Redacement of the AsGending Aorta and Aortic Valve with a Composite Graft: Results in 25 Patients Nicholas T. Kouchoukos, M.D., Robert B. Karp, M.D., and William A. Lell, M.D.

ABSTRACT Our experience with combined replacement of the ascending aorta and aortic valve with a composite prosthetic valve-Dacron tube graft in 25 patients from September, 1974, to December, 1976,is reviewed. The technique involves suture of the composite graft to the aortic annulus, to the aortic tissue surrounding the coronary ostia, and to the distal ascending aorta, closing the aortic wall over the graft before discontinuing cardiopulmonary bypass. Annuloaortic ectasia was the most common indication for operation (15patients). Perfusion of the coronary arteries was used in the first 5 patients. In the remaining 20, internal and external myocardial cooling with one period of ischemic arrest (average, 67 minutes) was used. There was 1 hospital death (4'/0), and there have been 3 late deaths (12%) in the 27month follow-up period. This technique appears to be applicable to most types of aneurysmal disease of the proximal ascending aorta associated with aortic valve incompetence. All aneurysmal tissue from the aortic annulus to the innominate artery is excluded, bleeding through the graft is eliminated, operative time is reduced, and the late results have been satisfactory to date.

Surgical treatment of aneurysmal disease of the ascending aorta in association with aortic valve incompetence usually involves replacing the aortic valve and varying lengths of the ascending aorta. In 1968, Bentall and DeBono [ll described a technique for total prosthetic replacement of the ascending aorta and aortic valve with implantation of the coronary arteries into the aortic graft. Results of this and similar techFrom the Division of Cardiovascular and Thoracic Surgery, Department of Surgery, and the Department of Anesthesiology, University of Alabama Medical Center, Birmingham, AL . Presented at the Thirteenth Annual Meeting of The Society of Thoracic Surgeons, Jan 24-26, 1977, San Francisco, CA. Address reprint requests to Dr. Kouchoukos, Department of Surgery, University of Alabama Medical Center, University Station, Birmingham, AL 35294.

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niques have since been reported by several 3, 5-8, 131. We present here our experience with combined replacement of the ascending aorta and aortic valve using a composite prosthetic valve-Dacron tube conduit during a 27-month period: Modifications of previously described techniques are detailed, and our current indications for the use of this prosthesis are presented. ~ O U P S[2,

Clinical Material Between September, 1974, and December, 1976, 25 patients (17 men, 8 women) on one surgical service underwent combined replacement of the aortic valve and ascending aorta by means of a composite prosthetic valve-Dacron tube graft. Patient ages ranged from 19 to 77 years (mean, 50 years). Twenty-three patients had clinical and angiocardiographic findings of moderate or severe aortic valve incompetence. The abnormalities of the ascending aorta, resulting in the aneurysmal changes, are listed in the Table. Fifteen patients had aneurysmal dilatation of the ascending aorta associated with dilatation of the aortic annulus or marked distortion of the aortic valve leaflets, which resulted in valve incompetence (annuloaortic ectasia). Five of these had the clinical stigmata of Marfan's syndrome, 4 had chronic DeBakey Type I dissecting aneurysms [4], and 3 had DeBakey Type 11 dissecting aneurysms (1 acute, 2 chronic). One of the last patients had Marfan's syndrome. The acute dissection occurred in a patient with severe calcific aortic stenosis and associated coronary artery disease. One patient developed aneurysmal dilatation of the sinuses of Valsalva and aortic valve incompetence four years after the ascending aorta was replaced with a Dacron tube graft for a Type I1 acute dissection. One patient had severe luetic aortitis with associated coronary artery disease. An additional patient had previously undergone replacement of the

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Kouchoukos, Karp, and Leu: Replacement of Ascending Aorta and Aortic Valve

Abnormalities of Ascending Aorta in 25 Patients Having Replacement of the Ascending Aorta and Aortic Valve No. of Pati en ts

Abnormality ~

Annuloaortic ectasia DeBakey type I dissection (chronic) DeBakey type I1 dissection Acute Chronic Aneurysmal dilatation of sinuses of Valsalva following repair of type JI dissection Luetic aortitis Poststenotic dilatation

15 4 3

1 2 1

1 1

aortic valve with a Starr-Edwards Model 2320 cloth-covered metallic ball prosthesis for calcific aortic stenosis. She developed late stenosis of the prosthesis [9] and at reoperation was found to have severe post-stenotic dilatation of the ascending aorta.

Operative Technique The basic technique, with modifications, is that described by Bentall and DeBono [l]and Edwards and Kerr [5]. A median sternotomy incision is used. The common femoral artery is exposed for cannulation, and a single large cannula is inserted into the right atrium for venous drainage. Cardiopulmonary bypass is established with a clear prime at a flow of 2.0 to 2.2 L/min/m2.A vent is inserted through the right superior pulmonary vein into the left ventricle (Fig 1A). Direct coronary perfusion, as described by Edwards and Kerr [51,was used in the first 5 patients. In the remaining 20 patients, internal and external cooling of the myocardium without direct coronary perfusion was used. This method represents a major difference from previously described techniques. Internal cooling of the myocardium is achieved by decreasing the temperature of the perfusate to 12°C over a period of 5 to 8 minutes. The heart continues to beat during this interval. Perfusion at 12°Cis maintained for an additional 3 to 5 minutes, if possible, or until ventricular fibrillation occurs. At this point, external cooling of the myocardium is begun with lactated

Ringer's solution (4°C) through a catheter placed in the posterior portion of the pericardial cavity. One to 2 liters of the solution is dripped into the pericardial cavity during the remainder of the procedure. A sump catheter is anchored to the pericardium inferiorly with the tip at the level of the lower end of the aortic incision. This allows continuous removal of fluid and a dry operative field while cooling as much of the left ventricular myocardium as possible. A second tube is sometimes placed through the opened aorta, and the inner aspect of the left ventricle is bathed in cold solution. The left ventricularvent can be adjusted so that this fluid can be removed slowly and the water level kept below the aortic annulus. When ventricular fibrillation or left ventricular distention develop, the aorta is occluded just below the innominate artery and the temperature of the perfusate is taken to 28" to 32°C. The ascending aorta is opened longitudinally in its midportion, and the incision is extended obliquely toward, but not into, the noncoronary sinus (see Fig 1A). None of the aneurysm is excised, and the edges are retracted with sutures (Fig 1B). The aortic leaflets are excised, and the appropriate-sized composite prosthesis (woven Dacron tube graft sutured to a Bjork-Shiley tilting-disc or Starr-Edwards ball valve prosthesis) is sutured to the aortic annulus using multiple double-armed 2-0 Ticron sutures and pledgets of Teflon felt (Fig 1C). The sutures are passed through the annulus, tied to the sewing ring of the prosthesis (Fig lD), and placed immediately adjacent to each other to assure a watertight closure. A button of graft, 8 to 10 mm in diameter, is excised from the area corresponding to the location of the left coronary ostium. A continuous 4-0 Prolene suture (Fig lD, E) is used to suture the graft to the aortic wall adjacent to the ostium. Similarly, a button of graft is excised anteriorly, and the graft is sutured to the aortic wall adjacent to the right coronary ostium (Fig 1E). If two or more branches of the right coronary artery originate directly from the aorta, a larger button can be excised. The left edge of the divided aorta is reflected anteriorly as this anastomosis is completed (Fig W). The graft is trimmed to the appropriate length

142 The Annals of Thoracic Surgery Vol 24 No 2 August 1977

A

B

C

D

E

143 Kouchoukos, Karp, and Leu: Replacement of Ascending Aorta and Aortic Valve

F

H

J

I

Fig 1. (A)Venous drainage is established with a single cannula in therightatrium, and avent isinserted through the right superior pulmonary vein into the left ventricle. Dashed line indicates aorticincision. (B-1) The operative technique (see text for details). (LC = left coronary ostium; RC = right coronary ostium).

144 The Annals of Thoracic Surgery Vol 24 No 2 August 1977

and is bevelled with the tip of the bevel anteriorly. A strip of Teflon felt is passed between the aorta and the pulmonary artery and is used to reinforce the distal suture line (Fig 1F). The graft is then anastomosed to the aorta just proximal to the clamp with a continuous 3-0 Prolene suture. If no dissection is present, the posterior half of the anastomosis can be completed from inside the aorta in an over-and-over fashion (Fig 1F). If a dissection is present, a horizontal mattress stitch is used, incorporating the strip of Teflon felt, both layers of the aorta, and the graft. In either situation the suture line is extended anteriorly as a mattress suture, everting the graft under the opened aorta, and the row is secured (Fig lG, H). Rewarming is begun, and the aortic clamp is opened briefly to evacuate air from the graft and to check for excessive bleeding from the suture lines. The clamp is reapplied and the edges of the aorta are trimmed (Fig 1H) and approximated with a continuous 3-0 Prolene suture reinforced by strips of Teflon felt (Fig 11). Prior to completion of the closure, a needle vent is placed in the aorta adjacent to the graft (Fig 11) and coronary perfusion is established. Closure is completed, the left atrial vent is removed, air is evacuated from the left ventricle and aorta, the heart is defibrillated, and cardiopulmonary bypass is discontinued (Fig IT). In the patient who developed aneurysmal dilatation of the sinuses of Valsalva following replacement of the ascending aorta, the composite graft was sutured distally to the previously inserted Dacron graft, and the remainder of the procedure was performed as described above. In 2 patients with associated coronary artery disease, segments of saphenous vein were inserted into the left anterior descending coronary artery during separate, short periods of ischemic arrest. The anastomoses to the ascending aorta adjacent to the graft were performed after rewarming and defibrillation had been completed. In 21 patients woven Dacron tube grafts were sutured to either Starr-Edwards Model 1260 aortic prostheses (4 patients) or to Bjork-Shiley tilting-disc prostheses (17 patients). The tube grafts were 3 to 5 mm larger in diameter than the outside diameter of the prosthetic sewing ring. Composite grafts, prepared by Shiley Lab-

oratories, were used in the remaining 4 patients. Mean duration (fstandard deviation) of car15 minutes diopulmonary bypass was 123 (range, 105to 140minutes) for the 5 patients who underwent coronary perfusion and 97 19 minutes (range, 77 to 150 minutes) in the 20 patients who had myocardial cooling. This difference was statistically significant ( p < 0.01). The duration of hypothermic ischemic arrest in the latter group averaged 67 10 minutes (range, 50 to 90 minutes).

*

*

*

Results Early There was 1hospital death (4%). A 65-year-old man with severe luetic aortitis, aortic valve incompetence, and three-vessel coronary disease died postoperatively. Because of severe distal coronary atherosclerosis, only the left anterior descending coronary artery could be bypassed. He had progressive hemodynamic deterioration following discontinuation of cardiopulmonary bypass despite maximal inotropic support. The intraaortic balloon device could not be inserted because of severe atherosclerosis in both the abdominal aorta and remainder of the ascending aorta. One patient required reoperation for bleeding, which was primarily from the substernal tissues. No discrete bleeding site on the aortotomy was identified. A second patient required reoperation because of acute prosthetic valvular incompetence occurring early postoperatively. This resulted from compression of the tube graft immediately above the valve by the aortic wall, which had been closed tightly over the proximal portion of the graft. At reoperation a Dacron patch was inserted into the aortic wall to relieve the compression. Both patients recovered uneventfully. Four of the 19 survivors who had hypothermic ischemic arrest, but none of the 5 who had coronary perfusion, required inotropic support with epinephrine or dopamine in the operating room following discontinuation of cardiopulmonary bypass. Two of the 4 required continued support in the postoperative period for 1and 2 days, respectively. Two additional patients required inotropic support in the postoperative pe-

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Kouchoukos, Karp, and Leu: Replacement of Ascending Aorta and Aortic Valve

riod-1 for 3 days (coronary perfusion), the other for 4 days (hypothermic ischemic arrest). Thus 1of 5 patients (20%) with coronary perfusion and 5 of 19 (26%) with hypothermic ischemic arrest required postoperative inotropic support. This difference was not statistically significant. Postoperative cardiac output determinations were obtained in 17 patients. The mean cardiac index obtained 4 to 8 hours after operation was 3.1 +0.9L/min/m2.Thevaluewas3.0k 1.3for4 patients who had coronary perfusion, and 3.2 k 0.9 L/min/m2 for 13 who had hypothermic ischemic arrest. During this same interval the mean left atrial pressure averaged 11.0 k 3.4 mm Hg for the 5 patients with coronary perfusion and 9.4 f 2.2 for the 19 survivors with hypothermic ischemic arrest. Preoperative and postoperative (seventh day) electrocardiograms were available for 18 patients. No changes diagnostic of myocardial infarction were observed in any patient. Postoperative aortic root angiograms were obtained in 7 patients. Widely patent graft-ostial

anastomoses were observed in 6 patients (Fig 2). In the seventh patient, who had Marfan’s syndrome and aortic incompetence but small sinuses of Valsalva proximal to a large aneurysm of the ascending aorta, compression of the left main coronary artery by the sewing ring of the Bjork-Shiley prosthesis was noted. At operation the coronary ostia were seen not to be displaced as far superiorly as with the more commonly occurring type of annuloaortic ectasia. The patient subsequently had a saphenous vein bypass graft to the anterior descending coronary artery.

Fig2. Postoperative aortic root angiogram showing widely patentgraft-ostial anastomoses. ( A )Right coronary artery. ( B ) Left coronary artery.

Late There have been 3 late deaths (12%). One patient died 3 weeks after discharge from the hospital of ventricular fibrillation following attempted cardioversion for atrial fibrillation. Preoperatively and early postoperatively she had had marked ventricular irritability, which was controlled with drug therapy. Postmortem examination disclosed a markedly enlarged heart (650 gm) with biventricular hypertrophy and dilatation. The composite conduit was functioning properly, and both coronary ostia were widely patent. A second patient died 6 weeks postoperatively after reoperation for

A

B

146 The Annals of Thoracic Surgery Vol 24 No 2 August 1977

prosthetic endocarditis. The third patient died suddenly 2 months postoperatively. She needed operation for a stenotic prosthetic aortic valve and had required insertion of a permanent pacemaker for control of arrhythmias following initial replacement of her calcified aortic valve. She had marked ventricular irritability following the second operation as well. All survivors improved symptomatically in the 27-month follow-up period. Marked reduction in heart size has been noted in the majority of patients. All patients have received anticoagulant therapy with warfarin. One patient sustained a cerebral embolism 4 months postoperatively and has a mild residual expressive aphasia. Comment In the evolution of surgical treatment of ascending aortic aneurysms associated with aortic valve incompetence, progressively larger segments of the ascending aorta have been replaced. A standardized approach involves replacement of the ascending aorta from the level of the aortic commissures to a site proximal to the origin of the innominate artery, with prosthetic replacement of the aortic valve. This technique does not eliminate the potential for aneurysmal dilatation of the sinuses of Valsalva to develop in patients with abnormalities of the aortic wall. This complication, reported by Symbas and associates [lo] in a patient with Marfan’s syndrome following replacement of the aortic valve and ascending aorta, was observed in 1patient in our series following repair of a DeBakey Type I1 dissection. In 1964 Wheat and colleagues [12] reported essentially total replacement of the ascending aorta and aortic valve for treatment of a large aneurysm of the ascending aorta associated with aortic valve incompetence, retaining only small cuffs of aortic wall surrounding the coronary ostia. This technique excluded the majority of the dilated aortic sinuses. However, postoperative bleeding was a problem, and periprosthetic leakage was not eliminated 1111. The technique reported by Bentall and DeBono [l] offered several advantages over previous techniques. The entire proximal ascending

aorta was excluded, and periprosthetic leakage was eliminated. After the aortic wall adjacent to the coronary ostia was sutured to the graft, the redundant aortic wall was tailored and wrapped around the graft, thus eliminating bleeding through the graft as a source of postoperative hemorrhage. In this and subsequent reports, direct perfusion of the coronary arteries was used [2, 3, 5-8, 101. Zubiate and Kay [13] reported 6 patients i n whom a similar graft was used. They advised direct anastomosis of the dilated and displaced coronary arteries to saphenous vein grafts. This modification was thought to be particularly useful when dissection was present around the coronary ostia. Direct coronary perfusion was not used, however, and the myocardium was protected by local surface cooling. In the present series, myocardial protection with internal and external myocardial cooling was used in 20 patients. No differences in early postoperative cardiac performance were observed between these patients and those who underwent coronary perfusion. Elimination of coronary perfusion significantly reduced the duration of cardiopulmonary bypass. The ischemia time (average, 67 minutes) in the group with myocardial hypothermia was well tolerated by the 19 patients who survived operation. Closure of the aortic wall over the Dacron graft before discontinuation of cardiopulmonary bypass has eliminated the problem of critical bleeding through the graft. Excessive blood loss can occur if closure of the aortic wall over the graft is delayed until cardiopulmonary bypass has been discontinued and protamine has been administered. One patient in our series developed malfunction of the aortic valve prosthesis as a result of compression of the tube graft by the aortic wall, which was closed too tightly. This complication can be prevented by transiently releasing the aortic cross-clamp after completion of the distal aortic anastomosis. This distends the graft and allows appropriate trimming of the aortic wall. Preclotting of the Dacron tube graft reduces the amount of bleeding through the prosthesis during this interval. Because the size of the composite graft often cannot be determined until the aorta has been opened and the valve excised, we now preclot the grafts

147 Kouchoukos, Karp, and Lell: Replacement of Ascending Aorta and Aortic Valve

by combining heparinized blood with topical thrombin.* We have not encountered the complication of compression of the graft by hematoma between the aortic wall and the graft. Use of a composite graft may be difficult in patients with very narrow aortic annuli, with small sinuses of Valsalva, or in whom the coronary ostia are in close proximity to the annulus. Compression of the left main coronary artery by the sewing ring of a Bjork-Shiley disc prosthesis was observed in 1 patient with Marfan's syndrome who had marked narrowing of the aorta above the aortic commissures, minimally dilated sinuses of Valsalva, and a normal aortic annulus. Subsequent grafting of the left coronary arterial system was required in this patient. If this situation is encountered, it may be preferable to replace the aortic valve separately and anastomose the graft to the aorta above the commissures. For instances of aortic dissection in which the tissue around the coronary ostia is friable, or for other situations in which this tissue may not support sutures, saphenous vein bypass grafts anastomosed directly to the coronary ostia [2, 133, or to suitable distal segments, are probably preferable. We believe that combined replacement of the ascending aorta and aortic valve, using the technique described, is applicable to most types of aneurysmal disease of the proximal ascending aorta associated with aortic valve incompetence. It appears suitable for the majority of patients with annuloaortic ectasia and for some patients with both acute and chronic dissections of the ascending aorta with coexisting aortic valve incompetence. It has also been used in patients with luetic aortitis, recurrent aneurysmal dilatation of the sinuses of Valsalva following resection of the ascending aorta, and poststenotic dilatation following aortic valve replacement. With this technique, in which all aneurysmal tissue from the aortic annulus to the innominate artery is excluded, significant bleeding through the graft and from anastomotic suture lines has been eliminated, operative time has been reduced, adequate cardiac function has been *Suggestion of Dr. Norman Shumway, 1976.

maintained postoperatively, and the late results have been satisfactory. References 1. Bentall HH, DeBono A: A technique for complete replacement of the ascending aorta. Thorax 23:338, 1968 2. Blanco G, Adam A, Carlo V: A controlled approach to annulo-aortic ectasia. Ann Surg 183:174, 1976 3. Crosby IK, Ashcraft WC, Reed WA: Surgery of proximal aorta in Marfan's syndrome. J Thorac Cardiovasc Surg 66:75, 1973 4. DeBakey ME, Cooley DA, Creech 0 Jr: Surgical considerations of dissecting aneurysm of the aorta. Ann Surg 142:586, 1955 5. Edwards WS, Kerr AR: A safer technique for replacement of the entire ascending aorta and aortic valve. J Thorac Cardiovasc Surg 59:837, 1970 6. Hashimoto A, Kitamura N, Koyanagi H, et al: Surgical treatment of annulo-aortic ectasia. J Cardiovasc Surg (Torino) 17:240, 1976 7. Helseth HK, Haglin JJ, Stenlund RR, et al: Evaluation of composite graft replacement of the aortic root and ascending aorta. Ann Thorac Surg 18:138, 1974 8. Singh MP, Bentall HH: Complete replacement of the ascending aorta and the aortic valve for the treatment of aortic aneurysm. J Thorac Cardiovasc Surg 63:218, 1972 9. Smithwick W III, Kouchoukos NT, Karp RB, et al: Late stenosis of Starr-Edwards cloth-covered prostheses. Ann Thorac Surg 20:249, 1975 10. Symbas I",Raizner AE, Tyras DH, et al: Aneurysms of all sinuses of Valsalva i n patients with Marfan's syndrome: an unusual late complication following replacement of aortic valve and ascending aorta for aortic regurgitation and fusiform aneurysm of ascending aorta. Ann Surg 174:902, 1971 11. Wheat MW Jr, Boruchow IB, Ramsey HW: Surgical treatment of aneurysms of the aortic root. Ann Thorac Surg 12:593, 1971 12. Wheat MW Jr, Wilson JR, Bartley TD: Successful replacement of the entire ascending aorta and aortic valve. JAMA 188:717, 1964 13. Zubiate P, Kay JH: Surgical treatment of aneurysm of the ascending aorta with aortic insufficiency and marked displacement of the coronary ostia. J Thorac Cardiovasc Surg 71:415,1976

Discussion DR. CONSTANTINE E. ANAGNOSTOPOULOS (Chicago, IL): Although some may disagree, Drs. Symbas, Kouchoukos, myself, and others have noted the postoperative development of sinus of valsalva aneurysms

148 T h e Annals of Thoracic Surgery Vol 24 No 2 August 1977

in inadequately replaced ascending aortic aneurysms or conditions characterized by uniformly poor aortic wall, even at the most proximal centimeter of tissue. Therefore, I agree with the authors that this simultaneous attack on congenital and acquired heart disease, valves, aorta, and coronary arteries is justified, especially when made simple and elegant. My three questions to Dr. Kouchoukos are: Why was the aortic valve replaced in the 2 patients with little or no aortic insufficiency? I gather there was 1 patient who had late prosthetic stenosis and that 1 other may have had luetic aortitis. How much myocardial cooling was used after the 12°C perfusion of the myocardium? You imply that only 2 liters of 4°C Ringer’s lactate is used for the whole period of anoxia; how much of this gets aspirated back into the pump? Was it used inside the left ventricle? Also, how many patients developed complete heart block? It may be part of the operation to get complete heart block, as some of these patients have no aortic ring. Nevertheless, I would like to know how many required permanent pacemakers. In our experience with 6 such successful procedures, in order to avoid the problem of obstruction of a proximal left main coronary artery (one in which the ostium is very close to the aortic ring), we have sutured the composite graft and valve under the aortic annulus posteriorly, essentially on the mitral valve. We have opened the graft for a true end-to-side coronary-graft anastomosis performed from within on a free cuff of the left main ostium. I think this is a more secure anastomosis. It was also necessary in 1 patient who developed a fistula six months after the side-to-side anastomosis. In another 5 patients with ascending aortic dilatation of less than 6 cm in the presence of indications for aortic valve replacement, a simple Dacron wrap was

utilized outside the aorta following discontinuation of bypass. This alternative may be of use when the surgeon is hesitant to undertake the complete composite graft and valve operation, especially in the absence of dissection, Marfan’s syndrome, or true atherosclerotic aneurysms. A warning: in cases of dissection the right coronary artery occasionally is disrupted. When one looks from inside the aorta there appears to be an opening of the right coronary artery. But looking in the medial space, one can see a disrupted intimal continuity. In these patients saphenous vein graft should be used. Finally, this operation may be the only way to treat the subgroup of patients with dissection who arrive alive and in shock with a free tear in the ascending aorta. In all likelihood the plane of dissection is so superficial that the proximal aortic adventitia has no residual tensile strength.

To answer Dr. Anagnostopoulos’ questions: The 2 patients who did not have severe aortic incompetence had aortic stenosis. One developed late stenosis of a Starr-Edwards cloth-covered prosthetic valve and at the time of reoperation also had developed progressive aneurysmal dilatation of the ascending aorta. The other patient had calcific aortic stenosis associated with an acute dissection. We irrigate the pericardial cavity with 1to 2 liters of fluid during the procedure. Most of this fluid is not aspirated into the heart-lung circuit; rather, it is removed by means of a sump catheter. None of the patients in this group developed complete heart block; therefore, none required a permanent pacemaker. Dr. Anagnostopoulos’ technique for managing the left coronary ostium when it is adjacent to the aortic annulus should prove useful when this situation is encountered. DR. KOUCHOUKOS:

Replacement of the ascending aorta and aortic valve with a composite graft: results in 25 patients.

Redacement of the AsGending Aorta and Aortic Valve with a Composite Graft: Results in 25 Patients Nicholas T. Kouchoukos, M.D., Robert B. Karp, M.D.,...
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