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Ann Thorac Surg 2006;82:2089-2095
© 2006 The Society of Thoracic Surgeons
a Departments of Surgery and Medicine, University of Chicago, Chicago, Illinois
b Department of Surgery, Temple University, Philadelphia, Pennsylvania
c Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
Accepted for publication July 7, 2006.
* Address correspondence to Dr Jeevanandam, Section of Cardiac and Thoracic Surgery, University of Chicago, 5841 S Maryland Ave, MC5040, Chicago, IL 60637. (Email: jeevan{at}uchicago.edu).
Presented at the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.
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Abstract |
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METHODS: Between April 1997 and March 1998, 60 patients (aged 18 to 70 years; 22 female) randomly received either standard bicaval orthotopic heart transplantation (group STD; n = 30) or bicaval orthotopic heart transplantation with DeVega TVA (group TVA; n = 30). Tricuspid valve annuloplasty was performed on the donor heart before implantation using pledgeted 2-0 polypropylene and sized to an annulus of 29 mm. Echocardiographic measurements, laboratory values, and hemodynamics were obtained prospectively and reviewed by an independent data analyst.
RESULTS: Follow-up of patients as of December 2003 was complete. Although there was a perioperative mortality advantage in group TVA, there was no difference between groups in long-term survival. At the end of the study, however, there was a statistical difference (group STD versus group TVA, p < 0.05) with regard to cardiac mortality (7 of 30 versus 3 of 30), average amount of tricuspid regurgitation (1.5 ± 1.3 versus 0.5 ± 0.4), percentage of patients with 2+ or greater tricuspid regurgitation (34% versus 0%), serum creatinine (2.9 ± 2.0 versus 1.8 ± 0.7), and difference in serum creatinine over baseline (2.0 ± 2.1 versus 0.7 ± 0.8).
CONCLUSIONS: Prophylactic DeVega TVA of the donor heart is durable and decreases the incidence of cardiac-related mortality and tricuspid regurgitation after orthotopic heart transplantation. In addition, there is improved protection of renal function. Considering the ease and safety of TVA and its advantages, it should be performed as a routine adjunct to orthotopic heart transplantation.
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Introduction |
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Moderate and higher grades of TR are associated with right-sided heart failure symptoms, renal and hepatic dysfunction, and decreased long-term survival [11, 12]. It remains unclear whether the TR is a reflection of poor allograft function or a primary abnormality, but once present, repair or replacement is often indicated. Renal dysfunction is also a long-term consequence of OHT, and is most commonly attributed to the calcineurin inhibitors and may also result from TR ([11, 13, 14], and International Society for Heart and Lung Transplantation registry data).
The DeVega type of tricuspid annuloplasty using a suture has been used to treat TR. It is simple, quick, inexpensive, and durable [15, 16]. We have previously reported short-term results on a population of randomized and prospectively studied patients, one group of whom received prophylactic DeVega tricuspid valve annuloplasty (TVA) to prevent TR after OHT [17]. We demonstrated less TR and improved perioperative heart function and survival. This paper reports on the long-term (6-year) follow-up of those patients and compares them with regard to survival, amount of TR, renal function, and hemodynamics.
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Material and Methods |
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The patients received a standard bicaval OHT (group STD) or bicaval OHT with TVA (group TVA). Data were obtained prospectively, and data analysts were masked to the assignment of patient groups. Data analyzed included operative and donor information, survival, amount of TR, hemodynamics, and serum blood urea nitrogen and creatinine levels.
Procedure
University of Wisconsin solution (Barr Laboratories, Pomona, New York) was used for cardioplegia and preservation solution. The recipient cardiectomy and recipient-donor anastomoses were done using the bicaval technique described by Sarsam and colleagues [18] and others [19]. All patients received a baseline inotropic regimen of T3 (0.08 µg/kg bolus, infusion 0.8 µg/kg for 3 hours), dobutamine, 5 µg · kg–1 · min–1, and dopamine, 3 µg · kg–1 · min–1. Any increase above baseline was considered as elevated inotropic requirement. Patients were considered weanable from cardiopulmonary bypass if they could sustain a mean systemic blood pressure greater than 70 mm Hg with a central venous pressure of less than 15 mm Hg, and a cardiac index greater than 2.1 L · min–1 · m–2 with a combination of inotropic and intra-aortic 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 caval or right atrial opening, and a double layer of pledgeted 2-0 polypropylene 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 immunnosuppression therapy with cyclosporine A (3.5 to 5.0 mg/kg daily), azathioprine (1.5 to 2.5 mg/kg daily), and steroids. Induction therapy was not routinely used. Patients either had the cyclosporine A switched to tacrolimus or had mycophenolate mofetill 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 greater than 4,000/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 (Scholten Surgical Instruments, Lodi, CA) [20]. Biopsy-proven rejection was graded using the modified Billingham system adopted by the International Society for Heart and Lung Transplantation [21].
Echocardiographic Assessment of TR
Patients routinely underwent intraoperative transesophageal echocardiography, and then transthoracic echocardiography studies at 1 week, 1 month, and then annually. As part of the echocardiographic studes, 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 were as follows: 0, 1+ (jet to area ratio <10%, trace); 2+ (ratio 10% to 24%, mild); 3+ (ratio 25% to 49%, moderate); and 4+ (ratio >50%, severe). Multiple views were obtained, and the regurgitation graded based upon the most abnormal views.
Hemodynamic Assessment
Intraoperative pulmonary artery monitoring with a Swan-Ganz catheter was performed in every patient. Right-side heart catheterization was routinely performed with biopsy at 1 week, 1 month, and annually, or when dictated by clinical condition. Intracardiac pressures were recorded at the levels of the right atrium, right ventricular body, and pulmonary artery. Thermodiluton cardiac outputs were also obtained.
Statistics
All numerical results are reported as mean ± SD. A p value of less than 0.05 was considered to be significant. Statistical analysis was performed using SPSS v.11 (SPSS, Chicago, Illinois). Fisher’s exact test was applied for associations of categorical variables, and the Wilcoxon rank-sum test was used to compare means of continuous variables. Survival analysis was performed using the log-rank statistic.
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Results |
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Comment |
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Tricuspid regurgitation can become a serious condition. If the TR progresses past moderate, a majority of patients can have peripheral edema, ascites, and renal dysfunction. Furthermore, the long-term survival among patients with moderate TR is decreased when compared with patients who have less than mild TR [5, 11]. In a study analyzing intraoperative echocardiograms, immediate significant TR was associated with a poor long-term survival. The authors suggest a role for concomitant TVA at the time of transplant [12].
When severe TR is present, repair with an annuloplasty or replacement has been reported [2, 24]. DeVega tricuspid annuloplasty is an inexpensive, quick, and stable method to reduce a dilated annulus. It has been primarily used to treat functional TR caused by elevated left-side pressures with excellent long-term results [15, 16]. This study defined the role of prophylactic TVA. Whether the TVA is best accomplished by a DeVega technique or by a ring is based on surgeon preference. Stabilization with an annuloplasty ring is preferable for patients with severe TR and dilatation of the annulus. In this study, however, none of the patients had an abnormally dilated annulus. The DeVega annuloplasty was performed to maintain the normal size of the annulus. That was clearly accomplished in the study, as there was no progression or development of new TR in group TVA. The technique employed in the performance of the DeVega annuloplasty is important: careful and closely spaced sutures with a double pledgeted repair is critical in maintaining the integrity of the annulus. We have used an annuloplasty ring in other patients, but have found the bulky prosthetic material to be a hindrance for biopsies, which makes these procedures time consuming and expensive. 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.
Tricuspid regurgitation after OHT is often a complication of the endomyocardial biopsy procedure [23, 25–27]. Many studies correlate the presence of flail leaflets and torn chordae with severe TR. In fact, almost all reported cases of TV repair or replacement after OHT have demonstrated mechanical disruption of the TV. There is no reason to believe that a TVA would prevent mechanical disruption of the valve mechanism. Since the annulus is decreased, however, TR from minor structural damage can be attenuated. Two patients in group TVA had biopsy-proven injury to the chordal structures. Subsequent echocardiograms confirmed ruptured chorde; however, the TR did not increase above a mild degree.
Other causes of TR have a functional basis. The presence of pulmonary hypertension may cause right ventricular and annular dilatation causing TR. One study demonstrated a correlation between pulmonary hypertension and TR. However, several other studies have shown no correlation between preoperative or postoperative recipient pulmonary hypertension and development of severe TR [7, 9, 23]. Pulmonary hypertension by itself with normal right ventricular function 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. The short-term results of this study [17] demonstrated improved perioperative survival, especially when these stresses were imposed on a donor organ. Long term, there was a decrease in cardiac-associated mortality. If a cardiac-related stress is superimposed on a transplant patient, the TVA allows of maintenance of myocardial efficiency, lower central venous pressure, and perhaps enough restoration of perfusion to allow these patients to survive. However, OHT is associated with many factors, such as infection and malignancy, that can cause death. Hence, despite being superior with regard to intraoperative and cardiac survival, the overall mortality rate in both groups was similar.
We exclusively used a bicaval technique for OHT. There is ample evidence that bicaval OHT is superior to biatrial OHT in preventing TR. This superiority is attributed to elimination of the RA/RV relationship caused by the biatrial implantation technique. In a study of 249 patients, Aziz and associates [11] report a 19.9% incidence of severe TR for the bicaval technique OHT group as opposed to 51% for the biatrial technique OHT group. Because there was evidence that bicaval OHT decreases TR and improves sinus node function [28, 29], we used this technique for all patients. If the biatral OHT technique had been utilized, the prophylactic TVA might theoretically be of additional benefit.
We tested the hypothesis that prophylactic TVA, done before OHT, could impact the incidence of TR, the need for further TVA procedures and patient outcomes. The method used for randomization has been previously described [17]. The pretransplant status of recipients and donors were similar in both groups. The significant differences at long-term follow-up included prevention of significant TR and renal protection. The amount of TR was low, as would be expected from the bicaval technique, but was still different among the groups. In the early peritransplant period, group STD had a mean of 1.1 versus group TVA, 0.33 TR. This is represented as a mean of only mild TR, but there was increased mortality among the patients who had more than moderate TR [17]. Group TVA patients had only trivial TR; even the patients with myocardial dysfunction had only mild TR. The difference in average TR continues to be present at 1 and 6 years of follow-up. Furthermore, in group STD, the percentage of patients with 2+ or greater TR remains stable at approximately 30% throughout the study. The incidence of moderate/severe TR (>3+) in group STD is 7.6% at 1 year and compares favorably with other reports using bicaval OHT techniques. At 6 years, the severe TR group increases to 22.7% of the survivors. At 1 and 6 years, there were no patients with more than mild TR in group TVA. In 3 patients in group STD, clinical symptoms developed from central venous hypertension; 2 required operative correction. It is evident from other reports that TR is progressive and can lead to worsening right heart failure symptoms. That is consistent with the STD group in this study. Furthermore, follow-up of patients in this study demonstrates that a TVA prevents development and progression of TR.
The other variable that we studied was renal function, as there are data to correlate renal dysfunction with worsening TR [11–13]. Increased central venous pressure in patients with TR contributes to increased renal venous pressure, which has been shown to be responsible for decreased renal artery flow, which in turn increases plasma renin activity, causes urinary protein leak, and decreases glomerular filtration rate. That explains the deterioration in renal function in patients with significant TR [11]. In this study, patients’ serum creatinine progressively increased during the first year in both groups. However, by 6 years, there is stabilization of renal function in group TVA, and the different average levels of serum creatinine and the difference from baseline compared with group STD are significant. Furthermore, there is significant correlation between development of increased creatinine and mortality. Calceneurin inhibitors can contribute to renal dysfunction, and that effect is present in both groups. However, the development of TR is an added insult and correlates with renal dysfunction. This effect is evident only after long-term follow-up and the development of moderate TR with deterioration in renal function.
There were several limitations for this study. Because it was a single-center study, it was relatively small. The study could not be properly blinded owing to the performance of a surgical procedure in the operating room and the visibility of the TVA on echocardiography. 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, Massachusetts).
In summary, we report long-term results of using prophylactic TVA to decrease TR after OHT. Previous reports using this patient population demonstrated 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. This cardiac protective effect is present long term as demonstrated by fewer cardiac-related deaths. However, the overall survival is similar. The study also demonstrates significant reduction in the mean severity and number of patients with significant TR. This prevention of TR has important long-term beneficial effects, as the presence of moderate TR is progressive and is associated with a poor prognosis. Since there is correlation between the development of TR and renal dysfunction, the TVA helps preserve renal function. Prophylactic DeVega TVA is inexpensive, quick to perform, durable at 1 year, and offers a survival advantage in the immediate postoperative period. Long term, there is better preservation of renal function and prevention of TR. Because TVA is beneficial, it should be routinely considered during preparation of a donor heart for transplantation. [22].
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Discussion |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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DR JEEVANANDAM: We have now used it routinely after this study, and we rarely see posttransplant tricuspid regurgitation. The excluded patients all received tricuspid annuloplasty. We have not studied them long term.
DR HIGGINS: You see the same impact on outcomes with respect to renal function and other things in those patients?
DR JEEVANANDAM: We haven’t studied them, but we would suspect that we would see the same improvement in outcomes. Renal function changes are multifactorial, and as you know, it is difficult to differentiate between mechanical and pharmacologic causes.
DR VIVEK RAO (Toronto, ON, Canada): Great study, Dr Jeevanandam. We have been watching your results with this technique for several years. I want to follow up with your response to the moderator. Have you been able to identify the patients who you think benefit the most from this from the technique? For example, was there an effect of gender mismatch? Were female donors in male patients more likely to develop tricuspid regurgitation and should that be a patient population to examine in more detail? And, again, the weight mismatch, you excluded those who had a ratio less than 0.5, but what about those on the cusp, 0.2, 0.3, who were often a donor mismatch? Were these patients prone to tricuspid insufficiency?
DR JEEVANANDAM: That is a great question. Right now we do it routinely, but if we weren’t going to do it routinely, the patients who have a higher incidence of developing tricuspid regurgitation, as you have pointed out, are the recipients with pretransplant pulmonary hypertension, high-dose inotropes, mechanical assistance, multiple sternotomies, and mechanical ventilation. Donor factors included high-dose inotropes, reduced right ventricular function, small donors (<0.5 ratio), or those for whom a long ischemic time would be anticipated. Those are the patients who I would think would have particular problems developing tricuspid regurgitation, but at this time we just do it routinely.
DR CHRISTOPH KNOSALLA (Berlin, Germany): Very nice presentation and an excellent study. I am wondering about the mechanism of tricuspid regurgitation you have observed in the patients who didn’t receive repair during your transplantation procedure. Is it due to right ventricular function, right ventricular remodeling, remodeling of the tricuspid valve annulus? Or may I ask you more specifically what is the morphology of your regurgitation jet in echocardiography? Is it a central or an eccentric jet? What is the reason and what is the mechanism?
DR JEEVANANDAM: We looked at that. Two reasons for tricuspid regurgitation are either a biopsy-induced iatrogenic mechanical disruption or ventricular dilatation. The amount of biopsy-induced regurgitation or injury was actually similar in both groups. It was interesting, in some of the patients who had DeVega annuloplasty, injured chordae were present but since the annulus was reduced, they did not develop significant regurgitation.
The clinical scenario where we saw the biggest difference was of patients who had hemodynamically significant rejection episodes. In the patients who had tricuspid annuloplasty, TR did not develop. In patients without TVA, TR developed, and as their hearts recovered, the TR would improve as well. However, prophylactic TVA prevented TR during the actual episode of cardiac dysfunction, and improved hemodynamics and end-organ perfusion.
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Acknowledgments |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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This article has been cited by other articles:
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  S. Jacob and F. Sellke Is bicaval orthotopic heart transplantation superior to the biatrial technique? Interactive CardioVascular and Thoracic Surgery, August 1, 2009; 9(2): 333 - 342. [Abstract] [Full Text] [PDF]
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 S. A. Hunt and F. Haddad The Changing Face of Heart Transplantation J. Am. Coll. Cardiol., August 19, 2008; 52(8): 587 - 598. [Abstract] [Full Text] [PDF]
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2+ TR.)