Marfan syndrome: defective synthesis, secretion, and extracellular matrix formation of fibrillin by cultured dermal fibroblasts.

We studied the synthesis, secretion, and aggregation into the extracellular matrix of fibrillin by dermal fibroblasts from 26 probands with the Marfan syndrome. Cells from seven probands synthesized approximately half the normal amount of fibrillin when compared with intrafamilial or unrelated controls. Cells from an additional seven probands synthesized a normal amount of fibrillin but secreted the protein less efficiently than control cells. Cells from a further eight probands synthesized and secreted normal amounts of fibrillin but the protein was poorly incorporated into extracellular matrix. Cells from the remaining four probands were indistinguishable from control cells in their synthesis and processing of fibrillin. Cells from 18 family members of 10 of the probands were also studied. Cells from affected individuals in the same family had the same biochemical defect and those from unaffected family members were indistinguishable from controls. These results indicate that mutations in the gene that encodes fibrillin are responsible for the Marfan syndrome in the majority of individuals (confirming recent immunohistochemical and genetic linkage studies) and that a variety of mutations can produce the phenotype associated with the syndrome.

The St. Jude valve prosthesis: analysis of the clinical results in 815 implants and the need for systemic anticoagulation.

Between July 1979 and December 1984, 785 patients received 815 St. Jude Medical valve prostheses. Valve-related mortality in the follow-up period was due to thromboembolism in seven cases, anticoagulant-related hemorrhage in three and perivalvular leak in two. Freedom from valve-related death or reoperation at 3 years was 96.4% for aortic valve replacement and 98.3% for mitral valve replacement. The overall rate of thromboembolism was 2.6%/patient-year with warfarin, 9.2%/patient-year with antiplatelet medication and 15.6%/patient-year in patients with no anticoagulant therapy. One episode of thrombotic obstruction of a mitral valve, in a patient receiving no anticoagulant therapy, resulted in an occurrence rate of such obstruction of 0.22%/patient-year. Valve replacement with the St. Jude valve produced excellent clinical results, but long-term anticoagulation with warfarin was required to minimize thromboembolic complications. The use of antiplatelet agents alone provided inadequate protection.

Aortic valve replacement in the patient with extensive calcification of the ascending aorta (the porcelain aorta).

The best management for patients requiring cardiac procedures with superimposed severe intimal atheromatous disease or medial calcification of the ascending aorta and transverse arch has yet to be established. Clamping such an aorta can produce embolization, dissection, mural laceration, and hemorrhage. Successful surgical treatment of two patients with a porcelain aorta requiring aortic valve replacement is reported. Traditional aortic cross-clamping was avoided with femoral artery cannulation, profound hypothermia, and circulatory arrest.

Surgical treatment of aneurysms of the intrathoracic segment of the subclavian artery.

From June 1969 to May 1986, 16 patients underwent 17 operations to treat 18 aneurysms of the intrathoracic segment of the subclavian artery. Surgical treatment in 12 cases involved Dacron tube graft replacement; in the remainder, patch graft angioplasty or exclusion with and without extra-anatomic revascularization were utilized. Twelve patients required simultaneous graft replacement of aortic aneurysms. Five procedures were performed through a median sternotomy and 12 through a left posterior lateral thoracotomy. Deep hypothermia and circulatory arrest was used on three occasions. All but one patient were early survivors, and there were no related cerebrovascular accidents. There were five late deaths unrelated to operative treatment. Surgical treatment of aneurysms of the intrathoracic segment of the subclavian artery is both well tolerated and durable.

Treatment of aneurysms of the aortic arch. A progress report.

Graft replacement therapy was employed in the treatment of 67 patients with aneurysms of the transverse aortic arch. Patients were divided into three groups according to the extent of the aneurysm, which determined method of treatment and results. Group I consisted of 37 patients with distal aneurysms treated by simple proximal and distal clamping and aortic reconstruction, with survival in 36. Similarly located lesions in three patients in Group II, in whom the aorta could not be clamped proximally, were treated by hypothermia and circulatory arrest without graft inclusion technique, with survival in one. In Group III, the 27 patients, three with recurrent lesions and 19 with extensive aneurysms including the entire aorta in four, were treated by hypothermia, brachiocephalic arterial clamping, graft inclusion, and direct brachiocephalic vessel reattachment. The distal aneurysmal disease was replaced in most cases by a staged operation including total aortic replacement in two patients. Of the 27 patients in this group, 26 survived both the arch and subsequent operations.

Successful treatment of primary aorta-esophageal fistula resulting from aortic aneurysm.

Most aneurysms of the descending thoracic aorta rupture unless treated surgically. Autopsy studies in these patients indicate that rupture occurs into the esophagus in 10% of the cases and constitutes the most common cause of aorta-esophageal fistula. A reasonable literature review has not revealed a previously successful treatment for this condition. Experience in the treatment of patients with aneurysms of the descending thoracic aorta partially obstructing the esophagus without fistula formation indicates that simple graft replacement is curative. When the disease has progressed to actual fistula formation and esophageal bleeding, as illustrated in these two case reports, operation is done to prevent exsanguination. Appropriate management involves control of hemorrhage and treatment of the chronic esophageal perforation. The former is accomplished by resection and graft replacement of the ruptured thoracic aneurysm. Alternatives in dealing with the chronic esophageal defect are planned, staged reconstruction in high-risk patients and immediate resection and intrathoracic esophagogastrostomy in selected patients.

Partial cardiopulmonary bypass, hypothermic circulatory arrest, and posterolateral exposure for thoracic aortic aneurysm operation.

Partial cardiopulmonary bypass, profound hypothermia, and circulatory arrest were used in the treatment of 25 patients with thoracic aortic aneurysms exposed through left posterolateral incisions. Indications included aortic clamp laceration (4 patients), pulmonary artery tear (1), treatment of ruptured aneurysm without clamping (5), right-sided arch (2), exposure of proximal aorta in a patient with a large aneurysm (1), inability to expose the proximal aorta for clamping (3), to permit removal of both arch and distal aorta (4), and to avoid distal arch clamping because of atheromatous disease (5). Aortic segments ranging from the upper descending thoracic aorta to most of the aorta were replaced, with early survival in 21 patients. Cerebral protection was satisfactory.

Treatment of aneurysm of transverse aortic arch.

Although aneurysms involving the aortic arch are usually well localized and amenable to reconstructive operation, the reported results of this form of therapy at this level are not as good as in other portions of the aorta. The difference is due to cerebral and bleeding disturbances associated with cerebral protection techniques. This report describes 30 patients and emphasizes the variability of extent of these lesions and the results of methods employed for cerebral protection, which varied according to extent of disease. The aneurysm involved all but the proximal ascending aorta in one patient and was replaced with a permanent ascending aorta-innominate and left common carotid artery bypass graft. Eight aneurysms were limited to the transverse arch; one was removed with the aid of temporary bypass and seven with cardiopulmonary bypass and separate brachiocephalic normothermic perfusion. Temporary and permanent bypass grafts were used in four patients with lesser involvement. None of these techniques was used in 17 patients who had distal arch involvement. Of the 30 patients, 26 survived and 18 are still alive despite the treatment being spread over a 22 year period. Cerebral complications occurred in 3 patients, two of whom died. These problems were avoided in five patients treated more recently by using lows flows under low pressures. Coagulopathies did not occur. Although the technique of cardiopulmonary bypass, profound hypothermia, and circulatory arrest provides a more convenient and technically simpler method of operation, the disadvantages of coagulopathies with excessive bleeding, pulmonary problems, and lack of consistent cerebral protection argue against its routine use at this time.

Surgical treatment of aneurysm and/or dissection of the ascending aorta, transverse aortic arch, and ascending aorta and transverse aortic arch. Factors influencing survival in 717 patients.

Ascending aorta and/or aortic arch reconstruction by composite valve graft (281, 39%), separate valve graft (117, 16%), graft only (256, 36%), and other procedures (63, 9%) was used for aneurysm or dissection caused by trauma (6), infection (20), aortitis (46), dissection (261: acute 72, chronic 189), and medial degeneration (384) in 717 patients during the 9-year period between Jan. 11, 1980, and Jan. 16, 1989. Of these, 150 had 173 previous heart or aortic operations and needed reoperation for progression or recurrence of aneurysm, rupture, valvular insufficiency, aortocutaneous or aorta-heart chamber fistulas, great vein or airway obstruction, and infection. Concurrent distal aneurysmal disease was present or developed in 267 (37%) patients, being most prevalent in patients with arch involvement (211/395, 53%). These patients were treated either simultaneously or later. The ages ranged from 10 to 88 years, median 61. Aneurysm symptoms were mild or absent in 593 (83%) and severe in 124 (17%). The 30-day survival rate was 91%. The independent determinants predictive of 30-day death were increasing age, severe aneurysm symptoms, diabetes, previous proximal aortic operation, need for cardiac support, postoperative tracheostomy, postoperative heart dysfunction, and stroke. Of the 319 patients who had none of the four preoperative factors, 308 (97%) survived. Survival decreased to 74% in those with two or more factors. After a total of 1193 operations, the entire aorta was replaced in 53, near total in 35, total thoracic replacement in 78, and total aorta except arch in 27. Late survival rates (Kaplan-Meier) were 66% and 57% at 5 and 7 years. Independent predictors of death were severe aneurysm symptoms, preoperative angina, extent of proximal replacement, associated residual distal aneurysm, balloon pump, renal dysfunction, cardiac dysfunction, and stroke. Five-year survival rates varied with the incidence of the four preoperative variables and age in a single patient: 78% in 413 patients with up to one variables, 57% in 193 patients with two or three, and 39% in 111 patients with three or four (p less than 0.0001).

Continuous monitoring of mixed venous oxygen saturation during aortic surgery.

The correlation between mixed venous oxygen saturation (SvO2) and hemodynamic measurements was studied in 13 patients undergoing descending thoracic aortic aneurysm resection (DTAAR). A significant correlation (p less than 0.05) was found between cardiac index (CI) and SvO2 after the induction of anesthesia and at the end of surgery. However, no significant correlation could be found between SvO2 and CI during the most critical periods of the surgery that included the collapse of the left lung, the aortic clamping, and the aortic declamping. During DTAAR, continuous SvO2 monitoring is useful, but it cannot substitute for intermittent cardiac output and oxygen consumption (VO2) determinations.

The impact of distal aortic perfusion and somatosensory evoked potential monitoring on prevention of paraplegia after aortic aneurysm operation.

Temporary distal aortic perfusion and somatosensory evoked potential monitoring were attempted prospectively in 198 patients to prevent neurologic complications from occurring after operation for descending thoracic and thoracoabdominal aortic aneurysm. These 198 patients were divided into two groups. Group 1 consisted of 99 (50%) patients in whom adequate (60 mm Hg) distal bypass was achieved and combined with somatosensory evoked potential monitoring. Group 2 consisted of 99 (50%) in whom this could not be achieved. Of the latter, four patients were excluded because of operative death in one and preexisting neurologic deficits in three. The rates of early and delayed neurologic complications were 8% and 12%, respectively, in the former and 7% and 8%, respectively, in the latter. Using the logistic regression method of statistical analysis, adjusting for the difference in patient mix, we found no statistical difference in the incidence of neurologic complications in the two groups. The incidence of false negative somatosensory evoked potential response was 13% and false positive response 67%. Localization of critical spinal arteries for reattachment was not possible. Thus, the method had no significant impact upon the prevention of neurologic deficits, which varied from mild or transient to severe and which either occurred during the operation or were delayed from 12 hours to 21 days.

Surgery for acute dissection of ascending aorta. Should the arch be included?

Thirty-day and 1-, 5-, 10-, and 20-year overall survivorships among 82 patients undergoing replacement of the ascending aorta with or without the arch for acute aortic dissection between 1968 and May 1989 were 79%, 66%, 56%, 46%, and 30%, respectively. The multivariably determined risk factors for death were the inclusion of the arch in the replacement, the year of the operation, the predissection New York Heart Association functional class, diabetes, and concomitant coronary artery bypass grafting. The current 30-day survivorship predicted by the multivariable equation when the operation involves only the ascending aorta is 97%, and the 10- and 20-year predicted survivorships are 61% and 39%, respectively. When the current era the replacement involves the arch as well as the ascending aorta, the predicted 30-day survivorship is 84%, and the 10- and 20-year ones are 48% and 31%. In 1990 sixteen additional patients (one hospital death) underwent ascending aortic replacement, and six (no hospital deaths) ascending aorta and arch replacement. The predictions for 1990 from the multivariable equation were similar to these actual experiences (Ps for differences were 0.6 and 0.4). Seventy percent of surviving patients with DeBakey type I dissection were free of a second aortic operation for aneurysmal dilation of the distal false channel, but this occurred in none of nine patients in whom an intimal tear in the transverse arch was included in the resection.

Deep hypothermia with circulatory arrest. Determinants of stroke and early mortality in 656 patients.

We have retrospectively evaluated our results after aortic surgery in adults using deep hypothermia with circulatory arrest to determine the patient predictors of early death and postoperative stroke by logistic regression analysis. Of the 656 patients operated on between July 7, 1979, and January 30, 1991, 43% (n = 283) were female, the median age of the patients was 64 years (range 10 to 88 years), 12% (n = 77) had acute dissection, 26% (n = 173) had previously undergone either cardiac or ascending aortic operations, and 13% (n = 85) had a history of cerebrovascular disease. Eighty-four patients underwent elephant trunk procedures. The median circulatory arrest time was 31 minutes (range 7 to 120 minutes). The univariable predictors of transient or permanent stroke, defined as clinical evidence of neurologic injury, either global or hemiparetic, which occurred in 44 patients (7%), were as follows (p < 0.05): increased age; a history of cerebrovascular disease; circulatory arrest time (7 to 29 minutes = 12/298 [4%], 30 to 44 minutes = 15/201 [7.5%], 45 to 59 minutes 9/84 [10.7%], 60 to 120 minutes 7/48 [14.6%]; cardiopulmonary bypass time; and concurrent descending thoracic aorta repair. The multivariably determined predictors were as follows (p < 0.05): a history of cerebrovascular disease; previous aortic surgery distal to the left subclavian artery; and cardiopulmonary bypass time. A history of aortic valve incompetence, however, was associated with a lower risk of stroke (adjusted odds ratio 0.42, p = 0.015). The multivariably determined predictors for increased risk of early death (p < 0.05), which occurred in 66 (10%) patients, were as follows: increased age; Marfan syndrome; concurrent distal aortic aneurysm; previous ascending aortic operation; cardiopulmonary bypass time; cardiac complications; renal complications; and stroke. In this study, the occurrence of stroke was observed to increase after 40 minutes of circulatory arrest; furthermore, the mortality rate increased markedly after 65 minutes of circulatory arrest. Thus the "safe" period for strokes not developing appeared to be limited to approximately 40 minutes. We conclude that deep hypothermia with circulatory arrest is a safe technique for the repair of complex aortic problems provided both the circulatory arrest and the cardiopulmonary bypass times are not excessive. In addition, the clinical characteristics of the patients are important determinants of stroke and death.

"Redo" surgery after operations for aneurysm and occlusion of the abdominal aorta.

During a 20 year period, 1,287 patients were submitted to arterial reconstruction for aneurysm and occlusion of the aorta and iliac arteries. Good results were obtained in 1,230 (95.6 percent). Of these, 83 (6.4 percent) returned for reoperation. Reoperation was performed also in 18 patients operated upon elsewhere. Thus this series of cases of reoperation consists of 101 patients. The most common cause for reoperation and interval after initial procedure were recurrent obstruction--44 to 90 months, false aneurysm--94 months, and infection--25 months. The most common complication in patients treated initially for aneurysm was false aneurysm and recurrent obstruction in the patients treated for aortoiliac artery occlusion. Infection was rare and occurred in both groups. False aneurysm was due to fragmentation of suture in most cases and recurrent obstruction was related to progression of the disease, the type of original procedure employed, and technical factors. Although various methods of treatment were employed, the preferred are (1) aneurysm replacement for false aneurysm, (2) bilateral aortofemoral or aortapopliteal bypass for recurrent obstruction with profundaplasty when necessary, and (3) bilateral axillofemoral or axillopopliteal bypass and graft removal for infection. The results of reoperation were considered to be satifactory with survival in 89 (88 percent) and good functional results in 84 (94 percent) of survivors. Amputation was necessary in only five (6 percent) patients.

Carotid and noncoronary operations: simultaneous, staged, and delayed.

Carotid operation has been shown to be effective in the control of stroke in patients with asymptomatic bruits and transient ischemic attacks (TIAs). This procedure also has been demonstrated to be effective in the control of this disorder when performed simultaneously with coronary artery bypass operations. Similar studies have been reported in patients submitted to other operations. This is a study of 130 patients who had first carotid artery operation and then 215 noncoronary operations. Simultaneous operation was performed in 42, staged in 40, and both in eight patients. In addition, 40 patients were submitted to operation over 3 months after carotid operations. TIAs and one stroke occurred after carotid operation but no deaths. The cumulative results were eight TIAs and three strokes. Only one patient died of stroke. Results were similar in all groups, and therefore it is thought that carotid operation reduces the incidence of stroke following these operations and that simultaneous procedures are feasible in the majority of cases on a selective basis. Moreover, carotid operation seems to protect patients from stroke after operation performed months later.

Occlusion of the innominate, common carotid, and subclavian arteries: long-term results of surgical treatment.

During the 23-year period from January 1959 to February 1982, 142 patients (78 men and 64 women) underwent arterial reconstructive operations for obstruction of the brachiocephalic arteries. A single vessel was involved in 75% and multiple vessels were involved in 25% of the cases. Distal involvement of internal carotid and vertebral arteries was present in 58 (41%) patients. Transthoracic operation was performed in 43 (31%) and extrathoracic operation was performed in 99 (69%) patients. One hundred and thirty-nine patients (98%) survived, and 134 (94%) experienced relief of symptoms. Follow-up was obtained for 136 patients for periods up to 22 years (mean of 7.5 years). Of these, 113 patients remained asymptomatic, eight developed transient strokes, four developed persistent strokes, and 11 (8%) died of stroke. The mean interval after operation in the latter cases was 9.3 years. Survival rates at 5, 10, and 15 years were 85%, 58%, and 25%, respectively.

Celiac axis, superior mesenteric artery, and inferior mesenteric artery occlusion: surgical considerations.

Occlusion of the celiac, superior mesenteric, and inferior mesenteric artery has been studied in 46 patients treated by operation. The condition was acute and was caused by embolic obstruction of the superior mesenteric artery in four cardiac patients and detachment of the inferior mesenteric artery in two patients during removal of infrarenal abdominal aortic aneurysms. The condition was chronic and involved two or all three of the vessels in 40 patient. Embolic obstruction caused severe abdominal pain but few physical signs early in the process,, but the picture of an acute abdomen indicating bowel gangrene developed in a few hours. Ischemia from inferior mesenteric detachment was observed at operation. Patients with chronic obstruction had abdominal pain, weight loss, and diarrhea. Patients with embolic obstruction were treated successfully by embolectomy, and patients developing intraoperative sigmoid ischemia were treated by reattachment of inferior mesenteric arteries to aortic graft. Various procedures were employed in patients with chronic multiple obstruction. However, graft bypass using Dacron tubing was preferable because of its simplicity and because the frequently (48%) associated occlusive disease and aneurysm of the distal aorta were treated at the same time. Confining operation to the abdomen significantly reduced the magnitude of operation and eliminated risks in this age group. Of the 46 patients, 91% survived and were relieved of their symptoms despite associated disease. The 5-year survival rate in this group of patients was 62%.

Aortoiliac occlusive disease: factors influencing survival and function following reconstructive operation over a twenty-five-year period.

During a period of slightly over 25 years, 949 new patients with aortoiliac atherosclerotic occlusive disease--409 (43%) with associated distal disease--were submitted to various reconstructive operations for claudication in 719 and rest ischemic problems in 230 patients. The ages ranged from 21 to 91 years with a medial age of 59. Men outnumbered women 2.5 to 1. Associated diseases were present in 695 (75%); heart disease and diabetes were most common. The mortality rate from operation--50% of which was from heart disease--8% in first 5 years and 3% during the last 15 years. Good function, i.e., restoration of femoral pulses, leg salvage, and relief of symptoms, was achieved in 95% of cases early after treatment. Early results were best in patients with claudication and those without associated distal disease. The long-term survival rates were significant--50%, 30%, and 15% at 10, 15, and 20 years, respectively--and successful function was maintained in survivors in 79%, 70%, and 56% at the same intervals. Amputation was performed in only 23 (3%) patients with claudication and 33 (14%) with rest ischemia during the period of study. Survival, functional results, and incidence of amputation varied with the numerous factors described in detail herein.

Graft replacement of aneurysm in descending thoracic aorta: results without bypass or shunting.

During the 24-year period from 1956 to 1980, 148 patients with aneurysms confined to the thoracic aortic segment, bounded above by the left subclavian artery and below the diaphragm, were treated with replacement therapy. From 1956 to 1967, 36 patients were treated by use of temporary bypass or shunts which carried a 6% incidence of paraplegia and a mortality rate of 22%. From 1962 to 1980, 112 patients were treated without shunts or bypass; this report is concerned with the latter cases. The incidence of paraplegia and the survival rate in this group were 0.9% and 91%, respectively. There were 89 men and 25 women in the series whose ages ranged from 22 to 87 years with an average age of 61. All types of aneurysms were represented; however, arteriosclerosis and dissection were the most common causes. The extent of aneurysm was variable, but most of the descending thoracic aorta was involved in more than half the cases. Associated diseases were present in 77% of cases. Operation consisted of aneurysmal replacement using inclusion technique with cardiac hemodynamics controlled by vasodilators and fluid replacement. During the past 4 years, proximal blood pressure has been controlled with nitroprusside. Cardiovascular hemodynamics, blood gases, electrolytes, and plasma osmolarity were monitored extensively and frequently to achieve the most desirable physiologic response to aortic clamping and operation. During this time 69 patients were treated. There were four (6%) deaths. None developed paraplegia or renal failure. Concomitant subclavian artery clamping was employed in 34 of these patients and in 22 additional patients with distal arch lesions. None in either group developed paraplegia. This indicated the safety of temporary subclavian artery occlusion. Death, both early and late, was due to a number of causes, but rupture of another aneurysm was the most common. This emphasizes the value of concomitant operation in patients with multiple aneurysms and careful follow-up in all patients.

Improved results of operation for ruptured abdominal aortic aneurysms.

Of 1,393 consecutive patients operated on for aneurysm of the abdominal aorta between 1964 and 1978, 61 consecutive patients had undergone emergency operation for ruptured abdominal aortic aneurysm, for an incidence of 4.4% (61 of 1,393). There were 57 men and four women; their mean age was 77.5 years, with a range of 49 to 93 years. In 21 patients the diagnosis of aneurysm had been known from 1 day to 5 years prior to rupture. Hypotension (less than 100 mm Hg systolic) was present in 27.9% of patients (17 of 61) on admission to hospital and prior to operation in a total of 44.3% patients (27 of 61). Operation was begun in eight patients with an initially unrecordable blood pressure. The perioperative mortality rate (30 day) was 14.8% (nine of 61). The two factors most influencing survival were age [no patient younger than 60 years died vs. 40% of patients (four of 10) older than 80 years] and the magnitude of blood loss (survivors lost a total of 4,513 ml vs. 8,500 ml in those who died). Thus the most common cause of death was myocardial infarction (six of eight) in elderly patients, secondary to poorly tolerated severe hypovolemia. The results of this study suggest the need for avoidance of technical problems during operations, earlier referral of patients with known abdominal aortic aneurysms, especially the elderly, and early diagnosis with immediate operation for ruptured aneurysms.