- Email: [email protected]
Vascular Surgery in Behcet’s Disease
1504
CORRESPONDENCE
Ann Thorac Surg 2008;85:1500 – 6
6. Powell SR, Gurzenda EM, Mantell LL, Teichberg S, Maulik D. Association of increased ubiquinated proteins with cardiac apoptosis. Antioxid Redox Signal 2000;2:103–12. 7. Cai Z, Semenza GL. PTEN activity is modulated during ischemia and reperfusion: involvement in the induction and decay of preconditioning. Circ Res 2005;97:1351–9. 8. Voortman J, Giaccone G. Severe reversible cardiac failure after bortezomib treatment combined with chemotherapy in a non-small cell lung cancer patient: a case report. BMC Cancer 2006;6:129.
that more work remains in bringing proteasome inhibition therapies to cardiovascular disease.
Reply
References
To the Editor:
MISCELLANEOUS
We greatly appreciate the comments regarding our article [1] by Dr Powell, clearly a leader in the field of the cardiac proteasome [2]. His thoughts and critique are valid. We share some skepticism, despite human clinical trial data demonstrating safety and efficacy, that proteasome inhibition will be a panacea for ischemic heart disease. Although much of our effort has been directed towards a more focused approach to inhibition of nuclear factor-B (NF-B) [3], we believe that manipulation of the proteasome offers some therapeutic opportunities in heart disease. In regards to our experimental protocols and data interpretation, we are confident that PS-519 was efficacious in inhibiting the 26S proteasome and the metabolism of inhibitory B␣ (IB␣). The proteasome assay is fairly burdensome and is reliably done in only a few centers. Fair enough, we did not perform this study in our protocol. Yet, we (A. S. B.) have previously performed assays with PS-519 in pigs [4], and the pharmacokinetics of proteasome inhibition using PS-519 has been extensively studied in rodents and humans [5, 6]. These studies have demonstrated that at a dose of 1 mg/kg, proteasome inhibition in peripheral blood leukocytes is achieved at a level of approximately 80% to 90% in 30 to 60 minutes, with an approximate duration of action of 24 hours. We therefore elected to focus our studies on the cardiovascular physiology related to the specific hypothesis of the paper. In demonstrating the effect of PS-519 on cardiac tissue, specifically its effects on the NF-B regulatory system, we elected to monitor levels of IB␣ and phospho-p65. We did not believe that changes in total p65 would be detectable within the short timeframe of the experiment. Although we did not use electrophoretic mobility shift assay techniques to show changes in NF-B binding activity, we did demonstrate significant changes in the physiologically relevant downstream indicator of NF-B function, tumor necrosis factor-␣. Dr Powell sites several articles that achieved different results using the proteasome inhibitor MG-132. MG-132 is known to be less specific in its inhibition of the 26S proteasome than lactacystin, which is similarly less specific than the lactacystin derivative PS-519. We agree that results and their interpretation are highly subject to the specificity of the inhibitor used. Similarly, the articles sited by Dr Powell that achieved conflicting results used the Langendorff system for cardiac perfusion. We agree that there are important caveats in the interpretation of the two types of experiments. In vivo ischemia and reperfusion experiments are typically more complex and subject to more variables, but are generally more physiologically relevant than the isolated heart perfusion systems. Again, we appreciate the opportunity to explain some of the decisions we made in pursuing this line of research and agree © 2008 by The Society of Thoracic Surgeons Published by Elsevier Inc
William E. Stansfield, MD Craig H. Selzman, MD Division of Cardiothoracic Surgery University of North Carolina 3040 Burnett Womack, CB #7065 Chapel Hill, NC 27599-7065 e-mail: [email protected]
1. Stansfield WE, Moss NC, Willis MS, Tang R, Selzman C. Proteasome inhibition attenuates infarct size and preserves cardiac function in a murine model of myocardial ischemiareperfusion injury. Ann Thorac Surg 2007;84:120 –5. 2. Powell SR. Proteasome inhibitors in myocardial ischemia, some concerns (letter). Ann Thorac Surg 2008;85:1503– 4. 3. Moss NC, Stansfield WE, Willis MS, Tang RH, Selzman CH. IKKbeta inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2007;293:H2248 –53. 4. Pye J, Ardeshirpour F, McCain A, et al. Proteasome inhibition ablates activation of NF-kappa B in myocardial reperfusion and reduces reperfusion injury. Am J Physiol Heart Circ Physiol 2003;284:H919 –26. 5. Campbell B, Adams J, Shin YK, Lefer AM. Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart. J Mol Cell Cardiol 1999;31:467–76. 6. Shah IM, Lees KR, Pien CP, Elliott PJ. Early clinical experience with the novel proteasome inhibitor PS-519. Br J Clin Pharmacol 2002;54:269 –76.
Vascular Surgery in Behcet’s Disease To the Editor: We read with great interest the article by Umehara and colleagues [1], in which they present successful treatment of a ruptured thoracoabdominal aneurysm in a patient with Behcet’s disease. They have performed an extensive operation with very good results. However, we believe certain points in the article should be emphasized. Behcet’s disease is an autoimmune multi-systemic disorder based on vasculitis. Vascular surgical procedures should be the last resort. Instead, medical management should be aimed, unless surgery is definitely required, because any intervention may lead to further complications such as new occlusions, aneurysms, or pseudoaneurysms [1–3]. When definitely required, operations should preferably be performed when the disease is under strict control with immunosuppressives. In case of an emergency, such as a rupture, the remission status of the patient should be re-evaluated. External (such as active uveitis, aphthae, and genital ulcers) and internal manifestations (such as cardiovascular complications) of the disease are strongly related with exacerbation of the disease. Prior to intervention, it has been shown that bolus dose of immunosuppressives (eg, prednisolone) may decrease perioperative and postoperative vascular complications [2]. It is understood from the article that the disease of the patient is not well controlled with 8 mg/day prednisolone. Another point is that based on the computerized tomography images, we could not be sure of the exact location of the rupture, and the aneurysms seemed to be located at the infrarenal abdominal aorta. We see an aortic dissection inferior to the renal level with 0003-4975/08/$34.00
Ann Thorac Surg 2008;85:1500 – 6
Dilek Erer, MD Erkan Iriz, MD Veli Yildirim Imren, MD Gursel Levent Oktar, MD Department of Cardiovascular Surgery Gazi University Medical Faculty Dede Korkut Sokak, No: 6/9 Çankaya, Ankara 06640, Turkey e-mail: [email protected]
References 1. Umehara N, Saito S, Ishii H, Aomi S, Kurosawa H. Rupture of thoracoabdominal aortic aneurysm associated with Behcet’s disease. Ann Thorac Surg 2007;84:1394 – 6. 2. Ugurlucan M, Sayin OA, Surmen B, et al. Complication of Behcet’s disease: spontaneous aortic pseudoaneurysm. J Card Surg 2006;21:589 –91. 3. Alpagut U, Ugurlucan M, Dayioglu E. Major arterial involvement and review of Behcet’s disease. Ann Vasc Surg 2007;21: 232–9.
Anatomical Model at Risk of Coarctation of the Pulmonary Artery To the Editor: We read with great interest the article by Shinkawa and colleagues [1] on the surgical treatment of coarctation of the pulmonary artery (CoPA) in neonates affected with complex congenital heart disease with pulmonary atresia. We completely agree with the authors that these complications, once clinically evident, should be treated by aggressive surgery on pulmonary artery branches early in life. In fact, such strategy prevents growth failure of the pulmonary branches, which would impair optimal results at the time of definitive surgery and the completion of a Fontan strategy in the univentricular heart. The CoPA represents the evolution of a process of migration of ductal tissue within the pulmonary tree [2], which may be clinically evident either soon after the weaning of Alprostadil (PGE1) or later after a modified Blalock-Taussig shunt (MBTS) procedure. Therefore, it would seem that the population of patients studied by Shinkawa and colleagues [1] belong to a © 2008 by The Society of Thoracic Surgeons Published by Elsevier Inc
1505
selective subgroup who presented with ductal constriction of pulmonary artery branches at the time of the first surgical procedure. A few years ago, in our department we analyzed a population of 53 neonates who underwent the MBTS procedure during a 5-year period in an attempt to define an anatomical model of patients at risk of developing CoPA [3]. In this subset of patients, the incidence of CoPA detected was 7.5%.We analyzed the anatomy of the patients affected and hypothesized that the patients at risk of CoPA were those with critical pulmonary outflow obstruction (not necessarily atretic) and a ventricular septal defect. We speculated that this kind of lesion was embryologically premature and perhaps had a greater predisposition to ductal migration in the pulmonary artery after birth. For this reason, it is not advisable to patch all pulmonary artery branches of neonates who require the MBTS procedure or to leave the pulmonary artery branches of all patients who have the MBTS procedure open to the risk of evolution of the CoPA into coarctation or atresia of a pulmonary artery. Therefore we suggest that the subset of patients who are at risk of having CoPA develop will require constant follow-up with frequent outpatient controls, especially in the weeks immediately after the MBTS procedure. Awareness of this potential complication is important, and the vessels should be evaluated by Doppler flow studies of the pulmonary artery on the ductal side or by computed tomographic scan evaluation of the pulmonary artery branches if echocardiographic images are poor. We agree with Shinkawa and colleagues [1] that once the lesion is detected, patients must be submitted to surgery, because from our point of view we believe that interventional catheterization may not be sufficiently radical to relieve the stenosis and eliminate the ductal tissue, which is universally accepted for the treatment of neonatal aortic coarctation. Dario E. Troise, MD Giovanna Favia Guarnieri, MD Giuseppe Balducci, MD Maria Rosaria Tagliente, MD Paolo M. Arciprete, MD Luigi de Luca Tupputi Schinosa, MD Pediatric Cardiac Surgery Department “Policlinico-Giovanni XXIII” Hospital University of Bari Piazza Giulio Cesare 11 Bari 70100, Italy e-mail: [email protected] Department of Obstetric Gynecology and Neonatology Section of Neonatal Cardiology University of Bari Piazza Giulio Cesare 11 Bari 70100, Italy
References 1. Shinkawa T, Yamagishi M, Shuntoh K, Miyazaki T, Hisaoka T, Yaku H. Pulmonary arterial reconstruction for pulmonary coarctation in early infancy. Ann Thorac Surg 2007;83:188 –92. 2. Waldman JD, Karp RB, Gittenberger-de Groot AC, Agarwala B, Glagov S. Spontaneous acquisition of discontinuous pulmonary arteries. Ann Thorac Surg 1996;62:161– 8. 3. Troise D, Vairo U, Tagliente MR, Arbues M, Arciprete P. Discontinuità acquisita delle arterie polmonari non correlata a shunt chirurgico succlavio-polmonare. G Ital Cardiol 1996; 26(Suppl 2):15. 0003-4975/08/$34.00
MISCELLANEOUS
hematoma formation around the aorta in Figure 1A (see Reference 1). Because of the tortuous appearance of the aorta in Figure 1B (see Reference 1), only the retroperitoneal hematoma is identifiable. Moreover, in Figure 1C (see Reference 1), we see aneurysms on both sides of the infrarenal aorta. Thus, the necessity for such a major procedure (thoracoabdominal aortic replacement with the use of cardiopulmonary bypass and separate reconstruction of each of the visceral arteries) in the presence of an active vasculitis may be speculated. Information on the duration of the operation would be a helpful addition. Although a 10-month follow-up was uneventful, the patient still faces the lifelong risk of stenosis and pseudoaneurysm because of interventions to the four visceral arteries and femoral artery, as well as proximal and distal anastomoses. Was just the replacement of the ruptured segment without interfering with the visceral arteries or only the renal arteries not possible? Would an endovascular treatment option be more appropriate? In addition, it would be helpful if the authors could provide more information on the medical precautions taken before, during, and after the surgery for a successful outcome by means of additional immunosuppressives and heparin.
CORRESPONDENCE
CORRESPONDENCE
Ann Thorac Surg 2008;85:1500 – 6
6. Powell SR, Gurzenda EM, Mantell LL, Teichberg S, Maulik D. Association of increased ubiquinated proteins with cardiac apoptosis. Antioxid Redox Signal 2000;2:103–12. 7. Cai Z, Semenza GL. PTEN activity is modulated during ischemia and reperfusion: involvement in the induction and decay of preconditioning. Circ Res 2005;97:1351–9. 8. Voortman J, Giaccone G. Severe reversible cardiac failure after bortezomib treatment combined with chemotherapy in a non-small cell lung cancer patient: a case report. BMC Cancer 2006;6:129.
that more work remains in bringing proteasome inhibition therapies to cardiovascular disease.
Reply
References
To the Editor:
MISCELLANEOUS
We greatly appreciate the comments regarding our article [1] by Dr Powell, clearly a leader in the field of the cardiac proteasome [2]. His thoughts and critique are valid. We share some skepticism, despite human clinical trial data demonstrating safety and efficacy, that proteasome inhibition will be a panacea for ischemic heart disease. Although much of our effort has been directed towards a more focused approach to inhibition of nuclear factor-B (NF-B) [3], we believe that manipulation of the proteasome offers some therapeutic opportunities in heart disease. In regards to our experimental protocols and data interpretation, we are confident that PS-519 was efficacious in inhibiting the 26S proteasome and the metabolism of inhibitory B␣ (IB␣). The proteasome assay is fairly burdensome and is reliably done in only a few centers. Fair enough, we did not perform this study in our protocol. Yet, we (A. S. B.) have previously performed assays with PS-519 in pigs [4], and the pharmacokinetics of proteasome inhibition using PS-519 has been extensively studied in rodents and humans [5, 6]. These studies have demonstrated that at a dose of 1 mg/kg, proteasome inhibition in peripheral blood leukocytes is achieved at a level of approximately 80% to 90% in 30 to 60 minutes, with an approximate duration of action of 24 hours. We therefore elected to focus our studies on the cardiovascular physiology related to the specific hypothesis of the paper. In demonstrating the effect of PS-519 on cardiac tissue, specifically its effects on the NF-B regulatory system, we elected to monitor levels of IB␣ and phospho-p65. We did not believe that changes in total p65 would be detectable within the short timeframe of the experiment. Although we did not use electrophoretic mobility shift assay techniques to show changes in NF-B binding activity, we did demonstrate significant changes in the physiologically relevant downstream indicator of NF-B function, tumor necrosis factor-␣. Dr Powell sites several articles that achieved different results using the proteasome inhibitor MG-132. MG-132 is known to be less specific in its inhibition of the 26S proteasome than lactacystin, which is similarly less specific than the lactacystin derivative PS-519. We agree that results and their interpretation are highly subject to the specificity of the inhibitor used. Similarly, the articles sited by Dr Powell that achieved conflicting results used the Langendorff system for cardiac perfusion. We agree that there are important caveats in the interpretation of the two types of experiments. In vivo ischemia and reperfusion experiments are typically more complex and subject to more variables, but are generally more physiologically relevant than the isolated heart perfusion systems. Again, we appreciate the opportunity to explain some of the decisions we made in pursuing this line of research and agree © 2008 by The Society of Thoracic Surgeons Published by Elsevier Inc
William E. Stansfield, MD Craig H. Selzman, MD Division of Cardiothoracic Surgery University of North Carolina 3040 Burnett Womack, CB #7065 Chapel Hill, NC 27599-7065 e-mail: [email protected]
1. Stansfield WE, Moss NC, Willis MS, Tang R, Selzman C. Proteasome inhibition attenuates infarct size and preserves cardiac function in a murine model of myocardial ischemiareperfusion injury. Ann Thorac Surg 2007;84:120 –5. 2. Powell SR. Proteasome inhibitors in myocardial ischemia, some concerns (letter). Ann Thorac Surg 2008;85:1503– 4. 3. Moss NC, Stansfield WE, Willis MS, Tang RH, Selzman CH. IKKbeta inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2007;293:H2248 –53. 4. Pye J, Ardeshirpour F, McCain A, et al. Proteasome inhibition ablates activation of NF-kappa B in myocardial reperfusion and reduces reperfusion injury. Am J Physiol Heart Circ Physiol 2003;284:H919 –26. 5. Campbell B, Adams J, Shin YK, Lefer AM. Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart. J Mol Cell Cardiol 1999;31:467–76. 6. Shah IM, Lees KR, Pien CP, Elliott PJ. Early clinical experience with the novel proteasome inhibitor PS-519. Br J Clin Pharmacol 2002;54:269 –76.
Vascular Surgery in Behcet’s Disease To the Editor: We read with great interest the article by Umehara and colleagues [1], in which they present successful treatment of a ruptured thoracoabdominal aneurysm in a patient with Behcet’s disease. They have performed an extensive operation with very good results. However, we believe certain points in the article should be emphasized. Behcet’s disease is an autoimmune multi-systemic disorder based on vasculitis. Vascular surgical procedures should be the last resort. Instead, medical management should be aimed, unless surgery is definitely required, because any intervention may lead to further complications such as new occlusions, aneurysms, or pseudoaneurysms [1–3]. When definitely required, operations should preferably be performed when the disease is under strict control with immunosuppressives. In case of an emergency, such as a rupture, the remission status of the patient should be re-evaluated. External (such as active uveitis, aphthae, and genital ulcers) and internal manifestations (such as cardiovascular complications) of the disease are strongly related with exacerbation of the disease. Prior to intervention, it has been shown that bolus dose of immunosuppressives (eg, prednisolone) may decrease perioperative and postoperative vascular complications [2]. It is understood from the article that the disease of the patient is not well controlled with 8 mg/day prednisolone. Another point is that based on the computerized tomography images, we could not be sure of the exact location of the rupture, and the aneurysms seemed to be located at the infrarenal abdominal aorta. We see an aortic dissection inferior to the renal level with 0003-4975/08/$34.00
Ann Thorac Surg 2008;85:1500 – 6
Dilek Erer, MD Erkan Iriz, MD Veli Yildirim Imren, MD Gursel Levent Oktar, MD Department of Cardiovascular Surgery Gazi University Medical Faculty Dede Korkut Sokak, No: 6/9 Çankaya, Ankara 06640, Turkey e-mail: [email protected]
References 1. Umehara N, Saito S, Ishii H, Aomi S, Kurosawa H. Rupture of thoracoabdominal aortic aneurysm associated with Behcet’s disease. Ann Thorac Surg 2007;84:1394 – 6. 2. Ugurlucan M, Sayin OA, Surmen B, et al. Complication of Behcet’s disease: spontaneous aortic pseudoaneurysm. J Card Surg 2006;21:589 –91. 3. Alpagut U, Ugurlucan M, Dayioglu E. Major arterial involvement and review of Behcet’s disease. Ann Vasc Surg 2007;21: 232–9.
Anatomical Model at Risk of Coarctation of the Pulmonary Artery To the Editor: We read with great interest the article by Shinkawa and colleagues [1] on the surgical treatment of coarctation of the pulmonary artery (CoPA) in neonates affected with complex congenital heart disease with pulmonary atresia. We completely agree with the authors that these complications, once clinically evident, should be treated by aggressive surgery on pulmonary artery branches early in life. In fact, such strategy prevents growth failure of the pulmonary branches, which would impair optimal results at the time of definitive surgery and the completion of a Fontan strategy in the univentricular heart. The CoPA represents the evolution of a process of migration of ductal tissue within the pulmonary tree [2], which may be clinically evident either soon after the weaning of Alprostadil (PGE1) or later after a modified Blalock-Taussig shunt (MBTS) procedure. Therefore, it would seem that the population of patients studied by Shinkawa and colleagues [1] belong to a © 2008 by The Society of Thoracic Surgeons Published by Elsevier Inc
1505
selective subgroup who presented with ductal constriction of pulmonary artery branches at the time of the first surgical procedure. A few years ago, in our department we analyzed a population of 53 neonates who underwent the MBTS procedure during a 5-year period in an attempt to define an anatomical model of patients at risk of developing CoPA [3]. In this subset of patients, the incidence of CoPA detected was 7.5%.We analyzed the anatomy of the patients affected and hypothesized that the patients at risk of CoPA were those with critical pulmonary outflow obstruction (not necessarily atretic) and a ventricular septal defect. We speculated that this kind of lesion was embryologically premature and perhaps had a greater predisposition to ductal migration in the pulmonary artery after birth. For this reason, it is not advisable to patch all pulmonary artery branches of neonates who require the MBTS procedure or to leave the pulmonary artery branches of all patients who have the MBTS procedure open to the risk of evolution of the CoPA into coarctation or atresia of a pulmonary artery. Therefore we suggest that the subset of patients who are at risk of having CoPA develop will require constant follow-up with frequent outpatient controls, especially in the weeks immediately after the MBTS procedure. Awareness of this potential complication is important, and the vessels should be evaluated by Doppler flow studies of the pulmonary artery on the ductal side or by computed tomographic scan evaluation of the pulmonary artery branches if echocardiographic images are poor. We agree with Shinkawa and colleagues [1] that once the lesion is detected, patients must be submitted to surgery, because from our point of view we believe that interventional catheterization may not be sufficiently radical to relieve the stenosis and eliminate the ductal tissue, which is universally accepted for the treatment of neonatal aortic coarctation. Dario E. Troise, MD Giovanna Favia Guarnieri, MD Giuseppe Balducci, MD Maria Rosaria Tagliente, MD Paolo M. Arciprete, MD Luigi de Luca Tupputi Schinosa, MD Pediatric Cardiac Surgery Department “Policlinico-Giovanni XXIII” Hospital University of Bari Piazza Giulio Cesare 11 Bari 70100, Italy e-mail: [email protected] Department of Obstetric Gynecology and Neonatology Section of Neonatal Cardiology University of Bari Piazza Giulio Cesare 11 Bari 70100, Italy
References 1. Shinkawa T, Yamagishi M, Shuntoh K, Miyazaki T, Hisaoka T, Yaku H. Pulmonary arterial reconstruction for pulmonary coarctation in early infancy. Ann Thorac Surg 2007;83:188 –92. 2. Waldman JD, Karp RB, Gittenberger-de Groot AC, Agarwala B, Glagov S. Spontaneous acquisition of discontinuous pulmonary arteries. Ann Thorac Surg 1996;62:161– 8. 3. Troise D, Vairo U, Tagliente MR, Arbues M, Arciprete P. Discontinuità acquisita delle arterie polmonari non correlata a shunt chirurgico succlavio-polmonare. G Ital Cardiol 1996; 26(Suppl 2):15. 0003-4975/08/$34.00
MISCELLANEOUS
hematoma formation around the aorta in Figure 1A (see Reference 1). Because of the tortuous appearance of the aorta in Figure 1B (see Reference 1), only the retroperitoneal hematoma is identifiable. Moreover, in Figure 1C (see Reference 1), we see aneurysms on both sides of the infrarenal aorta. Thus, the necessity for such a major procedure (thoracoabdominal aortic replacement with the use of cardiopulmonary bypass and separate reconstruction of each of the visceral arteries) in the presence of an active vasculitis may be speculated. Information on the duration of the operation would be a helpful addition. Although a 10-month follow-up was uneventful, the patient still faces the lifelong risk of stenosis and pseudoaneurysm because of interventions to the four visceral arteries and femoral artery, as well as proximal and distal anastomoses. Was just the replacement of the ruptured segment without interfering with the visceral arteries or only the renal arteries not possible? Would an endovascular treatment option be more appropriate? In addition, it would be helpful if the authors could provide more information on the medical precautions taken before, during, and after the surgery for a successful outcome by means of additional immunosuppressives and heparin.
CORRESPONDENCE