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(Chest. 2004;125:1629-1634.)
© 2004 American College of Chest Physicians

Mechanism of Reducing Platelet Activity by Percutaneous Transluminal Mitral Valvuloplasty in Patients With Rheumatic Mitral Stenosis*

Mien-Cheng Chen, MD; Chiung-Jen Wu, MD; Hsueh-Wen Chang, PhD; Hon-Kan Yip, MD; Yen-Hsun Chen, MD; Cheng-I Cheng, MD and Han-Tan Chai, MD

* From the Department of Internal Medicine (Drs. M.-C. Chen, Wu, Yip, Y.-H. Chen, Cheng, and Chai), Division of Cardiology, Chang Gung Memorial Hospital, Kaohsiung; and the Department of Biological Sciences (Dr. Chang), National Sun Yat-Sen University, Kaohsiung, Taiwan, ROC.

Correspondence to: Mien-Cheng Chen, MD, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, 123, Ta Pei Rd, Niao Sung Hsiang, Kaohsiung Hsien 83301, Taiwan, ROC; e-mail: chenmien{at}ms76.hinet.net


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Previous studies have demonstrated that platelet activity significantly decreased after optimal percutaneous transluminal mitral valvuloplasty (PTMV) in patients with rheumatic mitral stenosis (MS). However, the mechanism of reducing platelet activity by valvuloplasty remains unclear.

Methods and results: We studied 19 patients with symptomatic MS who were undergoing PTMV. The fractions of unstimulated platelets expressing P-selectin in the venous blood obtained before, and at the 1-week and 4-week follow-ups after PTMV were determined by flow cytometry. The mitral valve areas, measured before and at the 1-week follow-up after PTMV, were calculated by means of the Doppler pressure half-time method. The mean (± SD) area of the mitral valve increased significantly after PTMV (1.05 ± 0.17 vs 1.44 ± 0.27 cm2, respectively; p < 0.0001). The mean left atrial area was reduced in size significantly after PTMV (36.6 ± 11.4 vs 33.9 ± 13.4 cm2, respectively; p < 0.05). The mean left atrial pressure (23.3 ± 5.1 vs 18.0 ± 5.8 mm Hg, respectively; p < 0.0001) and the mean pulmonary arterial pressure (31.4 ± 7.8 vs 26.1 ± 7.7 mm Hg, respectively; p < 0.0001) fell significantly after PTMV. The fraction of platelets expressing P-selectin in the venous blood fell significantly after PTMV (before PTMV, 4.7 ± 2.4%; 1 week after PTMV, 2.2 ± 2.1%; 4 weeks after PTMV, 2.0 ± 1.7%; p < 0.0001). Correlation analysis demonstrated that there was a significantly direct relationship between the magnitude of increase in mitral valve area and the magnitude of decrease in the fraction of platelets expressing P-selectin in the venous blood 4 weeks after PTMV (p = 0.0013; r = 0.682). However, there was no significant correlation between the magnitude of decrease in the fraction of platelets expressing P-selectin in the venous blood and the magnitude of decrease in the left atrial area, the decrease in left atrial pressure, or the decrease in the pulmonary artery pressure after PTMV.

Conclusions: In patients with moderate-to-severe MS, increased platelet activation fell significantly after PTMV. It was the increase in mitral valve area by PTMV, instead of hemodynamic and echocardiographic factors, that accounted for the decrease in the fraction of venous platelets expressing P-selectin after PTMV.

Key Words: mitral stenosis • platelet • valvuloplasty


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Previous studies have demonstrated that platelet activation occurs in peripheral blood of patients with rheumatic mitral stenosis (MS).1234 Kataoka et al3 and Zaki et al4 have demonstrated that platelet activity significantly decreased after optimal percutaneous transluminal mitral valvuloplasty (PTMV). However, in these studies, platelet activation was evaluated by measuring the secretory substances of platelets (platelet factor 4 and ß-thromboglobulin),5 which are plasma markers used to evaluate platelet activation and cannot reflect changes in individual platelets. Therefore, no information regarding the correlation between the magnitude of increase in the mitral valve area after PTMV and the magnitude of decrease in the platelet activity after PTMV was provided in these studies. The importance of this information was to clarify whether the decreased platelet activity by valvuloplasty was attributed to the increase of mitral valve area by valvuloplasty or other mechanisms, such as hemodynamic or echocardiographic factors. On the other hand, the measurement of key biochemical markers, such as P-selectin (or CD 62p antigen, which is a biologically relevant molecule that is released to the surface of platelets from {alpha}-granules on activation),678 by flow cytometry allows us to see changes in individual platelets long before they can be detected in physiologic assays. Recently, we have demonstrated9 that the fraction of peripheral venous unstimulated platelets expressing P-selectin of patients with MS is significantly higher than that of healthy subjects or those who have experienced atrial fibrillation alone. In addition, we have demonstrated that there is a significantly direct relationship between the severity of MS and the fraction of left atrial unstimulated platelets expressing P-selectin. Accordingly, we undertook the present study to test the hypothesis about whether there was a correlation between the magnitude of increase in the mitral valve area after PTMV and the magnitude of decrease in the fraction of peripheral venous unstimulated platelets expressing P-selectin after PTMV.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
Nineteen patients who had symptomatic rheumatic MS (mean [± SD] mitral valve area, 1.05 ± 0.17 cm2; range, 0.6 to 1.29 cm2) without significant mitral, tricuspid, or aortic regurgitation, and left atrial thrombus, and had undergone PTMV were studied. There were 1 man and 18 women, ranging in age from 39 to 72 years (mean age, 57 ± 11 years). Fifteen patients were in permanent atrial fibrillation, and 4 patients were in sinus rhythm. Five patients had a history of cerebral thromboembolism. Ten patients were in New York Heart Association functional class III, and 9 patients were in New York Heart Association functional class II. No patient had a history of malignancy, inflammatory disease, collagen vascular disease, renal or liver disease, diabetes mellitus, hypertension, hyperlipidemia, infectious disease, deep venous thrombosis, pulmonary embolism, or recent surgery.

Informed consent was obtained from all study patients. The study protocol was approved by the Institutional Review Committee on Human Research in our institution.

Doppler Echocardiography and Medications
Transthoracic echocardiographic examinations were performed on the day of PTMV and before the valvuloplasty procedure, and 1 week after PTMV with a 2.5-MHz transducer attached to a commercially available echo Doppler machine (Sonos 5500; Hewlett-Packard; Palo Alto, CA) to assess atrial dimensions, left ventricular diameters, and mitral valve area. M-mode measurements were performed according to the recommendation of the American Society of Echocardiography. Left and right atrial areas were measured with a planimeter in the four-chamber view, and the maximum areas were measured (at the end of the T wave on the ECG) and averaged over 5 beats. The mitral valve area was calculated by means of the Doppler pressure half-time method, and the reliability of this method in the measurement of the mitral valve area has been confirmed in previous studies.1011 The severity of mitral, tricuspid, and aortic insufficiency was determined by Doppler color-flow mapping. The absence of left atrial cavity or appendage thrombi was confirmed by transesophageal echocardiography. All of the patients had swirling spontaneous echo contrast only in the left atrium confirmed by transesophageal echocardiography.

Warfarin therapy was discontinued for 3 to 4 days before patients underwent PTMV and was administered on the second day after PTMV. Warfarin therapy also was discontinued for 3 to 4 days before blood examinations were conducted during the follow-up studies. Heparin, 5,000 U, was administered into the left atrium after transseptal puncture in each patient. Diuretics were discontinued on the day of PTMV. Digoxin, ß-blockade, and Ca-blockade were discontinued for at least 5 half-lives before the study. No patient received aspirin or other antiplatelet regimens, and no patient received any nonsteroidal anti-inflammatory drugs.

Valvuloplasty Procedure
PTMV was performed by the transseptal approach with the use of an Inoue balloon catheter. Details of the procedure have been described previously.912 In brief, an Inoue balloon catheter was inserted into the left ventricle via the transseptal approach. The distal half of the balloon was inflated in this position, and the balloon was pulled back to the mitral valve orifice. The balloon was then fully inflated and pulled back to the left atrium before being deflated. When additional balloon dilatation was required, the same procedure was repeated. Invasive pressure measurements were performed immediately before and after valvuloplasty.

Blood Sample Collection and Assessment of Platelet Activity
Blood samples were obtained in the fasting, nonsedative state between 9:00 and 10:00 AM to exclude the possible influence of circadian variations.13 During cardiac catheterization, blood was obtained from the femoral vein through introducer sheaths immediately after puncture. The first 3 mL blood was discarded, and the following 3 mL was drawn into an evacuated tube containing 3.8% buffered sodium citrate (Vacutainer; Becton Dickinson; Franklin, Lakes, NJ). At the 1-week and 4-week follow-ups after PTMV, peripheral venous blood was obtained under minimal tourniquet pressure from the antecubital vein using a sterile 22-gauge needle and syringe in a single attempt, with the first 3 mL blood being discarded and the following 3 mL being drawn into a evacuated tube containing 3.8% buffered sodium citrate. Blood samples with gross hemolysis were discarded. Mixtures of blood and sodium citrate were centrifuged (model 5400; Kubota Corp; Tokyo, Japan) for 15 min at 1,500 revolutions per minute at room temperature. The supernatant platelet-rich plasma was used to assess the platelet activity. The time between blood collection and antibody labeling was standardized to within 1 h.

Platelet activity was determined with respect to {alpha}-granule degranulation (ie, surface expression of P-selectin or CD 62p antigen). Ten-microliter aliquots of platelet-rich plasma were placed in 5-mL polystyrene tubes (Falcon; Becton Dickinson) that contained 90 µL diluted sterile phosphate-buffered solution (pH 7.4; sodium chloride, 137 mmol/L; potassium chloride, 2.7 mmol/L; phosphate buffer, 10 mmol/L) to prevent the aggregation of platelets and 5 µL fluorochrome-labeled antibodies. Fluorescein isothiocyanate-conjugated antibody to glycoprotein IIIa (CD61; Becton Dickinson) was used as an activation-independent marker of platelets.1415 A phycoerythrin (PE)-conjugated anti-CD62 antibody (Becton Dickinson) was used to assess {alpha}-granule degranulation.678 To assess the extent of the nonspecific association of protein with platelets, a control tube containing fluorescein isothiocyanate-conjugated CD61 and nonfractionated PE-conjugated IgG (Becton Dickinson) was used for each blood sample. The reaction mixture was incubated at room temperature for 30 min in a dark room. Then, the antibody-bound platelets were fixed with a 1% paraformaldehyde solution, and platelet activity was assessed immediately after fixation to avoid further activation.16 The association of ligands with platelets was determined with a fluorescence-activated cell sorter (FACSCalibur system; Becton Dickinson; San Jose, CA). Platelets were identified with flow cytometry on the basis of size (based on the forward scatter and 90° side scatter) and association with the CD61 antibody. A control ligand (IgG-PE conjugate) was used to detect any nonspecific associations and to permit the definition of a threshold for activation-dependent binding. The percentage of platelets expressing P-selectin was defined as the fraction exhibiting specific binding (ie, CD62p-positive) minus that exhibiting nonspecific binding (ie, the percentage defined with the IgG-PE conjugate) in 10,000 platelets sorted. All samples were labeled, and assays for P-selectin expression in each blood sample were performed in duplicate with the mean level reported.17

Statistical Analysis
Continuous variables were described as the mean ± SD. Continuous variables before and after PTMV were compared using the Wilcoxon signed rank test. The fractions of platelets expressing P-selectin in the peripheral venous blood obtained before PTMV, and at the 1-week and 4-week follow-ups after PTMV, were compared using the repeated-measures analysis of variance. The Scheffé test was used for post hoc comparisons. The relationships between platelet P-selectin expression and mitral valve area, left atrial pressure, pulmonary artery pressure, or atrial dimension were performed using the Pearson correlation. Statistical analysis was performed with a statistical software package (SAS for Windows, version 8.02; SAS Institute; Cary, NC). A probability value of < 0.05 was considered to be statistically significant.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Baseline Characteristics, Echocardiographic Data, and Hemodynamic Variables of the Studied Patients
The baseline characteristics of the studied patients are summarized in Table 1 . The mean duration of atrial fibrillation in patients with permanent atrial fibrillation was 42.1 ± 43.4 months. The area of the mitral valve increased significantly after PTMV (p < 0.0001). The left atrial area reduced significantly after PTMV (p < 0.05). There were no significant changes in the right atrial area, the left atrial diameter, the left ventricular end-systolic and end-diastolic diameters, and ejection fraction after PTMV (Table 2 ). The mean left atrial pressure (23.3 ± 5.1 vs 18.0 ± 5.8 mm Hg, respectively; p < 0.0001), transmitral pressure gradient (11.3 ± 4.6 vs 7.6 ± 4.3 mm Hg, respectively; p = 0.0002), and mean pulmonary arterial pressure (31.4 ± 7.8 vs 26.1 ± 7.7 mm Hg, respectively; p < 0.0001) fell significantly after PTMV. However, there was no significant change in the mean right atrial pressure after PTMV (8.7 ± 6.0 vs 8.2 ± 6.0 mm Hg, respectively; difference not significant).


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  		Table 1. Characteristics of Study Population*

 

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  		Table 2. Echocardiographic Variables Before and After Percutaneous Transluminal Mitral Valvuloplasty*

 
Peripheral Venous Platelet P-Selectin Expression Before and After PTMV
In a previous study,9 we demonstrated that the mean fraction of unstimulated platelets expressing P-selectin in the peripheral venous blood of healthy volunteers who were in sinus rhythm (1.7 ± 0.9%) was consistent with that found in another study (2.3%)17 using 3.8% sodium citrate as the anticoagulant. In addition, the fraction of unstimulated platelets expressing P-selectin among patients with rheumatic MS was significantly higher than that among healthy volunteers who were in sinus rhythm or patients in permanent lone atrial fibrillation. Furthermore, the increased peripheral venous platelet activity of patients with rheumatic MS was evident both in patients who were in sinus rhythm and in those with atrial fibrillation. The platelet activation with respect to P-selectin expression of healthy volunteers in sinus rhythm did not differ from that of patients in permanent lone atrial fibrillation.

In this study, the fraction of unstimulated platelets expressing P-selectin in the peripheral venous blood obtained before PTMV fell significantly after PTMV (before PTMV, 4.7 ± 2.4%; 1 week after PTMV, 2.2 ± 2.1%; 4 weeks after PTMV, 2.0 ± 1.7%; p < 0.0001) [Fig 1 ]. The fraction of platelets expressing P-selectin in the peripheral venous blood obtained at the 1-week follow-up did not differ from that obtained at the 4-week follow-up after PTMV.



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  		Figure 1. Fraction of platelets expressing P-selectin was determined by use of flow cytometry in the peripheral venous blood (PB) obtained before (PB0), and at the 1-week (PB1) and 4-week (PB4) follow-ups after valvuloplasty in patients with rheumatic MS. The fraction of platelets expressing P-selectin in the peripheral venous blood obtained before valvuloplasty was significantly higher than that obtained after valvuloplasty. * = p < 0.0001.

 
Correlation of Mitral Valve Area and Peripheral Venous Platelet P-Selectin Expression
Correlation analysis demonstrated that there was a significantly direct relationship between the magnitude of increase in mitral valve area after PTMV and the magnitude of decrease in the fraction of unstimulated platelets expressing P-selectin in the peripheral venous blood 4 weeks after PTMV (ie, the more gain in the mitral valve area, the more decrease in the fraction of peripheral venous platelets expressing P-selectin; p = 0.0013; r = 0.682) [Fig 2 ]. However, there was no significant correlation among the magnitude of decrease in the fraction of unstimulated platelets expressing P-selectin in the peripheral venous blood 4 weeks after PTMV and the magnitude of decrease in the left atrial area (p = 0.573; r = –0.138), the magnitude of the decrease in left atrial pressure (p = 0.180; r = –0.321), or the magnitude of the decrease in pulmonary artery pressure (p = 0.880; r = –0.037) after PTMV.



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  		Figure 2. Correlation between the difference in the fraction of platelets expressing P-selectin in peripheral venous blood obtained before and 4 weeks after valvuloplasty, and the difference in mitral valve area obtained 1 week after and before valvuloplasty. The magnitude of decrease in the peripheral venous platelet P-selectin expression had a significantly direct relationship with the magnitude of increase in mitral valve area (r = 0.682; p = 0.0013). Each point ({diamondsuit}) represents one patient with MS.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study, in which we examined platelet activation in patients with symptomatic rheumatic MS undergoing PTMV by measuring unstimulated platelet P-selectin expression in the peripheral venous blood samples, produced two major findings. First, the fraction of unstimulated platelets expressing P-selectin in the peripheral venous blood obtained before PTMV fell significantly after PTMV. Second, with the area of mitral valve increasing significantly after PTMV, there was a significantly direct relationship between the magnitude of the increase in mitral valve area after PTMV and the magnitude of decrease in the fraction of unstimulated platelets expressing P-selectin in the peripheral venous blood after PTMV.

Mechanism of Reducing Platelet Activity by PTMV
Evidence from several studies18192021 has shown that shear stresses in turbulent flow as a result of stenotic valves induce platelet activation. Recently, we have demonstrated9 that the fraction of peripheral venous unstimulated platelets expressing P-selectin in patients with MS is significantly higher than that of healthy subjects or those who have experienced atrial fibrillation alone, and that there is a significantly direct relationship between the severity of MS and the fraction of left atrial unstimulated platelets expressing P-selectin. PTMV has been shown to effectively increase the mitral valve area in patients with moderate-to-severe rheumatic MS,1222 and, accordingly, it should reduce platelet activation in these patients. Previous studies34 have demonstrated that platelet activity significantly decreased after optimal PTMV results. In our study, we also provided evidence that the fraction of platelets expressing P-selectin in the peripheral venous blood obtained before PTMV fell significantly after PTMV. In addition, we found that the more gain there was in the mitral valve area, the more of a decrease there was in the fraction of peripheral venous platelets expressing P-selectin after PTMV. We also demonstrated that the magnitude of decrease in the fraction of peripheral venous platelets expressing P-selectin after PTMV had no significant correlation with the magnitude of decrease in the left atrial area, the magnitude of decrease in the left atrial pressure, or the magnitude of decrease in the pulmonary artery pressure after PTMV. Therefore, it was the increase in mitral valve area by PTMV, instead of hemodynamic and echocardiographic factors, that accounted for the decrease in the fraction of peripheral venous platelets expressing P-selectin after PTMV.

Clinical Implication
A large body of epidemiologic data indicates that patients with rheumatic MS, and in particular those with atrial fibrillation or left atrial spontaneous echo contrast, are at risk of developing left atrial thrombi.232425262728 Coagulation activity has been demonstrated2930 to be increased in patients with MS, even in the absence of echocardiographic visualized thrombi. Chiang and associates31 have demonstrated that PTMV is a negative predictor of systemic embolism in patients with rheumatic MS who are experiencing atrial fibrillation. One possible mechanism is the amelioration of regional left atrial hypercoagulability by PTMV.32 In this study, we demonstrated that the fraction of platelets expressing P-selectin in the peripheral venous blood obtained before PTMV fell significantly after PTMV, and that the more gain there was in the mitral valve area, the more decrease there was in the fraction of peripheral venous platelets expressing P-selectin after PTMV. Accordingly, we proposed that the amelioration of increased platelets activity by PTMV might contribute to the decreased incidence of systemic embolism by PTMV in patients with MS.

Study Limitations
There were several limitations in this study. First, as PTMV results in an immediate increase in thrombin generation,32 and subsequently in the activation of platelets, we did not measure venous platelet P-selectin expression immediately after PTMV. Second, physiologic assays, such as platelet aggregation or adherence, were not performed in this study; therefore, the changes in platelet P-selectin expression may not necessarily reflect in changes in platelet physiologic function. Third, platelet activity with respect to the activation of glycoprotein IIb/IIIa was not determined in this study; therefore, we could not provide the fibrinogen-binding affinity of our patients in this study. Fourth, although only a small amount of heparinized saline solution (ie, 2 U heparin per milliliter of saline solution) was flushed through sheaths into patients before the completion of blood sampling and valvuloplasty. We could not completely exclude the potential impact of heparinized saline solution on platelet P-selectin expression before valvuloplasty.33 However, in our previous study,9 we found that the fraction of platelets expressing P-selectin in the femoral venous or arterial blood obtained through introducer sheaths immediately after puncture without heparinized saline solution flushed into patients did not differ from that in the right atrial blood obtained after a small amount of heparinized saline solution was flushed through introducer sheaths into patients. Therefore, the use of heparinized saline solution should not be a concern in this study. Fifth, as the blood samples were drawn through femoral sheaths before valvuloplasty and through the antecubital vein using a syringe with a sterile 22-gauge needle during follow-up studies, we could not completely exclude the fact that different sampling techniques might affect P-selection expression in platelets. Theoretically, small needles might increase P-selectin expression in platelets. However, this did not occur in this study as increased platelet activation fell significantly after PTMV at follow-up visits. Finally, as the number of patients having a history of systemic arterial thromboembolism was small, it was not our aim to study the difference in platelet activity between patients with and without a history of systemic arterial thromboembolism.

In conclusion, in patients with moderate-to-severe MS, increased platelet activation, as reflected by the increased expression of P-selectin in platelets in peripheral venous blood, fell significantly after PTMV. It was the increase in mitral valve area by PTMV, instead of hemodynamic and echocardiographic factors, that accounted for the decrease in the fraction of peripheral venous platelets expressing P-selectin after PTMV.


   Footnotes
 
Abbreviations: MS = mitral stenosis; PE = phycoerythrin; PTMV = percutaneous transluminal mitral valvuloplasty

This study was supported by a grant from Chang Gung Memorial Hospital, Chang Gung University (grant No. CMRP1139).

Received for publication June 19, 2003. Accepted for publication October 30, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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