Spontaneous echocardiographic microbubbles associated with prosthetic mitral valves: Mechanistic insights from thrombolytic treatment results

Spontaneous Echocardiographic Microbubbles Associated with Prosthetic Mitral Valves: Mechanistic Insights from Thrombolytic Treatment Results Cihangir Kaymaz, Mehmet Özkan, Nihal Özdemir, Cevat Kirma, and Ubeydullah Deligönül, Istanbul, Turkey, and Tyler, Texas

The purpose of this study was to determine the prevalence of microbubbles (MBs) in patients with prosthetic mitral valves (PMVs). The clinical and echocardiographic predictors of MB were investigated. We also analyzed the temporal relation between MBs and the thrombolytic treatment of thrombotic PMV dysfunction. The study material comprised 307 transesophageal echocardiography examinations in 279 patients (170 women and 109 men with a mean age of 37.9 ± 13.3 years) with PMV. The PMV was mechanical in 245 patients (tiltingdisk valves in 129, and bileaflet aortic valves in 116) and bioprosthetic mitral valves in 34 patients. Twenty-eight sessions of thrombolytic treatment were performed because of the obstructive (n = 18) and nonobstructive (n = 10) thrombi involving the PMV. No MBs were seen in any of the bioprosthetic

H

igh-velocity, small, bright echoes (microbubbles [MBs]) concurrent with the closure of the prosthetic valves have been noted in transesophageal echocardiographic recordings.1-3 The MBs have been reported in both normal and dysfunctional prosthetic valves.1-8 However, the nature of these echoes, the mechanisms of their development, their prevalence, and clinical significance have not been clearly defined.1-8 In this study we aimed to determine the prevalence of MBs in patients with prosthetic mitral valves (PMVs). We correlated the MBs with clinical characteristics, with echocardiographic left atrial and left ventricular function, and with mitral prosFrom the Kosuyolu Heart and Research Hospital, Kosuyolu, Istanbul, Turkey, and the Cardiology Division, University of Texas Health Center at Tyler, Texas (U.D.). Reprint requests: Ubeydullah Deligönül, MD, FACC,11155 Dunn Rd, Suite 304E, St. Louis, MO 63136 (E-mail: deligonul@ earthlink.net). Copyright 2002 by the American Society of Echocardiography. 0894-7317/2002/$35.00 + 0 27/1/119005 doi:10.1067/mje.2002.119005

valves. The MBs were present in 128 of 227 (56.4%) PMV without obstruction compared with only 1 of 18 (5.5%) valves with thrombotic obstruction (P < .0001). The MB were documented in 75.4% of the normal bileaflet valves compared with 38.5% of the tilting-disk valves (P < .0001). The MB intensity score was also significantly higher in the bileaflet valves (2.0 ± 0.8 vs 0.7 ± 0.7, P < .05). The incidence of MBs increased from 5.5% to 68.7% after successful thrombolysis in patients with obstructive PMV thrombi (P < .001). There were no other predictors of MBs in this series. The passage of MBs in the aortic root was not documented in any instances. We conclude that MBs are normal echocardiographic findings depending on the type and function of the mechanical PMVs. (J Am Soc Echocardiogr 2002;15: 323-7.)

thetic hemodynamics. In a subgroup of patients we also analyzed the temporal relation between the thrombolytic treatment of prosthetic valve thrombus and the occurrence of MBs.

METHODS Study Population The study material consisted of 307 transesophageal echocardiography (TEE) examinations in 279 patients with mitral valve prosthesis. Patients with an aortic prosthesis were not included in this study.The patients were studied in our laboratory between 1993 and 1998.There were 109 men and 170 women with an average age of 37.9 ± 13.3 years. Atrial fibrillation was present in 172 (61.6%) of the patients.The valve was a bioprosthesis in 34 patients.A tilting-disk mechanical valve was present in 129 patients and a bileaflet aortic mechanical valve in 116. Twenty-eight patients underwent thrombolytic treatment for obstructive (n = 18) and nonobstructive (n = 10) thrombus involv-

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324 Kaymaz et al

A

B Figure 1 A, Demonstration of spontaneous microbubbles (arrows). B, Demonstration of spontaneous echocontrast in LA cavity of patient with thrombus (THR) superimposed on PMV. LA, Left atrium; LV, left ventricle; PMV, prosthetic mitral valve.

ing the prosthetic valve. In these 28 patients serial TEEs were performed; however, only the first and last TEE were included in the study. TEE was performed using a 5-MHz multiplane transducer connected to a Vingmed CFM 800 system (Vingmed, Horten, Norway) after oropharyngeal anesthesia (10% lidocaine) and conscious sedation (intravenous midazolam, 13 mg). Transthoracic echocardiography (TTE), to supplement gradient and valve-area calculations, was performed using the same system with 3.25-MHz transducers. Both TTE and TEE studies were recorded on videotape for subsequent review. Each recording were initially evaluated by 2 echocardiographers, independently, and in case of disagreement the consensus was achieved in a subsequent session.The indication for TEE was documented thrombus on TTE in 18 patients, transient ischemic attacks or systemic embolization in 20 patients, and findings suggesting paravalvular mitral regurgitation in 26 patients. TEE was performed in the remaining 181 patients within the con-

Journal of the American Society of Echocardiography April 2002

text of a prospective study investigating the development of postoperative left atrial and valvular thrombus.9 Written informed consent was obtained from each patient before entry into the study. The spontaneous MB (Figure 1, A) were defined as small (<1 mm in diameter), bright, intracavitary, high-velocity echoes, which appeared on the left atrial side during valve leaflet closure and disappeared in seconds.1 Microbubble density was scored as grade 1, less than 5 MBs; grade 2, 5 to 10 MBs; and grade 3, more than 10 MBs per frame.8 For the evaluation of the passage of MBs in the systemic circulation, multiple cross-sections from the aortic root to aortic arch were scanned for MBs. Spontaneous echocontrast was diagnosed when swirling, smokelike echodensities were documented in the left atrium (Figure 1, B). These echoes were distinct from the near-field and highgain artifacts. The mitral valve mean gradient was calculated from the continuous wave Doppler recordings (TTE or TEE). The mitral valve area was calculated by the pressure half-time method.10 The mobility of the leaflets and the presence of regurgitant jets were noted. The left atrial diameter was measured on the TTE images.11 The left atrial appendage fractional-area change was calculated from TEE images. The peak forward and backward left atrial appendage flow velocities were measured using pulsed Doppler mode of the TEE.12 The left atrial peak forward and backward velocities were measured by placing the pulsed Doppler sample volume in the mid left atrium (away from the mitral regurgitation jet when present). The left ventricular ejection fraction was determined on the TTE images by taking the average of the measurements by area length and Simpson’s methods.13,14 Prosthetic valve thrombi were recognized as soft and homogenous, mobile or fixed echodensities located at the valve occluder and/or valve struts. Presence or absence of limitation to the movement of the valve occluder was identified. A significant narrowing of the prosthesis was diagnosed when the Doppler mitral valve area was 1.5 cm2 or less and the mitral valve mean gradient was 10 mm Hg or greater. The response to thrombolytic treatment was defined as a complete success when significant narrowing of the valve (based on hemodynamic measurements mentioned previously) was no longer present and a 75% or greater reduction in the largest diameter of the thrombus mass was achieved. For nonobstructive thrombi, a reduction by 75% or greater in thrombus diameter or complete lysis of the mobile portion of the thrombus was required as criteria for complete success.15 Statistical Methods The unpaired Student t test was used for the comparison of means. The categorical variables were compared using

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Kaymaz et al 325

Table 1 Prevalence of microbubbles in different types of prosthetic mitral valves with no hemodynamic obstruction

Table 2 Clinical and echocardiographic characteristics associated with spontaneously appearing microbubbles (prosthetic valves with no obstruction)

Microbubble prevalence Valve type

1. Bileaflet valves St. Jude Sorin bileaflet ATS 2. Tilting-disk valves Sorin monoleaflet Medtronic-Hall Björk-Shiley

(no)

%

(83/110) (58/75) (12/17) (13/18) (45/117) (31/78) (9/31) (5/8)

75.4 77.0 70.6 65.2 38.5 39.7 29.0 62.5

the chi-square test. A P value of < .05 was considered significant.

RESULTS Because we detected no MBs in bioprosthetic valves, these 34 patients were excluded from further consideration. Spontaneous MB were documented in 128 (56.4%) of 227 patients with mechanical mitral prostheses and no evidence for valve obstruction. The prevalence of the MBs in different types of prosthetic mechanical valves is shown in Table 1. Spontaneous MB were documented in 83 of 110 (75.4%) patients with bileaflet valves compared with 45 of 117 (38.5%) with tilting-disk valves (P < .0001). The MB intensity score was also significantly higher in the bileaflet valves (2.0 ± 0.8 vs 0.7 ± 0.7, P < .05). By multivariate analysis the only independent significant predictor of MB intensity was the bileaflet valve type. Table 2 summarizes the clinical and echocardiographic variables in patients with mechanical PMV without obstruction. Age, male/female ratio, atrial fibrillation, left atrial diameter, age of the prosthesis, transmitral peak and mean gradient, mitral valve area, and mitral regurgitation were not found to be different in patients with and without MBs. The incidence of spontaneous echocontrast in left atrium and/or left atrium appendage, left atrial forward and backward velocities, fractional left atrium appendage-area change (percentage), left atrium appendage peak forward and backward velocities, and left ventricular ejection fraction were similar in patients with and without MBs. The mean international normalized ratio and the incidence of systemic arterial embolism were not different between these groups. The relation between mitral valve thrombosis and MB occurrence is shown in Table 3.The spontaneous

Age (y) Sex (man/woman) Atrial fibrillation (%) LA diameter (cm) Transmitral gradient Peak (mm Hg) Mean (mm Hg) Mitral valve area (cm2) Valve type Tilting-disk (%) Bileaflet (%) Age of the valve (wk) Paravalvular MR (>2) LA/LAA SEC (%) LA peak inflow velocity (m/s) LA peak outflow velocity (m/s) LAA FAC(%) LAA peak inflow velocity (m/s) LAA peak outflow velocity (m/s) LV EF(%) Nonobstructive thrombi (%) INR Systemic embolization (%)

SMB (+) (n = 128)

SMB (–) (n = 99)

P

38 ± 12.8 54/74 70 (54.6%) 5.1 ± 0.95

37.2 ± 12.2 36/63 59 (59.5%) 4.9 ± 1.2

NS NS NS NS

11.5 ± 4.4 4.5 ± 2.1 2.6 ± 0.6

12 ± 4.9 4.6 ± 1.8 2.67 ± 0.7

NS NS NS <.0001

45 (35%) 83 (65%) 133 ± 130 10 (7.8%) 42 (32.8%) 0.1 ± 0.09

72 (72.7%) 27 (27.3%) 130 ± 129 9 (9%) 34 (34.3%) 0.05 ± 0.04

NS NS NS NS

0.09 ± 0.08

0.07 ± 0.05

NS

45.2 ± 34.3 0.2 ± 0.18

45.9 ± 35.6 0.21 ± 0.2

NS NS

0.22 ± 0.21

0.21 ± 0.21

NS

65.1 ± 13.2 5 (3.9%)

64.5 ± 14.7 5 (5%)

NS NS

2.73 ± 1.33 7 (5.4%)

2.65 ± 1.43 6 (6%)

NS NS

EF, Ejection fraction; FAC, fractional area change; INR, International Normalized Ratio; LA, left atrium; LAA left atrial appendage; LV, left ventricle; MR, mitral regurgitation; NS, nonsignificant; SEC, spontaneous echocontrast; SMB, spontaneously appearing microbubbles.

Table 3 Results of thrombolytic treatment in patients with prosthetic mitral valve thrombus

Obstructive Bileaflet Tilting-disk Nonobstructive Bileaflet Tilting-disk Total

Total no.

Successful no.

Unsuccessful no.

6 12

6 10

0 2

8 2 28

7 2 25

1 0 3

MBs were present in only 1 of 18 valves with obstruction, compared with 128 of 227 without obstruction (5.5% vs 56.4%, respectively, P < .0001). Nonobstructive prosthetic valve thrombi were seen with equal frequency in patients with and without MBs (3.9% vs 5%). Thrombolytic treatment was administered to 18 patients who had prostheses

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Figure 2 Prevalence of spontaneous echocardiographic microbubbles before and after thrombolytic treatment in patient with hemodynamically obstructive and nonobstructive prosthetic mitral valve thrombus.

with thrombotic occlusion; successful results were achieved in 16 patients (Figure 2). In these 16 patients, the incidence of spontaneous MBs increased from 5.5% to 68.7% after thrombolysis (P < .001). On the other hand, the incidence of MBs in 10 patients with nonobstructive thrombi was similar before and after thrombolytic treatment (50% vs 55.5%). There were no documented instances of passage of MBs in the aortic root.

DISCUSSION Our study documented the prevalence of MBs in a very large series of patients with PMVs. No instances of MBs were documented in the bioprosthesis group. The spontaneous MBs were seen more frequently in mechanical bileaflet valves without obstruction. Limited data are available on the incidence and the prognostic significance of MBs. Although the phenomenon was noted in smaller series,2,4-6 the first descriptive study by Orsinelli et al1 in a large series reported the incidence of MBs as 41% and 15% in patients with mitral and aortic prosthetic valves, respectively. Similar to our findings, in their series the microbubble incidence was higher in bileaflet St Jude Medical valves (87%). They also noted the absence of MBs in bioprosthetic valves.1 The MBs occur at the inflow zone of the valve when flow velocity and pressure drop suddenly at the time of valve closing.1-7 The cavitation potential was correlated to valve design, occluder material, and the velocity of the leaflet closure.6,7,16,17 Our study brings clinical support to this concept.The MB

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incidence in our study was very low when there was thrombotic occlusion of the valve. In this study we, for the first time, showed the reappearance of MBs after successful thrombolytic treatment with relief of valvular obstruction (Figure 2). Furthermore, the presence of unobstructive thrombus was not a predictor of MB. This provides further evidence that unrestricted valve leaflet or occluder motion is essential for the development of MBs. Orsinelli et al,1 on the other hand, reported a higher incidence of MBs in abnormal prosthetic valve function. However, they combined valvular regurgitation, thrombosis, vegetation, and fibrinous strands in the group with abnormal findings. In our study the MBs were not correlated to the mitral valve area, mitral gradient, left atrial and appendage size and function, and mitral regurgitation. The hemolysis of red blood cells or cavitation of soluble blood gases have been implicated in the formation of MBs.1,6,7,16,17 It has been speculated that the MBs may damage the valve surface rendering it more thrombogenic.1,17,19 We found no relation between presence of MBs and the age of the mitral valve prosthesis or the existence of nonobstructive thrombi. The high-intensity transcranial signals (HITS) on Doppler recordings were reported to occur after valve replacement with mechanical but not bioprosthetic devices.8,20-27 The mechanical valves are also associated with a higher prevalence of spontaneous MB.3,8,21-25 Because of this concurrence, it has been speculated that these could represent the local (MB) and distant (HITS) signs of the same event.3,8,21-25 However, some authors argued against such correlation.26 In experimental models, the MBs have been shown to collapse in less than 2 ms, precluding the persistence of these anywhere else in the circulation other than the immediate vicinity of the valve.16,26 Thus microplatelet aggregates or fibrin thrombi rather than MBs20-24,26 may cause HITS. We have found no instances of MB passage into the aortic root. In our series the incidence of systemic embolism was similar in patients with and without MBs. Study Limitations Our study was limited to PMV. Therefore, we cannot comment on the incidence and significance of MBs in prosthetic aortic valves. Simultaneous transcranial Doppler study was not performed in our series. Although we have not seen MB survival in the aortic root in any of our recordings, we do not know whether these patients had concurrent HITS. In conclusion, the high-velocity spontaneous MBs

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on the TEE recordings are frequently observed in normal bileaflet mechanical prosthetic valves. An occlusive thrombus interfering with the leaflet motion decreased the MB generation. The return of adequate valve function after lysis of the thrombus was associated with reappearance of the MBs.

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