John A. Elefteriades

Yearly rupture or dissection rates for thoracic aortic aneurysms: simple prediction based on size

BACKGROUND Prior work has clarified the cumulative, lifetime risk of rupture or dissection based on the size of thoracic aneurysms. Ability to estimate simply the yearly rate of rupture or dissection would greatly enhance clinical decision making for specific patients. Calculation of such a rate requires robust data. METHODS Data on 721 patients (446 male, 275 female; median age, 65.8 years; range, 8 to 95 years) with thoracic aortic disease was prospectively entered into a computerized database over 9 years. Three thousand one hundred fifteen imaging studies were available on these patients. Five hundred seventy met inclusion criteria in terms of length of follow-up and form the basis for the survival analysis. Three hundred four patients were dissection-free at presentation; their natural history was followed for rupture, dissection, and death. Patients were excluded from analysis once operation occurred. RESULTS Five-year survival in patients not operated on was 54% at 5 years. Ninety-two hard end points were realized in serial follow-up, including 55 deaths, 13 ruptures, and 24 dissections. Aortic size was a very strong predictor of rupture, dissection, and mortality. For aneurysms greater than 6 cm in diameter, rupture occurred at 3.7% per year, rupture or dissection at 6.9% per year, death at 11.8%, and death, rupture, or dissection at 15.6% per year. At size greater than 6.0 cm, the odds ratio for rupture was increased 27-fold (p = 0.0023). The aorta grew at a mean of 0.10 cm per year. Elective, preemptive surgical repair restored life expectancy to normal. CONCLUSIONS This study indicates that (1) thoracic aneurysm is a lethal disease; (2) aneurysm size has a profound impact on rupture, dissection, and death; (3) for counseling purposes, the patient with an aneurysm exceeding 6 cm can expect a yearly rate of rupture or dissection of at least 6.9% and a death rate of 11.8%; and (4) elective surgical repair restores survival to near normal. This analysis strongly supports careful radiologic follow-up and elective, preemptive surgical intervention for the otherwise lethal condition of large thoracic aortic aneurysm.

Natural history of thoracic aortic aneurysms: indications for surgery, and surgical versus nonsurgical risks

BACKGROUND The natural history of thoracic aortic aneurysm is incompletely understood. Over the last 10 years, at Yale University we have maintained a large computerized database of patients with thoracic aortic aneurysms and dissections. Analysis of this database has permitted insight into fundamental issues of natural behavior of the aorta and development of criteria for surgical intervention. METHODS Specialized statistical methods were applied to the prospectively accumulated database of 1600 patients with thoracic aneurysm and dissection, which includes 3000 serial imaging studies and 3000 patient years of follow-up. RESULTS Growth rate: the aneurysmal thoracic aorta grows at an average rate of 0.10 cm per year (0.07 for ascending and 0.19 for descending). Critical sizes: hinge points for natural complications of aortic aneurysm (rupture or dissection) were found at 6.0 cm for the ascending aorta and 7.0 cm for the descending. By the time a patient achieved these critical dimensions the likelihood of rupture or dissection was 31% for the ascending and 43% for the descending aorta. Yearly event rates: a patient with an aorta that has reached 6 cm maximal diameter faces the following yearly rates of devastating adverse events: rupture (3.6%), dissection (3.7%), death (10.8%), rupture, dissection, or death (14.1%). Surgical risks: risk of death from aortic surgery for thoracic aortic aneurysm was 2.5% for the ascending and arch and 8% for the descending and thoracoabdominal aorta. Genetic analysis: family pedigrees confirm that 21% of probands with thoracic aortic aneurysm have first-order family members with arterial aneurysm. CONCLUSIONS In risk/benefit analysis the accumulated data strongly support a policy of preemptive surgical extirpation of the asymptomatic aneurysmal thoracic aorta to prevent rupture and dissection. We recommend intervention for the ascending aorta at 5.5 cm and for the descending aorta at 6.5 cm. For Marfans disease or familial thoracic aortic aneurysm, we recommend earlier intervention at 5.0 cm for the ascending and 6.0 cm for the descending aorta. Symptomatic aneurysms must be resected regardless of size. Family members should be evaluated.

What is the appropriate size criterion for resection of thoracic aortic aneurysms

Although many articles have described techniques for resection of thoracic aortic aneurysms, limited information on the natural history of this disorder is available to aid in defining criteria for surgical intervention. Data on 230 patients with thoracic aortic aneurysms treated at Yale University School of Medicine from 1985 to 1996 were analyzed. This computerized database included 714 imaging studies (magnetic resonance imaging, computed tomography, echocardiography). Mean size of the thoracic aorta in these patients at initial presentation was 5.2 cm (range 3.5 to 10 cm). The mean growth rate was 0.12 cm/yr. Overall survivals at 1 and 5 years were 85% and 64%, respectively. Patients having aortic dissection had lower survival (83% 1 year; 46% 5 year) than the cohort without dissection (89% 1 year; 71% 5 year). One hundred thirty-six patients underwent surgery for their thoracic aortic aneurysms. For elective operations, the mortality was 9.0%; for emergency operations, 21.7%. Median size at time of rupture or dissection was 6.0 cm for ascending aneurysms and 7.2 cm for descending aneurysms. The incidence of dissection or rupture increased with aneurysm size. Multivariable regression analysis to isolate risk factors for acute dissection or rupture revealed that size larger than 6.0 cm increased the probability by 32.1 percentage points for ascending aneurysms (p = 0.005). For descending aneurysms, this probability increased by 43.0 percentage points at a size greater than 7.0 cm (p = 0.006). If the median size at the time of dissection or rupture were used as the intervention criterion, half of the patients would suffer a devastating complication before the operation. Accordingly, a criterion lower than the median is appropriate. We recommend 5.5 cm as an acceptable size for elective resection of ascending aortic aneurysms, because resection can be performed with relatively low mortality. For aneurysms of the descending aorta, in which perioperative complications are greater and the median size at the time of complications is larger, we recommend intervention at 6.5 cm.

Pharmacology and Biological Efficacy of a Recombinant, Humanized, Single-Chain Antibody C5 Complement Inhibitor in Patients Undergoing Coronary Artery Bypass Graft Surgery With Cardiopulmonary Bypass

BACKGROUND Cardiopulmonary bypass (CPB) induces a systemic inflammatory response that causes substantial clinical morbidity. Activation of complement during CPB contributes significantly to this inflammatory process. We examined the capability of a novel therapeutic complement inhibitor to prevent pathological complement activation and tissue injury in patients undergoing CPB. METHODS AND RESULTS A humanized, recombinant, single-chain antibody specific for human C5, h5G1.1-scFv, was intravenously administered in 1 of 4 doses ranging from 0.2 to 2.0 mg/kg before CPB. h5G1.1-scFv was found to be safe and well tolerated. Pharmacokinetic analysis revealed a sustained half-life from 7.0 to 14.5 hours. Pharmacodynamic analysis demonstrated significant dose-dependent inhibition of complement hemolytic activity for up to 14 hours at 2 mg/kg. The generation of proinflammatory complement byproducts (sC5b-9) was effectively inhibited in a dose-dependent fashion. Leukocyte activation, as measured by surface expression of CD11b, was reduced (P<0.05) in patients who received 1 and 2 mg/kg. There was a 40% reduction in myocardial injury (creatine kinase-MB release, P=0.05) in patients who received 2 mg/kg. Sequential Mini-Mental State Examinations (MMSE) demonstrated an 80% reduction in new cognitive deficits (P<0.05) in patients treated with 2 mg/kg. Finally, there was a 1-U reduction in postoperative blood loss (P<0. 05) in patients who received 1 or 2 mg/kg. CONCLUSIONS A single-chain antibody specific for human C5 is a safe and effective inhibitor of pathological complement activation in patients undergoing CPB. In addition to significantly reducing sC5b-9 formation and leukocyte CD11b expression, C5 inhibition significantly attenuates postoperative myocardial injury, cognitive deficits, and blood loss. These data suggest that C5 inhibition may represent a novel therapeutic strategy for preventing complement-mediated inflammation and tissue injury.

Coronary artery bypass grafting in severe left ventricular dysfunction: Excellent survival with improved ejection fraction and functional state

OBJECTIVES The present study evaluated our experience with coronary artery bypass grafting in patients with severe left ventricular dysfunction. BACKGROUND Despite the ominous prognosis of advanced ischemic cardiomyopathy, coronary artery bypass grafting in this setting remains controversial because of concerns over operative risk and lack of functional or survival benefit. METHODS We analyzed the data of 83 consecutive patients (69 men, 14 women, aged 42 to 83 years [mean 66.8]) with a left ventricular ejection fraction < or = 30% who underwent isolated coronary artery bypass grafting (without aneurysmectomy, valve replacement or other open heart procedures) performed by one surgeon during a 6-year period. The ejection fraction ranged from 10% to 30% (mean 24.6%). Preoperatively, 49% of patients had angina, 52% had congestive heart failure (17% with pulmonary edema) and 30% manifested significant ventricular arrhythmia. The mean number of grafts was 2.7/patient. The internal mammary artery was used in 82% of grafts to the left anterior descending coronary artery. The intraaortic balloon pump was required therapeutically (for angina or pump failure) in 19% of patients and was prophylactically placed preoperatively in another 43% of patients. RESULTS The hospital mortality rate was 8.4% (7 of 83). The mortality rate was 3.3% (2 of 61) in those patients who did not require admission to an intensive care unit immediately before operation. Canadian Cardiovascular Society angina class improved postoperatively by 1.9 categories and New York Heart Association congestive heart failure class by 1 category. Left ventricular ejection fraction (assessed postoperatively in 68 of 76 hospital survivors) improved from 24.6% preoperatively to 33.2% postoperatively (36% increase) (p < 0.001). At 1 and 3 years, respectively, all-cause survival was 87% and 80% and freedom from cardiac death was 89.8% and 84.5%. CONCLUSIONS In patients with coronary artery disease and advanced ventricular dysfunction: 1) coronary artery bypass grafting can be performed relatively safely, 2) good medium-term survival is attained, 3) improvement in left ventricular function can be documented objectively after bypass grafting, 4) quality of life is improved (as reflected by improvement in anginal and congestive heart failure status), and 5) the internal mammary artery can safely be used as a conduit. The use of coronary artery bypass grafting is encouraged for this group of patients and may provide a viable alternative to transplantation in selected patients.

Penetrating ulcer of the thoracic aorta: What is it? How do we recognize it? How do we manage it?

BACKGROUND Although classic type A and B aortic dissections have been well described, less is known about the natural history of penetrating atherosclerotic ulcers of the thoracic aorta. This study differentiates penetrating ulcer from aortic dissection, determines the clinical features and natural history of these ulcers, and establishes appropriate correlates regarding optimal treatment. METHODS A retrospective review of patient records and imaging studies was conducted with 198 patients with initial diagnoses of aortic dissection (86 type A, 112 type B) at our institution from 1985 to 1997. RESULTS Of the 198 patients, 15 (7.6%) were found to have a penetrating aortic ulcer on re-review of computed tomographic scans, magnetic resonance images, angiograms, echocardiograms, intraoperative findings, or pathology reports. Two ulcers (13.3%) were located in the ascending aorta; the other 13 (86.7%) were in the descending aorta. In comparison with those with type A or B aortic dissection, patients with penetrating ulcer were older (mean age 76.6 years, p = 0.018); had larger aortic diameters (mean diameter 6.5 cm); had ulcers primarily in the descending aorta (13 of 15 patients, 86.7%); and more often had ulcers associated with a prior diagnosed or managed AAA (6 of 15 patients, 40.0%; p = 0.0001). Risk for aortic rupture was higher among patients with penetrating ulcers (40.0%) than patients with type A (7.0%) or type B (3.6%) aortic dissection (p = 0.0001). CONCLUSIONS Accurate recognition and differentiation of penetrating ulcers from classic aortic dissection at initial presentation is critical for optimal treatment of these patients. For penetrating ulcer, the prognosis may be more serious than with classic type A or B aortic dissection. Surgical management is advocated for penetrating ulcers in the ascending aorta and for penetrating ulcers in the descending aorta that exhibit early clinical or radiologic signs of deterioration.

NATURAL HISTORY, PATHOGENESIS, AND ETIOLOGY OF THORACIC AORTIC ANEURYSMS AND DISSECTIONS

The natural history of thoracic aortic aneurysms and dissections is diverse, reflecting a broad spectrum of etiologies which include increasing aortic size, hypertension, and genetic factors. The pathogenesis is related to defects or degeneration in structural integrity of the adventitia, not the media, which is required for aneurysm formation. The ascending and descending aorta appear to have separate underlying disease processor that lead to a weakened vessel wall and an increased susceptibility for dissection. Etiologic factors for aortic aneurysms and dissections are multifactorial, reflecting genetic, environmental, and physiologic influences.

Long-term experience with descending aortic dissection: The complication-specific approach

We analyzed long-term results in 71 patients (45 men and 26 women) treated over 17 years for documented descending aortic dissection. Forty-nine patients were treated medically and 22, surgically. Actuarial survival was 65% at 1 year, 57% at 3 years, 50% at 5 years, and 28% at 10 years for the whole group. For the group treated medically, survival was 73%, 63%, 58%, and 25% at 1 year, 3 years, 5 years, and 10 years, respectively, and for the group treated surgically, 47%, 40%, and 28% at 1 year, 3 years, and 5 years, respectively. Ten (20.4%) of the 49 medically treated patients died early (5 of rupture), and 14 (28.6%) died late (8 of dissection). Five medically treated patients crossed over to surgical management for complications of dissection. Among the surgically treated patients, 6 underwent standard graft replacement of the proximal descending aorta, 8 underwent the fenestration procedure (with a standardized retroperitoneal abdominal approach), and 4 underwent the thromboexclusion operation. Specific analysis of fenestration in 14 patients (including some with persistent descending aortic dissection after replacement of the ascending aorta for dissection) found it to be safe and effective. Actuarial survival after fenestration was 77%, 77%, and 53% at 1 year, 3 years, and 5 years, respectively. Thromboexclusion was found effective, and postoperative studies confirmed thrombosis of the descending aorta with preservation of the lowest intercostal arteries. Fifteen of the 21 surviving medically treated patients agreed to return for follow-up imaging. Nine had thrombosis of the false lumen. An interesting radiographic finding was that 4 of the 15 restudied patients had a saccular aneurysm in the aorta at the level of the left subclavian artery. We recommend a complication-specific approach to the management of descending aortic dissection. Uncomplicated dissection is treated medically, whereas complicated dissection is treated surgically, with realized rupture treated by standard graft replacement, limb ischemia treated by fenestration, and enlargement or impending rupture treated by thromboexclusion.

Failure to Improve Left Ventricular Function After Coronary Revascularization for Ischemic Cardiomyopathy Is Not Associated With Worse Outcome

Background-Preoperative identification of viable myocardium in patients with ischemic cardiomyopathy is considered important because CABG can result in recovery of left ventricular (LV) function. However, the hypothesis that lack of improvement of LV function after CABG is associated with poorer patient outcome is untested. Methods and Results-Outcome was compared in patients with ischemic LV dysfunction (LVEF </=0.30) with and without improvement in LVEF after CABG. Of 135 consecutive patients, 128 (95%) survived CABG and 104 (77%) had pre- and post-CABG LVEF assessment. Of these 104 patients, 68 (65%) had >0.05 increase in LVEF (group A) and 36 (35%) had no significant change, or </=0.05 decrease in LVEF (group B) compared with pre-CABG LVEF. No significant differences existed in age, gender, comorbidities, baseline symptoms, baseline LVEF, or intraoperative variables between groups A and B. Group A increased LVEF from 0.24+/-0.05 to 0.39+/-0.1 (P<0.005). In Group B, LVEF did not change significantly postoperatively, 0.24+/-0.05 to 0.23+/-0.06 (P=NS). Postoperative improvement in angina and heart failure scores were similar between the 2 groups. Survival free of cardiac death was similar for both groups (93% in group A and 94% in group B, P=NS) at a mean follow-up of 32+/-23 months. Conclusions-Lack of improvement of global LVEF after CABG is not associated with poorer outcome compared with that of patients with improved LVEF, presumably because effective revascularization of ischemic myocardium, even without improvement in ventricular function, protects against future infarction and death.

Surgical intervention criteria for thoracic aortic aneurysms : A study of growth rates and complications

BACKGROUND Evidence regarding the behavior of thoracic aortic aneurysm (TAA) is limited. This study reviews our ongoing efforts to understand the factors influencing aortic growth rates and the complications of rupture and dissection in order to define scientifically sound criteria for surgical intervention. METHODS Data from 370 patients with TAA treated at Yale University School of Medicine from January 1985 to June 1997 were analyzed. This computerized data base included 1063 imaging studies (magnetic resonance imaging, computed tomography, and echocardiography). RESULTS The mean size of the thoracic aorta in these patients at initial presentation was 5.2 cm (range 3.5-10). The mean growth rate was 0.10 cm/year. Median size at the time of rupture or dissection was 5.9 cm for ascending and 7.2 cm for descending aneurysms. The incidence of dissection or rupture increased with aneurysm size. Multivariable regression analysis to isolate risk factors for acute dissection or rupture revealed that size > or = 6.0 cm increased the probability of these devastating complications by 25.2% for ascending aneurysms (p = 0.006 compared with aneurysms 4.0-4.9 cm). For descending aneurysms > or = 7.0 cm, risk of dissection or rupture was increased by 37.3% (p = 0.031). CONCLUSIONS If the median size at time of dissection or rupture had been used as the indication for intervention, half the patients would have suffered a devastating complication before surgery. Accordingly, a criterion lower than the median is appropriate. We recommend 5.5 cm as an acceptable size for elective resection of ascending aortic aneurysms because this operation can be performed with relatively low mortality. For aneurysms of the descending aorta, where perioperative complications are greater and the median size at the time of complication is larger, we recommend intervention at 6.5 cm.