Severe tricuspid regurgitation after heart transplantation

Severe tricuspid regurgitation after heart transplantation

Severe Tricuspid Regurgitation After Heart Transplantation Michael C. Y. Chan, MBBS, FRCPC, FACC,a Nadia Giannetti, MD, FRCPC,a Tomoko Kato, MD,a Murr...

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Severe Tricuspid Regurgitation After Heart Transplantation Michael C. Y. Chan, MBBS, FRCPC, FACC,a Nadia Giannetti, MD, FRCPC,a Tomoko Kato, MD,a Murray Kornbluth, MD, FRCPC,a Phil Oyer, MD, PhD,b Hannah A. Valantine, MD,a Robert C. Robbins, MD,b and Sharon A. Hunt, MD, FACCa Background: Tricuspid regurgitation (TR) is common after heart transplantation. However, the incidence of severe TR and the incidence of symptoms after echocardiographic diagnosis of severe TR have not been documented. The purpose of this study is to determine the incidence of severe TR and its clinical significance in the heart transplant population. Methods: We reviewed echocardiograms (echo) of all heart transplant patients coming for regular echocardiographic follow-up between 1990 and 1995. We reviewed the charts of all patients who had echo diagnosis of severe TR. Results: A total of 336 patients had echo follow-up during this time period. The number of months post-heart transplant to last echo was 54 ⫾ 50 (range, 1 to 265 months). Ninety patients had moderate TR and 23 patients had severe TR. Mean time from heart transplantation to diagnosis of severe TR was 43 ⫾ 38 months (range, 1 to 132). Using Cutler-Ederer analysis, at 5 years, 92.2% of surviving patients were free from severe TR. At 10 years, 85.8% of surviving patients were free from severe TR. Of the 23 patients with severe TR, 17 had charts available for review. The mean number of prior endomyocardial biopsies was 28 ⫾ 21 (range, 3 to 88). These patients were followed for 35 ⫾ 18 months after diagnosis. During this period, they developed significant heart failure and peripheral edema. Six patients eventually underwent tricuspid valve replacement. Conclusions: Moderate to severe TR commonly occurs following heart transplantation. Severe TR is associated with significant morbidity. J Heart Lung Transplant 2001;20: 709–717.

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ricuspid regurgitation (TR) is often seen after orthotopic cardiac transplantation. The prevalence ranges from 47% to 98%.1– 4 The cause of TR is multifactorial, and a number of hypotheses have been proposed. These include elevation of pulmonary artery pressure after transplantation, and alter-

ation in the geometry of the tricuspid valve and right atrium related to the technique of right atrial anastomosis. However, the most widely accepted explanation is tricuspid-leaflet or chordal damage occurring during endomyocardial biopsy.2,3,5– 8 This procedure is almost universally used after heart

From the Division of Cardiovascular Medicinea and Department of Cardiothoracic Surgery,b Stanford University School of Medicine, Stanford, California, USA. This study was presented in abstract form at the American Heart Association Annual Scientific Meeting, November, 1999, Atlanta, Georgia. Abstract published in Circulation 1999; 100(suppl 1)(18):I–164. Submitted May 22, 2000; accepted November 29, 2000.

Reprint requests: Sharon A. Hunt MD, Division of Cardiovascular Medicine, Falk Cardiovascular Research Building, Stanford University Medical Center, 300 Pasteur Drive, Stanford, California 94305-5247. Telephone: 650-723-5771. Fax: 650-7253846. Copyright © 2001 by the International Society for Heart and Lung Transplantation. 1053-2498/01/$–see front matter PII S1053-2498(01)00258-3

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transplantation to detect rejection. The time course of occurrence and progression of TR has not been well documented in a large cohort of transplant recipients. Furthermore, those patients who have an initial echocardiographic diagnosis of severe TR have not been followed long term to see how many of them will progress to have clinical symptoms. We sought to evaluate the incidence of severe TR in the post– cardiac transplant population. We then followed patients with severe TR for development of clinical symptoms. Finally, we studied whether tricuspid valve replacement would benefit those with refractory symptoms.

METHODS This study included a sequential series of 336 orthotopic heart transplant recipients, who presented for routine transthoracic echocardiography between April 1990 and December 1995. Standard techniques had been used for both donor procurement and recipient operations. Preservation methods included topical cold saline and potassium-based crystalloid cardioplegia. The recipient cardiectomy and recipient– donor anastomosis was done using the standard Lower-Shumway technique.9 Triple-drug immunosuppressive therapy (cyclosporine, azathioprine, prednisone) with monoclonal cytolytic induction therapy were used in all patients. Surveillance endomyocardial biopsies were performed on the same day as echocardiography on a scheduled basis—weekly for the first month, biweekly for the following 2 months, monthly for Months 4 to 6, and then every 3 months. Beyond the second year, routine biopsies were performed every 4 to 6 months. Biopsies were performed more frequently with any suspicion of rejection. Clinical history, physical examination, and routine blood laboratory testing were performed on the same day as were the biopsy and echocardiogram. Biopsy-proven rejection was graded using the system devised by Billingham10 and later using the modified system adopted by the International Society for Heart and Lung Transplantation.11 Acute rejection was treated with steroid bolus and an increase and/or change in immunosuppression regimen. A treated episode of rejection was followed by a repeat biopsy 7 to 10 days after the initial procedure. Endomyocardial biopsy was performed using the standard Stanford technique12 with either a Caves-Shultz or disposable bioptome, using a percutaneous right internal jugular vein approach. A long sheath in the right ventricle was not used.

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TABLE I Ratio of jet area to right atrial area Trivial TR Mild TR Moderate TR Severe TR

⬍10% 10–24% 25–49% ⱖ50%

TR, tricuspid regurgitation.

Echocardiography All patients received 2-dimensional echocardiography on a scheduled basis (see above). The degree of TR was graded according to the ratio of the maximum area of the regurgitant jet in the right atrium to the area of the right atrium itself using color-flow Doppler echocardiography1–3 (Table I). A 1990 study first validated this method of quantifying the severity of TR in the post-transplant patient.13 The authors found that the ratio of the jet area to the right atrial area correlated better to the thermodilution-derived tricuspid regurgitant fraction than did the maximum jet area or the maximum jet length. We noted the most severe grade of TR for each of the patients during the course of this study and recorded the time of first appearance of this grade. We then performed chart review on those patients who had severe TR to determine the time from transplantation to diagnosis, the number of biopsies performed, and the progression of symptoms after the diagnosis. All procedures were in accordance with institutional guidelines.

Data Analysis We defined the time of diagnosis of severe TR as the time of first appearance of this condition on serial echocardiography. We compared continuous variables using paired Student’s t-test and compared categoric variables using Fisher exact test. Life table analysis was performed using the Cutler-Ederer method.14 Data are presented as mean ⫾ standard deviation and range. A p value ⱕ 0.05 was considered significant.

RESULTS Prevalence and Incidence of Severe TR A total of 336 patients who had undergone heart transplantation returned for echocardiography follow-up during the study period. The time from transplantation to time of last echocardiographic follow-up was 54 ⫾ 50 months (range, 1 to 265 months). Of the 336 patients, 23 (7%) had severe TR and 90 (27%) had moderate TR (see Table II).

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TABLE II Echocardiographic determination of severity of tricuspid regurgitation (TR) in 336 heart transplant patients followed during the study period (from April 1990 to December 1995) at Stanford University Number of patients

%

Patients with no TR or mild TR Patients with moderate TR Patients with severe TR

223 90 23

66% 27% 7%

Total Number of patients requiring Tricuspid valve replacement

336 6

100%

Using Cutler-Ederer analysis,14 we constructed a life table of events and show this in graphical form (see Figure 1). At 5 years, 92.2% of surviving patients were free from severe TR. At 10 years, 85.8% of surviving patients were free from severe TR. Of the 23 patients with severe TR, the mean age at time of transplantation was 46.5 ⫾ 10.9 years. The mean duration from the time of transplantation to

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diagnosis of severe TR was 43 ⫾ 38 months (range, 1 to 132 months).

Follow-up of Severe TR Patients We then assessed the impact of severe TR on these patients. Of the 23 patients identified with severe TR, 17 had follow-up for 35 ⫾ 18 (range, 12 to 77) months from the diagnosis of severe TR. We did not include 6 of the 23 patients in the follow-up because of the following: One patient died from coronary artery disease and post-transplant lymphoproliferative disease within 1 month of the diagnosis of severe TR. One patient had repeat heart transplantation for graft failure within 3 months of the diagnosis of severe TR. One patient died from coronary artery disease within 4 months of the diagnosis of severe TR. One patient died of infection 5 months after the diagnosis of severe TR. Two patients were followed elsewhere and had no chart available for review. The 17 patients followed for severe TR had 28 ⫾ 21 (range, 3 to 88) heart biopsies until the diagnosis of severe TR. Clinical and biochemical variables as well as diuretic usage were documented at the time

FIGURE 1 Cutler-Ederer curve for survival free from severe tricuspid regurgitation. Pts, patients; TR, tricuspid regurgitation; Tx, transplantation.

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of diagnosis and at the time of last clinical follow-up. At baseline, none of the 17 patients had significant peripheral edema (edema ⱖ 2⫹); whereas at followup, 10 of the 17 patients had this condition. At baseline, no patient had ascites, whereas at follow-up 7 patients had developed ascites. At baseline, 16 out of the 17 patients were in New York Heart Association (NYHA) Class I, whereas at follow-up only 8 of the 17 patients remained in Class I (p ⬍ 0.05). The serum creatinine rose significantly from 141 ⫾ 9 ␮mol/liter (1.6 ⫾ 0.1 mg/dl) to 176 ⫾ 17 ␮mol/liter (2.0 ⫾ 0.2 mg/dl) (p ⬍ 0.05). At baseline, no patient had elevated liver enzymes or serum total bilirubin levels. At follow-up, 2 patients had elevated serum aspartate aminotransferase (AST) of 1.0 ␮kat/liter (60 U/liter) and 2.0 ␮kat/liter (124 U/liter) and elevated serum total bilirubin of 39 ␮mol/liter (2.3 mg/dl) and 162 ␮mol/liter (9.5 mg/dl), respectively. (We found no statistical difference in the mean AST and serum total bilirubin at baseline and at follow-up for the group as a whole). No death was attributed to severe TR and the resultant right heart failure.

Tricuspid Valve Replacement Of the 17 patients with severe TR, 6 patients received tricuspid valve replacement (TVR) for refractory congestive symptoms, including severe peripheral edema, ascites, and hepatomegaly. At operation, all the excised valves showed evidence of severe chordal and/or leaflet damage. Porcine bioprostheses were used for replacement. The time from diagnosis of severe TR to time of operation in these 6 patients was 29 ⫾ 6 months. These patients were then followed for another 13 ⫾ 7 months post-TVR. All of these patients had almost complete relief of edema. All but 1 had improvement in NYHA class. The furosemide dose decreased from 51 ⫾ 18 mg/day to 15 ⫾ 13 mg/day (p ⫽ 0.024). We noted no significant improvement in creatinine, which remained at 176 ⫾ 61 ␮mol/liter (2.0 ⫾ 0.7 mg/dl).

DISCUSSION Prevalence and Incidence of TR Thus far this is the largest cohort of heart transplant patients studied by echocardiography for the presence of TR. The first reports of using pulsed Doppler to detect TR in this population were published in 1986.15–17 The first report of using color Doppler to quantify TR in the heart transplant patient was published in 1990.13 Here we used the color Doppler quantification method that is most widely accepted.1–3. The prevalence of TR by echocardiography in

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this population ranges from 47% to 98%1– 4,18. Previous studies showed that 70% to 83% of normal subjects had TR, although this was mostly trivial to mild in severity.1 One study showed more moderate/ severe TR in heart transplant patients than in normal subjects (12% vs 3%, p ⬍ 0.05).1 As in previous studies,1– 4 we found a significant number of patients post-transplant to have moderate or severe TR. Williams et al3 found a 32% prevalence of moderate or severe TR. Huddleston et al2 found that 10.4% had moderate TR and 10.9% had severe TR. Rees et al1 found 12% of patients had moderate TR and none had severe TR. Lewen et al4 found that 20% of patients had severe TR and 50% had moderate TR, but theirs was a small study with only 20 patients. Ours is the largest study to date, with 336 patients, of which 27% had moderate TR and 7% had severe TR. Our study is the second study to use a life table analysis to document the incidence of echocardiographic, severe TR at different times post-transplantation, and ours has the longest follow-up. At 5 years posttransplant, 7.8% of remaining patients had developed severe TR; at 10 years post-transplant, 14.2% of remaining patients had developed severe TR. Hausen et al7 documented “grade 3” echocardiographic, moderate/severe TR occurring in 50% of patients at 4 years post-transplantation.

Causes of TR There are several possible causes of TR post-transplantation. The presence of pulmonary hypertension and right ventricular injury at the time of transplantation may cause right ventricular and tricuspid annular dilatation, which in turn can cause TR. In the non-transplant population, pulmonary artery pressure above 55 mm Hg is associated with functional TR. One study showed that pulmonary hypertension before transplantation and elevated pulmonary vascular resistance after transplantation were associated with significant TR.4 However, Williams et al3 showed no association between posttransplant pulmonary artery pressure and pulmonary vascular resistance and the occurrence of significant TR. Rees et al1 also showed no correlation between post-transplant pulmonary artery pressure and the severity of TR, but their study followed patients for only 5 months post-transplant and only 6 patients had moderate TR and none had severe TR. Three studies found no association between pre-transplant pulmonary artery pressure/pulmonary vascular resistance and subsequent development of severe TR.2,7,19 Haverich19 has proposed that TR

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may be caused by a size mismatch of the donor heart and recipient pericardial cavity, resulting in distortion of the tricuspid valve ring. They performed intraoperative echocardiography to detect TR and performed pericardial reduction plasty that successfully prevented TR up to 8 weeks of follow-up. Surgical atrial anastomosis, which creates a large right atrium and abnormal geometry of the tricuspid annulus, might also lead to TR.2,20,21 This technique was originally described by Lower and Shumway.9 De Simone’s study of 25 patients showed that the severity of TR immediately post-transplantation correlates to an increased ratio of the recipient atrium to the donor atrium.21 A newer technique of bicaval anastomosis may be associated with a lower incidence of TR. This technique involves total excision of the right atrium with a minimal cuff of left atrium remaining around the 4 pulmonary veins, followed by direct anastomoses of the venae cavae. One study found no difference of incidence and severity of TR at rest but during exercise found less TR in the bicaval group than in the standard atrial anastomosis group.20 In a study involving 78 patients, the bicaval group had less incidence of TR at rest than did the standard group (57% vs 82%).22 In a more recent study involving 249 patients, recipients who underwent the standard operation had a higher incidence of moderate and severe TR than did bicaval operation recipients.23 None of the patients in our study had the bicaval anastomosis.

Biopsy-Induced Flail Tricuspid Leaflet The most widely accepted cause of severe TR in this population is a complication of the endomyocardial biopsy procedure, with mechanical disruption of the tricuspid valve apparatus, including the leaflet or the chordae or both. Although we did not tabulate the number of patients with ruptured chordae in this study, a flail tricuspid leaflet is associated with more severe TR.3,7 Torn chordae of the tricuspid valve post-transplantation was first reported by echocardiography in 1987.4; in this report 2 of 20 transplant patients had torn or partially torn chordae. Other echocardiographic reports have been published since.8 In the Braverman study,6 5 patients out of a total of 81 patients had ruptured chordae. In the Huddleston study,2 12 out of 183 patients had a flail tricuspid leaflet, presumably biopsy induced. In the Williams study,3 10 out of 72 patients had a flail leaflet. In the Tucker study,5 21 out of 181 patients had flail leaflets. Aside from these echocardiographic studies, torn chordae or leaflets were found

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in almost all reported cases of tricuspid valve surgery post-transplantation. Data conflict on the correlation between the number of heart biopsies performed and the development of TR. In the Hausen study,7 patients with moderate/severe TR had an average of 45 ⫾ 21 biopsies compared with an average of 27 ⫾ 13 biopsies in patients without TR (p ⬍ 0.01). Tucker et al5 also reported that the prevalence of a flail tricuspid leaflet was related to the number of biopsies performed. Other studies have, however, found no difference in the number of biopsies performed between those patients with and without flail leaflets.2,3 Also, the degree of TR does not seem to correlate to the number of episodes of rejection.2 In our study, of the 17 patients with severe TR, 28 ⫾ 21 (range, 3 to 88) heart biopsies were performed up until the first diagnosis of severe TR. This number is in the same range as in studies of the number of biopsies performed before first diagnosis of flail tricuspid leaflet.5,7 The mean duration from the time of transplantation to first diagnosis of severe TR was 43 ⫾ 38 months (range, 1 to 132 months) in our study, and this also is in the same range as the time for development of flail tricuspid leaflet.5 Transvenous endomyocardial biopsy is the gold standard for assessing heart transplant rejection. Major complications such as cardiac perforation and tamponade occur in ⬍0.4% of cases. The standard technique is to place a short sheath in the right internal jugular vein. Through this sheath the bioptome is then passed into the right atrium and then through the tricuspid valve into the right ventricle using fluoroscopic guidance. The chordae tendineae usually arise from the papillary muscles but also from the septal wall and thus are subject to trauma by the bioptome each time it traverses the tricuspid valve. Recent studies report using a long sheath that is placed through the tricuspid valve into the right ventricle. The bioptome is then exposed only for 1 or 2 cm to get to the ventricular septum, therefore avoiding potential trauma with each pass of the bioptome and preventing the tricuspid valve apparatus from getting caught in the bioptome.2,3,24 In one study, the prevalence of flail tricuspid leaflet and severe TR was lower with the use of the newer long sheath than with the traditional short sheath.3

Outcome of Patients with Severe TR Although most patients are asymptomatic at the time of first echocardiographic diagnosis of even

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FIGURE 2 Flail tricuspid valve leaflets seen on echocardiogram.

severe TR, our data indicate that this is not a benign condition. Severe TR seems to be associated with developing impairment of right ventricular performance; these patients have a lower cardiac index and higher right atrial pressure than do those with less severe TR.3,7 No study thus far has systematically reported the clinical course of patients once a diagnosis of severe TR is made by echocardiography. In the Huddleston study,2 of the 12 patients with flail tricuspid leaflet and severe TR, 5 patients were entirely asymptomatic, 3 patients had mild exercise intolerance and were taking diuretics, 2 patients were less tolerant of exercise and had peripheral edema only moderately responsive to diuretics, and 2 patients had severe refractory symptoms requiring TVR. Their study did not state the time course of follow-up of these 12 patients. Our study is the largest study to date of clinical

follow-up of these patients. Of 23 patients initially identified with severe TR, 3 patients died of other causes within 5 months of the diagnosis of severe TR, 1 had repeat heart transplantation within several months for graft failure unrelated to TR, and 2 patients did not have complete charts for follow-up. The remaining 17 patients were followed for 35 ⫾ 18 (range, 12 to 77) months after the initial diagnosis of severe TR. At the time of initial echocardiographic diagnosis, almost all patients were completely asymptomatic: none had significant peripheral edema, none had ascites, and all but 1 were in NYHA Class I. None had hepatomegaly, and all had normal liver enzymes and normal serum total bilirubin. However, at last follow-up, most patients became symptomatic: only 8 of the 17 patients remained in NYHA Class I and 10 patients developed ⱖ 2⫹ peripheral edema. Seven patients devel-

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FIGURE 3 Severe tricuspid regurgitation on color Doppler echo, with color jet occupying almost the whole right atrium.

oped ascites. The serum creatinine also rose significantly. Interestingly, only 2 patients developed elevated AST and elevated serum total bilirubin.

TVR Six patients in our study developed refractory symptoms and received TVR, at a mean 29 ⫾ 6 months (range, 19 to 35) after the initial diagnosis of severe TR. These 6 patients were then followed for another 13 ⫾ 7 months (range, 6 to 24) after the operation. All of these patients had almost complete relief of peripheral edema. All but 1 had improvement in NYHA class. The furosemide dose decreased significantly. The 1 patient with a serum total bilirubin of 39 ␮mol/liter (2.3 mg/dl) before TVR dropped to 17 ␮mol/liter (1.0 mg/dl) after the operation, and his AST of 1.0 ␮kat/liter (60 U/liter) dropped to 0.66 ␮kat/liter (40 U/liter). (The 1 patient with serum AST of 2.0 ␮mol/liter (124 U/liter) and serum total

bilirubin of 162 ␮mol/liter (9.5 mg/dl) did not undergo TVR). In summary, all 6 patients have done well after TVR. In 1993, Votapka et al25 reported the first case of TVR in the heart transplant patient, and Crumbley et al24 reported the first tricuspid valve repair in 199424. Since then there have been several case reports of TVR or tricuspid valve repair, all of which produced immediate reduction in TR and right atrial pressures post-operatively, but no long-term follow-up has been reported. The largest series to date of TVR or tricuspid valve repair is from Wahlers et al.26 They had 8 replacements and 4 repairs. Two patients died within 1 year post-operatively. Ten patients were alive at 3 to 21 months post-operatively, but the clinical outcome was not reported. In almost all patients reported, ruptured chordae was identified at the time of operation, further supporting the theory that severe TR is biopsy induced. Ours is the largest reported

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FIGURE 4 No more tricuspid regurgitation seen on color Doppler after tricuspid valve replacement.

series of the long-term outcome of TVR in heart transplant patients. (See Figures 2, 3, 4 for illustration of a heart transplant recipient before and after TVR for severe TR.) The present study has several limitations. First, the data were collected retrospectively in a population followed by echocardiography. However, to our knowledge no published prospective study exists of severe TR and TVR in the heart transplant population. Second, the TR volume depends on afterload and pre-load and compliance of the heart chambers. The area of the color Doppler regurgitant jet may be underestimated because of jet eccentricity. However, to date, all other studies of this condition have used similar study methods. Third, as with other studies of survival analysis, over time, a large proportion of the study patients is lost to follow-up, either because of death, change to another transplant center, or non-compliance.

In conclusion, tricuspid valve regurgitation is common after heart transplantation and the incidence of severe TR increases with time. Most patients are asymptomatic at the time of diagnosis of even severe TR; however, symptoms will often progress over time and some patients may require TVR for refractory symptoms. This procedure appears to be safe and effective when required. Further study is needed to determine whether the following measures are useful in reducing the incidence of significant TR: bicaval anastomosis, use of a long sheath during heart biopsy, and/or use of echocardiogram-guided biopsy. REFERENCES 1. 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(1):82–7.

The Journal of Heart and Lung Transplantation Volume 20, Number 7 2. Huddleston CB, Rosenbloom M, Goldstein JA, Pasque MK. Biopsy-induced tricuspid regurgitation after cardiac transplantation. Ann Thorac Surg 1994;57(4):832– 6. 3. 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(15): 1339 – 44. 4. Lewen MK, Bryg RJ, Miller LW, Williams GA, Labovitz AJ. Tricuspid regurgitation by Doppler echocardiography after orthotopic cardiac transplantation. Am J Cardiol 1987;59(15):1371– 4. 5. Tucker PA II, Jin BS, Gaos CM, Radovancevic B, Frazier OH, Wilansky S. Flail tricuspid leaflet after multiple biopsies following orthotopic heart transplantation: echocardiographic and hemodynamic correlation. J Heart Lung Transplant 1994;13(3):466 –72. 6. Braverman AC, Coplen SE, Mudge GH, Lee RT. Ruptured chordae tendineae of the tricuspid valve as a complication of endomyocardial biopsy in heart transplant patients. Am J Cardiol 1990:66(1):111–3. 7. Hausen B, Albes JM, Rohde R, Demertzis S, Mugge A, Schafers HJ. Tricuspid valve regurgitation attributable to endomyocardial biopsies and rejection in heart transplantation. Ann Thorac Surg 1995;59(5):1134 – 40. 8. Reddy SC, Rath GA, Ziady GM, Matesic C, Kormos R. Tricuspid flail leaflets after orthotopic heart transplant: a new complication of endomyocardial biopsy. J Am Soc Echocardiogr 1993;6:223– 6. 9. Lower RR, Shumway NE. Studies in orthotopic homotransplantation of the canine heart. Surg Forum 1960;11:18 –9. 10. Billingham ME. Diagnosis of cardiac rejection by endomyocardial biopsy. J Heart Transplant 1982;1:25–30. 11. Billingham ME, Cary NBB, Hammond ME, et al. A working formulation for standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant 1990;9(6):587–93. 12. Caves PK, Stinson EB, Billingham ME, Shumway NE. Percutaneous transvenous endomyocardial biopsy in human heart recipients: experience with a new technique. Ann Thorac Surg 1973;16(4):325–36. 13. Mugge A, Daniel WG, Herrmann G, Simon R, Lichtlen PR. Quantification of tricuspid regurgitation by Doppler color flow mapping after cardiac transplantation. Am J Cardiol 1990;66(10):884 –7. 14. Cutler SJ, Ederer F. Maximum utilization of the life table

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