Search

Young male pigs consumed a diet of fatty minced beef, safflower oil, skim milk powder, sucrose, cornstarch and wheat bran. Starch provided 50% of total daily energy either as low amylose cornstarch, high amylose (amylomaize) cornstarch or as a 50/50 mixture of corn and high amylose starch. Neither feed intake nor body weight gain as affected by dietary starch. Final plasma cholesterol concentrations were significantly higher than initial values in pigs fed the 50/50 mixture of corn and high amylose starch. Biliary concentrations of lithocholate and deoxycholate were lower in pigs fed high amylose starch. Large bowel length correlated positively with the dietary content of high amylose starch. Concentrations of butyrate in portal venous plasma were significantly lower in pigs fed high amylose starch than in those fed cornstarch. Neither large bowel digesta mass nor the concentrations of total or individual volatile fatty acids were affected by diet. However, the pool of propionate in the proximal colon and the concentration of propionate in feces were higher in pigs fed amylose starch. Concentrations of starch were uniformly low along the large bowel and were unaffected by starch type. In pigs with cecal cannula, digesta starch concentrations were higher with high amylose starch than with cornstarch. Electron micrographic examination of high amylose starch granules from these animals showed etching patterns similar to those of granules obtained from human ileostomy effluent. It appears that high amylose starch contributes to large bowel bacterial fermentation in the pig but that its utilization may be relatively rapid.

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.

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.

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.

The current methods for a reference dose (RfD) determination can be enhanced through the use of biologically-based dose response analysis. Methods developed here utilizes information from tetrachlorodibenzo-p-dioxin (TCDD) to focus on noncancer endpoints, specifically TCDD mediated immune system alterations and enzyme induction. Dose-response analysis, using the Sigmoid-Emax (EMAX) function, is applied to multiple studies to determine consistency of response. Through the use of multiple studies and statistical comparison of parameter estimates, it was demonstrated that the slope estimates across studies were very consistent. This adds confidence to the subsequent effect dose estimates. This study also compares traditional methods of risk assessment such as the NOAEL/safety factor to a modified benchmark dose approach which is introduced here. Confidence in the estimation of an effect dose (ED10) was improved through the use of multiple datasets. This is key to adding confidence to the benchmark dose estimates. In addition, the Sigmoid-Emax function when applied to dose-response data using nonlinear regression analysis provides a significantly improved fit to data increasing confidence in parameter estimates which subsequently improve effect dose estimates.

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.

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.

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.

Lipid peroxidation may be important in the development of cardiovascular disease, a common cause of mortality and morbidity in non-insulin dependent diabetes mellitus (NIDDM). We assessed the degree of lipid peroxidation by measuring plasma malondialdehyde, as thiobarbituric acid reacting substances (TBARS), in 23 non-insulin diabetic patients. Plasma levels of standardised alpha-tocopherol (vitamin E), lipid content of whole plasma and lipoprotein fractions, glycosylated haemoglobin, glycosylated low density lipoprotein (LDL) and fasting blood glucose were also measured. On completion of the baseline studies patients randomly received either fish oil or matching olive oil capsules in a double blind crossover fashion for 6 weeks followed by a 6 week washout period and a final 6 week treatment phase. Studies, identical to the initial baseline studies, were performed at the end of the of the active treatment periods at 6 and 18 weeks. Treatment with olive oil did not change levels of TBARS, vitamin E or indices of glycaemic control compared with baseline. Total cholesterol and triglyceride (TG) content of plasma and lipoprotein fractions were not significantly altered. Treatment with fish oil resulted in elevation of TBARS (P < 0.001) and reduction of vitamin E (P < 0.01) compared with baseline and olive oil treatment. Plasma cholesterol was unchanged. A reduction in plasma TG compared with baseline occurred but failed to reach significance (P =0.07). Changes in apo B containing lipoproteins induced by fish oil failed to reach significance. No significant changes were observed in concentration or composition of high density lipoprotein (HDL). Fish oil treatment showed no change in glycaemic control as assessed by glycosylated haemoglobin and LDL although a rise in fasting blood glucose just failed to reach significance (P = 0.06). Lipid peroxidation in NIDDM can be exacerbated by dietary fish oil. This potentially adverse reaction may limit the therapeutic use of fish oils in such patients.

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.

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.

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.

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.

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.

Two fluorescent probes were used for the measurement of membrane fluidity in patients on haemodialysis and continuous ambulatory peritoneal dialysis. 1,6-Diphenyl-1,3,5-hexatriene (DPH) anisotropy gives an indication of lipid order and pyrene measures lateral diffusion through the membrane. Pyrene dimer/monomer ratio was significantly lower than controls in both pre-dialysis and post-dialysis samples but DPH anisotropy was unchanged. Both methods showed an increase in membrane fluidity across a 4 hour haemodialysis session. There was an increase in membrane fluidity in CAPD patient samples which was more marked using DPH than pyrene. These results suggest that the two probes give different but complementary information about changes in membrane fluidity and may be more informative when used together rather than singly.

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.

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.

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.

Pulmonary microvascular pressures (PMVP) have important diagnostic and therapeutic implications when utilized to monitor pulmonary dysfunction after cardiopulmonary bypass. Elevations in PMVP may lead to interstitial pulmonary edema and right ventricular failure. This study evaluated the influence of Dobutamine on PMVP in a trial of 80 consecutive patients undergoing isolated coronary artery bypass grafting (CABG). Forty patients were randomized to the Dobutamine study group and received 5 micrograms/kg/min of Dobutamine for 24 hours, starting at the completion of bypass. In the control group, patients received postoperative inotropic support as indicated (dopamine [n = 10] or amrinone [n = 6]) by the clinical situation. PMVP values were computed based on continuous hemodynamic monitoring at 6, 12, 18 and 24 hours. Preoperative demographic descriptors and operative variables were comparable between the two groups. Postoperative fluid requirements and nonpulmonary complications were also similar between groups. Upon completion of cardiopulmonary bypass, PMVP (mean +/- SD) were PMVP decreased over time in the Dobutamine group, while it did not change in the control group. Clinically mean time to extubation was reduced from 18 to 12 hours (p < 0.06) in the Dobutamine group. We conclude that in patients undergoing cardiopulmonary bypass, the postoperative administration of Dobutamine significantly reduces the PMVP. This may reduce pulmonary interstitial edema and pulmonary complications. Upon completion of cardiopulmonary bypass, PMVP (mean +/- SD) were measured at 6 hours, 12 hours, 18 hours and 24 hours. The control group measured 25 +/- 5 mmHg, 26 +/- 2 mmHg, 27 +/- 3 mmHg and 28 +/- 3 mmHg. The Dobutamine group measured 25 +/- 6 mmHg, 24 +/- 3 mmHg, 22 +/- 2 mmHg and 18 +/- 5 mmHg. PMVP decreased over time in the Dobutamine group (p < 0.001), while it did not change in the control group. Clinically mean time to extubation was reduced from 18 to 12 hours (p < 0.06) in the Dobutamine group. We conclude that in patients undergoing cardiopulmonary bypass, the post-operative administration of Dobutamine significantly reduced PMVP. This may reduce pulmonary interstitial edema and pulmonary complications post cardiopulmonary bypass.

As part of the current reassessment of dioxin, the empirical relationships between administered tetrachlorodibenzo-p-dioxin and selected immune and biochemical endpoints were investigated. A dose-response analysis from the published literature was performed using Linear, Sigmoid-Emax and Power Law functions. The results of this analysis indicate that the use of a wide dose range may bias the interpretation of low-dose phenomenon. The Power Law function was applied exclusively to low-dose subsets enabling estimation of dose response in the low-dose range. Subsequently, high-dose data were fit using Power Law subset analysis. This approach resulted in a change in slope value from low- to high-dose subsets for thymic atrophy, immune suppression, benzo(a)pyrene hydroxylase activity, and ethoxyresorufin-o-deethylase activity. This change suggests that there is a high probability that there is a tissue concentration along the dose-response continuum which results in biological activity from low to high dose. This analysis also demonstrates that the Power Law functional fit to the low-dose data differs quantitatively from the fit to the high-dose data for several noncancer endpoints. Therefore, by using the Power Law function a more accurate and biologically relevant assessment of risk can be produced for non-cancer endpoints.

The risks associated with resternotomy are largely related to loss of pericardial integrity. No satisfactory substitute for pericardium has been identified. The structural similarity between pericardium and peritoneum prompted an assessment of the latter as a biologic substitute. Two peritoneal patches were harvested from four juvenile swine, which then underwent left thoracotomies. In each pig, two pericardial defects were created and repaired with fresh and glutaraldehyde treated autologous peritoneal patches. Three weeks post operatively, the chest and abdomen were re-explored and the patches evaluated. In all cases, extrapericardial adhesions were insignificant. On gross examination of the intrapericardial surfaces, the fresh patches appeared smooth and glistening, with neither degenerative changes nor adherence to the epicardium. The treated patches were easily separated from the epicardium in two cases, but the other two patches were moderately to severely adherent. Histologic examination demonstrated well preserved morphology in all patches. C proline uptake and autoradiography revealed preserved fibroblast viability in the fresh patches. Intra abdominally, in all cases, there was complete reperitonealization without adhesion formation. In conclusion, fresh autologous peritoneum performed well as a pericardial substitute after heart surgery.

The major mammalian stress-inducible protein, heat shock protein 72, protects cells from certain stresses and rapidly accumulates in cells after ischemia. Heat shock protein 72 is rapidly synthesized in the myocardium of various species in response to ischemia, but it has not been investigated in human heart. To determine if heat shock protein 72 accumulated in the ischemic myocardium of patients undergoing cardiac operations, we obtained sequential right atrial biopsy specimens from 12 patients undergoing repair at three intervals: before bypass, after reperfusion, and after bypass. Immunoblot analysis for heat shock protein 72 demonstrated a high expression in the human heart compared with other mammalian hearts, p (Binomial) = 0.01. Compared with before bypass, heat shock protein 72 contents after reperfusion and after bypass were 98.2% +/- 8.9%, p (signed-rank) = 0.65, and 87.6% +/- 17.1%, p (signed-rank) = 0.28, respectively. Although heat shock protein 72 concentration was unchanged in hearts after reperfusion and after bypass, the initial prebypass level of heat shock protein 72 was high. The high heat shock protein 72 level detected in human hearts may reflect preoperative disease and drug therapy, or inherently high levels may be usual in the human myocardium. These findings indicate that the myocardium of patients undergoing cardiac operations contains relatively high concentrations of heat shock protein 72, which are not increased during the surgical procedure.

Twenty patients with left ventricular hypertrophy (LVH) undergoing isolated aortic valve replacement were prospectively randomized to receive either continuous retrograde normothermic (n = 8) or intermittent retrograde hypothermic (n = 12) methods of myocardial protection. Biopsies of the left ventricular septum were evaluated for ultrastructure and assayed for ATP. There was no mortality, no requirement for intra-aortic balloon pump nor neurological events in any of the patients from either group. Myocardial ATP (warm 23.2 +/- 1.8 nmol/mg protein; cold 22.4 +/- 1.2 nmol/mg protein; p = 0.72) and myocardial CPK-MB (warm 43.6 +/- 5.2 U/l; cold 39.0 +/- 2.5 U/l; p = 0.67) were not significantly different. Ultrastructure was generally well preserved in the biopsies from both groups, with the exception of one patient in the normothermic group. Systemic lactate sampled after 40 minutes of cardiopulmonary bypass was significantly higher in the normothermic group (warm 3.4 +/- 0.27 mmol/l; cold 2.3 +/- 0.21 mmol/l; p = 0.01), however, the myocardial lactate production was not significantly different between the two groups (extraction ratio; warm 0.01 +/- 0.3; cold 0.13 +/- 0.1; p = 0.45). We conclude that the continuous normothermic retrograde method of myocardial protection is effective in patients with left ventricular hypertrophy; however, the higher systemic lactate levels using this technique raises concerns regarding the adequacy of systemic perfusion at 37 degrees C.

Epidemiological studies have pointed to the role of alcohol, and red wine in particular, in reducing the incidence of coronary heart disease. This study attempted to distinguish, in vivo, the effects of components specific to red wine and those of alcohol on lipoproteins, antioxidant status and membrane fluidity. Volunteers (n = 20) were given 200 ml of red wine per day for 10 days. Following a 6-week washout, this was repeated with white wine. Changes within treatment groups were analysed by paired t tests and repeated measures analysis of variance was used to distinguish effects of red wine components and alcohol. LDL was prepared by ultracentrifugation and all other assays were by conventional laboratory techniques. No effect with either treatment was detected on total cholesterol, triglycerides, HDL or measures of antioxidant status, including the susceptibility of LDL to oxidation. Red wine reduced LDL cholesterol (p < 0.01), and both treatments reduced LDL apo B (p < 0.01) and increased LDL chol:apo B ratio (p < 0.01), implying an increase in LDL size. Potential anti-atherogenic changes specific to red wine were reduction in lipoprotein (a) (p < 0.001) and increased membrane fluidity (p < 0.01). These results are not in keeping with the proposed role of red wine components in free-radical protection, but the reduction in lipoprotein (a) merits further investigation.

Coronary artery bypass grafting was carried out in a 61-year-old man 42 years after he had undergone right pneumonectomy. At the time of operation, the heart was displaced into the right hemithorax, which required modification of the operative techniques. Despite poor pulmonary function tests results preoperatively, the patient had an uneventful postoperative course. The success in this patient may be attributed to careful preoperative preparation, flexibility in the choice of techniques for establishment of cardiopulmonary bypass and coronary artery bypass grafting, and careful attention to perioperative fluid management.

Study Design: Aprotinin has recently been shown to reduce postoperative bleeding and transfusion requirements associated with coronary artery bypass grafting. One concern with its use, however, is that it may have a deleterious effect on graft patency because it promotes hemostasis. Forty-seven patients undergoing coronary artery bypass. Forty-seven patients undergoing coronary artery bypass grafting were enrolled in a prospective, randomized double-blind trial of aprotinin to determine the effect of this agent on postoperative bleeding, transfusion requirements, renal function, and graft patency. The study group was comprised of the 32 patients who underwent technically adequate ultrafast CT scans 6 to 8 weeks postoperatively to determine graft patency. Sixteen patients received aprotinin (aprotinin group) and 16 received placebo (control group)., Results: Demographic and operative descriptors were comparable between groups. Postoperative mediastinal and chest tube drainage in the aprotinin group was significantly less than that in the control group (722 vs 1,540 mL; p = 0.0006) and the mean blood transfusion requirements were less, but this did not reach significance (125 vs 297 mL; p = 0.42). Analysis of graft patency by patients revealed that 5 patients in the aprotinin group (31%) had at least one occluded graft, while none of the patients in the control group had an occluded graft (p = 0.04). Analysis by graft revealed that 38 of 43 grafts placed in the aprotinin group were patent, while all 38 grafts placed in the placebo group were patent (88.4 vs 100%; p = 0.057). There was no difference in the incidence of myocardial infarction, renal dysfunction or hematologic indexes at discharge between the groups, or evidence of other thrombotic complications., Conclusion: We conclude that high-dose aprotinin is effective in reducing hemorrhage after coronary artery bypass grafting. However, its routine use should be approached cautiously due to its possible adverse effects on graft patency.

A 71-year-old asymptomatic man who had previously undergone mitral valve replacement with a 31-mm Björk-Shiley 60-degree convexo-concave valve was evaluated noninvasively and found to have a single leg outlet strut separation. Elective valve explantation was performed, and valve testing confirmed that a strut separation was indeed present. Diagnosis and early reoperation to replace a fractured prosthesis may improve patient survival.

A case is reported of a 22-year-old man with heparin-induced thrombocytopenia and thrombosis syndrome and a right atrial foreign body (Greenfield filter). Heparinless cardiopulmonary bypass for removal of the foreign body was conducted by pretreatment with ancrod, a rapid-acting antifibrinolytic of pit viper venom origin. Treatment protocol and a literature review are included in this article.

The rate of calcification within the human thoracic aorta from completion of body growth to advanced old age was examined. Fifty-eight aortae, obtained at necropsy, were dissected into four layers: the complete intima and the separated media, which was subdivided into three tissue samples of equal thickness, defined as the media-inner, -middle, and -outer layers. The sampling sites selected for analysis were from regions of the aortic surface that were free of atherosclerotic plaques. The calcium content within each tissue layer of the aorta was determined. Arterial wall thickness and the cholesterol content of the four layers were also measured. Intimal calcification increased progressively during aging: from 1.6 micrograms Ca/mg tissue at 20 years of age to 5.2 micrograms Ca/mg tissue by 90 years of age. When intima calcium concentration was expressed by tissue volume (w/v), no significant change during aging was found. Medial calcification, as w/v and by w/w, increased throughout aging. Calcium accumulation was most marked in the middle, elastin-rich layer of the media, increasing from 1.4 micrograms Ca/mg tissue at 20 years of age to 49.50 micrograms Ca/mg tissue by 90 years of age. Calcium levels also increased in the other media layers, but at a slower rate than that found within the middle media.

From May 1982 to August 1991, 1200 patients underwent valve replacement with the St. Jude Medical (St. Jude Medical, Inc., St. Paul, Minn.) valve: 615 men (51%) and 585 women, mean age 58 years. Preoperatively, 830 patients (69%) were in functional class III or IV. A total of 611 patients (51%) had the aortic valve replaced, 490 (41%) the mitral valve, 2 (0.2%) the tricuspid valve, and 97 (8%) multiple valves. There were 81 hospital deaths (6.8%). Risk factors included older age (p = 0.0001), female gender (p = 0.02), higher preoperative left ventricular end-diastolic pressure (p = 0.05), previous cardiac operation (p = 0.003), longer aortic crossclamp time (p = 0.0001), and longer cardiopulmonary bypass time (p = 0.0001). Follow-up was 98% complete (3153 patient-years). There were 152 late deaths; 32 (21%) were considered valve-related: six thromboembolism, four valve thrombosis, five anticoagulant-related hemorrhage, eight prosthetic valve endocarditis, one paravalvular leak, and seven sudden death. The 5-year actuarial survival was 75%. Risk factors for late death included older age (p = 0.03), lower preoperative ejection fraction (p = 0.005), longer aortic crossclamp time (p = 0.001), longer cardiopulmonary bypass time (p = 0.0001), previous cardiac operation (p = 0.02), and higher preoperative functional class (p = 0.0001). Actuarial freedom at 5 years from major thromboembolic events and anticoagulant-related hemorrhage was 97% and 95%, respectively. This value for valve thrombosis was 99%, for reoperation 96%, for prosthetic valve endocarditis 98%, and for paravalvular leak 96%. Actuarial freedom from all valve-related events and valve-related death at 5 years was 74% and 94%, respectively. We conclude that the low incidence of valve-related events and low mortality supports the continued use of the St. Jude Medical valve.

The risks for reoperative cardiac surgery are related to the presence of intrapericardial adhesions and the possibility of catastrophic injury at repeat sternotomy. In an attempt to develop an improved pericardial substitute and vascular patch, the feasibility of using autologous peritoneum was evaluated. Twelve mongrel dogs were studied. A peritoneal-rectus fascia patch, including the overlying posterior rectus sheath was harvested, via a lateral abdominal incision, and stored in normal saline. In the first group of six animals, a pulmonary artery (PA) window was created and then closed with the peritoneal-rectus fascia patch. In the second group a secundum atrial septal defect was created and then closed with the peritoneal patch on cardiopulmonary bypass (CPB). In each animal, the peritoneal-rectus fascia patch was used to permit pericardial closure. Autopsies performed at 90 days postoperatively revealed only slight intrapericardial adhesion formation and a mild epicardial reaction. Histological examination of the peritoneal-rectus fascia patches revealed intact morphology with active fibroblasts and smooth muscle cells. Proline 14C absorption and autoradiography detected viable cells in the implanted patches. These findings suggest that a peritoneal-rectus fascia allograft could be useful as a biological membrane, and as a satisfactory pericardial substitute in the development of strategies to reduce the risk for reoperative cardiac surgery.

Acute aortic pathology temporally related to cocaine inhalation may lead to frank rupture or acute aortic dissection. This is a report of an unusual case of a 43-year-old man who presented 9 weeks after experiencing a tearing sensation in his chest while smoking cocaine. The diagnosis was chronic type A aortic dissection with 4+ aortic insufficiency. The successful surgical management included resuspension of the aortic valve and placement of a Dacron tube graft in the ascending aorta such that flow was maintained distally in both the true and false lumens.

Objective: To evaluate the effect of prophylactic procainamide on the frequency of postoperative atrial fibrillation in patients undergoing myocardial revascularization., Design: Prospective, randomized, double-blind, placebo-controlled pilot study., Setting: Surgical intensive care unit and wards at a university hospital affiliate., Patients: A total of 46 patients undergoing myocardial revascularization., Interventions: Twenty-two patients received procainamide (procainamide group) and 24 patients received placebo (control group). Procainamide was administered to the procainamide group within 1 hr of the patient's arrival in the intensive care unit and consisted of an intravenous loading dose (12 mg/kg) followed by a maintenance dose (2 mg/min) of procainamide. The control group received a similar volume of placebo. When the patient was able to take oral medication, the study drug was administered orally in a weight-adjusted dosage., Measurements: Electrocardiograms (EKGs) were continuously monitored. Procainamide and N-acetyl procainamide serum concentrations were measured, and the dosages in the procainamide group were adjusted by an independent observer. The study drug was continued for 5 days or until an event occurred that resulted in dismissal from the study., Main Results: The procainamide group and control group had similar preoperative demographic descriptors and operative variables, except for the mean left ventricular ejection fraction, which was lower in the control group than in the procainamide group (60% vs. 68%, p = .03 [Wilcoxon rank-sum test]). There were no hospital deaths. The number of episodes of postoperative atrial fibrillation was significantly reduced in the procainamide group (5 episodes in 129 patient days at risk [3.9%/day at risk]) compared with the control group (17 episodes in 161 patient days at risk [10.6%/day at risk], p = .04 [Fisher's exact test]). Complication rates were similar in both groups., Conclusions: In a pilot trial, prophylactic procainamide reduced the number of episodes of atrial fibrillation in patients after coronary artery bypass grafting. Procainamide also decreased the number of patients who experienced postoperative atrial fibrillation. However, due to the small sample size, this latter difference was not statistically significant. Further studies are needed to confirm this encouraging trend.

The effect of intraoperative autotransfusion during coronary artery bypass grafting was studied in a randomized double-blind trial involving 38 patients. Nineteen patients had the collected RBCs washed and autotransfused (autotransfusion group), while the remaining patients had their washed cells discarded (control group). Postoperative hemoglobin and hematocrit values were similar. Exposure to banked blood was markedly decreased in the autotransfusion group compared with the control group. In addition, the mean volume of banked packed RBCs transfused per patient was significantly less in the autotransfusion group compared with the control group. Platelet utilization also was markedly decreased in the autotransfusion group. Cryoprecipitate and fresh frozen plasma utilization also was less in the autotransfusion group than in the control group, but this did not reach statistical significance. We conclude that the intraoperative use of autotransfusion decreases the volume of homologous blood products transfused, which results in reduced exposure of the patients to banked blood products.

A 76-year-old woman was found to have a 4 x 2.5-cm saccular aneurysm at the origin of the innominate artery at the time of a reoperative open heart operation. The operative procedure was modified to include repair of the aneurysm with a Dacron patch. During the period of innominate artery occlusion, the patient was cooled to 25 degrees C and the mean arterial pressure was maintained at 90 mm Hg to maximize cerebral protection.

The aim of this study has been to determine whether the presence of lymphocytic infiltrates observed in the histology of ocular allergic conditions in humans or in the late phase of ocular anaphylactic reactions in experimental animals is a non-specific event dependent only on the degranulation of mast cells, or is conditioned by a specific response to antigen. With this in mind, responses to antigen and to a non-immunological mast cell degranulator (compound 48/80) were compared in an experimental model of allergic conjunctivitis. Rats were sensitised to ovalbumin and challenged topically in the left conjunctival sac either with ovalbumin or compound 48/80. The presence of T cells and activated T cells in the infiltrate was studied by immunohistochemical staining on conjunctival tissue obtained at 4, 24, and 48 hours after challenge. Ovalbumin sensitised and challenged rats showed increased numbers of T cells in the conjunctival infiltrate, statistically significant when compared with compound 48/80 challenged rats at 48 hours and with controls at 4, 24, and 48 hours. The number of T cells was significantly higher in compound 48/80 challenged rats only at 48 hours when compared with controls. As for the number of activated T cells, only ovalbumin sensitised and challenged rats showed significantly increased levels of these cells compared with both sensitised animals challenged with compound 48/80 and controls at 4 and 24 hours after challenge. These results suggest that the infiltration of the conjunctiva by activated T lymphocytes is, at least in part, dependent on a specific response to antigen.

To assess the early and late valve-related events, 340 consecutive patients undergoing mitral valve repair from 1969 to 1988 were evaluated. Follow-up was complete, with a mean of 7.5% years and range from 2 to 22 years (cumulative 2456 patient-years). There were 221 (65%) female patients. Rheumatic valvular disease was present in 246 (68%) patients. The remaining patients had ischemic or congenital valve disease, floppy valve or infective endocarditis. At surgery, 47% of the patients had pure mitral incompetence, 43% had mixed mitral stenosis and incompetence and 10% had predominant mitral stenosis. Seventy-three percent of the patients were in functional class III or IV. Twelve percent had had prior heart surgery. Concomitant valve procedures including coronary revascularization were performed in 62.3%. There were 23 hospital deaths (6.8%) but only 3 of these (0.8%) were valve-related in patients who died at reoperation for valve repair failure. There were 4 other early repair failures who survived early reoperation. Of the 317 hospital survivors, there were 127 late deaths, and an actuarial survival of 44 +/- 3.7% (70% CL) at 14 years. Of these, 13 were valve-related or 0.5% patient-year. Late events included thromboembolism (TE) 1% patient-year, anticoagulant bleeding 0.4% patient-year, infective endocarditis (IE) 0.2% patient-year and late reoperation for mitral valve repair failure in 63 patients or 2.8% patient-year. At the late follow-up, 88% of the hospital survivors were in functional class I or II.(ABSTRACT TRUNCATED AT 250 WORDS)

Decreased release of nitric oxide from damaged endothelium is responsible for the impaired endothelium-dependent vasodilator responses found in animal models of vascular disease. Dietary supplementation with fish oils has been shown to augment endothelium-dependent relaxations, principally by improving the release of nitric oxide from injured endothelium. Using forearm venous occlusion plethysmography we studied vascular responses to 60, 120, 180 and 240 nmol/min of acetylcholine (an endothelium-dependent vasodilator) and 3, 6 and 9 nmol/min of glyceryl trinitrate (an endothelium-independent vasodilator) infused into the brachial artery in 23 patients with Type 2 (non-insulin-dependent) diabetes mellitus. NG monomethyl-L-arginine was employed to inhibit stimulated and basal release of nitric oxide from the endothelium. On completion of the baseline studies patients randomly received either fish oil or matching olive oil capsules in a double-blind crossover fashion for 6 weeks followed by a 6-week washout period and a final 6-week treatment phase. Studies, identical to the initial baseline studies, were performed at the end of the active treatment periods at 6 and 18 weeks. Fish oil supplementation significantly improved forearm blood flow responses to each dose of acetylcholine when compared to the vasodilator responses recorded at baseline and after olive oil administration (p < 0.01). Neither fish oil nor olive oil supplementation produced any significant changes in forearm blood flow to the incremental infusions of glyceryl trinitrate when compared with responses recorded during the baseline studies.(ABSTRACT TRUNCATED AT 250 WORDS)

A protocol was developed for the analysis of volatile short chain fatty acids in microsamples of feces, short chain fatty acid (SCFA) extraction was from fecal samples using ethanol incorporating n-hexanoic acid as an internal standard. The SCFAs were converted to pentafluorobenzyl esters with alpha-2,3,4,5,6-pentafluorotoluene and analyzed on a gas-liquid chromatograph equipped with an electron capture detector. One hundred milligrams of sample was routinely used but analysis could be carried out on 20 mg of sample.

Traditional autologous conduits are sometimes unavailable or unsuitable to permit total revascularization during coronary artery bypass grafting. In these patients the results of using nonautologous alternative conduits has been disappointing. Encouraged by the excellent long-term results seen with cryopreserved allograft valves, a clinical protocol was developed to evaluate the use of a commercially cryopreserved allograft saphenous vein (CPV). Our protocol consisted of using CPV when left internal mammary arteries and autologous saphenous vein grafts were unavailable or unsuitable for complete revascularization. Blood group (ABO) typed CPVs were thawed and implanted as required using standard surgical techniques. From December 1989 through June 1991, 19 of 1,602 patients who underwent coronary revascularization had CPVs implanted (1.2%). There were no operative deaths. An attempt was made to evaluate the patency of all grafts with coronary arteriography or ultrafast computed tomographic scans. Fourteen patients were available for patency evaluation. Patency rate in the 14 patients studied at a mean of 7 +/- 2 months (range, 2 to 16 months) were: internal mammary artery, 93% (14/15); saphenous vein graft, 80% (4/5); and CPV, 41% (7/17). The patency of the CPV was significantly less than the patency rate for the saphenous vein and internal mammary artery (p = 0.004). We conclude that the short-term patency rate of CPVs is inferior to that of autologous vessels. Due to its poor patency, we recommend that CPV should only be used when no other autologous conduit is available.

From 1961 through 1987, 9,247 patients underwent an intracardiac repair for valvular heart disease. Five hundred thirty patients had a procedure that included a tricuspid valve operation (6%), with tricuspid valve replacement performed in 175 patients (2%), of whom 154 had a bioprosthetic valve implanted (1.7%). These 154 patients with a bioprosthetic valve in the tricuspid position are the subject of this review. There were 27 males and 127 females. Ages ranged from 10 to 75 years. There was tricuspid valve insufficiency in 139 patients (90%), and stenosis plus insufficiency in 15 (10%). Carpentier-Edwards prostheses were implanted in 83 (54%), Ionescu-Shiley in 55 (35%), Hancock in 12 (8%), and Mitroflow in 4 (3%). Concomitant procedures were performed in 146 patients (95%). At least one previous operation had been performed in 86 patients (56%). Preoperatively, 139 patients were in functional Class III or IV (90%). Hospital death occurred in 20 patients (13%). Logistic regression analysis revealed that incremental risk factors for hospital death included increasing peripheral edema preoperatively (p = 0.04), and use of a Hancock prosthesis in the tricuspid position (p = 0.03). All 134 hospital survivors were followed at a mean of 66.01 months, range 1 to 162 months. There were 70 late deaths (52%). Log-rank test indicated that incremental risk factors for late death were: longer cross-clamp time at repair (p = 0.0007); higher pulmonary artery systolic pressure preoperatively (p = 0.01); earlier date of surgery (p = 0.03); and larger tricuspid prosthesis size (p = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

From a very heterogeneous group of 340 patients undergoing mitral valve reconstruction from 1969 through 1988, 313 hospital survivors were analyzed for factors affecting the occurrence of reoperative mitral valve procedures related to native mitral valve dysfunction. Follow-up was 100% and extended from 1 year to 20 years (mean follow-up, 7.2 years). Sixty-three patients (18.5% of the 340) required mitral valve reoperation at a mean postoperative interval of 6 years (range, 1 to 15 years). Incremental risk factors analyzed for the event late mitral valve failure included age, sex, preoperative New York Heart Association class, cause of valvular disease, pathophysiology of the mitral valve, previous mitral valve operation, mitral valve pathology, and estimation of mitral valve function at operation after repair. Mitral valve pathophysiology affected the actuarial freedom from mitral valve replacement (p = 0.023 [log-rank]). Actuarial freedom from mitral valve reoperation was 90% at 5 years and 80% at 8 years in patients who had either pure mitral regurgitation or isolated mitral stenosis compared with 80% and 72% at 5 and 10 years, respectively, in patients who had mixed mitral stenosis and regurgitation (p = 0.023). Patients undergoing late reoperation were younger (51.7 +/- 1.56 years [+/- the standard error of the mean]) than those not having reoperation (p less than 0.0003). Durability of the repair was less in patients with rheumatic heart disease (p less than 0.025) and greater in patients with ischemic heart disease (p less than 0.004). Seventy-three percent of patients undergoing reoperation had concomitant operations compared with 68% of those not having reoperation (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

The endothelium plays a pivotal role in modulating the reactivity of vascular smooth muscle through the formation of several vasoactive substances. We examined the effects of endothelium-dependent and independent vasodilators on forearm blood flow in 29 patients with Type 2 (non-insulin-dependent) diabetes mellitus and in 21 control subjects, using venous occlusion plethysmography. Via a brachial artery cannula, increasing amounts of acetylcholine and glyceryl trinitrate were infused in doses of 60, 120, 180 and 240 mmol per min and 3, 6 and 9 nmol per min respectively. NG monomethyl-L-arginine, a stereospecific inhibitor of endothelium derived relaxing factor, was infused to inhibit basal and stimulated release of this dilator substance. Reactive hyperaemic forearm blood flow did not differ between groups. Forearm blood flow responses to each dose of acetylcholine were significantly greater in control than diabetic subjects (p less than 0.01 for all doses). NG monomethyl-L-arginine attenuated forearm blood flow from maximal stimulated values when responses were compared with the natural decline to acetylcholine in forearm flow in both control and diabetic subjects (p less than 0.05 for both groups), but had no effect on basal blood flow responses. Forearm blood flow responses to each dose of glyceryl trinitrate were significantly greater in control than diabetic subjects (p less than 0.05 for all). These data provide evidence for endothelial and smooth muscle dysfunction in diabetes which may have important therapeutic implications.