An In Vitro Assay for Sonothrombolysis Based on the Spectrophotometric Measurement of Clot Thickness.

OBJECTIVES: For improved thrombolysis therapy based on ultrasound irradiation, researchers and practitioners would strongly benefit from an easy and efficient in vitro assay system of thrombolysis activity involving irradiated ultrasound. For the present study, we designed a new in vitro sonothrombolysis assay system using a sheet-type clot. METHODS: We designed a cell for clot assay, and we confirmed that this clot cell did not significantly intervene in the acoustic field. Using human plasma, we made a sheet-type clot in the cell. Clot thicknesses at 100 points along 4 directions were measured photometrically at a rate of approximately 4 points/s. RESULTS: The sonothrombolysis effects at 13 levels of ultrasonic intensity were obtained with only one sheet-type clot. With this method, we used a clinically oriented probe at 0.7 and 0.3 W/cm2 to confirm that sonothrombolysis took place. CONCLUSIONS: We successfully established a new, easy, and efficient method for conducting in vitro sonothrombolysis assays. This method involves little intervention of either ultrasound reflection or standing waves in the clot cell. We believe that this new assay method is very useful for fundamental analyses of ultrasound's thrombolysis effects.

Hyperuricemia and transesophageal echocardiographic thromboembolic risk in patients with atrial fibrillation at clinically low-intermediate risk.

BACKGROUND: There is no clear consensus on thromboprophylaxis in patients with nonvalvular atrial fibrillation (AF) at low-intermediate thromboembolic risk. Although hyperuricemia is a risk factor for cardiovascular diseases, the relationship between serum uric acid (UA) levels and thromboembolic risk has not been fully elucidated in patients with AF. METHODS AND RESULTS: Serum UA levels and the score for congestive heart failure, hypertension, age, diabetes mellitus, prior stroke/transient ischemic attack, vascular disease and sex (ie, CHA2DS2-VASc score) were determined in 470 patients with nonvalvular AF who underwent transesophageal echocardiography (TEE) to evaluate their risk of thromboembolism. Serum UA levels were similar between the low-intermediate risk (CHA2DS2-VASc score=0 or 1) and high-risk (≥2) groups, although serum D-dimer levels were lower in the low-intermediate risk than in the high-risk group. Among patients at low-intermediate risk, serum UA levels were higher in those with TEE thromboembolic risk (TEE risk: low left atrial appendage flow, spontaneous echo contrast, thrombi, or aortic atherosclerosis) than in those without TEE risk. On multivariate analysis, the serum UA level was an independent predictor of TEE risk in AF patients at low-intermediate risk (odds ratio, 1.45; 95% confidence interval 1.09-2.00; P=0.016). CONCLUSIONS: The serum UA level was associated with thromboembolic risk on TEE in patients with nonvalvular AF at low-intermediate risk stratified by clinical risk factors.

Association between Right Ventricular Function and Exercise Capacity in Patients with Chronic Heart Failure.

BACKGROUND: The association between right ventricular function and exercise capacity in patients with chronic heart failure remains uncertain. Several studies very recently mentioned the association between right ventricular reserve and exercise capacity, whereas the implication of tricuspid annular plane systolic excursion (TAPSE) remains uninvestigated. We aimed to assess the impact of TAPSE on exercise capacity in cardiac rehabilitation candidates. METHODS: Data from patients with chronic heart failure who received cardiopulmonary exercise tests and transthoracic echocardiography prior to cardiac rehabilitation were retrospectively collected, and their association was investigated. RESULTS: A total of 169 patients with chronic heart failure (70.3 ± 11.7 years old, 74.6% men) were included. Tertiled tricuspid annular plane systolic excursion significantly stratified anaerobic threshold (10.2 ± 2.2, 11.4 ± 2.2, and 12.2 ± 2.8 mm; p < 0.01) and peak oxygen consumption (15.9 ± 4.5, 18.3 ± 5.3, and 19.8 ± 5.6 mm; p < 0.01). In the multivariate logistic regression analyses, TAPSE was an independent factor associated with anaerobic threshold and peak oxygen consumption (p < 0.05 for both). CONCLUSIONS: Right ventricular impairment was associated with reduced exercise capacity in patients with chronic heart failure. Such knowledge would be useful to estimate patients' exercise capacity and prescribe cardiac rehabilitation. Its longitudinal association and clinical implication need further studies.

Transesophageal echocardiographic thromboembolic risk is associated with smoking status in patients with atrial fibrillation.

BACKGROUND: Smoking is a risk factor for cardiovascular diseases, but it is unclear whether smoking status, including environmental tobacco smoke, increases stroke risk in patients with atrial fibrillation (AF). Abnormalities of the left atrium (LA) and aortic atherosclerosis, as detected by transesophageal echocardiography (TEE), are risk factors for stroke and thromboembolism in AF patients. We investigated the impact of smoking status on thromboembolic risk by TEE in patients with nonvalvular AF. METHODS: In 122 patients with AF (mean age, 63 years; chronic AF 50%) who underwent TEE before catheter ablation of AF or for detection of the potential cardioembolic source, urinary concentrations of cotinine and clinical variables including smoking status and the CHA2DS2-VASc score were determined. RESULTS: Severe aortic atherosclerosis and increased aortic wall thickness were more frequently detected by TEE in current smokers than in non-smokers (p<0.05), though these findings did not significantly differ between non-smokers and environmental smokers. Patients in AF rhythm during TEE, who were environmental smokers and at relatively low risk, as stratified by their CHA2DS2-VASc score (≤ 2), showed lower LA appendage flow velocity than those without environmental smoking (47±22 vs. 34±13 cm/sec, p<0.05). CONCLUSIONS: TEE findings indicated that smoking status could be associated with thromboembolic risk in patients with AF.

Impact of persistent smoking on long-term outcomes in patients with nonvalvular atrial fibrillation.

BACKGROUND: Although smoking is a risk factor for cardiovascular diseases, little is known about the impact of smoking on long-term outcomes in patients with atrial fibrillation (AF). METHODS: In 426 consecutive patients with nonvalvular AF (mean age, 66 years; 307 men; mean follow-up, 5.8±3.2 years), clinical variables including smoking status, CHADS2, and CHA2DS2-VASc score, incidences of cardiovascular events (stroke, myocardial infarction, or admission for heart failure), bleeding, and mortality were determined. RESULTS: Incidences of intracranial bleeding (0.7% vs 0.1%/year, p<0.01), all-cause mortality (4.9% vs 2.6%/year, p<0.01), and death from stroke (0.8% vs 0.2%/year, p<0.05) were higher in patients with history of smoking than in those without it. Incidence of intracranial bleeding was significantly higher in persistent smokers than in non-persistent smokers (1.2% vs 0.2%/year, p<0.01). History of smoking predicted all-cause mortality [hazard ratio (HR), 2.7; 95% confidence interval (CI), 1.7-4.5; p<0.01] and death from stroke (HR 4.7; 95% CI 1.0-22.3; p<0.05) independent of age, antithrombotic treatment, CHADS2, and CHA2DS2-VASc score. Persistent smoking predicted intracranial bleeding (HR 4.4; 95% CI 1.1-17.6; p<0.05) independent of age and antithrombotic treatment. CONCLUSIONS: Smoking status, independent of age, antithrombotic treatment, and clinical risk factors, predicted long-term adverse outcomes including bleeding events in patients with nonvalvular AF. There might be an obvious impact of persistent smoking on intracranial bleeding.

Clinical and transesophageal echocardiographic variables for prediction of thromboembolic events in patients with nonvalvular atrial fibrillation at low-intermediate risk.

BACKGROUND: There is no clear consensus about antithrombotic treatment in atrial fibrillation (AF) patients at low-intermediate thromboembolic risk. Transesophageal echocardiography (TEE) is useful for prediction of thromboembolic events in AF. METHODS AND RESULTS: Of 498 patients with nonvalvular AF, incidence of stroke, cardiac events, and mortality was investigated in 280 patients with CHADS(2) score 0 or 1 (mean age 64 years, mean follow-up 6.4 ± 3.1 years). Left atrial abnormality (low left atrial appendage flow, spontaneous echo contrast, or thrombi), complex aortic plaque (mobile, ulcerated, pedunculate, or thickness ≥ 4mm), or both were defined as TEE risk. The incidences of ischemic stroke, cardiovascular events, and death were higher in patients with TEE risk than in those without the risk (2.0%/year vs. 0.5%/year, p<0.05; 4.7%/year vs. 1.9%/year, p<0.01; and 4.7%/year vs. 2.0%/year, p<0.01, respectively). This was also true for patients with CHADS(2) score of 0 (1.7%/year vs. 0.3%/year, p<0.05; 4.1%/year vs. 1.6%/year, p<0.05; and 3.9%/year vs. 1.4%/year, p<0.01; respectively). On multivariate analysis, TEE risk predicted ischemic stroke, cardiovascular events, and mortality independently of clinical variables or CHADS(2) score. CONCLUSIONS: TEE could be useful for further stratification of patients with nonvalvular AF stratified at low-intermediate risk (CHADS(2) score 0 or 1) and could indicate who should receive anticoagulation treatment.

Transesophageal echocardiographic findings are independent and relevant predictors of ischemic stroke in patients with nonvalvular atrial fibrillation.

BACKGROUND AND PURPOSE: Not only clinical factors, including the CHADS(2) score, but also echocardiographic findings have been reported to be useful for predicting the risk of ischemic stroke in patients with nonvalvular atrial fibrillation (NVAF). However, it remains to be determined which of these factors might be more relevant for evaluation of the risk of stroke in each patient. METHODS: In 490 patients with NVAF who underwent transesophageal echocardiography (TEE), we examined the long-term incidence of ischemic stroke events (mean follow-up time, 5.7±3.3 years). For each patient, the predictive values of gender, the CHADS(2) risk factors (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, history of cerebral ischemia), the CHADS(2) score, and the findings on echocardiography, including TEE risk markers, were assessed. RESULTS: The ischemic stroke rate was significantly correlated with the CHADS(2) score (p<0.05). According to the results of univariate analyses, age ≥75 years, history of cerebral ischemia, CHADS(2) score ≥2, and presence of TEE risk were significantly correlated with the incidence of ischemic stroke. Cox proportional hazards regression analyses identified age ≥75 years and presence of TEE risk as significant predictors of subsequent ischemic stroke events in patients with NVAF. As compared with that in persons below 75 years of age without TEE risk, the ischemic stroke rate was significantly higher in persons who were ≥75 years of age with TEE risk (4.3 vs. 0.56%/year, adjusted hazard ratio=8.94, p<0.001). CONCLUSIONS: TEE findings might be more relevant predictors of ischemic stroke than the CHADS(2) score in patients with NVAF. The stroke risk was more than 8-fold higher in patients aged ≥75 years with TEE risk.

Relation of the severity of mitral regurgitation to thromboembolic risk in patients with atrial fibrillation.

BACKGROUND: Patients with atrial fibrillation (AF) are at risk for thromboembolism. Although mitral regurgitation (MR) could be protective against left atrial (LA) blood stasis, the relationship between the severity of MR and thromboembolic risk has not been clarified in patients with AF. METHODS: 271 patients with permanent AF underwent transesophageal echocardiography (TEE). The severity of MR was assessed by Doppler echocardiography. LA blood stasis on TEE and plasma D-dimer levels were used to evaluate the thromboembolic risk. RESULTS: Patients with severe MR (n=20) had significantly higher LA appendage peak flow velocity compared to those with no MR (n=114) and those with only mild MR (n=92) (p<0.05). The grade of LA spontaneous echo contrast (SEC) was lower in patients with severe MR compared to those with no, mild or moderate MR (severe MR 0.7±0.7 grade vs moderate MR 1.7±1.0 grade, mild MR 2.2±1.3 grade, and no MR 1.9±1.3 grade, p<0.05). Multivariate analysis revealed severe MR as a negative predictor of LA blood stasis on TEE findings (odds ratio 0.27; 95% confidence interval 0.09-0.86, p<0.05). By contrast, D-dimer level was significantly higher in patients with moderate MR compared to those with any other type of severity of MR (moderate MR 1.72±1.45 µg/ml vs severe MR 0.76±0.95 µg/ml, mild MR 0.97±1.09 µg/ml, and no MR 0.82±1.15 µg/ml, p<0.05). CONCLUSIONS: There is a protective effect of MR on LA blood stasis, but this beneficial effect on thromboembolic risk appears to be limited to patients with severe MR.

Chronic kidney disease and CHADS(2) score independently predict cardiovascular events and mortality in patients with nonvalvular atrial fibrillation.

Chronic kidney disease is a risk factor for cardiovascular events, but how it relates to the prognosis associated with clinical risk factors for thromboembolism in patients with nonvalvular atrial fibrillation (AF) is not well known. Estimated glomerular filtration rate (eGFR), score for congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and stroke/transient ischemic attack (CHADS(2)), and clinical outcomes of cardiovascular events were determined in 387 patients with nonvalvular AF (mean age 66 years, 289 men, mean follow-up 5.6 ± 3.2 years). Decreased eGFR (<60 ml/min/1.73 m(2)) combined with CHADS(2) score ≥2 was associated with higher all-cause (12.9% vs 1.4% per year, hazard ratio [HR] 6.9, p <0.001) and cardiovascular (6.5% vs 0.2% per year, HR 29.7, p <0.001) mortalities compared to preserved eGFR (≥60 ml/min/1.73 m(2)) combined with CHADS(2) score <2. This was also true for rates of cardiac events (cardiac death, nonfatal myocardial infarction, or hospitalization for worsening of heart failure, 10.4% vs 1.3% per year, HR 8.9, p <0.001), ischemic stroke (3.6% vs 0.2% per year, HR 11.0, p <0.001), and cardiovascular events (cardiac events and ischemic stroke, 13.6% vs 1.5% per year, HR 8.3, p <0.001). On multivariate analysis, CHADS(2) score ≥2, decreased eGFR, and male gender independently predicted all-cause mortality. In conclusion, combined eGFR and CHADS(2) score could be an independent powerful predictor of cardiovascular events and mortality in patients with nonvalvular AF. Long-term mortality, cardiac events, and stroke risk were >8 times higher when decreased eGFR (<60 ml/min/1.73 m(2)) was present with higher CHADS(2) score (≥2).

Significant impairment of left atrial function in patients with cardioembolic stroke caused by paroxysmal atrial fibrillation.

OBJECTIVE: Patients with cardioembolic stroke (CE) caused by paroxysmal atrial fibrillation (Paf) sometimes show normal sinus rhythm on admission, which makes it difficult to diagnose them as having CE. The present study examined the differences in echocardiographic findings between patients with CE caused by Paf (the Paf-CE group) and those with non-cardiogenic embolic ischemic stroke (the Non-CE group). METHODS: We examined thirty-two patients with embolic ischemic stroke presenting with a normal sinus rhythm upon admission to our hospital; 13 patients in the Paf-CE group and 19 patients in the Non-CE group. During admission, all patients underwent transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) at a normal sinus rhythm. The left atrial dimension, left ventricular end-diastolic dimension and left ventricular ejection fraction were measured using TTE. The left atrial appendage peak flow velocity (LAAPV), spontaneous echo-contrast in the left atrium (LASEC) and thrombus in the left atrium were evaluated using TEE. RESULTS: Among the clinical background characteristics, hypertension was significantly more frequent in the Non-CE group than in the Paf-CE group (p<0.01). Congestive heart failure was significantly more frequent in the Paf-CE group than in the Non-CE group (p<0.05). LAAPV was significantly lower in the Paf-CE group than in the Non-CE group (34.7 cm/s vs. 64.0 cm/s, p<0.01), and the LASEC grade was significantly higher in the Paf-CE group than in the Non-CE group (p<0.01). A thrombus in the left atrium was detected in two patients in the Paf-CE group, but no thrombi were detected in any of the patients in the Non-CE group. CONCLUSION: Echocardiographic evaluation is useful, as the above data indicate that the left atrial function is apparently impaired in patients with CE caused by Paf, even in a patient with an apparently normal sinus rhythm.

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

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 CHADS(2) score (an acronym for Congestive heart failure, Hypertension, Age >or=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 CHADS(2) score (p<0.001). Severity of aortic atherosclerosis also increased in correlation with an increase in the risk levels (p<0.001). Even at the comparable risk level, patients with chronic atrial fibrillation (AF) (n=268) had higher LASEC (p<0.001) and lower LAA flow velocity (p<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.

Accumulation of risk factors enhances the prothrombotic state in atrial fibrillation.

BACKGROUND: The present study was conducted to investigate the relation between the accumulation of the risk factors of thromboembolism and the levels of hemostatic markers in patients with nonvalvular atrial fibrillation (NVAF). METHODS: Five hundred ninety-one NVAF patients and 129 control subjects were categorized into low, moderate or high risk of thromboembolism, according to CHADS(2) index. One point each was given to patients with advanced age (> or =75 years), hypertension, congestive heart failure, and diabetes mellitus, and 2 points, to those with prior ischemic stroke or transient ischemic attack. Patients with CHADS(2) score of 0, 1 or 2, and > or =3 were classified as low, moderate and high risk, respectively. Levels of hemostatic markers (platelet factor 4, beta-thromboglobulin, prothrombin fragment F1+2 and D-dimer) were determined. RESULTS: Of 591 patients with NVAF, 302 were treated with warfarin (mean international normalized ratio 1.88). D-dimer levels increased as the risk level increased irrespective of warfarin use. Particularly, NVAF patients without receiving warfarin (n=289) had significantly higher D-dimer levels than control patients (e.g., for high risk patients, 175+/-144 vs 75+/-87 ng/ml, p<0.001), while NVAF patients receiving warfarin had intermediate levels (136+/-156 ng/ml). F1+2 levels increased as the risk level increased, and were significantly suppressed by warfarin. Levels of markers of platelet activation (platelet factor 4 and beta-thromboglobulin) were increased in NVAF patients but not affected by the risk level. CONCLUSION: Coagulation and fibrinolytic activity is increased along with the accumulation of the risk factors of thromboembolism in NVAF patients.

Thoracic aortic plaque enhances hypercoagulability in patients with nonrheumatic atrial fibrillation.

BACKGROUND: Patients with atrial fibrillation (AF) are at risk for thromboembolism, and coexistent cardiovascular diseases could affect their prothrombotic profiles. The relationship between plasma hemostatic markers and aortic atherosclerosis was determined in patients with AF or in sinus rhythm (SR). METHODS AND RESULTS: Sixty patients with nonrheumatic AF and 46 patients in SR who underwent transesophageal echocardiography and did not receive anticoagulant therapy constituted the study group. Markers for platelet activity (platelet factor 4 and beta-thromboglobulin), thrombotic status (thrombin-antithrombin III complex and prothrombin fragment 1+2 (F1+2)) and fibrinolytic status (plasmin-alpha2-plasmin inhibitor complex (PIC) and D-dimer) were determined. Levels of F1+2, PIC and D-dimer were higher in AF patients with severe atheroma than in those without severe atheroma (p<0.05). In patients in SR, hemostatic markers were not significantly increased even if they had severe aortic atherosclerosis. AF (Odds ratio (OR) 4.06, p=0.04) and age>or=75 years (OR 3.98, p=0.02) were independently predictive of elevated D-dimer levels and severe atheroma was predictive of elevated F1+2 levels (OR 5.52, p=0.04). CONCLUSIONS: Elderly patients with AF and severe aortic atherosclerosis might be in a prothrombotic state, and could benefit from intensive antithrombotic therapy.