Caspase-activated DNase (CAD)-independent oligonucleosomal DNA fragmentation in chronic myeloid leukaemia cells; a requirement for serine protease and Mn2+-dependent acidic endonuclease activity.

We have previously reported that the pro-apoptotic pyrrolobenzoxazepine, PBOX-6, induces apoptosis in chronic myelogenous leukaemia (CML) cells which is accompanied by oligonucleosomal DNA fragmentation. In this study we show that PBOX-6-induced oligonucleosomal DNA fragmentation occurs in the absence of caspase and CAD activation in CML cells. Dissection of the signalling pathway has revealed that induction of apoptosis requires the upstream activation of a trypsin-like serine protease that promotes the phosphorylation and inactivation of anti-apoptotic Bcl-2. In addition, in this system chymotrypsin-like serine proteases are dispensable for high molecular weight DNA fragmentation, however are required for the activation of a relatively small manganese-dependent acidic endonuclease that is responsible for oligonucleosomal fragmentation of DNA. Furthermore, we demonstrate mitochondrial involvement during PBOX-6-induced apoptosis and suggest the existence of unidentified mitochondrial effectors of apoptosis.

Perioperative risk factors affecting hospital stay and hospital costs in open heart surgery for patients > or = 65 years old.

OBJECTIVE: Demographic changes, associated with increased demands for open heart surgery in the elderly, place increased burden on financial resources. To evaluate perioperative risk factors affecting incidence of hospital events and estimation of hospital charges, 2577 patients > or = 65 years (range 65-91), operated on from January 1991 to December 1994, were compared with a concurrent cohort of 2642 younger patients. METHODS: Statistical analysis, by surgical procedure, focused on hospital mortality, key postoperative complications affecting length of hospital stay and hospital charges. RESULTS: Overall hospital mortality was 4.7%, 3.5% in younger patients versus 6.1% in the older group (P << 0.01). Mortality was significantly lower in patients less than 65 years undergoing coronary artery bypass grafting (3% versus 5%, P < 0.01) and valve replacement (4% versus 9%, P = 0.01). Significant risk factors for hospital death in the elderly: diabetes (P < 0.01), hypertension (P < 0.01), myocardial infarction (P < 0.01) and congestive heart failure (P < 0.01). Significant postoperative events, more common in older patients, included prolonged ventilation (P << 0.01), congestive heart failure (P << 0.01), infection (P << 0.01), cerebrovascular accident (P < 0.01), and intra aortic balloon pump (P < 0.01). Incremental risk factors for morbidity in the elderly were: higher New York Heart Association class, congestive heart failure, emergent operation, and female gender. Mean length of hospital stay for the < 65 group was 15.3 versus > 19.5 days for the > 65 group (P << 0.01). Length of stay over 18 days positively correlated with increased morbidity in both age groups. For patients > or = 65 years of age, the average hospital charge for open heart surgery was 172% higher for patients with a length of stay greater than 18 days compared with 165% for patients less than 65 years of age. CONCLUSIONS: Higher operative mortality and longer length of stay in elderly patients, resulting in increased health care costs, was associated with more co-morbidities. These results suggest interventions designed to reduce congestive heart failure and other co-morbidities may improve patient's recovery and reduce costs.

Coronary artery bypass grafting in patients with chronic congestive heart failure: a 10-year experience with 203 patients.

From 1983 to 1992, 203 patients with chronic congestive heart failure and no angina underwent primary coronary artery bypass. This represented 3% of patients undergoing coronary artery bypass grafting. Ninety-two percent of the patients were in New York Heart Association (NYHA) functional class III or IV prior to undergoing coronary artery bypass grafting. Thallium perfusion imaging was performed in 21% of the patients, with a reversible defect present in 88%. An internal mammary artery graft was used in 70% of the patients. The hospital mortality was 6.0% and the actuarial survival at 5 years was 59%. An improvement in NYHA functional class occurred in 75% of the surviving patients with a mean improvement of 1.6 +/- 0.6 functional classes. Univariate analysis identified risk factors for hospital death as emergency operation, recent myocardial infarction (< 30 days), and the need for an intra-aortic balloon pump. A trend emerged for nonuse of an internal mammary artery to predict hospital death. A positive thallium perfusion scan was not a predictor of early or late survival, nor did it influence NYHA functional class. The use of the internal mammary artery significantly enhanced late survival (p = 0.01), however, did not affect the functional class of survivors. We conclude that coronary artery bypass grafting is effective in ameliorating symptoms of chronic congestive heart failure in patients suffering from chronic ischemic cardiomyopathy and can be performed with acceptable early and late mortality.

A new biologic membrane in cardiovascular surgery.

Reconstruction techniques for major vessels and intracardiac defect repair use synthetic grafts or autogenic pericardium. Here, autologous abdominal parietal peritoneum with the overlying posterior rectus sheath as a biologic membrane are evaluated. Twelve adult canines were used. Via a midline subumbilical incision, the parietal peritoneum and overlying posterior rectus sheath were harvested. In the first group of six, the membrane was used to repair the right ventricular infundibulum and perform pulmonary artery annuloplasty. In the second group of six, under cardiopulmonary bypass and moderate hypothermia, the right atrium was opened and a secundum type defect was created. Autopsies performed 90 days after surgery revealed mild intrapericardial adhesions and moderate pericardial reaction over the cardiotomy incisions. The right ventricular outflow tract patch was nonaneurysmal. The interatrial patch was intact without thrombi. Histologic examination revealed intact membrane morphology, fibroblasts, smooth muscle cells, and endothelialization. Proline C14 uptake and autoradiography detected cellular viability of implanted membranes. These findings suggest that the peritoneum with overlying sheath repaired vascular and intracardiac defects and substituted for pericardium. Future studies are needed before clinical use.

Enhancement of calcium cycling by atrial sarcoplasmic reticulum after cardiopulmonary bypass and cardioplegia during open heart surgery.

We studied myocardial Ca2+ cycling during cardiopulmonary bypass and cold-blood cardioplegia (CPB/CBC) in patients with coronary heart disease undergoing coronary artery bypass grafting. Right atrial biopsies were taken from 13 patients before and after CPB/CBC: after pericardiotomy, immediately after aortic cross-clamp removal, and following termination of CPB/CBC. Changes in ionized Ca2+ concentration (nM) were monitored with indo 1 during Ca2+ uptake and Ca2+ release by sarcoplasmic reticulum in a medium containing 1% homogenized myocardium. Ryanodine inhibition was used to estimate Ca2+ release channel activity. With CPB/CBC, the initial Ca2+ concentration of reaction media increased 33%, (962 +/- 150 to 1262 +/- 106 nM; mean +/- SD). Ca2+ cycling increased asymmetrically, 108% for Ca2+ uptake (3.91 +/- 1.32 to 8.15 +/- 3.17 nM/s), 197% for Ca2+ release (0.90 +/- 0.80 to 2.73 +/- 1.13 nM/s), and 68% for the ratio of Ca(2+)-release to Ca(2+)-uptake activities (0.22 +/- 0.14 to 0.37 +/- 0.13). The dissociation constant of the Ca2+ pump for Ca2+ was unaltered by CPB/CBC (289 +/- 76 nM). During the time period that was studied post-bypass, Ca(2+)-pump activity remained increased, although the Ca(2+)-channel activity returned to pre-bypass values (all p < 0.05). We conclude that CPB/CBC produces increased myocardial Ca2+ load, twofold increased Ca2+ uptake, and threefold increased Ca2+ release by sarcoplasmic reticulum.

The small aortic root and the Medtronic Hall valve: ultrafast computed tomography assessment of left ventricular mass following aortic valve replacement.

BACKGROUND AND AIMS OF THE STUDY: The selection of an appropriate size aortic valve substitute with respect to patient size and life-style, in the presence of a small aortic root, is problematic, and a decision to enlarge the aortic annulus is often arbitrary. An aortic valve substitute-patient mismatch may place an excessive load on the left ventricle resulting in residual left ventricular mass with attendant patient morbidity and mortality. The aim of this study was to assess the adequacy of the Medtronic Hall valve in the small aortic root using ultrafast computed tomography analysis of left ventricular mass. MATERIALS AND METHODS: In 13 patients the smallest Medtronic Hall valves (size 20 and 21; measured internal orifice area of 2.01 cm2 for both) were used to replace the native aortic valve. All patients had aortic stenosis, and left ventricular hypertrophy was established by echocardiography. The mean body surface area was 1.8 +/- 0.2 m2 (range 1.50-2.06 m2) and the mean weight was 75 +/- 15 Kg (range 50-97 Kg). The mean preoperative New York Heart Association functional class was 3.54 +/- 0.5. RESULTS: There was no operative or late mortality. At a mean follow up of 22 months after aortic valve replacement, the mean left ventricular mass index was 89 +/- 11.4 g/m2 (normal left ventricular mass index by ultrafast computed tomography = 97 +/- 14 g/m2) and mean New York Heart Association functional class was 1.6 +/- 0.8 (p (Binomial) = 0.0001 compared to preoperative). Doppler echocardiogram demonstrated a mean gradient across the prosthetic valve of 17 +/- 7 mmHg. There was no trend towards greater left ventricular mass index in patients with greater body surface area or weight. In no patient was the aortic annulus enlarged. CONCLUSIONS: Trends from this preliminary data suggest that implanting the smallest Medtronic-Hall aortic valves (sizes 20 and 21) results in normal left ventricular mass following aortic valve replacement in patients up to a body surface area of 2.06 m2 and provides support for the notion that an aortic annulus enlarging procedure was not necessary in this group of patients.

Predictive value of prosthetic valve area index for early and late clinical results after valve replacement with the St Jude Medical valve prosthesis.

BACKGROUND: Previous studies indicate that a minimal prosthetic valve area index (VAI) of > or = 0.9 cm2/m2 for aortic and > or = 1.3 cm2/m2 for mitral valves minimizes postoperative pressure gradients. METHODS AND RESULTS: To determine VAI as an independent risk factor for postoperative events, 607 isolated aortic valve replacement (AVR) and 482 isolated mitral valve replacement (MVR) operations with the St Jude Medical valve were studied. End points included hospital deaths, NYHA functional class, late death and late valve-related death, major thromboembolism, anticoagulant-related hemorrhage, and reoperation. VAI was calculated from the ratio of prosthetic valve area to body surface area for each patient, and a range and mean were obtained for each valve size. Follow-up ranged from 1 to 120 months, totaled 2964 patient-years, and was 98% complete. Mean and range of VAI (cm2/m2) were 1.31 (0.74 to 2.86) in the aortic and 2.5 (1.4 to 6.32) in the mitral group. There were 33 AVR (5.4%) and 38 MVR (7.9%) hospital deaths. VAI was not a risk factor for NYHA class, early death, late death, or other postoperative events. The actuarial survival rates, 84% for AVR and 80% for MVR at 5 years, were not affected by VAI. CONCLUSIONS: Within the ranges measured, VAI did not influence the end points of the study.

Effectiveness of fibrin glue in the reduction of postoperative intrapericardial adhesions.

The hemostatic properties of fibrin sealant have been well described. Previously published reports have attempted to clarify the possible role of fibrin glue in the inhibition of the formation of intrapericardial adhesions following cardiac surgery. Earlier work hypothesized that fibrin glue may reduce the severity of postoperative adhesions and that the use of autologous fibrin glue may have similar effects, without the risks that accompany homologous blood products. Six juvenile farm pigs were utilized to test this hypothesis. Conventional fibrin glue and single-donor fibrin glue were tested in open-heart surgery. This experimental model was also reexamined and found to be of significant utility in simulating adult reoperative cardiac surgery. The fibrin glue subjects were universally easier to reoperate due to fewer adhesions, as demonstrated grossly and histologically. The single-donor fibrin glue had no significant advantage on adhesion formation, when compared to the conventional fibrin glue group, but the ramifications of formulating fibrin glue in this fashion offer a significant benefit toward the complete use of autologous blood products in open-heart surgery.

Paraganglioma of the interatrial septum.

The case of a patient undergoing successful resection of an interatrial septal paraganglioma is presented. The diagnosis of an interatrial mass was established preoperatively by echocardiography, ultrafast cine computed tomographic scan, and cardiac catheterization. The tumor was excised in total, and the interatrial septum and the roof of the left atrium were reconstructed using a bovine pericardial patch.

Esmolol and percutaneous cardiopulmonary bypass enhance myocardial salvage during ischemia in a dog model.

Despite recent advances in techniques of reperfusion for acute myocardial ischemia, myocardial salvage remains suboptimal. Beta-blockers have been shown to limit infarct size during acute ischemia, but their negative inotropic properties have limited their use. Cardiopulmonary bypass is an attractive technique for cardiac resuscitation because it can stabilize a hemodynamically compromised patient and potentially reduce myocardial oxygen consumption. In an attempt to maximize myocardial salvage in the setting of acute ischemia, the combination of esmolol, an ultrashort-acting beta-blocker, with percutaneous cardiopulmonary bypass was evaluated. Four groups of instrumented dogs underwent 2 hours of myocardial ischemia induced by occlusion of the proximal left anterior descending coronary artery, followed by 1 hour of reperfusion. Throughout the period of ischemia and reperfusion, esmolol plus percutaneous cardiopulmonary bypass was compared with esmolol alone, percutaneous cardiopulmonary bypass alone, and control conditions. After the reperfusion period, the extent of infarction of the left ventricle at risk was determined. Four animals had intractable arrhythmias: one in the esmolol plus bypass group, one in the esmolol group, and two in the control group. The extent of infarction of the left ventricle at risk was significantly reduced in the esmolol plus bypass group (30%) compared with bypass alone (52%), with esmolol alone (54%), and with the control groups (59%; p < 0.05). We conclude that in this experimental model the combination of esmolol with bypass improves myocardial salvage after ischemia and reperfusion.

Repair of ventricular septal rupture through the right atrium.

The right atrial approach for repair of ventricular septal rupture associated with myocardial infarction is an alternative technique to the conventional approach of exposing the septum through the left ventricle. This technique may be combined with mitral valve replacement, infarct excision, or aneurysm resection, by avoiding a direct incision in the ventricle reduce postrepair bleeding and impairment of ventricular contractile function. We present a case of ventricular septal rupture repaired through the right atrium and review our surgical technique. This technique may be applied to most cases of ventricular septal rupture, and is particularly useful when the ventricular wall is not infarcted or aneurysmal, and the defect involves the central portion of the muscular septum, the inlet septum, and the subaortic and membranous area.

Evaluation of cyropreserved internal thoracic artery as an alternative coronary graft: evidence for preserved functional, metabolic and structural integrity.

The internal thoracic artery (ITA) is the conduit of choice for coronary artery bypass grafting (CABG). This study, utilizing a canine model, evaluates cryopreserved ITA. Sixteen ITAs were harvested and cryopreserved according to United CryoInstitute protocol. Test conduits, 5 cm long and 4 mm mean diameter, were anastomosed to the ligated carotid artery of an unmatched mongrel recipient, above and below the site of native artery ligation. Graft patency was assessed by angiography at 14 days (early) and 980 days (late) postoperatively. Catheterization of the 16 vessels identified three (18%) early and one (6%) late graft occlusion. Ninety days postoperatively, each dog was killed and the graft harvested for histopathological and functional evaluation. Morphologic evaluation, using conventional staining, showed preserved cellular structure, decrease in smooth muscle cells and distorted endothelial layer. Immunocytochemistry, using an antibody against prostacyclin (PGI2), detected PGI2 immunoactivity in the ITA smooth muscle cells. An in vitro assay performed on the arterial rings confirmed preserved functional integrity of the vascular endothelium and smooth muscle. These findings suggest that cryopreserved ITA may have potential as a substitute graft, in devising conduit strategies for primary or reoperative coronary bypass surgery.

CABG in octogenarians: early and late events and actuarial survival in comparison with a matched population.

BACKGROUND: With important demographic changes in cardiac surgical practice, more older patients are undergoing complex cardiac operations. Controversy exists as to whether the expenditure of healthcare resources on the growing elderly populations represents an effective approach in maintaining a meaningful quality of life. METHODS: From January 1982 through April 1991, 121 consecutive octogenarians underwent a surgical procedure that included coronary artery bypass grafting. Retrospective review of patient medical records was performed; follow-up information was obtained via telephone contact with the patient, the patient's family, or the patient's physician. RESULTS: There were 67 men (55%) and 54 women (45%). Mean age was 82.1 years (range, 80 to 89 years). Sixty-nine percent of the patients were having class III or IV symptoms. There were 11 hospital deaths (9.1%); risk factors included longer cardiopulmonary bypass time (p = 0.01), higher preoperative left ventricular end-diastolic pressure (p = 0.02), advanced age (p = 0.05), history of renal disease (p = 0.02), and myocardial infarction (p = 0.04). Late death occurred in 34 patients (30.9%) at a mean of 27 months postoperatively; univariate risk factors included chronic obstructive pulmonary disease (p = 0.009), higher left-ventricular end-diastolic pressure (p = 0.03), and recent myocardial infarction (p = 0.03). Actuarial survival, including hospital death, was 32.8% at 80 months, compared with 37.6% for an age; sex; and race-matched population (p > 0.3). Most late survivors (84%) were in New York Heart Association class I or II. CONCLUSIONS: We conclude that coronary artery bypass grafting can be performed in octogenarians with an acceptable, although increased risk. Hospital survivors have a good late functional status but are at risk for pulmonary and other atherosclerosis-related events, which impair overall survival.

Upper extremity vascular access for continuous arteriovenous hemofiltration and dialysis after cardiac operations.

BACKGROUND: There is increasing interest in the use of continuous arteriovenous hemofiltration/dialysis for treatment of profound renal failure after cardiovascular operations. Vascular access for this is usually accomplished by percutaneous cannulation of the femoral artery and vein, with the inherent risks of vascular trauma, patient immobilization, hemorrhage, or infectious complications. METHODS: Fifteen (0.36%) of 4,166 patients receiving cardiovascular surgical procedures sustained postoperative renal failure requiring treatment with continuous arteriovenous hemofiltration/dialysis. Each patient had creation of acute arteriovenous forearm access using a modified Allen-Brown shunt. Shunts were monitored continuously for hemorrhage, malfunction, infection, and thrombus, and were explanted when no longer required. RESULTS: Sixteen shunts were implanted in 15 patients over the 41-month period. All shunts functioned satisfactorily, with the duration of implantation ranging from 1 to 64 days. There were no infectious or hemorrhagic complications. CONCLUSIONS: The acute creation of a simple forearm shunt for postoperative continuous arteriovenous hemo-filtration/dialysis is preferred over femoral arterial and venous cannulation because it can be constructed rapidly and easily in the operating room or at the bedside, has a low complication rate, is available for immediate use, may be left in place indefinitely, does not interfere with patient mobilization or ambulation, and is easily removed.

Efficacy of combined coronary revascularization and valve procedures in octogenarians.

From January 1982 to October 1991, 42 consecutive patients 80 years of age and older underwent a combined cardiac procedure with coronary revascularization and valve repair or replacement. There were 20 women and 22 men. Mean age at operation was 82.8 years (range, 80 to 89.7 years). Twenty-seven patients (64%) were in New York Heart Association (NYHA) functional class III or IV preoperatively. Six patients (14.3%) had undergone previous cardiac procedures. There were six hospital deaths (14.3%). The only significant preoperative risk factor identified for the event hospital death was aortic insufficiency (p = 0.005). The 36 hospital survivors were followed up at a mean of 21.1 months after hospital discharge. There were nine (21%) late deaths occurring at a mean of 21.3 months postoperatively: two from acute myocardial infarctions and seven from chronic heart failure. Survival analysis indicated that higher preoperative NYHA class (p = 0.0003), hypertension (p = 0.015), hypercholesterolemia (p = 0.03), and elevated left atrial/left ventricular gradient (p = 0.04) were incremental risk factors for overall mortality. The actuarial survival at 40 months was 51.9%, with no significant difference as compared with an age-, sex-, and race-matched population. Of the 27 late survivors, 26 were in NYHA class I or II. We conclude that octogenarians may undergo complex cardiac surgical procedures with an expectation of an acceptable mortality rate and significant improvement in their functional status. These results must be taken into consideration in light of reported strategies to ameliorate health-care costs by limiting availability of complex medical care to the elderly.

Comparison of low-pressure versus standard-pressure fixation Carpentier-Edwards bioprosthesis.

Intermediate-phase clinical results of 51 low-pressure (LP) and 234 standard-pressure (SP) fixation porcine Carpentier-Edwards (CE) valves implanted between 1977 and 1991 were compared for valve-related events. Group similarities included New York Heart Association functional class, ejection fraction, and sex. Patients with SP valves were younger (mean age, 58 versus 68 years; p = 0.0001). There were 20 in-hospital deaths (8.6%) in the SP valve group and 5 (9.8%) in the LP valve group (p = 0.79). Follow-up was 99%, with a mean of 104 months in the SP valve group versus 55 months in the SP valve group (p = 0.0001). The actuarial survival rate was 48.2% and 22.3% at 10 and 15 years, respectively, in the SP valve group and 34.1% at 10 years in the LP valve group (p = 0.42). Freedom from events at 5, 10, and 15 years in the SP valve group and at 5 years in the LP valve group was as follows: for late valve-related events, 86.3%, 51.4% and 20.2%, respectively, in the SP valve group versus 85% in the LP valve group (p = 0.44); for valve-related death, 96.4%, 93.6%, and 87.3% in the SP valve group versus 100% in the LP valve group (p = 0.20); for structural valve failure, 96%, 68%, and 35% in the SP valve group versus 100% in the LP valve group (p = 0.09); and for reoperation, 95%, 61%, and 30% in the SP valve group versus 92% in the LP valve group (p = 0.82). In conclusion, this study revealed no significant statistical difference between LP and SP valves. In the LP valve group, structural valve failure/valve-related death was not observed, perhaps indicating a more favorable result. Absolute verification of this trend awaits long-term follow-up.

Perioperative events in patients with failed mechanical and bioprosthetic valves.

From 1963 through 1991, 1037 patients underwent reoperative valvular procedures. The 478 patients having reoperations for either failed bioprosthetic (n = 212) or mechanical (n = 266) valves were evaluated. There were 210 male (44%) and 268 female (56%) patients. The mean age at reoperation of the patients in the bioprosthesis group was 59.7 years and and that in the mechanical valve group was 56.1 years (p = 0.0006). The mean interval to the time of reoperation was 84.7 months in the mechanical valve group and 74 months in the bioprosthesis group. There was no difference between the two groups in the functional class at reoperation. More severe mitral valve stenosis and incompetence, more severe aortic valve stenosis, and higher right ventricular and pulmonary arterial pressures were noted in the bioprosthesis group than in the mechanical valve group. Hemolysis (p = 0.05) was more prevalent in the patients with mechanical valves than in the ones with bioprostheses. A longer aortic occlusion time (p = 0.0001) and longer cardiopulmonary bypass time (p = 0.0001) were required for the reoperations in the bioprosthesis group. The operative mortality was 13.2% for the bioprosthesis patients and 12.4% for the mechanical valve patients. The risk factors for hospital death included the cross-clamp time (p = 0.0001), the functional class (p = 0.00001), the presence of ascites (p = 0.02), hepatomegaly (p = 0.002), and decreasing ejection fraction (p = 0.05). We conclude that mechanical valve failures do not produce catastrophic events resulting in poor reoperative results.

Myocardial self-preservation: absence of heat shock factor activation and heat shock proteins 70 mRNA accumulation in the human heart during cardiac surgery.

Following myocardial ischemia, heat shock proteins (HSPs) have been found to be associated with a reduction in infarct size and enhanced postischemic functional recovery. Stress-induced regulation of the HSPs is mediated by the activation and binding of the heat shock transcription factor (HSF) to a specific DNA sequence located in front of all HSP genes, known as the heat shock element (HSE). To determine whether HSPs were induced in the human heart following the ischemic stress experienced during cardiac surgery, biopsies were performed of the right atrium at three sequential times: prior to establishing cardiopulmonary bypass; immediately after aortic declamping; and following termination of bypass. These samples from the atria of patients undergoing coronary bypass surgery were assessed for HSF activation using mobility shift gels, and analyzed for HSP 72 mRNA by Northern blot. Although a high level of the HSP 72 protein was noted at all intervals, no HSF activation was detected, nor was an accumulation of HSP 72 mRNA observed at any time during surgery. These data suggest that HSPs are not induced during cardiac surgery and that the high "constitutive" level of the HSP 72 protein detected in these hearts may not be secondary to an HSF-HSE interaction, but rather, the result of other transcription factors acting at alternative regions of the HSP 70 promoter.