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Tricuspid Valve Chordal Tissue in Endomyocardial Biopsy Specimens of Patients With Significant Tricuspid Regurgitation
CLINICAL HEART TRANSPLANTATION
Tricuspid Valve Chordal Tissue in Endomyocardial Biopsy Specimens of Patients With Significant Tricuspid Regurgitation Lisa Mielniczuk, MD,a Haissam Haddad, MD,a Ross A. Davies, MD,a and John P. Veinot, MDb Objectives:
Methods:
Results:
Conclusion:
Tricuspid regurgitation is the most common valvular abnormality after orthotopic heart transplantation, with multiple etiologic factors implicated. The purpose of this study was to determine if the endomyocardial biopsy specimens of patients who developed significant tricuspid valve regurgitation (TVR) after cardiac transplantation had evidence of chordal tissue. The echocardiograms of 98 patients who had cardiac transplantation between 1986 and 2002 were reviewed for evidence of significant TVR greater than mild. The biopsy specimens of all patients with significant TVR were then reviewed for histologic evidence of tricuspid chordal tissue and frequency and severity of rejection episodes. Clinical information collected included the presence of any systolic murmurs, significant dyspnea, and invasive hemodynamic measurements. The incidence of significant TVR was 19% (n ⫽ 19 patients). Histologic evidence of chordal tissue was present in 9 patients (47%) with significant TVR. Patients whose biopsy specimens evidenced chordal tissue tended to have a greater degree of TVR, but this was not statistically significant (odds ratio, 2.07; 95% confidence interval, 0.537– 8.01, p ⫽ 0.32). There was no statistically significant difference in the number of biopsy specimens (p ⫽ 0.798), the number of rejection episodes (p ⫽ 0.73), or overall left or right ventricular systolic function between the patients with and without biopsy specimen evidence of chordal tissue disruption. Most of the patients with evidence of significant TVR after chordal tissue biopsy were clinically asymptomatic, with no significant change in their hemodynamics. Histologic evidence of chordal tissue in endomyocardial biopsy specimens was present in 47% of patients with significant TVR and did not relate to the number of biopsy procedures performed or the frequency of rejection episodes. This study provides histologic evidence that chordal tissue damage can occur after cardiac biopsy, resulting in significant TVR; however, it is clinically well tolerated by affected patients. J Heart Lung Transplant 2005;24:1586 –90. Copyright © 2005 by the International Society for Heart and Lung Transplantation.
Tricuspid regurgitation is the most common valvular abnormality after orthotopic heart transplantation, with a prevalence and severity greater than that seen in healthy subjects.1 Multiple etiologic factors have been implicated, including allograft rejection, increased pulmonary arterial pressure, asynchronous contraction of the donor and recipient atrial compartments, disturbed geometry of the right atrial anastomosis and tricuspid
From the aDivision of Cardiology, University of Ottawa Heart Institute, and Department of Medicine, University of Ottawa; and bDivision of Anatomical Pathology, Department of Laboratory Medicine, Ottawa Hospital, and Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada. Submitted June 22 2004; revised November 10, 2004; accepted November 12, 2004. Reprint requests: John P. Veinot, MD, Department of Laboratory Medicine, Room 123, Ottawa Hospital, Civic Campus, 1053 Carling Avenue, Ottawa, Ontario, Canada, K1Y 4E9. Telephone: 613-7614344. Fax: 613-761-4846. E-mail: [email protected] Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2004.11.007
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annulus, and damage to the sub-valvular apparatus during endomyocardial biopsy.2 The purpose of this study was to determine whether patients with significant tricuspid valve regurgitation (TVR) after orthotopic heart transplant had histologic evidence of valvular disruption and chordal tissue due to the endomyocardial biopsy procedure. METHODS AND PATIENTS Between 1986 and 2003, 213 orthotopic heart transplantations with biatrial anastomosis were performed at the University of Ottawa Heart Institute. Ninety-eight (46%) of these patients had echocardiographic assessments available at either 1 and/or 2 years after transplantation and were included in the study. Twenty-two patients (22%) were women and 76 (77%) were men. The average patient age at transplantation was 48.5 ⫾ 6.3 years. Endomyocardial Biopsy Patients underwent routine surveillance right heart catheterization and endomyocardial biopsy weekly for
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Table 1. Ratio of Jet Area to Right Atrial Area for the Evaluation of Tricuspid Regurgitation Degree Trivial TR Mild TR Moderate TR Severe TR
Ratio (%) ⬍10% 10–24% 25–49% ⱖ50%
TR, tricuspid regurgitation.
the first 1 to 3 months and then every 1 to 4 months after. Biopsies were performed through the right internal jugular vein under fluoroscopy. Nineteen patients with severe TVR had 205 biopsy procedures (mean number per patient, 10.7 ⫾ 4.2). Biopsy specimens were fixed in 10% neutral buffered formalin, paraffin embedded, and multiple histologic slides were prepared using serial sections at different levels. A cardiac pathologist, blinded to the diagnosis of TVR, reviewed the slides for the presence of tricuspid chordal or valvular tissue. Chordal tissue was identified by its characteristic structure with longitudinally oriented collagen fibers and surrounded by endocardium. Biopsy specimens were also assessed for the number and grade of acute cellular rejection. Any that demonstrated greater than International Society of Heart Lung Transplantation (ISHLT) grade 1A or 1B rejection was classified as an episode of significant rejection. Echocardiographic Assessment of TVR All echocardiographic reports were reviewed retrospectively. Echocardiograms were performed with a Hewlett-Packard Sonos machine (Hewlett-Packard Labs, Andover, MA) with a 2.5-MHz transducer used for 2-dimensional and continuous wave Doppler evaluation with color flow mapping. All studies were recorded on 0.75-in SVHS videotape. The tricuspid valve was examined in the parasternal short axis and apical 4-chamber views. The degree of regurgitation was graded according to the ratio of maximum area of the regurgitant jet in the right atrium to the area of the right atrium itself using color flow Doppler echocardiography (Table 1).3 All echocardiographic assessments at 1 and 2 years after transplantation were reviewed for the presence of significant TVR, which was defined as regurgitation classified as more than mild (Table 1). Clinical Assessment Detailed chart reviews were done in patients with significant TVR to evaluate for the presence of a holosystolic murmur or right heart failure on exam and functional status or limitations due to dyspnea. Pulmonary artery and right atrial pressures were assessed from right heart catheterization at the time of biopsy.
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Data Analysis Continuous variables were compared using an unpaired Student’s t test and categorical variables were compared using Fisher’s exact test. Data are presented as means ⫾ standard deviation unless otherwise indicated. A p value ⬍0.05 was considered significant. RESULTS Prevalence of Significant TVR The study comprised 98 patients. Thirty patients (31%) had only echocardiographic assessments at 1 year posttransplant, 2 (2%) had echocardiograms only at 2 years post-transplant, and 66 (67%) had echocardiograms available at both 1 and 2 years post-transplant. Significant TVR between 1 and 2 years after cardiac transplant in this study occurred in 19 patients (19%), 2 (10%) of which had severe regurgitation (Table 2). Prevalence and Significance of Chordal Tissue Nineteen of 98 patients in this study had significant TVR by echocardiogram. A total of 205 biopsies (10.7 ⫾ 4.2 each) were performed in these 19 patients. The specimen slides were examined for the presence of chordal tissue, which was found in 9 patients (47%). Two patients (10%) had evidence of chordal tissue on more than 1 biopsy specimen at different times. Patients with evidence of chordal tissue on biopsy were more likely to have more significant TVR, although this did not reach statistical significance. The odds ratio for moderate-to-severe TVR in the presence of chordal tissue was 2.07 and the 95% confidence interval was 0.537 to 8.01 (p ⫽ 0.32). Biopsy specimens that contained chordal tissue were all performed less than 4 months after cardiac transplantation, with a mean time of 70 days. The average time from the first echocardiogram to the biopsy specimen demonstrating chordal tissue was 40 ⫾ 16 days. The average time from this biopsy to the second echocardiogram was 94 ⫾ 22 days. Supplemental echocardiograms done before and after the biopsy specimen of interest were reviewed to determine whether a true relationship existed between the development of TVR and the presence of chordal
Table 2. Echocardiographic Determination of Tricuspid Regurgitation in 98 Patientsa Severity of TR None or trivial Mild Moderate Severe
n 42 37 17 2
Percentage 43% 38% 17% 2%
TR, tricuspid regurgitation. a Echocardiographic assessments were at 1 and/ or 2 years following cardiac transplant.
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Table 3. Changes in Degree of Tricuspid Regurgitation in Patients with Proven Chordal Disruption on Biopsy Time interval (days) Patient number 1 2 3 4 5 6 7 8 9
TR pre-biopsy Mild Mild Mild Moderate Mild Moderate Trivial Mild Trivial
TR post-biopsy Mild–moderate Severe Mild Severe Mild Moderate Moderate Moderate Mild–moderate
Time before biopsy 15 62 96 1 11 90 37 10 35
Time after biopsy 104 7 131 8 137 8 210 161 84
TR, tricuspid regurgitation.
tissue in that particular specimen (Table 3, Figure 1). Most patients with proven chordal tissue disruption had an increase in the degree of regurgitation after biopsy compared with the echocardiogram done before the biopsy specimen that demonstrated chordal tissue. TVR increased by an average of 1.4 grades in severity in 7 of the 9 patients with chordal tissue. No change in TVR was noted in the other 2 patients; both had mild regurgitation both before and after the biopsy. Only 1 patient had a flail segment. Number of Biopsies and Rejection Episodes There was no statistically significant difference in the number of biopsy procedures performed in patients whose biopsy specimens had evidence of chordal tissue (10.5 ⫾ 3.6) compared with those whose biopsy specimens did not (11.0 ⫾ 5.1, p ⫽ 0.798). There was also no evidence that the number of rejection episodes was greater in patients whose biopsy specimens had evidence of chordal tissue (3.0 ⫾ 1.5) than in the in the group whose biopsy specimens did not (3.5 ⫾ 2.6, p ⫽ 0.73). However, patients with evidence of chordal tissue on biopsy were more likely to have a greater mean worst rejection episode (ISHLT 2, vs. ISHLT 1B, p ⬍ 0.02). Clinical and Hemodynamic Assessment The charts of patients with echocardiographic evidence of significant TVR were reviewed to evaluate for clinical implications. Of the 9 patients with significant TVR and evidence of chordal tissue on biopsy, only 1 had documented evidence of dyspnea and a significant systolic murmur on clinical exam. This was demonstrated within 2 weeks of the biopsy. This patient had severe regurgitation with a flail segment and had a tricuspid valve repair 51 days after the biopsy specimen that demonstrated chordal tissue. Right atrial and pulmonary artery pressures were compared just before the
Figure 1. Changes in the degree of tricuspid regurgitation (TR) after chordal tissue disruption from endomyocardial biopsy.
biopsy specimen that showed chordal tissue and at the next right heart catheterization, an average of 87.3 ⫾ 41.5 days later (minimum 7 days, maximum 240 days). There were no significant differences in right atrial pressure (p ⫽ 0.26), pulmonary artery systolic pressure (p ⫽ 0.37), or pulmonary artery diastolic pressure (p ⫽ 0.71) before the biopsy of chordal tissue or at the next right heart catheterization (Table 4). Cardiac Function on Echocardiography There were no statistically significant differences in the left ventricular systolic function, right ventricular systolic function, and right ventricular size in patients who had evidence of chordal tissue disruption on biopsy. In addition, mean right ventricular systolic pressure, assessed by echocardiography, was not statistically different between the 2 groups (38.5 mm Hg in patients with chordal disruption vs 37 mm Hg in patients without, p ⫽ 0.74). DISCUSSION Prevalence of TVR After Cardiac Transplantation TVR has a reported prevalence of 65% to 85% in echocardiographic studies of patients after cardiac transplantation.1 It is the most common valvular abnormality after orthotopic heart transplantation, with a prevalence and severity greater than in healthy subjects. Color Doppler studies show that the prevalence of any degree of TVR in the general population can be as high as 15% to 70%. Almost all of this regurgitation is Table 4. Intra-Cardiac Pressures Before and After the Biopsy of Chordal Tissue and Significant Tricuspid Regurgitation (9 patients) Mean pressure (mm Hg) After biopsy (mean 87.3 Before biopsy days later) p Right atrial pressure 8.6 ⫾ 7.3 7.4 ⫾ 6.6 0.26 Pulmonary artery systolic pressure 35.6 ⫾ 5.4 33.0 ⫾ 13 0.37 Pulmonary artery diastolic pressure 12.6 ⫾ 12.4 12.0 ⫾ 6 0.71
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trivial and of no physiologic significance. In our study, the prevalence of significant (moderate or severe) TVR was 19%. This is slightly less than that reported in the largest series by Chan et al4 of 336 patients, in whom TVR was moderate in 27% and severe in 7%. Reported prevalence rates have been as low as 12% with moderate TVR and none with severe TVR in a study by Rees et al3 to as high as 50% with moderate and 20% with severe in a study by Lewen et al.5 The incidence of severe TVR has been found to increase over time in transplant patients. Chan et al4 reported that 92.2% of their cohort remained free of severe TVR at 5 years, and this decreased to 85.8% at 10 years. In a similar study, Hausen et al6 reported that the incidence of moderate TVR increased from 5% at 1 year to 50% at 4 years after transplantation. Causes of Significant TVR Several causes of TVR after cardiac transplantation have been reported. The presence of pulmonary hypertension and right ventricular injury at the time of transplantation may cause right ventricular and tricuspid annular dilatation that results in TVR. TVR resulting from pulmonary hypertension should be present early after transplantation and improve as pulmonary pressures decrease; however, multiple studies have shown no association between pretransplant pulmonary artery pressure or pulmonary vascular resistance and the subsequent development of severe TVR after transplantation.6,7 Surgical atrial anastomosis creates a large right atrium and abnormal geometry of the tricuspid annulus. This has also been postulated to disrupt the valve annulus or cause asynchronous contraction of donor and recipient atrial compartments. In a multivariate analysis by Aziz et al,1 the use of the standard atrial anastomosis was the most independent predictor for early and late TVR in heart transplant recipients. The bicaval anastomosis technique was associated with a lower incidence of TVR.1 Another postulated mechanism of TVR in this patient population is damage to the sub-valvular apparatus secondary to endomyocardial biopsy. The chordae tendineae of the tricuspid valve are often elongated, and the papillary muscles can be short and anchored at different levels in the ventricle. In addition, the bioptome must negotiate multiple muscular bands, including the trabeculae carneae and the moderator band, to approach the interventricular septum. These anatomic complexities of the right ventricle, combined with the difficulty of distinguishing chordae from other tissues by fluoroscopy, may all increase the risk of chordal apparatus damage from the bioptome jaws. Previous reports have documented that the number of biopsy procedures correlates with the increasing
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prevalence and severity of TVR.1,8 The mechanism responsible for this is thought to be traumatic disruption of the chordal supporting mechanism at the time of multiple biopsies. It is postulated that damage to the chordae may place increased stress upon the remaining chordae, with subsequent rupture and flail segment.8 The use of a long sheath to minimize the number of passages of the bioptome across the tricuspid valve has also been associated with a lower prevalence of flail leaflets and decreased severity of regurgitation.5 Severity of TVR has been correlated to severity of rejection.1 Although the underlying mechanism may be secondary to a higher number of biopsy procedures in those with rejection, Williams et al5 found no relation between the number of biopsy procedures performed and the presence of flail leaflets. The present study did not find any relation between the number of biopsy procedures performed, nor the number of rejection episodes and the chordal tissue on biopsy. TVR in our patient population may also have been related to the surgical intervention at transplantation, as all patients had a biatrial anastomosis, or possibly post-transplant right ventricular remodeling. Although pacemaker wires can interfere with tricuspid valve function and create valvular insufficiency, pacemaker wires were not present in any of our 19 patients with significant TVR at the time it developed. TVR may result from papillary muscle edema/dysfunction or asymmetrical contraction of the right ventricle during an episode of acute rejection.9 Very few studies have reported on the histologic analysis of endomyocardial biopsies in patients with significant TVR after orthotopic cardiac transplant. Wiklund et al 10 prospectively observed the incidence of chordal tissue in consecutive biopsy samples from heart transplant recipients. They detected chordal tissue in 24 of 206 biopsies (50% of patients, similar to the 48% of patients in the present study). However, when echocardiograms were reviewed, there was no significant increase in TVR and no major valvular abnormality in any patient after biopsy clearly showing chordal tissue.10 It should be recognized that various types of valvular chordae exist. The biopsy of a small tertiary chord may not result in significant change, whereas biopsy of a primary chord may result in significant valvular dysfunction. Our study confirms that chordal tissue damage can occur at endomyocardial biopsy. To our knowledge, this is the first study to evaluate histologic specimens for evidence of chordal disruption in a group of patients previously identified with significant TVR. The prevalence of chordal tissue disruption in this patient population was 47%, indicating that chordal biopsy may be an important cause of TVR in this patient population. In addition, almost all patients had clear echocardiographic evidence of a change in the degree of TVR
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before and after the chordal tissue biopsy. This supports the idea that the etiology of the TVR was biopsyinduced damage of chordal tissue. Interestingly, despite the degree of significant TVR on echocardiographic study, most of the patients remained clinically asymptomatic on follow-up. In addition, right atrial or pulmonary artery pressures did not change significantly despite a change in the degree of TVR. TVR after orthotopic cardiac transplant may have multiple etiologies. Biopsy-related injury to the tricuspid valve apparatus is infrequent but rarely clinically significant. This study of histologic specimens indicates that injury to the tricuspid valve apparatus can result from endomyocardial biopsy. Despite echocardiographic evidence of significant TVR, most of the patients in this sample were asymptomatic when followed over time. REFERENCES 1. Aziz TM, Burgess MI, Rahman AN, Campbell AS, Deiranita AK, Yonan NA. Risk factors for tricuspid valve regurgitation after orthotopic heart transplantation. Ann Thorac Surg 1999;68:1247–51. 2. Aziz TM, Saad RA, Burgess MI, Campell CS, Yonan NA. Clinical significance of tricuspid valve dysfunction after orthotopic heart transplantation. J Heart Lung Transplant 2002;21:1101– 8.
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3. Rees AP, Milani RV, Lavie CJ, Smart FW, Ventura HO. Valvular regurgitation and right-sided cardiac pressures in heart transplant recipients by complete Doppler and color flow evaluation. Chest 1993;104:82–7. 4. Chan M, Giannetti N, Kornbluth M, et al. Severe tricuspid regurgitation after heart transplantation. J Heart Lung Transplant 2001;20:709 –17. 5. Williams MJ, Lee MY, DiSalvo TG, et al. Biopsy induced flail tricuspid leaflet and tricuspid regurgitation following orthotopic cardiac transplantation. Am J Cardiol 1996;77: 1339 – 44. 6. Hausen B, Albes J, Rohde R, Demertzis S, Mugge A, Schafers H. Tricuspid valve regurgitation attributable to endomyocardial biopsies and rejection in heart transplantation. Ann Thorac Surg 1995;59:1134 – 40. 7. Huddleson CB, Rosenbloom M, Goldestein JA, Pasque MK. Biopsy induced tricuspid regurgitation after cardiac transplantation. Ann Thorac Surg 1994;57:832– 6. 8. Stahl R, Karwande S, Olsen S, Taylor D, Hawkins J, Renlund D. Tricuspid valve dysfunction in the transplanted heart. Ann Thorac Surg 1995;59:477– 80. 9. Herrmann G, Simon R, Haverich A, et al. Left ventricular function, tricuspid incompetence and incidence of coronary artery disease late after orthotopic heart transplantation. J Cardiothorac Surg 1989;3:111– 8. 10. Wilkund L, Suukula M, Kjellstrom C, Berglin E. Chordal tissue in endomyocardial biopsies. Scand J Thorac Cardiovasc Surg 1994;28:13– 8.
Tricuspid Valve Chordal Tissue in Endomyocardial Biopsy Specimens of Patients With Significant Tricuspid Regurgitation Lisa Mielniczuk, MD,a Haissam Haddad, MD,a Ross A. Davies, MD,a and John P. Veinot, MDb Objectives:
Methods:
Results:
Conclusion:
Tricuspid regurgitation is the most common valvular abnormality after orthotopic heart transplantation, with multiple etiologic factors implicated. The purpose of this study was to determine if the endomyocardial biopsy specimens of patients who developed significant tricuspid valve regurgitation (TVR) after cardiac transplantation had evidence of chordal tissue. The echocardiograms of 98 patients who had cardiac transplantation between 1986 and 2002 were reviewed for evidence of significant TVR greater than mild. The biopsy specimens of all patients with significant TVR were then reviewed for histologic evidence of tricuspid chordal tissue and frequency and severity of rejection episodes. Clinical information collected included the presence of any systolic murmurs, significant dyspnea, and invasive hemodynamic measurements. The incidence of significant TVR was 19% (n ⫽ 19 patients). Histologic evidence of chordal tissue was present in 9 patients (47%) with significant TVR. Patients whose biopsy specimens evidenced chordal tissue tended to have a greater degree of TVR, but this was not statistically significant (odds ratio, 2.07; 95% confidence interval, 0.537– 8.01, p ⫽ 0.32). There was no statistically significant difference in the number of biopsy specimens (p ⫽ 0.798), the number of rejection episodes (p ⫽ 0.73), or overall left or right ventricular systolic function between the patients with and without biopsy specimen evidence of chordal tissue disruption. Most of the patients with evidence of significant TVR after chordal tissue biopsy were clinically asymptomatic, with no significant change in their hemodynamics. Histologic evidence of chordal tissue in endomyocardial biopsy specimens was present in 47% of patients with significant TVR and did not relate to the number of biopsy procedures performed or the frequency of rejection episodes. This study provides histologic evidence that chordal tissue damage can occur after cardiac biopsy, resulting in significant TVR; however, it is clinically well tolerated by affected patients. J Heart Lung Transplant 2005;24:1586 –90. Copyright © 2005 by the International Society for Heart and Lung Transplantation.
Tricuspid regurgitation is the most common valvular abnormality after orthotopic heart transplantation, with a prevalence and severity greater than that seen in healthy subjects.1 Multiple etiologic factors have been implicated, including allograft rejection, increased pulmonary arterial pressure, asynchronous contraction of the donor and recipient atrial compartments, disturbed geometry of the right atrial anastomosis and tricuspid
From the aDivision of Cardiology, University of Ottawa Heart Institute, and Department of Medicine, University of Ottawa; and bDivision of Anatomical Pathology, Department of Laboratory Medicine, Ottawa Hospital, and Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada. Submitted June 22 2004; revised November 10, 2004; accepted November 12, 2004. Reprint requests: John P. Veinot, MD, Department of Laboratory Medicine, Room 123, Ottawa Hospital, Civic Campus, 1053 Carling Avenue, Ottawa, Ontario, Canada, K1Y 4E9. Telephone: 613-7614344. Fax: 613-761-4846. E-mail: [email protected] Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2004.11.007
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annulus, and damage to the sub-valvular apparatus during endomyocardial biopsy.2 The purpose of this study was to determine whether patients with significant tricuspid valve regurgitation (TVR) after orthotopic heart transplant had histologic evidence of valvular disruption and chordal tissue due to the endomyocardial biopsy procedure. METHODS AND PATIENTS Between 1986 and 2003, 213 orthotopic heart transplantations with biatrial anastomosis were performed at the University of Ottawa Heart Institute. Ninety-eight (46%) of these patients had echocardiographic assessments available at either 1 and/or 2 years after transplantation and were included in the study. Twenty-two patients (22%) were women and 76 (77%) were men. The average patient age at transplantation was 48.5 ⫾ 6.3 years. Endomyocardial Biopsy Patients underwent routine surveillance right heart catheterization and endomyocardial biopsy weekly for
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Table 1. Ratio of Jet Area to Right Atrial Area for the Evaluation of Tricuspid Regurgitation Degree Trivial TR Mild TR Moderate TR Severe TR
Ratio (%) ⬍10% 10–24% 25–49% ⱖ50%
TR, tricuspid regurgitation.
the first 1 to 3 months and then every 1 to 4 months after. Biopsies were performed through the right internal jugular vein under fluoroscopy. Nineteen patients with severe TVR had 205 biopsy procedures (mean number per patient, 10.7 ⫾ 4.2). Biopsy specimens were fixed in 10% neutral buffered formalin, paraffin embedded, and multiple histologic slides were prepared using serial sections at different levels. A cardiac pathologist, blinded to the diagnosis of TVR, reviewed the slides for the presence of tricuspid chordal or valvular tissue. Chordal tissue was identified by its characteristic structure with longitudinally oriented collagen fibers and surrounded by endocardium. Biopsy specimens were also assessed for the number and grade of acute cellular rejection. Any that demonstrated greater than International Society of Heart Lung Transplantation (ISHLT) grade 1A or 1B rejection was classified as an episode of significant rejection. Echocardiographic Assessment of TVR All echocardiographic reports were reviewed retrospectively. Echocardiograms were performed with a Hewlett-Packard Sonos machine (Hewlett-Packard Labs, Andover, MA) with a 2.5-MHz transducer used for 2-dimensional and continuous wave Doppler evaluation with color flow mapping. All studies were recorded on 0.75-in SVHS videotape. The tricuspid valve was examined in the parasternal short axis and apical 4-chamber views. The degree of regurgitation was graded according to the ratio of maximum area of the regurgitant jet in the right atrium to the area of the right atrium itself using color flow Doppler echocardiography (Table 1).3 All echocardiographic assessments at 1 and 2 years after transplantation were reviewed for the presence of significant TVR, which was defined as regurgitation classified as more than mild (Table 1). Clinical Assessment Detailed chart reviews were done in patients with significant TVR to evaluate for the presence of a holosystolic murmur or right heart failure on exam and functional status or limitations due to dyspnea. Pulmonary artery and right atrial pressures were assessed from right heart catheterization at the time of biopsy.
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Data Analysis Continuous variables were compared using an unpaired Student’s t test and categorical variables were compared using Fisher’s exact test. Data are presented as means ⫾ standard deviation unless otherwise indicated. A p value ⬍0.05 was considered significant. RESULTS Prevalence of Significant TVR The study comprised 98 patients. Thirty patients (31%) had only echocardiographic assessments at 1 year posttransplant, 2 (2%) had echocardiograms only at 2 years post-transplant, and 66 (67%) had echocardiograms available at both 1 and 2 years post-transplant. Significant TVR between 1 and 2 years after cardiac transplant in this study occurred in 19 patients (19%), 2 (10%) of which had severe regurgitation (Table 2). Prevalence and Significance of Chordal Tissue Nineteen of 98 patients in this study had significant TVR by echocardiogram. A total of 205 biopsies (10.7 ⫾ 4.2 each) were performed in these 19 patients. The specimen slides were examined for the presence of chordal tissue, which was found in 9 patients (47%). Two patients (10%) had evidence of chordal tissue on more than 1 biopsy specimen at different times. Patients with evidence of chordal tissue on biopsy were more likely to have more significant TVR, although this did not reach statistical significance. The odds ratio for moderate-to-severe TVR in the presence of chordal tissue was 2.07 and the 95% confidence interval was 0.537 to 8.01 (p ⫽ 0.32). Biopsy specimens that contained chordal tissue were all performed less than 4 months after cardiac transplantation, with a mean time of 70 days. The average time from the first echocardiogram to the biopsy specimen demonstrating chordal tissue was 40 ⫾ 16 days. The average time from this biopsy to the second echocardiogram was 94 ⫾ 22 days. Supplemental echocardiograms done before and after the biopsy specimen of interest were reviewed to determine whether a true relationship existed between the development of TVR and the presence of chordal
Table 2. Echocardiographic Determination of Tricuspid Regurgitation in 98 Patientsa Severity of TR None or trivial Mild Moderate Severe
n 42 37 17 2
Percentage 43% 38% 17% 2%
TR, tricuspid regurgitation. a Echocardiographic assessments were at 1 and/ or 2 years following cardiac transplant.
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Table 3. Changes in Degree of Tricuspid Regurgitation in Patients with Proven Chordal Disruption on Biopsy Time interval (days) Patient number 1 2 3 4 5 6 7 8 9
TR pre-biopsy Mild Mild Mild Moderate Mild Moderate Trivial Mild Trivial
TR post-biopsy Mild–moderate Severe Mild Severe Mild Moderate Moderate Moderate Mild–moderate
Time before biopsy 15 62 96 1 11 90 37 10 35
Time after biopsy 104 7 131 8 137 8 210 161 84
TR, tricuspid regurgitation.
tissue in that particular specimen (Table 3, Figure 1). Most patients with proven chordal tissue disruption had an increase in the degree of regurgitation after biopsy compared with the echocardiogram done before the biopsy specimen that demonstrated chordal tissue. TVR increased by an average of 1.4 grades in severity in 7 of the 9 patients with chordal tissue. No change in TVR was noted in the other 2 patients; both had mild regurgitation both before and after the biopsy. Only 1 patient had a flail segment. Number of Biopsies and Rejection Episodes There was no statistically significant difference in the number of biopsy procedures performed in patients whose biopsy specimens had evidence of chordal tissue (10.5 ⫾ 3.6) compared with those whose biopsy specimens did not (11.0 ⫾ 5.1, p ⫽ 0.798). There was also no evidence that the number of rejection episodes was greater in patients whose biopsy specimens had evidence of chordal tissue (3.0 ⫾ 1.5) than in the in the group whose biopsy specimens did not (3.5 ⫾ 2.6, p ⫽ 0.73). However, patients with evidence of chordal tissue on biopsy were more likely to have a greater mean worst rejection episode (ISHLT 2, vs. ISHLT 1B, p ⬍ 0.02). Clinical and Hemodynamic Assessment The charts of patients with echocardiographic evidence of significant TVR were reviewed to evaluate for clinical implications. Of the 9 patients with significant TVR and evidence of chordal tissue on biopsy, only 1 had documented evidence of dyspnea and a significant systolic murmur on clinical exam. This was demonstrated within 2 weeks of the biopsy. This patient had severe regurgitation with a flail segment and had a tricuspid valve repair 51 days after the biopsy specimen that demonstrated chordal tissue. Right atrial and pulmonary artery pressures were compared just before the
Figure 1. Changes in the degree of tricuspid regurgitation (TR) after chordal tissue disruption from endomyocardial biopsy.
biopsy specimen that showed chordal tissue and at the next right heart catheterization, an average of 87.3 ⫾ 41.5 days later (minimum 7 days, maximum 240 days). There were no significant differences in right atrial pressure (p ⫽ 0.26), pulmonary artery systolic pressure (p ⫽ 0.37), or pulmonary artery diastolic pressure (p ⫽ 0.71) before the biopsy of chordal tissue or at the next right heart catheterization (Table 4). Cardiac Function on Echocardiography There were no statistically significant differences in the left ventricular systolic function, right ventricular systolic function, and right ventricular size in patients who had evidence of chordal tissue disruption on biopsy. In addition, mean right ventricular systolic pressure, assessed by echocardiography, was not statistically different between the 2 groups (38.5 mm Hg in patients with chordal disruption vs 37 mm Hg in patients without, p ⫽ 0.74). DISCUSSION Prevalence of TVR After Cardiac Transplantation TVR has a reported prevalence of 65% to 85% in echocardiographic studies of patients after cardiac transplantation.1 It is the most common valvular abnormality after orthotopic heart transplantation, with a prevalence and severity greater than in healthy subjects. Color Doppler studies show that the prevalence of any degree of TVR in the general population can be as high as 15% to 70%. Almost all of this regurgitation is Table 4. Intra-Cardiac Pressures Before and After the Biopsy of Chordal Tissue and Significant Tricuspid Regurgitation (9 patients) Mean pressure (mm Hg) After biopsy (mean 87.3 Before biopsy days later) p Right atrial pressure 8.6 ⫾ 7.3 7.4 ⫾ 6.6 0.26 Pulmonary artery systolic pressure 35.6 ⫾ 5.4 33.0 ⫾ 13 0.37 Pulmonary artery diastolic pressure 12.6 ⫾ 12.4 12.0 ⫾ 6 0.71
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trivial and of no physiologic significance. In our study, the prevalence of significant (moderate or severe) TVR was 19%. This is slightly less than that reported in the largest series by Chan et al4 of 336 patients, in whom TVR was moderate in 27% and severe in 7%. Reported prevalence rates have been as low as 12% with moderate TVR and none with severe TVR in a study by Rees et al3 to as high as 50% with moderate and 20% with severe in a study by Lewen et al.5 The incidence of severe TVR has been found to increase over time in transplant patients. Chan et al4 reported that 92.2% of their cohort remained free of severe TVR at 5 years, and this decreased to 85.8% at 10 years. In a similar study, Hausen et al6 reported that the incidence of moderate TVR increased from 5% at 1 year to 50% at 4 years after transplantation. Causes of Significant TVR Several causes of TVR after cardiac transplantation have been reported. The presence of pulmonary hypertension and right ventricular injury at the time of transplantation may cause right ventricular and tricuspid annular dilatation that results in TVR. TVR resulting from pulmonary hypertension should be present early after transplantation and improve as pulmonary pressures decrease; however, multiple studies have shown no association between pretransplant pulmonary artery pressure or pulmonary vascular resistance and the subsequent development of severe TVR after transplantation.6,7 Surgical atrial anastomosis creates a large right atrium and abnormal geometry of the tricuspid annulus. This has also been postulated to disrupt the valve annulus or cause asynchronous contraction of donor and recipient atrial compartments. In a multivariate analysis by Aziz et al,1 the use of the standard atrial anastomosis was the most independent predictor for early and late TVR in heart transplant recipients. The bicaval anastomosis technique was associated with a lower incidence of TVR.1 Another postulated mechanism of TVR in this patient population is damage to the sub-valvular apparatus secondary to endomyocardial biopsy. The chordae tendineae of the tricuspid valve are often elongated, and the papillary muscles can be short and anchored at different levels in the ventricle. In addition, the bioptome must negotiate multiple muscular bands, including the trabeculae carneae and the moderator band, to approach the interventricular septum. These anatomic complexities of the right ventricle, combined with the difficulty of distinguishing chordae from other tissues by fluoroscopy, may all increase the risk of chordal apparatus damage from the bioptome jaws. Previous reports have documented that the number of biopsy procedures correlates with the increasing
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prevalence and severity of TVR.1,8 The mechanism responsible for this is thought to be traumatic disruption of the chordal supporting mechanism at the time of multiple biopsies. It is postulated that damage to the chordae may place increased stress upon the remaining chordae, with subsequent rupture and flail segment.8 The use of a long sheath to minimize the number of passages of the bioptome across the tricuspid valve has also been associated with a lower prevalence of flail leaflets and decreased severity of regurgitation.5 Severity of TVR has been correlated to severity of rejection.1 Although the underlying mechanism may be secondary to a higher number of biopsy procedures in those with rejection, Williams et al5 found no relation between the number of biopsy procedures performed and the presence of flail leaflets. The present study did not find any relation between the number of biopsy procedures performed, nor the number of rejection episodes and the chordal tissue on biopsy. TVR in our patient population may also have been related to the surgical intervention at transplantation, as all patients had a biatrial anastomosis, or possibly post-transplant right ventricular remodeling. Although pacemaker wires can interfere with tricuspid valve function and create valvular insufficiency, pacemaker wires were not present in any of our 19 patients with significant TVR at the time it developed. TVR may result from papillary muscle edema/dysfunction or asymmetrical contraction of the right ventricle during an episode of acute rejection.9 Very few studies have reported on the histologic analysis of endomyocardial biopsies in patients with significant TVR after orthotopic cardiac transplant. Wiklund et al 10 prospectively observed the incidence of chordal tissue in consecutive biopsy samples from heart transplant recipients. They detected chordal tissue in 24 of 206 biopsies (50% of patients, similar to the 48% of patients in the present study). However, when echocardiograms were reviewed, there was no significant increase in TVR and no major valvular abnormality in any patient after biopsy clearly showing chordal tissue.10 It should be recognized that various types of valvular chordae exist. The biopsy of a small tertiary chord may not result in significant change, whereas biopsy of a primary chord may result in significant valvular dysfunction. Our study confirms that chordal tissue damage can occur at endomyocardial biopsy. To our knowledge, this is the first study to evaluate histologic specimens for evidence of chordal disruption in a group of patients previously identified with significant TVR. The prevalence of chordal tissue disruption in this patient population was 47%, indicating that chordal biopsy may be an important cause of TVR in this patient population. In addition, almost all patients had clear echocardiographic evidence of a change in the degree of TVR
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before and after the chordal tissue biopsy. This supports the idea that the etiology of the TVR was biopsyinduced damage of chordal tissue. Interestingly, despite the degree of significant TVR on echocardiographic study, most of the patients remained clinically asymptomatic on follow-up. In addition, right atrial or pulmonary artery pressures did not change significantly despite a change in the degree of TVR. TVR after orthotopic cardiac transplant may have multiple etiologies. Biopsy-related injury to the tricuspid valve apparatus is infrequent but rarely clinically significant. This study of histologic specimens indicates that injury to the tricuspid valve apparatus can result from endomyocardial biopsy. Despite echocardiographic evidence of significant TVR, most of the patients in this sample were asymptomatic when followed over time. REFERENCES 1. Aziz TM, Burgess MI, Rahman AN, Campbell AS, Deiranita AK, Yonan NA. Risk factors for tricuspid valve regurgitation after orthotopic heart transplantation. Ann Thorac Surg 1999;68:1247–51. 2. Aziz TM, Saad RA, Burgess MI, Campell CS, Yonan NA. Clinical significance of tricuspid valve dysfunction after orthotopic heart transplantation. J Heart Lung Transplant 2002;21:1101– 8.
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3. Rees AP, Milani RV, Lavie CJ, Smart FW, Ventura HO. Valvular regurgitation and right-sided cardiac pressures in heart transplant recipients by complete Doppler and color flow evaluation. Chest 1993;104:82–7. 4. Chan M, Giannetti N, Kornbluth M, et al. Severe tricuspid regurgitation after heart transplantation. J Heart Lung Transplant 2001;20:709 –17. 5. Williams MJ, Lee MY, DiSalvo TG, et al. Biopsy induced flail tricuspid leaflet and tricuspid regurgitation following orthotopic cardiac transplantation. Am J Cardiol 1996;77: 1339 – 44. 6. Hausen B, Albes J, Rohde R, Demertzis S, Mugge A, Schafers H. Tricuspid valve regurgitation attributable to endomyocardial biopsies and rejection in heart transplantation. Ann Thorac Surg 1995;59:1134 – 40. 7. Huddleson CB, Rosenbloom M, Goldestein JA, Pasque MK. Biopsy induced tricuspid regurgitation after cardiac transplantation. Ann Thorac Surg 1994;57:832– 6. 8. Stahl R, Karwande S, Olsen S, Taylor D, Hawkins J, Renlund D. Tricuspid valve dysfunction in the transplanted heart. Ann Thorac Surg 1995;59:477– 80. 9. Herrmann G, Simon R, Haverich A, et al. Left ventricular function, tricuspid incompetence and incidence of coronary artery disease late after orthotopic heart transplantation. J Cardiothorac Surg 1989;3:111– 8. 10. Wilkund L, Suukula M, Kjellstrom C, Berglin E. Chordal tissue in endomyocardial biopsies. Scand J Thorac Cardiovasc Surg 1994;28:13– 8.