Severe Mitral Regurgitation May Prevent Mural Thrombus Formation within the Left Ventricle with Systolic Dysfunction

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1 Severe Mitral Regurgitation May Prevent Mural Thrombus Formation within the Left Ventricle with Systolic Dysfunction Nihal ÖZDEMIR, 1 MD, Cihangir KAYMAZ, 1 MD, Enver DAGLAR, 1 MD, Osman KARAKAYA, 1 MD, Murat AKçAY, 1 MD, and Mehmet ÖZKAN, 1 MD SUMMARY The protective effect of severe mitral regurgitation (MR) against left atrial thrombus formation has been well documented. It was also proposed that severe MR may prevent thrombus formation within the left ventricle (LV) with systolic dysfunction. Therefore, we investigated whether ischemic MR prevents thrombus formation within the LV in patients with systolic dysfunction. The study population was comprised of 1313 patients (1133 males, 180 females, age 56±18) with ischaemic LV dysfunction documented by coronary angiography and left ventriculography. None of the patients had a history of chronic anticoagulation. Epicardial coronary arteries were normal in 91 patients, and single-vessel, two-vessel, and triple-vessel disease were detected in 328, 330, and 564 patients, respectively. Left ventricular thrombus and severe MR were detected in 191 (14.5%) and 125 (9.5%) patients, respectively. Overall incidence of LV thrombus was lower in patients with severe MR than in patients without severe MR (4% vs 15.6%, OR: 0.2, P). Severe MR compared with absence of severe MR was associated with a lower incidence of LV thrombus both in patients with ischemic dilated cardiomyopathy (6.8% vs 34.2%, OR: 0.19, P), and in patients with aneurysm (3% vs 18%, OR: 0.14, P<0.0001) involving anterolateral, septal and/or apical LV segments. A similar trend without statistical significance was also observed in patients with dyskinesia (4.7% vs 16%, OR: 0.26, P=0.1) related to anterolateral, septal and/or apical LV segments. However, MR had no impact on the incidence of LV thrombus in patients with aneurysm or dyskinesia related to posterior and/or inferior segments (3.7% vs 3%, OR: 1.2, P>0.05). In conclusion, severe MR seems to prevent LV mural thrombus formation in patients with ischemic dilated cardiomyopathy, and in patients with aneurysm related to anterolateral, septal, and/or apical LV segments. This relative risk reduction may be associated with diastolic volume overloading due to severe MR which may overcome stagnation and a procoagulant state within the LV with severe systolic dysfunction. (Jpn Heart J 2002; 43: ) Key words: Mitral regurgitation, Left ventricle, Thrombus From 1 the Department of Cardiology, Kosuyolu Heart and Research Hospital, Istanbul, Turkey. Address for correspondence: Nihal Özdemir, MD, Department of Cardiology, Kosuyolu Heart and Research Hospital, Kadlkoy, 81020, Istanbul, Turkey. Received for publication February 21, Revised and accepted April 11,

2 496 OZDEMIR, ET AL Jpn Heart J September 2002 THROMBUS formation within the cardiac chambers has been documented to be associated with Virchow's triad, which includes blood stagnation, endothelial injury, and increased tendency of blood for coagulation. 1) The importance of blood stagnation has been documented in patients with atrial fibrillation and/or mitral stenosis complicated by left atrial thrombus. 2-8) However, severe mitral regurgitation (MR) has been shown to decrease the incidence of spontaneous echo contrast and thrombus formation within the left atrium, and the risk of systemic embolism in patients with mitral stenosis and/or atrial fibrillation. 9-14) The left ventricle (LV) has been reported to be the primary location of thrombus formation in patients with global or segmentary LV systolic dysfunction in association with endocardial injury, wall motion abnormalities, and coagulation disturbances ) The abnormal flow patterns within the left ventricle due to systolic dysfunction have been correlated to LV thrombus formation ) Recently, some echocardiographic series have reported that the incidence of LV thrombus formation was significantly decreased with increasing MR severity in patients with dilated cardiomyopathy, and in patients with ischemic LV dysfunction ) However, another echocardiographic study reported that the incidence of LV thrombus was increased in patients with severe MR after acute myocardial infarction. 27) Therefore, the aim of the present study was to investigate whether severe MR has any impact on the incidence of LV thrombus formation in patients with global and segmentary LV systolic dysfunction due to ischemia using coronary angiography and left ventriculography. METHODS The study population was comprised of 1313 patients (1133 males, 180 females, mean age 56±18) with ischemic left ventricle dysfunction documented by coronary angiography and left ventriculography. None of the patients had a history of chronic anticoagulation. Cardiac rhythm was sinus rhythm in 1022 patients, atrial fibrillation in 285, and paced rhythm in 6. Coronary angiography was performed using a Siemens Coroscop T.D.P. Digital angiography system, and was filmed at 12.5 frames/second. Significant coronary disease was defined as the presence of angiographic percent diameter stenosis 50%, and/or diffuse narrowing throughout the coronary arteries. Left ventriculography was performed using 20 to 40 ml of radiopaque media injected in 3 seconds at 14 atm pressure by an Angiomat 6000 EKG-gated power injector, and was filmed at 60 left anterior oblique and 30 right anterior oblique planes. Left ventricular wall segments were assessed using the generally accepted criteria, and wall motion abnormalities were categorized as hypokinesia, akinesia,

3 Vol 43 No 5 IMPACT OF MITRAL REGURGITATION ON LEFT VENTRICLE THROMBI 497 dyskinesia, and aneurysm. Left ventricle global ejection fraction <0.50 was classified as global dysfunction. Dilated cardiomyopathy was defined as global hypokinesia with an ejection fraction <0.30. Patients with global hypokinesia and normal coronary angiograms were classified as non-ischemic dilated cardiomyopathy and excluded from the study. In the presence of a normal coronary angiogram with segmentary wall motion abnormalities related to scar and/or ischemia detected by myocardial perfusion scintigraphy, left ventricle dysfunction was classified as ischemic. Mitral regurgitation was graded from 1 to 4 according to the intensity of systolic opacification of the left atrial area during left ventriculography, and grade 3 and 4 MR were defined as severe regurgitation. 28) Left ventricular mural thrombus was assessed by left ventriculography, and was defined as a filling defect based on the estimated endocardial border of the wall segments with motion abnormalities and having a distinct and convex contour at the luminal side. Coronary arteriography and left ventriculography were assessed by two independent observers, and in the case of disagreement a consensus was reached in a third session. Statistical analysis: The continuous variables are presented as mean ± SD. Student's t-test for comparison of continuous variables and chi-square test for comparison of categorical variables were used. Patients with and without severe mitral regurgitation were compared in reference to left ventricular thrombus. The impact of mitral regurgitation on the incidence of left ventricular thrombus is presented as an odds ratiol (OR) and 95% confidence intervals (CI). A P value <0.05 was accepted as statistically significant. RESULTS The clinical and angiographic characteristics of the patients are presented in Table I. Epicardial coronary arteries were found to be normal or having non-significant plaques in 91 patients, and single-vessel, two-vessel, and triple-vessel disease were documented in 328, 330, and 564 patients, respectively. Left ventricular dyskinesia or aneurysm was detected in 1155 patients. Dyskinesia and aneurysm related to septal, apical and/or anterolateral LV segments were found in 394 and 470 patients, respectively. Dyskinesia and aneurysm associated with posterobasal, posterolateral, and/or inferior LV wall segments were detected in 110 and 181 patients, respectively. Ischemic dilated cardiomyopathy was found in 158 patients. Severe mitral regurgitation and LV mural thrombus were detected in 125 (9.5%) and 191 (14.5%) patients, respectively. The incidence of LV thrombus related to segmentary wall motion abnormalities, and the odds ratio (95% CI) values concerning the impact of severe MR on

4 498 OZDEMIR, ET AL Jpn Heart J September 2002 Table I. Comparison of the Characteristics of Patients with and without Severe Mitral Regurgitation Overall Severe mitral regurgitation P value (n=1313) Present (n=125) Absent (n=1188) Gender (male/ female) (%) Mean age (years) Single-vessel disease (%) Two-vessel disease (%) Triple-vessel disease (%) Normal epicardial arteries (%) Septal, anterolateral, and/or apical segments Aneurysm (%) Dyskinesia (%) Posterobasal, inferior and/or posterolateral segments Aneurysm (%) Dyskinesia (%) Ischemic dilated cardiomyopathy (%) Left ventricular thrombus (%) 1133/180 (86.2/13.8) (25) 330 (25) 564 (43) 91 (7) 470 (35.8) 394 (30) 181 (13.8) 110 (8.4) 158 (12) 191 (14.5) 104/21 (83.2/16.8) (25.6) 36 (28.8) 51 (40.8) 6 (4.8) 33 (26.4) 21 (16.8) 14 (11.2) 13 (10.4) 44 (35.2) 5 (4) 1029/159 (86.6/13.4) (27) 310 (26) 439 (37) 119 (10) 437 (36.8) 373 (31.4) 167 (14) 97 (8.2) 114 (9.6) 186 (15.6) Data are expressed as mean+sd or number (%); =P>0.05. the incidence of LV thrombus are presented in Table II. The overall incidence of LV thrombus was significantly lower in patients with severe MR compared to those without severe MR (4% vs 15.6%, OR: 0.2, 95% CI: ; P). Severe MR was associated with a lower incidence of LV mural thrombus in patients with ischaemic dilated cardiomyopathy (6.8% vs 34.2%;OR:0.19; 95% CI: , P). Severe MR compared with the absence of severe MR was also associated with a lower incidence of LV mural thrombus in patients with severe segmentary wall motion abnormalities (2.5% vs 13.7% ; OR: 0.2, 95% CI: , P<0.01). Among the patients with aneurysm related to septal, anterolateral, and/or apical V wall segments, the incidence of LV thrombus was lower in patients with severe MR than in patients without severe MR (3% vs 18%; OR: 0.14; 95% CI: ; P<0.0001) (Table II and Figure). Although severe MR was associated with a lower incidence of LV thrombus in patients with dyskinesia related to these segments, this difference was not statistically significant (4.7% vs 16%; OR 0.26, 95% CI: , P = 0.1) (Table II and Figure). However, among the patients with dyskinesia or aneurysm related to posterobasal, inferior, and/or posterolateral LV segments, the incidence of LV thrombus was not different between patients with and without severe MR (3.7% vs 3%; OR:1.2 ; 95% CI: ; P>0.05) (Table II and Figure).

5 Vol 43 No 5 IMPACT OF MITRAL REGURGITATION ON LEFT VENTRICLE THROMBI 499 Table II. Impact of Severe Mitral regurgitation on Incidence of Left Ventricular Thrombi in patients with Global and Segmentary Left Ventricular Dysfunction Left ventricular thrombus (%) Severe Mitral Regurgitation Present Absent P value OR % 95 CI Anterolateral / apical Dyskinesia Aneurysm Overall Posterobasal / posterolateral / inferior Dyskinesia / aneurysm Segmentary left ventricular dysfunction (overall) Ischaemic dilated cardiomyopathy Overall patients with left ventricular dysfunction < <0.01 >0.05 < ( ) ( ) ( ) ( ) ( ) ( ) ( ) Data are expressed as number (%); OR=odds ratio; CI=confidence intervals. Figure. Incidence of left ventricular thrombi in patients with left ventricular dysfunction with respect to severe mitral regurgitation (%). DISCUSSION Our study demonstrates that severe MR is associated with a decreased incidence of LV thrombus both in patients with ischemic dilated cardiomyopathy and in patients with aneurysm related to septal, anterolateral, and/or apical LV segments. A similar trend without statistical significance was also found in patients with dyskinesia related to those segments. However, severe MR seems to have no

6 500 OZDEMIR, ET AL Jpn Heart J September 2002 impact on the incidence of LV thrombus in patients with aneurysm or dyskinesia related to posterobasal, inferior, and/or posterolateral LV segments. Relief of slow flow states within the left atrium has been shown to decrease the incidence of spontaneous echo contrast and thrombus formation, as well as the risk of systemic embolism. 9-14) Normalization of flow rates within the left atrium may be due to restoration of the sinus rhythm in atrial fibrillation, an increase in the mitral valve area in patients who underwent mitral commisurotomy, or the high shear stress of severe MR concomitant with severe mitral stenosis and/or atrial fibrillation. Clinicopathologic series, and more recently, echocardiographic series have showed a preventive effect of severe MR against left atrial thrombus formation and systemic embolism in patients with rheumatic mitral valve disease and/or atrial fibrillation. 9-14) This protective effect of severe MR on the left atrium may be observed both in patients with native mitral valves, and in patients with paravalvular MR. 9-14) Recently, in patients who underwent mitral valve replacement because of severe rheumatic MR, we reported that the incidence of left atrial spontaneous echo contrast and thrombus were significantly increased in the postoperative period compared with the preoperative period. 13) New-onset left atrial thrombus after correction of severe MR by mitral valve replacement was considered to be indirect evidence for an antithrombotic effect of severe MR on the left atrium. 13) Moreover, the protective effect of severe MR against thrombus formation seems to be not limited to the left atrium. Another study from our institution demonstrated a significantly lower incidence of mechanical mitral valve thrombus in patients with severe paravalvular MR than in patients with normofunctioning mitral valve prostheses. 29) The low incidence of mechanical mitral valve thrombus related to severe MR was found to be independent of anticoagulation status, and was correlated to increased transmitral diastolic flow rates due to high turn-over between the left ventricle and left atrium. 29) Left ventricular thrombus formation has been frequently correlated to LV wall motion abnormalities ) The documented incidence of LV thrombus varies between 30% and 40% in patients with LV dysfunction, and increases up to 75% in patients with dilated cardiomyopathy ) A limited number of echocardiographic studies suggest that abnormal flow patterns within the LV may also be asscociated with LV thrombus formation ) The incidence of LV thrombus has been reported to decrease with increasing MR severity in patients with dilated cardiomyopathy, and in patients with ischemic LV dysfunction ) An echocardiographic study performed in patients with dilated cardiomyopathy reported a 5.5 times lower incidence of LV thrombus in patients with severe MR than in patients without severe MR. 25) Despite these data suggesting a possible preventive effect of severe MR against thrombus formation within the LV, another

7 Vol 43 No 5 IMPACT OF MITRAL REGURGITATION ON LEFT VENTRICLE THROMBI 501 echocardiographic study reported an increased incidence of LV thrombus in patients with severe MR due to acute myocardial infarction. 27) This possible antagonism between severe MR and LV mural thrombus formation may relate to increased diastolic velocities within the LV as a result of diastolic volume overloading, and/or a relatively less deteriorated systolic performance due to increased preload despite the increased end-systolic volumes. 30) The main difference between our study and previous series performed by echocardiography originates from the screening method for MR and thrombus. Our study was based on data obtained by left ventriculography. The present results confirm the impact of severe MR on LV thrombus formation in patients with global and segmentary dysfunction due to ischemia. This relative risk reduction due to severe MR seems to be apparent in patients with severe LV dysfunction. Despite the comparable global and segmentary LV dysfunction parameters between patients with and without severe MR, severe MR was associated with a significantly lower incidence of LV thrombus both in patients with severe global dysfunction, and in patients with aneurysm involving the septal, anteroseptal, and/or apical LV segments. A similar trend was also observed in patients with dyskinesia involving these segments. However, severe MR seems to offer no advantage in reference to LV thrombus in patients with aneurysm or dyskinesia related to posterobasal, inferior, or posterolateral LV segments. This difference may be associated with a lower risk profile in patients with dysfunction involving posterobasal, inferior, and/or posterolateral segments than in patients with anterior and/or apical segment dysfunction regardless of the MR. Limitations of this study: The absence of documentation of left ventricular thrombi by echocardiography or radionuclide ventriculography may be considered a limitation of this study. However, a diagnosis of thrombus by ventriculography was based on strict criteria of apparent filling defects related to segments with severe motion abnormalities. We think that this may lead to an increased specificity, and a decreased sensitivity for thrombus, and from a theoretical standpoint, an underestimation in the diagnosis of mural thrombus seems to be possible. However, this limitation should not be expected to attenuate the relationship between the severity of MR and decreased incidence of left ventricular thrombus. The absence of data concerning LV luminal flow characteristics which may be detected by echocardiography, and the lack of a prospective follow-up evaluating the association between severe MR and future embolic events are other limitations of the present study. Moreover, coagulation disturbances that may increase the risk of LV thrombus were not addressed. In conclusion, severe mitral regurgitation seems to be associated with a decreased incidence of LV thrombus both in patients with ischemic dilated cardiomyopathy and in patients with severe dysfunction related to septal, anterosep-

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