Duke E. Cameron

A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2

We report heterozygous mutations in the genes encoding either type I or type II transforming growth factor β receptor in ten families with a newly described human phenotype that includes widespread perturbations in cardiovascular, craniofacial, neurocognitive and skeletal development. Despite evidence that receptors derived from selected mutated alleles cannot support TGFβ signal propagation, cells derived from individuals heterozygous with respect to these mutations did not show altered kinetics of the acute phase response to administered ligand. Furthermore, tissues derived from affected individuals showed increased expression of both collagen and connective tissue growth factor, as well as nuclear enrichment of phosphorylated Smad2, indicative of increased TGFβ signaling. These data definitively implicate perturbation of TGFβ signaling in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease and mental retardation, and suggest that comprehensive mechanistic insight will require consideration of both primary and compensatory events.

Replacement of the Aortic Root in Patients with Marfan's Syndrome

BACKGROUND Replacement of the aortic root with a prosthetic graft and valve in patients with Marfans syndrome may prevent premature death from rupture of an aneurysm or aortic dissection. We reviewed the results of this surgical procedure at 10 experienced surgical centers. METHODS A total of 675 patients with Marfans syndrome underwent replacement of the aortic root. Survival and morbidity-free survival curves were calculated, and risk factors were determined from a multivariable regression analysis. RESULTS The 30-day mortality rate was 1.5 percent among the 455 patients who underwent elective repair, 2.6 percent among the 117 patients who underwent urgent repair (within 7 days after a surgical consultation), and 11.7 percent among the 103 patients who underwent emergency repair (within 24 hours after a surgical consultation). Of the 675 patients, 202 (30 percent) had aortic dissection involving the ascending aorta. Forty-six percent of the 158 adult patients with aortic dissection and a documented aortic diameter had an aneurysm with a diameter of 6.5 cm or less. There were 114 late deaths (more than 30 days after surgery); dissection or rupture of the residual aorta (22 patients) and arrhythmia (21 patients) were the principal causes of late death. The risk of death was greatest within the first 60 days after surgery, then rapidly decreased to a constant level by the end of the first year. CONCLUSIONS Elective aortic-root replacement has a low operative mortality. In contrast, emergency repair, usually for acute aortic dissection, is associated with a much higher early mortality. Because nearly half the adult patients with aortic dissection had an aortic-root diameter of 6.5 cm or less at the time of operation, it may be prudent to undertake prophylactic repair of aortic aneurysms in patients with Marfans syndrome when the diameter of the aorta is well below that size.

Predictors of stroke risk in coronary artery bypass patients

BACKGROUND Stroke occurs after coronary artery bypass grafting with an incidence ranging between 0.8% and 5.2%. To identify factors associated with stroke, we prospectively examined a study cohort and tested findings in an independent validation sample. METHODS The study cohort comprised 456 patients undergoing coronary artery bypass grafting only, and the validation sample comprised 1,298 patients. Stroke was detected postoperatively by the study team and confirmed by neurologic consultation and computed tomographic scanning. RESULTS Five factors taken together were correlated with stroke: previous stroke, presence of carotid bruit, history of hypertension, increasing age, and history of diabetes mellitus. The only significant intraoperative factor was cardiopulmonary bypass time. Probabilities were calculated, and patients were placed into low, medium, and high stroke-risk groups. In the validation sample, this model was able to rank the majority of patients with stroke into the high-risk group. CONCLUSIONS These five factors taken together can identify the risk of stroke in patients having coronary artery bypass grafting. Recognition of the high-risk group will aid studies on the mechanism and prevention of stroke by modification of surgical procedures or pharmacologic intervention.

Cognitive Outcome After Coronary Artery Bypass: A One-Year Prospective Study

BACKGROUND Cognitive deficits have been reported in patients after coronary artery bypass grafting, but the incidence of these deficits varies widely. We studied prospectively the incidence of cognitive change and whether the changes persisted over time. METHODS Cognitive testing was done preoperatively and 1 month and 1 year postoperatively in 127 patients undergoing coronary artery bypass grafting. Tests were grouped into eight cognitive domains. A change of 0.5 standard deviation or more at 1 month and 1 year from patients preoperative Z score was the outcome measure. RESULTS We identified four main outcomes for each cognitive domain: no decline; decline and improvement; persistent decline; and late decline. Only 12% of patients showed no decline across all domains tested; 82% to 90% of patients had no decline in visual memory, psychomotor speed, motor speed, and executive function; 21% and 26% had decline and improvement in verbal memory and language; approximately 10% had persistent decline in the domains of verbal memory, visual memory, attention, and visuoconstruction; and 24% had late decline (between 1 month and 1 year) in visuoconstruction. CONCLUSIONS This study establishes that the incidence of cognitive decline varies according to the cognitive domain studied and that some patients have persistent and late cognitive changes in specific domains after coronary artery bypass grafting.

Surgical treatment of aneurysms of the ascending aorta in the Marfan syndrome. Results of composite-graft repair in 50 patients

The life expectancy of patients with the Marfan syndrome is reduced by complications caused by dilatation of the ascending aorta. Because surgical therapy with a composite graft may alter this natural history, we analyzed the preoperative and long-term postoperative status of 50 consecutive patients who received such a graft. At surgery, the patients had a mean age of 32.2 years and a mean aortic diameter of 7.1 cm (range, 5.3 to 10). Dissection of the ascending aorta was present in 14 patients and was acute in 5. None of the 44 patients who underwent elective repair, and only one of the six patients who had emergency surgery, died in the hospital; thus, the overall hospital mortality was 2 percent. Five of the 49 survivors died during a follow-up period of up to eight years (10.2 percent late mortality). During the most recent four years of evaluation of this series (38 patients), no postoperative deaths due to intrathoracic problems occurred. Actuarial survival was 87 percent at both two and five years. Composite-graft repair of the ascending aorta in patients with the Marfan syndrome can be performed with low operative and long-term mortality. Because of the unfavorable natural history of the Marfan syndrome and the potential for dissection in moderately dilated aortic roots, we recommend prophylactic repair when the aneurysm reaches a diameter of 6 cm.

Aortic root replacement. Risk factor analysis of a seventeen-year experience with 270 patients.

Between September 1976 and September 1993, 270 patients underwent aortic root replacement at our institution. Two hundred fifty-two patients underwent a Bentall composite graft repair and 18 patients received a cryopreserved homograft aortic root. One hundred eighty-seven patients had a Marfan aneurysm of the ascending aorta (41 with dissection) and 53 patients had an aneurysm resulting from nonspecific medial degeneration (17 with dissection). These 240 patients were considered to have annuloaortic ectasia. Thirty patients were operated on for miscellaneous lesions of the aortic root. Thirty-day mortality for the overall series of 270 patients was 4.8% (13/270). There was no 30-day mortality among 182 patients undergoing elective root replacement for annuloaortic ectasia without dissection. Thirty-six of the 270 patients having root replacement also had mitral valve operations. There was no hospital mortality for aortic root replacement in these 36 patients, but there were seven late deaths. Twenty-two patients received a cryopreserved homograft aortic root; 18 of these were primary root replacements and four were repeat root replacements for late endocarditis. One early death and two late deaths occurred in this group. Actuarial survival for the overall group of 270 patients was 73% at 10 years. In a multivariate analysis, only poor New Year Heart Association class (III and IV), non-Marfan status, preoperative dissection, and male gender emerged as significant predictors of early or late death. Endocarditis was the most common late complication (14 of 256 hospital survivors) and was optimally treated by root replacement with a cryopreserved aortic homograft. Late problems with the part of the aorta not operated on occur with moderate frequency; careful follow-up of the distal aorta is critical to long-term survival.

Valve replacement in patients with endocarditis and acute neurologic deficit

BACKGROUND Acute neurologic deficits occur in up to 40% of patients with left heart endocarditis. Appropriate evaluation and management of patients with acute neurologic dysfunction who require valve operations for endocarditis remain controversial. This retrospective review was undertaken to develop recommendations for the evaluation and treatment of these challenging patients. METHODS From 1983 to 1995, 247 patients underwent operations for left heart native valve endocarditis at the Johns Hopkins Hospital. From a review of medical and pathology records, 34 patients (14%) with preoperative neurologic deficits were identified. Data on these 34 patients were recorded and analyzed. RESULTS Causes of neurologic dysfunction included embolic cerebrovascular accident (n = 23, 68%), embolic cerebrovascular accident with hemorrhage (n = 4, 12%), ruptured mycotic aneurysm (n = 3, 9%), transient ischemic attack (n = 2, 6%), and meningitis (n = 2, 6%). Preoperative diagnostic studies included computed tomography (32 patients), magnetic resonance imaging (11 patients), cerebral angiogram (14 patients), and lumbar puncture (2 patients). Computed tomography demonstrated structural lesions in 29 of 32 patients; in only 1 patient did magnetic resonance imaging reveal a lesion not already seen on computed tomography. Of 14 patients having cerebral angiograms, 7 had a mycotic aneurysm. Three mycotic aneurysms had ruptured, and these were clipped before cardiac operations. The mean interval from onset of neurologic deficit to cardiac operation was 22.2 +/- 2.8 days for all patients and 22.1 +/- 3.0 days for those with embolic cerebrovascular accident. The hospital mortality rate was 6%. New or worse neurologic deficits occurred in 2 patients (6%). CONCLUSIONS Neurologic deficits are common in patients with endocarditis referred for cardiac operations. Despite substantial preoperative morbidity, most of these patients do well if the operation can be delayed for 2 to 3 weeks. Computed tomography scan is the preoperative imaging technique of choice, as routine magnetic resonance imaging and cerebral angiogram are unrewarding. Cerebral angiogram is indicated only if computed tomography reveals hemorrhage.

Aortic Root Replacement in 372 Marfan Patients: Evolution of Operative Repair Over 30 Years

BACKGROUND We reviewed the evolution of practice and late results of aortic root replacement (ARR) in Marfan syndrome patients at our institution. METHODS A retrospective clinical review of Marfan patients undergoing ARR at our institution was performed. Follow-up data were obtained from hospital and office records and from telephone contact with patients or their physicians. RESULTS Between September 1976 and September 2006, 372 Marfan syndrome patients underwent ARR: 269 had a Bentall composite graft, 85 had valve-sparing ARR, 16 had ARR with homografts, and 2 had ARR with porcine xenografts. In the first 24 years of the study, 85% received a Bentall graft; during the last 8 years, 61% had a valve-sparing procedure. There was no operative or hospital mortality among the 327 patients who underwent elective repair; there were 2 deaths among the 45 patients (4.4%) who underwent emergent or urgent operative repair. There were 74 late deaths (70 Bentalls, 2 homograft, and 2 valve-sparing ARRs). The most frequent causes of late death were dissection or rupture of the residual aorta (10 of 74) and arrhythmia (9 of 74). Of the 85 patients who had a valve-sparing procedure, 40 had a David II remodeling operation; there was 1 late death in this group, and 5 patients required late aortic valve replacement for aortic insufficiency. A David I reimplantation procedure using the De Paulis Valsalva graft has been used exclusively since May 2002. All 44 patients in this last group have 0 to 1+ aortic insufficiency. CONCLUSIONS Prophylactic surgical replacement of the ascending aorta in patients with Marfan syndrome has low operative risk and can prevent aortic catastrophe in most patients. Valve-sparing procedures, particularly using the reimplantation technique with the Valsalva graft, show promise but have not yet proven as durable as the Bentall.

Composite graft repair of Marfan aneurysm of the ascending aorta: Results in 100 patients

One hundred consecutive patients with the Marfan syndrome underwent composite graft repair of an ascending aortic aneurysm between September 1976 and June 1989. Twenty-two patients had ascending aortic dissection at the time of composite graft repair; 18 patients also had a mitral valve procedure. There were no hospital deaths among 92 patients undergoing elective repair. One of 8 patients undergoing emergency repair of a ruptured aneurysm died in the operating room. The overall hospital mortality rate was 1%. There have been ten late deaths among the 99 hospital survivors (10.1%). Five deaths occurred among the first 11 patients in this series and five occurred among the last 88 patients (5.7%). Three late deaths resulted from composite graft endocarditis; 3 other patients with endocarditis are alive after aortic root replacement with cryopreserved homografts. Late coronary dehiscence caused death in 1 patient and was successfully repaired in a second. Actuarial survival for the 100 patients was 92.6% at 5 years and 75.8% at 10 years. Currently, composite graft repair of Marfan aneurysms of the ascending aorta can be performed with low hospital and late mortality. Marfan aneurysms with a diameter of 6 cm or greater should be repaired with the Bentall composite graft procedure, even if the patient is asymptomatic.

Long-term results of flap reconstruction in median sternotomy wound infections.

Reconstruction of infected median sternotomy wounds using muscle and omental flaps has been shown to result in significantly reduced morbidity, mortality, and length of hospital stay. Despite these benefits, very little is known about the potential long-term sequelae of such procedures. The purpose of this study was therefore to evaluate the ultimate functional outcome in such patients. One-hundred and thirty-three consecutive patients underwent debridement and flap reconstruction of their infected median sternotomy wounds over an 8-year period. Eighty patients were available for follow-up and responded to a questionnaire. Forty-eight patients consented to a physical examination. The length of follow-up ranged from 15 to 108 months (average 48 months). Healed wounds were obtained in 99 percent of patients. Fifty-one percent of patients noted persistent pain or discomfort, particularly in the chest and shoulder. Forty-four percent noted areas of numbness/paresthesias, mainly on the chest. Thirty-four patients (42.5 percent) noted symptoms of sternal instability; of those consenting to an examination, 45 percent were confirmed to have instability. Twenty-six patients (32.5 percent) claimed postoperative weakness (shoulder/abdomen). Significant shoulder weakness was not demonstrated; however, abdominal weakness was substantial. Thirty-six percent of patients reported an inability to perform the same preoperative activities that were of importance to them (sports, housework, etc.). Of those patients eligible to return to work, 52 percent did not. Patients younger than age 60 had a somewhat higher chance of not returning to work. Scars were noted to be good to excellent in 75 percent, but contour abnormalities of the chest and abdomen were found in 85 percent. Abdominal-wall pathology (hernias/bulges) was present in 31 percent of patients, including 10 of 19 patients having rectus abdominis flaps, 2 of 3 patients having omental flaps, and 3 of 41 patients having isolated pectoralis major flaps. Shoulder range of motion was not noticeably affected by operation. Despite the proven advantages of flap reconstruction in mediastinitis, these procedures are not without long-term sequelae. Possible methods of preventing these problems are discussed. (Plast. Reconstr. Surg. 93: 1208, 1994.)