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Ann Thorac Surg 2004;78:759-766
© 2004 The Society of Thoracic Surgeons
a Departments of Surgery and Medicine, University of Chicago, Chicago, Illinois, USA
b Departments of Surgery and Medicine, Temple University, Philadelphia, Pennsylvania, USA
Accepted for publication March 30, 2004.
* Address reprint requests to Dr Jeevanandam, Section of Cardiac and Thoracic Surgery, University of Chicago, 5841 S Maryland Ave, MC5040, Chicago, IL 60637, USA
jeevan{at}uchicago.edu
Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.
Abstract
BACKGROUND: The bicaval technique for orthotopic heart transplantation decreases the incidence of tricuspid valve regurgitation when compared with the standard biatrial technique. This study was designed to study the effects of prophylactic tricuspid valve annuloplasty during bicaval orthotopic heart transplantation on survival, renal function, and amount of tricuspid valve regurgitation.
METHODS: Between April 1997 and March 1998, 60 patients (age 18 to 70 years, 22 women) randomly received either bicaval orthotopic heart transplantation (n = 30) or bicaval orthotopic heart transplantation with DeVega tricuspid valve annuloplasty (n = 30). Tricuspid valve annuloplasty was performed on the donor heart before implantation using pledgeted 2-0 polypropylene suture and sized to an annulus of 29 mm. Echocardiographic variables, laboratory values, and hemodynamics were obtained prospectively and reviewed by an independent data analyst.
RESULTS: Intraoperatively, the group undergoing tricuspid valve annuloplasty had a shorter reperfusion time (46 ± 29 minutes versus 65 ± 48 minutes; p < 0.05) and higher mean pulmonary artery to central venous pressure difference (11.8 ± 3.7 mm Hg versus 15.3 ± 4.1 mm Hg; p = 0.001). Additional differences between the two groups included early mortality from donor dysfunction (4 of 30 patients versus 0 of 30 patients; p < 0.05), amount of tricuspid valve regurgitation at 1 year (1.3 ± 1.0 versus 0.2 ± 0.3; p < 0.05), and percentage of patients with 2+ or greater tricuspid valve regurgitation (34% versus 0%; p < 0.05).
CONCLUSIONS: Tricuspid valve annuloplasty of the donor heart before bicaval orthotopic heart transplantation improves immediate donor heart function as demonstrated by better right ventricular performance, lower perioperative mortality, and shorter reperfusion times. At 1 year, there is less tricuspid valve regurgitation but no difference in renal function. Considering the ease and safety of tricuspid valve annuloplasty and its advantages, it should be performed as a routine adjunct with bicaval orthotopic heart transplantation.
Tricuspid regurgitation (TR) is often present after orthotopic heart transplantation [1, 2]. The reported incidence of TR varies from 47% to 98% [3–5]. The cause of TR is multifactorial. The standard biatrial technique of orthotopic heart transplantation (sOHT) is associated with more TR than the bicaval (bOHT) technique. This difference may be attributed to alteration in the geometry of the tricuspid valve and right atrium related to the technique of right atrial anastomosis. Other possible causes of TR include (1) allograft dysfunction with right ventricular dilatation as a result of poor preservation, reperfusion injury, donor factors, or rejection; (2) pulmonary hypertension; (3) severe donor–recipient size mismatch; and (4) structural damage occurring during endomyocardial biopsy [6–10].
In several studies, moderate and greater grades of TR are associated with right-sided heart failure symptoms, renal and hepatic dysfunction, and decreased long-term survival [11]. It remains unclear whether the TR is a reflection of poor allograft function or a primary abnormality, but once present, the consequences can be devastating.
DeVega type of tricuspid valve annuloplasty (TVA) has been used to treat TR. It is simple, quick, inexpensive, and durable [12, 13]. We report on the 1-year results of a randomized and prospective comparison of patients: one group received a prophylactic DeVega TVA before bOHT and the other group did not. The groups were compared with regard to survival, amount of TR, renal function, and hemodynamics.
Material and methods
Study design
Of all the patients receiving heart transplants at Temple University Hospital between April 1997 and March 1998, 60 patients met selection criteria for this comparison. Institutional Review Board permission was received before studying these patients. Patients were excluded from the comparison if they met the following criteria: (1) multiple organ transplantation, (2) retransplantation, (3) donor-to-recipient weight ratio less than 0.5, (4) pulmonary vascular resistance more than 4 Woods units, (5) greater than mild TR documented on donor echocardiography, (6) donor ejection fraction less than 0.35, (7) donor coronary artery disease requiring revascularization, and (8) donors requiring two inotropic agents or dopamine at more than 12 µg · kg–1 · min–1. These patients were excluded because, in accordance with our practice at that time, they routinely received TVA before the transplant procedure. Two surgeons performed the procurement and implantation during this period, and the procedures were evenly distributed among them. Tricuspid valve annuloplasty was performed during preparation of the donor heart. To ensure consistency and standardization, only one of the surgeons performed the TVA. By strictly adhering to an evenly distributed procurement call schedule, randomization was achieved. Patients were not included in the comparison if unforeseen circumstances caused deviation from the on-call schedule. In the majority of cases, implantation was a combined effort of the two surgeons. The patients received a bOHT (group STD) or bOHT with TVA (group TVA). Data were obtained prospectively, and data analysts were blinded to the assignment of patient groups. Data were analyzed at 1 week, 1 month, and 1 year after orthotopic heart transplantation and included operative and donor information, survival, amount of TR, hemodynamics, and serum blood urea nitrogen and creatinine.
Procedure
University of Wisconsin (Barr Laboratories, Pomona, NY) solution was used for cardioplegia and preservation solution. The recipient cardiectomy and recipient–donor anastomosis were performed using the bicaval technique described by Sarsam and colleagues [14] and Aziz and associates [15]. All patients received a baseline inotropic regimen of triiodothyronine (0.08 µg/kg bolus, infusion 0.8 µg/kg for 3 hours), 5 µg · kg–1 · min–1 of dobutamine, and 3 µg · kg–1 · min–1 of dopamine. Any increase above baseline was considered as elevated inotropic requirement. Patients were considered capable of being weaned from cardiopulmonary bypass (CPB) if they could sustain a mean systemic blood pressure more than 70 mm Hg with a central venous pressure (CVP) of less than 15 mm Hg and a cardiac index more than 2.1 L · min–1 · m–2 with a combination of inotropic and intraaortic balloon pump support.
Group TVA patients received a DeVega type annuloplasty on the donor graft before implantation. The tricuspid valve was visualized through the inferior right atrial opening, and a double layer of pledgeted 2-0 polypropylene suture was used to stabilize the annulus. The annulus was sized to a 29-mm dilator. If the annulus was less than 29 mm, it was stabilized to a size just a little smaller than the native annulus.
Management
All patients received triple-drug immunosuppression therapy with cyclosporine (3.5 to 5.0 mg · kg–1 · d–1), azathioprine (1.5 to 2.5 mg · kg–1 · d–1), and steroids. Induction therapy was not routinely used. Patients either had the cyclosporine switched to tacrolimus or had mycophenolate mofetil substituted for azathioprine for repeated rejection. Cyclosporine therapy was adjusted to maintain serum trough levels of 250 to 300 ng/mL during the first year after heart transplantation. Azathioprine dose was adjusted to maintain white blood cell counts more than 4,000 cells/mL. Steroid dose was tapered gradually after the peritransplant period to 0.05 mg/kg within 6 months after surgery. Acute rejection (>1b or with hemodynamic compromise) was treated with a steroid bolus. Cytolytic therapy was added for repeated rejections or significant hemodynamic compromise. Endomyocardial biopsy was performed using the standard Stanford technique with either a Caves-Shultz or disposable bioptome [16]. Biopsy-proven rejection was graded using the modified Billingham system adopted by the International Society for Heart and Lung Transplantation [17].
Echocardiographic assessment of tricuspid regurgitation
Patients routinely underwent intraoperative transesophageal echocardiography, and then transthoracic echocardiography studies at 1 week, 1 month, and at 1 year. Patients received two-dimensional and continuous-wave Doppler evaluation with color flow mapping. The tricuspid valve was examined in the parasternal short-axis and apical four-chamber views. Tricuspid regurgitation was graded by qualitative echocardiographic assessment according to the ratio of the regurgitant jet area to the right atrial area, as described previously [18]. Grades of TR included 0, 1+ (jet to area ratio < 10% trace), 2+ (ratio 10% to 24%, mild), 3+ (ratio 25% to 49%, moderate), 4+ (ratio > 50%, severe). Multiple views were obtained, and the regurgitation was graded on the basis of the most abnormal view.
Hemodynamic assessment
Intraoperative pulmonary artery monitoring with a Swan-Ganz catheter was performed in every patient. Right heart catheterization was routinely performed with biopsy at 1 week, 1 month, and 1 year, or if dictated by clinical condition. Intracardiac pressures were recorded at the levels of the right atrium, right ventricular body, and pulmonary artery. Thermodilution cardiac outputs were also obtained.
Statistics
All numerical results are reported as mean ± standard deviation. A p value of less than 0.05 was considered to be significant. Statistical analysis was performed using SPSS v.11 (SPSS Inc, Chicago, IL). Fisher's exact test was applied for categorical variables, and the Wilcoxon rank sum test was used to compare means of continuous variables.
Results
General
There were 30 patients in each group. Recipient and donor demographics are presented in Tables 1 and 2, respectively. Pretransplantation pulmonary artery pressures were similar in both groups (mean pulmonary artery pressure, 28.6 ± 9.2 mm Hg versus 29.3 ± 8.9 mm Hg; pulmonary capillary wedge pressure, 23.2 ± 8.9 mm Hg versus 23.8 ± 9.0 mm Hg; pulmonary vascular resistance, 2.3 ± 0.9 Woods units versus 2.1 ± 1.1 Woods units, STD versus TVA, respectively). The two surgeons who performed the procedures were randomly distributed among the procurement and implantation groups. Both groups followed the identical routine biopsy schedule. The average number of biopsies for the first year in survivors of both groups was 15.2.
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Tricuspid regurgitation is the most common valvular abnormality after heart transplantation [11]. Williams and colleagues [19] found a 32% prevalence of moderate to severe TR after heart transplantation. In the largest study to date, the Stanford group analyzed 336 patients and found 34% had greater than moderate TR [5]. In addition, the studies that follow patients for a period of time demonstrate the progressive nature of this abnormality. For instance, in the Stanford experience, the incidence of severe TR increases in survivors from 7.8% at 5 years to 14.2% at 10 years [5].
The most widely accepted cause of TR after orthotopic heart transplantation is a complication of the endomyocardial biopsy procedure [20–22]. There is no reason to believe that a TVA would prevent mechanical disruption of the valve mechanism. However, TR from minor structural damage might be attenuated by reduction of annular size.
Other causes of TR have a functional basis. The presence of pulmonary hypertension may cause right ventricular and annular dilatation, causing TR [3, 9, 19]. Pulmonary hypertension by itself with a normal right ventricle appears to be well tolerated; superimposition of pulmonary injury or right ventricular dysfunction may contribute to a process leading to development of TR. Right ventricular dysfunction can be caused in the intraoperative period by preservation or reperfusion injury, air embolus, donor risk factors, or accelerated rejection. Another cause of TR is the distortion of the right atrial–right ventricular relationship caused by the implantation technique. There is ample evidence that bOHT is superior to sOHT in terms of preventing TR. Aziz and coworkers [11] report a 19.9% incidence of severe TR in the bOHT group as opposed to 51% for the sOHT group. Because there was evidence that bOHT decreases TR and improves sinus node function [23, 24], we used this technique for all patients. If the sOHT technique had been used, the prophylactic TVA might theoretically have been of additional benefit.
Tricuspid regurgitation is not a benign condition. Once TR has developed, a majority of patients can develop peripheral edema, ascites, and renal dysfunction. Furthermore, the long-term survival in patients with TR is decreased when compared with patients with less than mild TR [5, 11]. When severe TR is present, repair with an annuloplasty or replacement has been reported [2, 25]. DeVega tricuspid annuloplasty is an inexpensive, quick, and stable method to reduce a dilated annulus and support a repair as required. It has been primarily used to treat functional TR caused by elevated left-sided pressures with excellent long-term results [12, 13]. Whether the TVA is best accomplished by a DeVega technique or by a ring is left up to surgeon preference. Complications of the TVA are uncommon, and are primarily related to injury of the conduction system. It is also important not to create stenosis by reducing the annulus excessively. Tricuspid stenosis or heart block did not occur in any patient.
All reports to date retrospectively review the experience of particular centers with TR and describe procedures to rectify the problem. This study was designed to test the hypothesis that prophylactic TVA performed during orthotopic heart transplantation could decrease the incidence of TR and to evaluate whether this would have any clinical significance. This was a single center study and was, therefore, small. Two surgeons were responsible for all the transplant procedures. It was important not to alter normal practice, while standardizing the TVA and removing surgeon variability as a confounding factor in the comparison. Therefore, only one surgeon performed the TVA. Randomization was ensured by strictly following an evenly distributed on-call schedule. Implantation was also evenly distributed among the two surgeons. Of the 60 implantation procedures, 45 were a combined effort of the surgeons. There was no correlation between surgeon and intraoperative complications. All significant intraoperative complications occurred in cases with combined surgeon efforts. This study could not be blinded to the surgeon. Data analysts were blinded as much as possible, but in a majority of cases, the pledgets of the TVA were evident on transesophageal echocardiography or transthoracic echocardiography as an echocardiographic density and were reported as such.
The demographics and cardiac status of recipients and donors were similar in both groups. The significant differences were in intraoperative hemodynamics, mortality within 10 days of transplant, and amount of TR. The preoperative pulmonary vascular resistance and mean pulmonary artery pressures were similar in both groups. After separation from and stabilization after CPB, group STD had a higher CVP for similar mean pulmonary artery pressure and cardiac index. We interpreted the difference between mean pulmonary artery pressure and CVP as efficiency of the right ventricle and tricuspid valve apparatus. As TR increases, the efficiency of the right ventricle decreases and a higher CVP is required to generate similar forward pressure and output. Although the mean amount of TR in group STD was only 1+ (mild), this was statistically higher than group TVA. This improved performance is evident as shorter reperfusion times in group TVA.
Tricuspid valve annuloplasty made an impact on mortality within 10 days of transplantation (Table 7). It is during this period that patients are most vulnerable to fatal complications. Perioperative mortality rates have been reported up to 15%. The combined mortality in this study was 4 of 60 (6%). This mortality is attributed to many variables occurring during the perioperative period. The donor heart is subject to ischemia–reperfusion injury, and the right ventricle has to adjust to recipient pulmonary artery pressures. In addition, CPB, bleeding, and the trauma of surgery cause an inflammatory reaction that can exacerbate the elevation in pulmonary vascular resistance. In this study, the number of perioperative complications (bleeding, pulmonary hypertension with right heart failure, donor dysfunction, acute rejection) was similar in both groups. All patients were able to leave the operating room with a combination of intraaortic balloon pump and increased inotropic support. However, in group STD, the persistent poor cardiac output with hypotension and elevated CVP caused poor systemic perfusion. This initiated the substrate for multiple-system organ failure and death in 3 patients. The other patient had marginal hemodynamics, and further deteriorated on postoperative day 7. Postmortem examination revealed acute rejection with severe myocardial necrosis. All patients within group STD with perioperative complications experienced at least moderate TR with elevated CVP. Group TVA patients, despite having similar complications, experienced a maximum of mild TR and were able to tolerate homodynamic instability. The patients who experienced these complications were a high-risk group: 2 had malfunctioning HeartMate inflow cannulas, 2 had left ventricular assist device pocket infections, 3 were multiple resternotomy (>2) on Coumadin, 3 had borderline pulmonary vascular resistance (4 Woods units), and 2 were on ventilator and intraaortic balloon pump.
These data show that for routine recipients or those high-risk patients in whom there are no complications, the TVA has minimal effect in the perioperative period. But if a complication is superimposed on a high-risk patient, the TVA allows for improved myocardial efficiency, lower CVP, and perhaps enough improvement in perfusion to allow these patients to survive. The 1-year survival was similar in both groups. No further group STD patients died, and 3 in group TVA died of routine causes attributed to transplantation.
The amount of TR was as low as would be expected from the bicaval technique, but was still different among the groups. In the early perioperative period, group STD had a mean of 1.1 versus group TVA with a mean of 0.33 TR. This is represented as a mean of only mild TR, but there was increased mortality in the patients who had greater than moderate TR. Group TVA patients had only trivial TR; even the patients with myocardial dysfunction had only mild TR. The difference in TR is not present at 1 week: this is because the patients with the most TR died, and TR naturally improves as the stresses of surgery decrease. The difference in TR is once again present at 1 month and 1 year. Furthermore, in group STD, the percentage of patients with greater than 2+ TR progressively increases from 11% at 1 week to 23% at 1 month and 34% at 1 year. The incidence of moderate TR (>3+) in group STD is 7.5% and compares favorably to other reports using bOHT techniques. At 1 year, there were no patients with greater than mild TR in group TVA. Two patients in group STD developed mild clinical symptoms with peripheral edema. It is clear from other reports that TR is progressive and can lead to worsening heart failure symptoms. Longer follow-up of patients in this study would demonstrate whether a TVA prevents the progression of TR.
The other variable that we studied was renal function. Increased CVP in patients with TR contributes to increased renal venous pressure and decreased glomerular filtration rate. This explains the deterioration in renal function in patients with significant TR [11]. In this study, patients' serum creatinine progressively increased during the first year. However, we could not demonstrate a difference in renal function between the two groups. This is perhaps because the TR had not progressed to the point at which it could affect renal function.
There were several limitations of this study. Because it was a single-center study, it was relatively small. A larger study might have demonstrated differences in renal function and other variables. This portion of the study focused on the 1-year results. The current data are being analyzed to determine the long-term effects of TVA. The study could not be properly blinded because of the performance of a surgical procedure in the operating room and the visibility of the TVA on echocardiography. One could argue that both surgeons should have performed the TVA. We thought that inasmuch as this was a small study, it was important to remove any variability in the TVA technique and standardize the procedure. If this had been a larger study, involvement of other surgeons would have decreased some of the variability. The study was also conducted before approved use of nitric oxide and expanded use of mechanical devices to support the right ventricle. It is possible that the mortality benefit might have decreased with routine early use of a right ventricular assist device such as the Abiomed BVS 5000 (Abiomed, Danvers, MA).
In summary, we report using prophylactic TVA to decrease TR after bOHT. This study demonstrates a survival benefit to TVA in the immediate postoperative period. This is the period when the heart is maximally stressed and the patients are vulnerable to the effects of a low perfusion state. The study also demonstrates significant reduction in the mean severity and number of patients with significant TR. This prevention of TR should have an important long-term beneficial effect as the presence of moderate TR is progressive and associated with a poor prognosis. Prophylactic DeVega TVA is inexpensive, quick to perform, durable at 1 year, and offers a survival advantage in the immediate postoperative period. Because TVA is beneficial, it should be routinely considered during preparation of a donor heart for transplantation.
Discussion
DR JOHN V. CONTE (Baltimore, MD): Doctors Guyton, Murray, Jeevanandam, members, and guests. I would like to thank the Society for the privilege of discussing this paper. Doctor Jeevanandam, I would like to congratulate you for a well-presented paper and acknowledge your well-earned share of the Chamberlain Award this year.
Tricuspid regurgitation has long been known to be a complication of orthotopic heart transplantation and in part has led to the development of the bicaval anastomotic technique. You have shown that by prophylactic tricuspid annuloplasty you can further reduce the incidence of tricuspid regurgitation and decrease perioperative mortality as well as improve long-term function and long-term reduction of tricuspid regurgitation. Knowing the difficulty in performing prospective randomized trials, I think you and your colleagues deserve further congratulations. I have several questions, however, related to the methodology of conducting such a study when the randomization scheme was really luck of the draw: it depended on the night that someone was on call and how the donor matched up with potential recipients.
First of all, did your Institutional Review Board have any trouble with the randomization scheme or did they have any comments that could be useful to those of us who might propose prospective randomized trials in such patient populations in the future? And second, related to that, how did you obtain consent from these patients and at what time did you obtain consent? Did all patients who were admitted to the transplant program consent for this procedure given the exclusions you have described for us or did you try and get consent the night of the transplant?
A second question is you alluded to Dr Michael Borkon and his colleagues from Kansas City, who presented at the International Society for Heart and Lung Transplantation meeting in 2002 in 50 patients a decreased incidence of tricuspid regurgitation using a biatrial anastomotic technique, which is the standard Shumway technique most people grew up using modified by Dr Cabrol and his colleagues. Like your study, they showed almost no tricuspid regurgitation; however, they did not show an improvement in short-term or long-term mortality. That was a much shorter study.
Given that they have also decreased tricuspid regurgitation, can you elucidate for us reasons why you would still recommend the bicaval anastomotic technique as opposed to the biatrial anastomotic technique if you do recommend the bicaval technique? Do you still think the bicaval technique is the optimal technique to use? You also noted that there was no requirement for long-term pacemaker therapy and no complications related to tricuspid annuloplasty, but you did have 3 patients in each group who did require temporary pacemaking. My question is, did they require temporary pacemaking because of temporary heart block or did they require it because of hemodynamic compromise and your desire to improve their hemodynamics during the operation?
And finally, would you recommend tricuspid annuloplasty for all patients and in what other groups of patients in the heart failure population would you recommend prophylactic tricuspid annuloplasty for?
Again, I would like to thank you for such a nice paper and congratulate you on your presentation today.
DR PATRICK MCCARTHY (Cleveland, OH): I would like to congratulate Dr Jeevanandam and his group on a paper that, besides winning the Chamberlain Award, also is a standout because it will change the way surgeons practice. You have shown that tricuspid annuloplasty is safe and effective; but also it is very quick and it is easy to do. We have been doing a DeVega tricuspid annuloplasty through a biatrial approach for about 2 years, and at the upcoming International Society for Heart and Lung Transplantation meeting we will report similar results to yours regarding decrease in tricuspid regurgitation. But our study was not randomized and it is not as good a paper as yours.
My question is regarding left ventricular assist device patients. Many also have pulmonary hypertension and at least moderate tricuspid regurgitation. Has this experience with tricuspid valve repair changed your practice? Do you now perform tricuspid valve repair in that group of patients, and are you planning a trial for that group also?
DR JEEVANANDAM: I would like to thank Dr McCarthy and Dr Conte for their kind comments.
We used a procurement on-call schedule for randomization. As you stated, it was luck of the draw and as long as it was strictly followed, randomization was unbiased. Patients gave their consent while on the transplant list.
With regard to bicaval versus standard orthotopic heart transplant, I think tricuspid regurgitation is one component of that that is very important. The other component, which we have shown at Temple with Steve Rothman, is that sinus node dysfunction is also different between the standard technique and the bicaval technique. Sinus node function studies done on these patients demonstrated a dramatically better sinus node recovery time after the bicaval technique. This eliminates the need for pacemakers because of sinus node dysfunction after heart transplantation. Therefore, we will continue to do bicaval versus the standard technique.
Three patients needed to be paced in this study in each group to increase their heart rate and improve their cardiac output. These patients did not have heart block.
Would we recommend this routinely in transplant patients? Yes, we would. What other type of patients do we recommend this on? As Dr McCarthy has alluded to, we routinely perform tricuspid valve annuloplasty in patients with right heart failure and severe tricuspid regurgitation, who require left ventricular assist devices. I do not think we do enough left ventricular assist device patients to actually do a trial like the current study. Also, in a lot of our ventricular reconstruction patients or patients with severe mitral regurgitation in whom we may do a bypass and a mitral valve, we will augment them with tricuspid annuloplasties if they have any evidence of tricuspid regurgitation.
Thank you very much.
Acknowledgments
We thank Karen Bradfield, Dathine Brown, and Anthony Houston for their assistance in preparation of this manuscript.
References
This article has been cited by other articles:
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  M. Schnoor, T. Schafer, D. Luhmann, and H. H. Sievers Bicaval versus standard technique in orthotopic heart transplantation: a systematic review and meta-analysis. J. Thorac. Cardiovasc. Surg., November 1, 2007; 134(5): 1322 - 1331. [Abstract] [Full Text] [PDF]
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 V. Jeevanandam, H. Russell, P. Mather, S. Furukawa, A. Anderson, and J. Raman Donor Tricuspid Annuloplasty During Orthotopic Heart Transplantation: Long-Term Results of a Prospective Controlled Study Ann. Thorac. Surg., December 1, 2006; 82(6): 2089 - 2095. [Abstract] [Full Text] [PDF]
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 R. H. Jones The Year in Cardiovascular Surgery J. Am. Coll. Cardiol., May 3, 2005; 45(9): 1517 - 1528. [Full Text] [PDF]
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