Risk factors for tricuspid valve regurgitation after orthotopic heart transplantation

Risk Factors for Tricuspid Valve Regurgitation After Orthotopic Heart Transplantation Tarek M. Aziz, FRCS, Malcolm I. Burgess, MRCP, Ali N. Rahman, FRCS, Colin S. Campbell, FRCS, Abdul K. Deiraniya, FRCS, and Nizar A. Yonan, FRCS Cardiac Transplantation Unit, Wythenshawe Hospital, Manchester, England

Background. Tricuspid regurgitation (TR) may occur following orthotopic heart transplantation (OHT) and although a number of etiological factors have been suggested, the relative contribution of each of these remains to be elucidated. We aimed to assess the risk factors for TR in our 10-year experience of orthotopic heart transplantation (OHT). Methods. OHT was performed in 249 patients (161 by the standard technique and 88 by the bicaval technique). TR was assessed using transthoracic color Doppler echocardiography. Results. Recipients who underwent operation by the standard technique displayed higher incidence of moderate and severe TR than did bicaval-technique recipients. The development of early TR was also correlated to

rejection greater than or equal to grade 2, preoperative raised transpulmonary gradient, and raised pulmonary vascular resistance. Risk factors for late TR were standard technique (p < 0.0001), number of rejection greater than or equal to grade 2 (p < 0.004), and the total number of heart biopsies (p < 0.02). Recipients with moderate and severe TR revealed elevated right-side pressures and advanced New York Heart Association statues compared to those with no, trivial, or mild TR. Conclusions. Various factors contribute to TR after OHT, the prevalence of which might be lowered by adopting the bicaval technique, early treatment of rejection, and reduction of the number of biopsies performed. (Ann Thorac Surg 1999;68:1247–51) © 1999 by The Society of Thoracic Surgeons

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recipients and by the bicaval technique in 88 patients as previously described by Sarsam and colleagues [8]. Sixty-nine patients underwent transplantation by the standard technique during the period 1987 to 1990. After 1990, patients underwent operation by either standard or bicaval techniques, alternatively. Patients who had retransplantation (domino recipients) have been excluded from this study. There was no difference in preoperative pulmonary hemodynamics, age, ischemic time, or postoperative incidence of rejection between patients undergoing OHT by either technique. Triple drug immunosuppression with cyclosporin, azathioprine, and steroid therapy was used in all patients in addition to an initial 3-day course of cytolytic induction therapy. Surveillance endomyocardial biopsies were performed using a percutaneous right internal jugular approach. The biopsies were performed on a scheduled basis, weekly for the first month, every 2 weeks for the next 2 months, monthly until 6 months, then at 9, 12, and 18 months after transplantation, and yearly after. In the event of clinical suspicion of rejection in the interim, further biopsies were performed as clinically indicated. Biopsies were evaluated for rejection using International Society of Heart and Lung Transplantation (ISHLT) criteria [9]. Acute rejection is treated with bolus methylprednisolone (500 mg daily for 3 days) and follow-up endomyocardial biopsy (EMB) is performed every 1 to 2 weeks to assess outcome of treatment. Treatment is given only when the degree of rejection is greater than or equal to 3A or when the patient is clinically compromised.

ricuspid valve regurgitation (TR) is often observed following orthotopic cardiac transplantation with a prevalence of 67% to 85% in echocardiographic series [1–3]. Attempts have been made to explain the risk factors and significance of TR after heart transplantation [4]. However, quantification of its severity and evolution remains disputed. The presence of TR might be expected to have a detrimental effect on cardiac performance, particularly in transplant recipients who have persistent pulmonary hypertension after transplantation [5, 6]. The aims of this study were to assess tricuspid valve function in orthotopic heart transplantation (OHT) recipients by serial Doppler echocardiography from the early postoperative period and to estimate the potential risk factors for TR at different stages following OHT.

Patients and Methods We studied 249 heart transplant recipients (46.5 ⫾ 12 years, range 12 to 64 years, 18% female) who underwent orthotopic heart transplantation between 1987 and 1996 at Wythenshawe Hospital, Manchester, England. Preoperative pathology was ischemic heart disease in 133 patients, cardiomyopathy in 92 patients, valvular heart disease in 17 patients, and other heart conditions in 7 patients. Cardiac transplantation was performed according to the technique of Lower and Shumway [7] in 161 Accepted for publication April 20, 1999. Address reprint requests to Dr Aziz, Cardiac Transplant Unit, Wythenshawe Hospital, Southmoor Rd, Manchester M23 9LT, England.

© 1999 by The Society of Thoracic Surgeons Published by Elsevier Science Inc

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Table 1. Risk Factors for Tricuspid Valve Regurgitation in Each Technique During the First 4 Weeks After Heart Transplantation Spearman’s Correlation Coefficients ( p Value) Criteria Raised TPG ⬎ 10 mm Hg Raised PVR ⱖ 4 wu Weight mismatch ⬎ 15% Old donor age ⬎ 50 years Ischemic time Sex mismatch Rejection ⱖ grade 2 during the first 4 weeks PVR ⫽ pulmonary vascular resistance;

Standard Technique

Bicaval Technique

0.41 (0.002) 0.49 (0.001) 0.29 (0.01) 0.27 (0.04) 0.2 (0.06) 0.19 (0.07) 0.39 (0.003)

0.26 (0.04) 0.33 (0.02) 0.02 (0.05) 0.16 (0.08) 0.1 (0.09) 0.09 (0.5) 0.26 (0.02)

TPG ⫽ transpulmonary gradient.

Transthoracic two-dimensional and continuous-wave echocardiography (with color flow mapping) was performed. The assessment of TR was semiquantitative, the major criterion for the severity of regurgitation being the ratio of regurgitation jet area. The major criterion for the severity of regurgitation was qualitative assessment according to the ratio of regurgitation jet area as previously described. In general, a regurgitation jet area/atrial area of less than 10% was considered trivial, 10%–25% mild, 25%–50% moderate, and greater than 50% severe. Echocardiographic and clinical assessments at 1 year, 2 years, and recently, were performed in the absence of rejection, following the same policy of hemodynamics. Follow-up was completed to December 1998, or at time of recipient’s death. Mean follow-up was 59 ⫾ 35 months for standard technique recipients and 51 ⫾ 12 months for the bicaval technique recipients. Data are expressed as mean ⫾ standard deviation. Continuous data were compared by the Mann-Whitney test and Student’s t test; and categorical data was compared by ␹2. Correlation was made using Spearman correlation analysis (r ⫽ correlation coefficient). Multiple logistic regression analysis was performed to identify predictors of TR. A p value of less than 0.05 was defined as significant.

Results The prevalence of TR at week 4 was affected in all recipients by preoperative pulmonary hemodynamics, weight mismatch, donor age, and cellular rejection episodes (Table 1). However, cardiac transplant recipients who underwent operation by the standard technique displayed a higher incidence of significant degree of moderate and severe TR than bicaval technique recipients did. The incidence of TR at week 4 did not correlate with ischemic time or gender mismatch between donor and recipient. The prevalence of significant TR (moderate and severe echocardiographically detected TR) was higher in the standard recipients as compared to the bicaval technique recipients, at 1 and 2 years duration following heart transplantation (Table 2). The severity of TR was always significantly higher in recipients who were transplanted by standard technique, in all time scales following transplantation (Table 3). The incidence of TR at 1- and 2-year intervals correlates significantly with the number of cellular rejection episodes greater than or equal to grade 2 (r ⫽ 0.573, r ⫽ 0.595, p ⬍ 0.0006, p ⬍ 0.0001 at 1- and 2-years of follow-up, respectively). Right heart catheterization at 1 year following transplantation revealed elevated right-side pressures in the recipients with moderate and severe TR (mean right atrial pressure 13 ⫾ 4.9 mm Hg, mean pulmonary artery pressure was 24 ⫾ 6.9 mm Hg) compared with those who presented with no, trivial, or mild TR (mean RA pressure 6.9 ⫾ 3.6 mm Hg, mean PA pressure 16.3 ⫾ 4.6 mm Hg, p ⫽ 0.002, and p ⫽ 0.001, respectively). Recipients who underwent transplantation by the standard technique showed higher right-sided pressures compared to the bicaval technique recipients at 12 months following transplantation (Figure 1). The severity of TR was higher in the standard technique recipients compared to the bicaval recipients at all stages following transplantation (Table 4). A multivariate analysis identified standard technique as the most independent predictor for early and late TR in heart transplant recipients (p ⬍ 0.0001). The development of longterm significant TR after transplantation was also affected by the number of rejection episodes greater than 2 and number of endomyocardial biopsy performed (Table 4).

Table 2. Difference in Incidence and Severity of Tricuspid Valve Regurgitation Between Cardiac Transplant Recipients Had Standard Technique Versus Bicaval Technique Standard Technique

Bicaval Technique

Time After Transplant

No TR to Mild TR

Moderate to Severe

No TR to Mild TR

Moderate to Severe

p Value

1 month 12 months 24 months Recently

93/156 (59%) 73/146 (50%) 67/138 (48%) 38/119 (31%)

63/156 (41%) 73/146 (50%) 71/138 (52%) 81/119 (69%)

72/84 (85%) 62/81 (76%) 56/79 (70%) 49/70 (70%)

12/84 (15%) 19/81 (24%) 23/79 (30%) 21/70 (30%)

0.0001 0.002 0.002 0.0001

p value compares the prevalence of significant TR (moderate and severe TR) between each technique at different stages following transplantation. TR ⫽ tricuspid valve regurgitation.

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Table 3. Multiple Logistic Regression Analysis of Long Term Risks of TR in Heart Transplant Recipients No 1 2 3 5 6 7 8 CI ⫽ cardiac index; gradient.

Variable

Expected Risk

95% CI

p Value

Technique “Standard” Rejection episode ⱖ 2 No of EMB High preoperative PVR ⱖ 4 Wu Old donor age ⬎ 50 Raised preoperative TPG ⬎ 10 mm Hg Weight mismatch ⬎ 15%

7.33 1.6/episode 0.81/Bx 0.43 0.2 0.11 0.06

6.6 –7.6 1.41–1.72 0.61– 0.92 0.36 – 0.51 0.09 – 0.29 ⫺0.06 – 0.18 ⫺0.12– 0.1

0.0001 0.004 0.02 0.039 NS NS NS

EMB ⫽ endomyocardial biopsy;

NS ⫽ not significant;

The possible addition of other variables (old donor age, ischemic time, gender mismatch, weight mismatch, development of coronary artery disease) had no apparent influence on the long-term analysis result. Clinically, 85% (86 of 102) of our recipients with echocardiographically detected moderate-to-severe TR (63 had standard and 13 had a bicaval technique) presented with classic signs of right heart failure, including progressive fatigue (35%), chronic fluid congestion (61%), lower extremity edema (78%), hepatomegaly (29%), and jugular venous distention (59%). At the most recent examination, the mean New York Heart Association status for recipients presented with a relevant echocardiographic picture of moderate to severe TR was 2.3 ⫾ 0.7, compared to 1.1 ⫾ 0.4 (Figure 2) for recipients with lesser degrees of TR (p ⫽ 0.003). Diuretic therapy was given to 91% of our recipients with moderate or severe TR; of these, 71% (78/91) received intensive doses (more than 120 mg frusemide or equivalent /day). In the nonclinical TR group, (trivial and mild TR) only 19% (21/115) received diuretics (p ⬍ 0.0001).

PVR ⫽ pulmonary vascular resistance;

TPG ⫽ transpulmonary

reported to be highly prevalent [11–13]. Theories to explain this include acute allograft edema, which diminishes with time [14], papillary muscle dysfunction [15], preoperative annular dilatation [2], disturbed geometry of the right atrial anastomosis with subsequent impairment of the functional integrity of the valvular apparatus [11], cyclic torsion of the atria during ventricular systole and diastole [11], asynchronous contraction of the donor and recipient atrial compartment [11], and biopsyinduced flail tricuspid valve [16]. Alteration in right ventricular structure may also contribute to the occurrence of TR, because a significantly greater percentage of patients with post-transplant right ventricular enlargement have been found to have moderate TR [1]. However, the presence of this relationship does not infer that right ventricular enlargement has an unequivocal causative role. The clinical importance of TR following OHT has not been elucidated previously. Previous studies have reported that trivial, mild, and some moderate degrees of TR usually have a benign course [2]. However, a consid-

Comment Studies using Doppler echocardiography have demonstrated trivial degrees of TR in normal individuals with a quoted prevalence of 17% in the general population [10]. Both immediately after and late following OHT, TR is

Fig 1. Right-heart catheter measurements in standard and bicaval patients before and after transplantation.

Fig 2. New York Heart Association class among heart transplant recipients with different grade TR.

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Table 4. Difference in Incidence and Severity of Tricuspid Valve Regurgitation Between Cardiac Transplant Recipients Who Had Standard Technique Versus Bicaval Technique Standard Technique Time Period TR TR TR TR

at 4 weeks at 12 months at 24 months recently

Bicaval Technique

Median TR

Interquartile Range 25th–75th Percentile

Median TR

Interquartile Range 25th–75th Percentile

p Value

U Value

2.5 2.5 3 3

1.5 1.8 1.9 2.3

1.5 2 1 1.8

0.2 1.2 0.8 1.2

0.002 0.0001 0.001 0.001

3888.0 3421.0 1761.0 3344.5

p value compares the prevalence of significant TR (moderate and severe TR) between each technique at different stages following transplantation. TR ⫽ tricuspid valve regurgitation.

erable degree of TR may cause intractable right heart failure, which itself may contribute to early and late morbidity and mortality after heart transplantation [4, 17]. The significance of TR in heart transplant recipients is that it may reflect a significant degree of right ventricular dilatation. It is also important to emphasize that 80% of recipients in our study with moderate-to-severe TR (75% of them were operated by standard technique) had symptoms related to chronic right ventricular volume overload. Right-sided pressures were persistently elevated at the end of the first post-transplant year in this subgroup of recipients compared to patients with a less severe degree of TR. The hemodynamics studies underline the advantage of technique selection, because there was a significant reduction in right heart pressures associated with diminishing in the incidence, severity, and subsequent longterm influence of TR in these recipients. The improvement in the right-heart hemodynamics correlated with a reduction in the degree of TR in the bicaval recipients. Leyh and coworkers [18] reported larger right ventricular enddiastolic dimensions with the standard technique compared with matched recipients undergoing the bicaval procedure. The improvement in the right-sided hemodynamics for the bicaval technique recipients reflects improvement in their right ventricular function for this group of patients. There are several possible explanations for this, such as improved atrial geometry with reduction in the incidence of tricuspid valve [19, 20] and improved right ventricular dimension [18]. Because the preoperative pulmonary vascular resistance and mean pulmonary artery pressure were similar in both groups, our data suggest that transplantation by the bicaval technique leaving the right atrium intact was an important factor in improved right-sided pressures compared to the standard technique. Endomyocardial biopsy remains the method of choice for detecting graft rejection in patients who have undergone heart transplantation. However, damage to the valve apparatus during EMB could account for the high prevalence of TR in these patients [3, 16, 17, 21]. It has recently been reported that flail tricuspid valve leaflets following EMB occur in 6.2% to 10% of the patients [22] and may ultimately lead to the need for tricuspid valve

repair for the management of right-heart failure [18]. Our results are consistent with this finding, in that the incidence of TR correlated with the number of EMBs performed. Our data showed that the prevalence of TR was closely correlated with the number of cellular rejection episodes greater than or equal to grade 2 in both standard and bicaval technique recipients. The long-term effect of cellular rejection in the development of TR following OHT has not been clarified. Some degree of TR is recognized to be associated with cardiac allograft rejection [21]. The cause of TR during the course of cardiac rejection was explained by papillary muscle edema/ dysfunction or asymmetrical contractility of the right ventricle during the course of cellular rejection [21]. Glycoprotein, present in the basic fundamental substance of valves (glycosaminoglycan), has hydrophilic capacity, which would create pressure swelling in the extracellular matrix [23], and cause valvular edema, which could impede normal valve action. The relation between the preoperative pulmonary hemodynamics [1, 14], weight mismatch, gender mismatch, ischemic time, and the development of early posttransplant TR have been previously described and attributed to increases in the right ventricular size during the early postoperative period [24, 25]. Bhatia and associates [1] reported that exposure of the right ventricle to abnormal recipient pulmonary pressure resistance resulted in early temporary right ventricular dilatation and subsequent early TR. However, these influences have been reported to be limited to the early postoperative stage in most cases [25]. In conclusion, tricuspid valve regurgitation is a significant clinical finding following orthotopic heart transplantation. Adopting of the bicaval technique, early and effective treatment of cellular rejection, and reduction of the number of endomyocardial biopsies performed might lower the incidence of TR following OHT.

The authors acknowledge Dr Alison Wynn Hann from University Department of Statistics at Withington Hospital for her excellent help and great assistance during preparation and revision of this manuscript.

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References 1. Bhatia SJS, Kirshenbaum JM, Shemin RJ, et al. Time course of resolution of pulmonary hypertension after orthotopic cardiac transplantation. Circulation 1987;76:819–26. 2. Rees AP, Milani RV, Lavie CJ, Smart FW, Ventura HO. Valvular regurgitation and right-side cardiac pressures in heart transplant recipients by complete Doppler and color flow evaluation. Chest 1993;104:82–7. 3. Huddleston CB, Rosenbloom M, Goldstein JA, Pasque MK. Biopsy-induced tricuspid regurgitation after cardiac transplantation. Ann Thorac Surg 1994;57:832–7. 4. Cladellas M, Oriol A, Caralps JM. Quantitative assessment of valvular function after cardiac transplantation by pulsed Doppler echocardiography. Am J Cardiol 1994;73:1197–201. 5. Mugge A, Daniel WG, Herrmann G, Simon R, Litchlen PR. Quantification of tricuspid regurgitation by Doppler color flow mapping after heart transplantation. Am J Cardiol 1990; 66:884–7. 6. Fisher EA, Goldman ME. Simple, rapid method for quantification of tricuspid regurgitation by two-dimensional echocardiography. Am J Cardiol 1989;63:1375– 8. 7. Lower RR, Stofer RC, Shumway NE. Homovital transplantation of the heart. J Thorac Cardiovasc Surg 1961;41:196 – 201. 8. Sarsam MA, Campbell CS, Yonan NA, Deiraniya AK, Rahman AN. An alternative technique in orthotopic cardiac transplantation. J Card Surg 1993;8:344 –9 9. Billingham ME, Cary NRB, Hammond ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. J Heart Transplant 1990;9:587–93. 10. Yoshida K, Yoshikawa J, Shakudo M, et al. Color Doppler evaluation of valvular regurgitation in normal subject. Circulation 1988;78:840–7. 11. Angerman CE, Spes CH, Tammen A, et al. Anatomic characteristics and valvular function of the transplanted heart: transthoracic versus transesophageal echocardiographic findings. J Heart Transplant 1990;9:331– 8. 12. Stevenson LW, Dadourian BJ, Kobashigawa J, Child JS, Clark SH, Laks H. Mitral regurgitation after cardiac transplantation. Am J Cardiol 1987;60:119–22. 13. Lewen MK, Bryk RJ, Miller LW, Williams GA, Labowtiz AJ. Tricuspid regurgitation by Doppler echocardiography after

14. 15.

16.

17. 18. 19.

20.

21.

22.

23. 24. 25.

1251

orthotopic cardiac transplantation. Am J Cardiol 1987;59: 1371– 4. Cladellas M, Abdal ML, Pons-Llado G, et al. Early transient multivalvular regurgitation detected by pulsed Doppler in cardiac transplantation. Am J Cardiol 1986;58:1122– 4. Akasaka T, Lythall DA, Kushawaha SS, Yoshida K, Yoshikawa J, Yacoub MH. Valvular regurgitation in heart-lung transplant recipients. A Doppler color flow study. J Am Coll Cardiol 1990;15:576– 81. Williams MAJ, Lee MY, Di Salvo TG, et al. Biopsy-induced flail tricuspid leaflets and tricuspid regurgitation following orthotopic cardiac transplantation. Am J Cardiol 1996;77: 1339 – 44. Stahl RD, Karwande S, Olsen S, Taylor DO, Hawkins J, Renlund DG. Tricuspid valve dysfunction in the transplanted heart. Ann Thorac Surg 1995;59:477– 80. Leyh RG, Jahnke AW, Kraatz EG, Sievers HH. Cardiovascular dynamics and dimensions after bicaval and standard cardiac transplantation. Ann Thorac Surg 1995;59:1459 –500. Beniaminovitz A, Savoia MT, Galantowicz M, Di Tullio MR, Homma S, Mancini D. Improved atrial function in bicaval versus standard orthotopic techniques in cardiac transplantation. Am J Cardiol 1997;80:1631–5. Forni A, Faggian G, Chiominto B, et al. Avoidance of atrioventricular valve incompetence following orthotopic heart transplantation using direct bicaval anastomosis. Transplant Proc 1995;27:3478 – 82 Hermann G, Simon R, Haverich A, et al. Left ventricular function, tricuspid incompetence and incidence of coronary artery disease late after orthotopic heart transplantation. Eur J Cardiothorac Surg 1989;3:111– 8. Braveman AC, Coplen SE, Mudge GM, Lee RT. Ruptured chordae tendineae of the tricuspid valve as a complication of endomyocardial biopsy in heart transplant patients. Am J Cardiol 1990;66:111–3. Albert B, Abary D, Lewis J, Raff M, Robert K, Watson JD. Molecular biology of the cell. New York: Garland Publishing, 1983:705–7. Copeland JG, Emery RV, Levinson MM, et al. Selection of patients for cardiac transplantation. Circulation 1987;75:2– 6. Hosenpud J, Norman D, Cobanoglu A, Floten S, Corner R, Star A. Serial echocardiographic findings early after heart transplantation: evidence of reversible right ventricular dysfunction and myocardial oedema. J Transplant 1987;6:343–7.