Background
It is important to evaluate left atrial appendage (LAA) dysfunction for primary and secondary prevention of stroke in patients with atrial fibrillation (AF). LAA dysfunction can reportedly be evaluated by LAA wall velocity (LAWV) measured by transthoracic echocardiographic (TTE) imaging. The aim of this study was to examine whether TTE-LAWV can predict long-term cerebrovascular events in patients with ischemic stroke with AF.
Methods
TTE imaging and transesophageal echocardiographic imaging were performed <7 days after onset in 179 consecutive patients with stroke with AF. TTE-LAWV was measured using Doppler tissue imaging at the LAA tip from the parasternal short-axis view on TTE imaging, as previously reported. All patients were followed up prospectively.
Results
Cerebrovascular events were defined as cerebrovascular death and/or recurrent ischemic stroke requiring hospitalization. There were 32 cerebrovascular events during a median follow-up period of 397 days. TTE-LAWV was significantly lower in patients with cerebrovascular events than in patients without (8.3 ± 2.8 vs 11.3 ± 4.0 cm/sec, P < .01). Cox multivariate hazard analysis showed that low TTE-LAWV (<8.7 cm/sec) was an independent predictor of cerebrovascular events (hazard ratio, 3.460; P < .05). Kaplan-Meier analysis showed that cerebrovascular event rates were significantly higher in patients with low TTE-LAWV (<8.7 cm/sec) compared with those with high TTE-LAWV (34% vs 7%, P < .01).
Conclusions
Impaired LAA function was associated with long-term cerebrovascular events in patients with stroke with AF. TTE-LAWV may be a feasible parameter for risk stratification in patients with AF.
The National Institute of Neurological Disorders and Stroke has characterized cardioembolic stroke as an important clinical issue because it is the most common cause of death in cases of acute ischemic stroke. It is well known that the left atrial (LA) appendage (LAA) is a major thromboembolic source in patients with stroke with atrial fibrillation (AF). Many clinical studies have shown a close relationship between LAA thrombus formation and LA mechanical remodeling, on the basis of findings from transesophageal echocardiographic (TEE) imaging. Spontaneous echocardiographic contrast (SEC) and LAA peak flow velocity measured by TEE imaging have been shown to be useful for evaluating LAA dysfunction. However, TEE imaging may not be routinely performed to quantify the risk for stroke in patients with AF, because it is a semi-invasive procedure. Although transthoracic echocardiographic (TTE) imaging can be widely used as a screening procedure because of its noninvasive nature, it is commonly thought to be difficult to detect LAA thrombus and evaluate LAA dysfunction using TTE imaging.
Doppler tissue imaging (DTI) reflects regional myocardial function and is also reportedly useful for evaluating LAA function. Recently, we and others reported that LAA wall velocity (LAWV) measured using TTE imaging can noninvasively evaluate LAA function. However, it is still unclear whether TTE-LAWV is associated with long-term cerebrovascular events in patients with ischemic stroke with AF. In the present study, we compared TTE-LAWV with conventional markers of LAA dysfunction and investigated whether decreased TTE-LAWV can predict cerebrovascular events.
Methods
Study Patients
Of 420 consecutive patients with acute ischemic stroke, a total of 179 who satisfied all of the following criteria were enrolled: (1) abrupt stroke onset while awake with maximal neurologic deficit; (2) admission within 24 hours of symptom recognition; (3) history of AF before admission and/or the presence of transient AF documented on continuous electrocardiographic monitoring during hospitalization; (4) both TTE and TEE imaging performed within 7 days (mean, 6 ± 1 days) of onset; (5) success in measuring TTE-LAWV; (6) no in-hospital death caused by extensive stroke progression, no malignant tumor, and no severe infectious disease; and (7) no severe mitral regurgitation, mitral stenosis, or previous mitral valve surgery ( Figure 1 ). Paroxysmal AF was detected in 66 patients (37%) (40 of 66 were in sinus rhythm at the time of TEE imaging), and chronic AF was detected in 113 patients (63%).
The admission assessment included the prevalence of risk factors for cerebral infarction, clinical ischemic stroke category (National Institute of Neurological Disorders and Stroke), and disease severity using the National Institutes of Health Stroke Scale. The study patients included 76 with cardioembolic stroke (42%), 46 with atherothrombotic infarction (26%), 16 with lacunar infarction (9%), and 41 with undetermined etiology (23%).
We previously demonstrated that TTE-LAWV is useful to detect LAA dysfunction and LAA thrombus, retrospectively. In the present study, we prospectively investigated whether TTE-LAWV is useful for risk stratification in patients with ischemic stroke with AF and for predicting cerebrovascular events. We classified the patients into two groups on the basis of the cutoff value of TTE-LAWV for predicting LAA thrombus formation, as previously reported. We entered 54 patients with AF who were included in the previous study into the present study. The local ethics committee approved the study protocol, and informed consent was given by all subjects.
Echocardiography
TTE imaging was done using a Hewlett-Packard Sonos 7500 ultrasound system (Hewlett-Packard Corporation, Palo Alto, CA) equipped with a sector transducer (carrier frequency, 2.5 or 3.75 MHz). Using standard views and techniques, LA dimension (LAD), left ventricular (LV) end-diastolic dimension, and LV fractional shortening (LVFS) were measured. The severity of mitral regurgitation was defined using a multiparametric approach according to current guidelines and graded on a four-point scale: mild = 1+, moderate = 2+, moderate severe = 3+, and severe = 4+. Patients with moderate severe and severe mitral regurgitation were excluded. Mitral stenosis was defined by mitral valve area measured by pressure half-time < 1.5 cm 2 .
A 5-MHz phased-array multiplane probe was used for TEE imaging. Patent foramen ovale and atrial septal aneurysm were determined as previously reported. SEC was considered present when dynamic “smokelike” echoes were seen within the atria that could not be eliminated by changes in gain settings. LAA thrombus was diagnosed when a fixed or mobile echogenic mass could be clearly differentiated from the wall of the left atrium or LAA.
LAA emptying flow velocity (eV) was assessed using pulsed-wave Doppler with the sample volume placed 1 cm distal from the mouth of the appendage by TEE imaging. Peak flow velocity within each RR interval was obtained by scanning the appendage at angles from 0° to 90°. All echocardiographic measurements were obtained as the mean of five consecutive cardiac cycles.
LAWV Measurement
LAWV, defined as LAA peak wall velocity, was measured using DTI with the sample volume of pulsed-wave Doppler placed on the LAA tip, as reported previously. DTI records showed that a triphasic or biphasic wave pattern was seen in sinus rhythm, and a multiphasic fibrillatory wave pattern was seen in AF. LAWV was defined as the averaged peak wall velocities at diastole in five consecutive cardiac cycles. We could not measure TTE-LAWV in 20 patients (5%), because of obesity, chronic obstructive pulmonary disease, or emaciation, and these patients were excluded from the study.
All findings were evaluated by two independent, experienced echocardiologists who did not know the patients’ clinical and other characteristics. All echocardiographic measurements obtained by the two echocardiologists had good reproducibility. The intraobserver and interobserver reliability of TTE-LAWV was assessed in 20 patients by two echocardiologists, each repeated once. The intraclass correlation coefficient for mean intraobserver reliability of TTE-LAWV was 98.6% and for mean interobserver reliability of TTE-LAWV was 98.9%.
Aortic and Carotid Echographic Studies
Aortic images were obtained using TEE imaging after the cardiac examination. The prevalence of a protrusion > 5 mm and/or mobile plaques in the arch were examined.
Bilateral carotid artery imaging was performed using a 7.5-MHz linear transducer connected to the Sonos 7500 system. The prevalence of protruding plaque with 50% luminal stenosis in the common and/or proximal internal carotid artery was examined.
Hemostatic Markers
Blood samples were obtained at the time of the echocardiographic studies. General biochemical parameters were measured using routine laboratory methods.
End Points
Patients were prospectively followed until the recurrence of cerebrovascular events, and no patients were lost to follow-up after discharge. Cerebrovascular events included cerebrovascular death and recurrent ischemic stroke requiring hospitalization.
Statistical Analysis
Results are expressed as mean ± SD for continuous variables and as the percentages of total patients for categorical variables. Skewed variables are expressed as medians and interquartile ranges. Patient characteristics, echocardiographic parameters, and hemostatic markers were compared between patients with and without stroke recurrence using Student’s t tests for unpaired continuous variables and χ 2 tests for categorical variables. We used the cutoff value of TTE-LAWV (8.7 cm/sec) for detecting LAA thrombus formation to predict cerebrovascular events. If data were not distributed normally, the Mann-Whitney U test was used. Simple linear regression analysis was used for comparisons between TTE-LAWV, TEE-LAWV, and LAA eV. Bland-Altman analysis was performed to provide an analysis of agreement between TTE-LAWV and TEE-LAWV. To determine independent predictors of cerebrovascular events for all patients, we performed univariate Cox proportional-hazard analysis for all variables. Then, significant variables selected in the univariate analysis were entered into the multivariate analysis. The cerebrovascular event-free curve was prepared using the Kaplan-Meier method, and the log-rank test was used to compare the cerebrovascular event-free survival in patients with high TTE-LAWV and low TTE-LAWV. P values < .05 were considered significant.
Results
Patient Characteristics and Clinical Outcomes
The median follow-up period was 397 days (range, 31–1,200 days). No patients were lost to follow-up. There were three nonischemic cerebrovascular deaths (one from pulmonary fibrosis and two from cancer) and 32 cerebrovascular events (18%; 28 hospitalizations for stroke recurrence and four deaths). No patients had hemorrhage events in cerebrovascular deaths. No patients had ischemic heart disease during follow-up. Twenty-six cerebrovascular events (15%) occurred within 12 months of initial admission.
The baseline characteristics of the 179 patients with ischemic stroke are shown in Table 1 . The mean age and CHADS 2 score before stoke onset were 72 ± 11 years and 2.0 ± 1.3, respectively. The mean prothrombin time international normalized ratio was 1.61 ± 0.55. Relatively low-intensity warfarin treatment (prothrombin time international normalized ratio, 1.6–2.6) was recommended for the prevention of stroke in elderly Japanese patients with nonvalvular AF in the guidelines of the Japanese Circulation Society. There were 52 patient with poor LV systolic function (LVFS < 30%) in the present study.
| Variable | Value |
|---|---|
| Age (y) | 72 ± 11 |
| Men/women | 123/56 |
| Heart rate (beats/min) | 79 ± 20 |
| Hypertension | 128 (72%) |
| Diabetes mellitus | 46 (26%) |
| Dyslipidemia | 66 (37%) |
| Current smoking | 98 (55%) |
| Prior stroke | 35 (20%) |
| Ischemic heart disease | 7 (4%) |
| NIHSS score | 5.2 ± 6.3 |
| CHADS 2 score (before onset) | 2.0 ± 1.3 |
| Medication (before onset) | |
| Antiplatelet agents | 64 (36%) |
| Anticoagulant agents | 63 (35%) |
| PT-INR | 1.61 ± 0.55 |
| NINDS clinical categories | |
| Cardioembolic stroke | 76 (42%) |
| Atherothrombotic stroke | 46 (26%) |
| Lacunar stroke | 16 (9%) |
| Others or undetermined | 41 (23%) |
Table 2 shows that patients with low TTE-LAWV (<8.7 cm/sec) had significantly higher CHADS 2 scores after onset than those with high TTE-LAWV (≥8.7 cm/sec). There were no significant differences between the two groups in age, prevalence of hypertension, diabetes mellitus, dyslipidemia, current smoking, National Institutes of Health Stroke Scale, and the use of oral antithrombotic medications.
| Variable | High LAWV (≥8.7 cm/sec) ( n = 112) | Low LAWV (<8.7 cm/sec) ( n = 67) | P |
|---|---|---|---|
| Age (y) | 71 ± 11 | 74 ± 11 | .0655 |
| Men/women | 82/30 | 41/26 | .0932 |
| Heart rate (beats/min) | 76 ± 22 | 82 ± 15 | .0524 |
| Hypertension | 77 (69%) | 51 (76%) | .2905 |
| Diabetes mellitus | 28 (25%) | 18 (27%) | .7822 |
| Dyslipidemia | 43 (38%) | 23 (34%) | .5854 |
| Current smoking | 59 (53%) | 38 (56%) | .7906 |
| Ischemic heart disease | 4 (4%) | 3 (4%) | .7560 |
| NIHSS score | 5.0 ± 6.1 | 5.5 ± 6.6 | .7537 |
| CHADS 2 score (after onset) | 3.4 ± 0.9 | 3.7 ± 0.8 | .0254 |
| Medication (before onset) | |||
| Antiplatelet agents | 54 (48%) | 25 (37%) | .5162 |
| Anticoagulant agents | 35 (31%) | 28 (42%) | .1530 |
| PT-INR | 1.53 ± 0.50 | 1.72 ± 0.60 | .1867 |
| Blood markers | |||
| BNP (pg/mL) | 85 (36−173) | 128 (73–245) | .0160 |
| C-reactive protein (mg/dL | 0.2 (0.1−1.0) | 0.6 (0.1−2.5) | .0072 |
| Fibrinogen (mg/dL) | 379 ± 156 | 469 ± 217 | .0016 |
| Plasminogen (%) | 95 ± 18 | 93 ± 23 | .5418 |
| PAI-1 (ng/mL) | 17 ± 14 | 18 ± 11 | .7875 |
| d -dimer (μg/mL) | 0.8 (0.4−2.1) | 1.5 (0.7−3.4) | .0071 |
| FDP (mg/mL) | 3.3 (2.5−5.8) | 4.8 (3.4−7.5) | .0022 |
| Echocardiography | |||
| LAD (mm) | 42 ± 6 | 48 ± 8 | <.0001 |
| LVDd (mm) | 48 ± 6 | 49 ± 7 | .2604 |
| LVFS (%) | 34 ± 7 | 31 ± 8 | .0224 |
| Atrial septal aneurysm | 10 (9%) | 0 (0%) | .0510 |
| Patent foramen ovale | 15 (13%) | 6 (9%) | .3719 |
| Aortic plaque | 15 (13%) | 9 (13%) | .9878 |
| Carotid plaque | 12 (11%) | 7 (10%) | .9553 |
| SEC | 10 (9%) | 43 (64%) | <.0001 |
| LAA thrombus | 10 (9%) | 26 (39%) | <.0001 |
| LAA eV (cm/sec) | 46 ± 19 | 14 ± 9 | <.0001 |
| TEE-LAWV (cm/sec) | 12.5 ± 5.5 | 8.3 ± 2.5 | <.0001 |
| TTE-LAWV (cm/sec) | 12.9 ± 9.5 | 7.1 ± 1.0 | <.0001 |
| Stroke recurrence | 6 (6%) | 26 (33%) | <.0001 |
There were no significant differences in the use of antiplatelet drugs and warfarin between high TTE-LAWV and low TTE-LAWV after the first stroke. Seventy-three patients with cardioembolic stroke (96%) and 93 patients with noncardioembolic stroke (90%) were receiving warfarin treatment.
Blood Markers
Patients with low TTE-LAWV had significantly higher levels of brain natriuretic peptide, C-reactive protein, fibrinogen, d -dimer, and fibrinogen degradation products than those with high TTE-LAWV. There were no significant differences between the two groups in plasminogen and plasmin activator inhibitor–1 ( Table 2 ).
Echocardiographic Parameters
Patients with low TTE-LAWV had larger LADs and lower LVFS than those with high TTE-LAWV. LAA eV was lower and SEC more prevalent in patients with low TTE-LAWV compared with those with high TTE-LAWV. As a result, there was a higher prevalence of LAA thrombus in patients with low TTE-LAWV than in those with high TTE-LAWV. There were no significant differences between the two groups in LV end-diastolic dimension, the prevalence of atrial septal aneurysm and patent foramen ovale, and significant aortic or carotid atherosclerotic plaques ( Table 2 ).
TTE-LAWV and Long-Term Recurrence of Ischemic Stroke
We previously reported that the waveform of TTE-LAWV was quite similar to that of TEE-LAWV, as to appear as a specular image, and patients with LAA thrombus frequently had smaller amplitudes of DTI waveforms compared with those without LAA thrombus. In the present study, there were significant correlations between TEE-LAWV and LAA eV ( Figure 2 A). TTE-LAWV was also correlated with LAA eV ( Figure 2 B). The Bland-Altman plot showed good agreement of LAWV assessment between TTE and TEE ( Figure 2 C).
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