NVAF
SR
with previous stroke without stroke (n = 20) (n = 20)
with previous stroke controls (n « 20) (n = 40)
2-D findings
Left atrial thrombus Left ventricular thrombus Severe wall motion abnormalities Congestive cardiomyopathy Left ventricular dilatation Hypertrophic cardiomyopathy None of the above findings Mitral annulus calcification Mitral valve prolapse Mitral sclerosis Aortic sclerosis Aortic stenosis
1(5)
1 (5)
2 ( 10)
0 6 (30)* 0
5(25)* 3(15) 3(15) 3(15) 14(70) 4(20) K5) 1 (5) 8(40) 2 ( 10)
0 0
0 0
1(5) 1(5)
2(5)
0
0 0
3(15) 1(5) 13(65) 4(20) 1(5) 1(5) 6(30)
1(3)
0
16(80) 2 ( 10)
0 2 ( 10) 12(60) 3(15)
0
37 (92) 7(18) 1(3) 4(10) 20(50) 4(10)
Values within parentheses are percentages. * p < 0.05 vs. controls, by y}.
Table 3. M-mode échocardiographie variables in patients with NVAF with and without stroke, stroke patients with SR and age-matched controls M-mode findings
NVAF
Left atrial diameter, mm Left ventricular diastolic diameter, mm Right ventricular diastolic diameter, mm Septal will thickness, mm Posterior wall thickness, mm Left ventricular muscular mass, g STI Left ventricular fractional shortening, %
with previous stroke (n = 20)
without stroke (n = 20)
mean
mean
47***. o 53
20 10**°°
9» 327° 0.48 32
1st—3rd quartiles
^•y***, o
40-55 47-57 10-23
51 2 s***. o°° 10°
8-12 8-10
10
229-309 0.31-0.36 27-37
327° 0.38 32
1st—3rd quartiles
44-52 44-57 20-29
8-12 9-10 218-361 0.36-0.41 24-36
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*■**• *** p < 0.05.0.01,0.001. respectively, vs. controls by two-tailed t test: o. °°.°°° p < o.05,0.01,0.001, respectively, vs. stroke patients with SR.
Our aim was to study cardiac disturbances that could explain the high risk of stroke in NVAF patients. All four groups were well matched with respect to age and gender. Congestive heart failure was more frequent in the two NVAF groups, and ischemic heart disease in the NVAF stroke group. Both are well-known risk factors for stroke in the popu lation [14]. The AFASAK study [15] and the Boston Area Anticoagulant Study [16] found previous myocardial infarction and angina pectoris, respectively, to be predictors of stroke. Severe left-ventricular-wall-motion abnormalities were more common in both our NVAF groups. Data from the SPAF study showed such abnormalities to be a risk factor for stroke, as were hypertension, recent con
SR with previous stroke (n = 20) mean
1st—3rd
controls (n = 40) mean
1st—3rd quartiles
39 51 15
34-44 47-55 11-18
11 10
10-12
10-12 298-440 0.33-0.41 28-42
336 0.37 36
quartilcs 41 52 16
12 11* 398* 0.40 37
38-45 48-58 10-19 10-13
9-10 276-381 0.29-0.41 33-40
gestive heart failure, and earlier stroke or transient ischemic attack (TI A) [6,8]. It seems that in the NVAF population the same risk factors for stroke operate as in the population in general. Some of the conditions might pre dispose to thrombus formation in the left ven tricle but they could also be independent markers of an atherosclerotic process in which atrial fibrillation and stroke arc others. Stroke is common in patients with conges tive cardiomyopathy and thought to be re lated to intracardiac thrombi [ 17], Two thirds of NVAF stroke patients with echocardiographic signs of congestive cardiomyopathy had left ventricular thrombi. One stroke pa tient with SR had congestive cardiomyopathy without a ventricular thrombus. Hypertro phic cardiomyopathy associated with a 510% yearly risk of embolism in patients with atrial fibrillation was only found in the NVAF groups [18]. The only left atrial thrombus found was in a patient in the NVAF stroke group. This finding supports those in other transthoracic echocardiographic studies and is an underestimation, as shown by trans esophageal echocardiography [19, 20], Left atrial diameter has been shown to increase with increased duration of NVAF [21], The fact that the NVAF patients in our study had had NVAF for a minimum duration of 1 year could explain why we found no association with duration. Left atrial diameter was in creased in both NVAF groups. This has been confirmed by some authors [19, 22] but not by others, who found larger atria in the stroke group of NVAF patients [23. 24]. Atrial diam eter > 4 0 mm has been shown to be the stron gest predictor of increased risk of emboliza tion [7], Left atrial size was also an indepen dent predictor of later thromboembolism in the SPAF study but not in the other two large primary-prevention studies [8, 15. 16]. MAC is associated with an increased risk of retinal emboli and TIA but is more often a
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Discussion
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atria were significantly larger in both NVAF groups. These results in the two NVAF groups indicate that cardiac function is impaired with a poorer cardiac output. This predis poses for intracardiac thrombus formation and this was verified by the greater prevalence of thrombi found in the NVAF groups. A lower cardiac output also decreases cerebral blood flow [31] and this, in combination with atherosclerosis, may predispose for thrombus formation. This risk is further increased by the blood hypercoagulability that also accom panies NVAF [4], Thus the NVAF patients are at a high risk for both embolic and thrombotic stroke.
Acknowledgements This study was supported by grants from the Foun dations of Serafimerlasarettet. Clas Groschinskv. Loo and Hans Osterman. Fredrik and Ingrid Thuring. Eirs 50-years Foundation. 1987 years Foundation for Stroke Research and Fonus.
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marker of generalized atherosclerosis [25]. About half of the patients with MAC and cerebral ischemia have coexistent atrial fibril lation [26]. MAC was an obvious risk factor for stroke in the Boston study, but not in the SPAF or AFASAK studies [8, 15, 16]. In our study, no difference in the frequency of MAC was found between the groups. The association between mitral valve pro lapse and stroke has only been established for young adults and therefore our low frequency was not surprising. Aortic sclerosis might be a rare source of small calcified emboli [27]. The prevalence increases with age [29], Angiography has shown the aortic valve area to contract by 0.1cm 2/ycar [30], The higher frequency of these age-related changes in echogenicity on the aortic valves in our study compared to other echocardiographic studies is probably due to the higher mean age of our patients. We found no patients with left ventricular aneurysm or myxoma. Left ventricular hypertrophy is a wellknown risk factor for stroke [23, 30], and stroke has been found to be associated with left ventricular hypertrophy in patients with chronic atrial fibrillation [23], In our study, the stroke group with SR. but not the NVAF stroke group, had significantly higher left ven tricular muscular mass. We found at least one aberrant echocardio graphic finding in 65-75% of subjects in all four groups. This high frequency was presum ably due to the high age of the subjects, show ing that age has to be considered when defin ing ‘normality’. Patients in both NVAF groups differed from those in the groups with SR in that more of them had a history of congestive heart fail ure. The patients in the NVAF stroke group had ischemic heart disease significantly more often. Severe abnormalities of left-ventricuiar-wali motion were more frequent and left
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