Secondary alcohol metabolites mediate iron delocalization in cytosolic fractions of myocardial biopsies exposed to anticancer anthracyclines. Novel linkage between anthracycline metabolism and iron-induced cardiotoxicity.

The cardiotoxicity of doxorubicin (DOX) and other quinone-containing antitumor anthracyclines has been tentatively attributed to the formation of drug semiquinones which generate superoxide anion and reduce ferritin-bound Fe(III), favoring the release of Fe(II) and its subsequent involvement in free radical reactions. In the present study NADPH- and DOX-supplemented cytosolic fractions from human myocardial biopsies are shown to support a two-step reaction favoring an alternative mechanism of Fe(II) mobilization. The first step is an enzymatic two-electron reduction of the C-13 carbonyl group in the side chain of DOX, yielding a secondary alcohol metabolite which is called doxorubicinol (3.9 +/- 0.4 nmoles/mg protein per 4 h, mean +/- SEM). The second step is a nonenzymatic and superoxide anion-independent redox coupling of a large fraction of doxorubicinol (3.2 +/- 0.4 nmol/mg protein per 4 h) with Fe(III)-binding proteins distinct from ferritin, regenerating stoichiometric amounts of DOX, and mobilizing a twofold excess of Fe(II) ions (6.1 +/- 0.7 nmol/mg protein per 4 h). The formation of secondary alcohol metabolites decreases significantly (Pi < 0.01) when DOX is replaced by less cardiotoxic anthracyclines such as daunorubicin, 4'-epi DOX, and 4-demethoxy daunorubicin (2.1 +/- 0.1, 1.2 +/- 0.2, and 0.6 +/- 0.2 nmol/mg protein per 4 h, respectively). Therefore, daunorubicin, 4'-epi DOX, and 4-demethoxy daunorubicin are significantly (P < 0.01) less effective than DOX in mobilizing Fe(II) (3.5 +/- 0.1, 1.8 +/- 0.2, and 0.9 +/- 0.3 nmol/mg protein per 4 h, respectively). These results highlight the formation of secondary alcohol metabolites and the availability of nonferritin sources of Fe(III) as novel and critical determinants of Fe(II) delocalization and cardiac damage by structurally distinct anthracyclines, thus providing alternative routes to the design of cardioprotectants for anthracycline-treated patients.

Relation of the -174 G/C polymorphism of interleukin-6 to interleukin-6 plasma levels and to length of hospitalization after surgical coronary revascularization.

Interleukin (IL)-6 plasma levels are predictive of major cardiovascular events. The -174 G/C promoter polymorphism of the IL-6 gene affects basal levels in vivo and transcription rates in vitro, but its association with IL-6 acute phase levels among patients with coronary artery disease has not been investigated. In 111 patients with multivessel coronary artery disease undergoing elective coronary artery bypass graft surgery, we prospectively assessed genotype at position -174 and serial blood levels of IL-6 and other inflammatory indexes. Clinical and surgical characteristics did not differ among genotypic groups. IL-6 levels--measured daily up to 72 hours before surgery, after surgery, and at discharge--showed a mean 17-fold increase, peaking at 24 hours (p <0.0001). IL-6 levels (but not fibrinogen, white-blood cell count, and C-reactive protein values) differed significantly according to the -174 genotype (p = 0.042 for difference between areas under the curve), the 62 GG homozygotes exhibiting higher concentrations than the 49 carriers of the C allele (widest difference at 48 hours, p = 0.015 in multivariate analysis). GG homozygosity was associated with longer stays in the intensive care unit (2.5 +/- 3.4 vs 1.4 +/- 0.9 days, p = 0.02) and in the hospital (6.7 +/- 4.0 vs 5.3 +/- 1.4 days, p = 0.02) than C carriership. Rates of postoperative death, myocardial infarction, and stroke were 8% in GG homozygotes and 2% in C-carriers (p = 0.16). The IL-6-174 GG genotype is associated with higher acute phase levels of IL-6 and with longer stays in the hospital and in the intensive care unit than C allele carriership after surgical coronary revascularization.

Elevated levels of C-reactive protein before coronary artery bypass grafting predict recurrence of ischemic events.

C-reactive protein was measured in 86 patients undergoing coronary artery bypass graft surgery. Patients were followed up for 3.2 years (range 1 to 6). Patients with C-reactive protein > or = 3 mg/L had significantly increased risk of recurrent ischemia at 1 to 6 years after intervention.

Comparison of response to serotonin of radial artery grafts and internal mammary grafts to native coronary arteries and the effect of diltiazem.

We studied the response of radial artery (RA) or left internal mammary artery grafts to the intraluminal infusion of serotonin in 22 consecutive patients 1 year after the operation, subsequently evaluating the effect of diltiazem in 9 patients. Serotonin causes a significant vasoconstriction of the RA grafts, but not of the left internal mammary artery grafts, whereas oral diltiazem treatment does not prevent the effect of the higher dose of serotonin on RA grafts.

Superior extension of intraoperative brain damage in case of normothermic systemic perfusion during coronary artery bypass operations.

OBJECTIVE: Despite the controversies on the potential detrimental effects of normothermic cardiopulmonary bypass on neurologic outcome, to date no correlation between the severity of intraoperative brain lesions and the cardiopulmonary bypass temperature used at operation has been reported. This study compares the prevalence and the severity of brain lesions in patients who underwent operation in condition of normothermic versus hypothermic systemic perfusion. METHODS: Data are derived from the analysis of 2987 consecutive primary isolated myocardial revascularizations performed at our institution between April 1990 and January 1997. Of these cases, 1385 procedures were hypothermic and 1602 procedures were normothermic systemic perfusion. In all cases the neurologic outcome and extent of ischemic areas were prospectively recorded. RESULTS: Overall, 31 patients had a perioperative stroke (1.0%). The prevalence of neurologic events was similar in the 2 groups (15 cases in the hypothermic group and 16 cases in the normothermic perfusion group; P, not significant). However, the mean Glasgow Outcome Scale score and computed tomography-demonstrated extent of brain lesions were significantly worse in the normothermic group. CONCLUSIONS: Although the prevalence of intraoperative stroke was similar with hypothermic or normothermic cardiopulmonary bypass, the use of normothermic systemic perfusion was associated with more extended brain damage at computed tomographic scan and with a worse neurologic outcome. These results demand caution in the use of normothermic cardiopulmonary bypass and claim further investigation on the neurologic safety of normothermia.

Topical use of tranexamic acid in coronary artery bypass operations: a double-blind, prospective, randomized, placebo-controlled study.

OBJECTIVES: We sought to investigate the effect of topical application of tranexamic acid into the pericardial cavity in reducing postoperative blood loss in coronary artery surgery. METHODS: A prospective, randomized, double-blind investigation with parallel groups was performed. Forty consecutive patients undergoing primary coronary surgery were randomly assigned to group 1 (tranexamic acid group) or group 2 (placebo group). Tranexamic acid (1 g in 100 mL of saline solution) or placebo was poured into the pericardial cavity and over the mediastinal tissues before sternal closure. The drainage of mediastinal blood was measured hourly. RESULTS: Chest tube drainage in the first 24 hours was 485 +/- 166 mL in the tranexamic acid group and 641 +/- 184 mL in the placebo group (P =.01). Total postoperative blood loss was 573 +/- 164 mL and 739 +/- 228 mL, respectively (P =.01). The use of banked donor blood products was not significantly different between the two groups. Tranexamic acid could not be detected in any of the blood samples blindly collected from 24 patients to verify whether any systemic absorption of the drug occurred. There were no deaths in either group. None of the patients required reoperation for bleeding. CONCLUSIONS: Topical application of tranexamic acid into the pericardial cavity after cardiopulmonary bypass in patients undergoing primary coronary bypass operations significantly reduces postoperative bleeding. Further studies must be carried out to clarify whether a more pronounced effect on both bleeding and blood products requirement might be seen in procedures with a higher risk of bleeding.

The role of antithrombin III in the perioperative management of the patient with unstable angina.

BACKGROUND: To evaluate the effectiveness of intraoperative administration of antithrombin III (AT III) to improve anticoagulation and preserve the hemostatic mechanisms during cardiopulmonary bypass (CPB) in patients with unstable angina under heparin treatment. METHODS: We divided 22 patients, scheduled for coronary artery bypass grafting, into two groups. Group A (11 patients) received 3000 International Units (IU) of AT III concentrates plus heparin before aortic cannulation. Group B (11 patients) received only heparin. Blood drainage, allogeneic blood transfusions, and intraoperative activated coagulation time were recorded. Also, AT III, thrombin-antithrombin complex (TAT), fragment 1.2 (F 1.2), and D-dimers were measured during the operation and the first postoperative day. RESULTS: Group A patients had fewer transfusions and had less chest-tube drainage. In group A, AT III levels increased after AT III concentrates administration and were always higher than in group B. In group B, F 1.2 and TAT increased significantly more after CPB and at the end of operation. Differences in D-dimers between the groups were not significant. CONCLUSIONS: Intraoperative administration of AT III concentrates allowed adequate anticoagulation during CPB and attenuated the coagulative cascade activation and the consequent consumptive coagulopathy.

Individualized surgical strategy for the reduction of stroke risk in patients undergoing coronary artery bypass grafting.

BACKGROUND: This study was designed to evaluate the efficacy of a protocol of systematic screening of the ascending aorta and internal carotid arteries and individualization of the surgical strategy to the ascending aorta and internal carotid arteries status in reducing the stroke incidence among patients undergoing coronary artery bypass grafting. METHODS: On the basis of a pre- and intraoperative screening of the ascending aorta and internal carotid arteries, 2,326 consecutive patients undergoing coronary artery bypass grafting were divided in low, moderate, and high neurologic risk groups. In the high-risk group dedicated surgical techniques were always adopted and the reduction of the neurologic risk was considered more important than the achievement of total revascularization. RESULTS: The incidence of perioperative stroke in the high-risk group was similar to those of the other two groups (1.1 versus 1.3 and 1.1%, respectively; p = not significant); however, angina recurrence was significantly more frequent in the high-risk group. CONCLUSIONS: The described strategy allows a low rate of perioperative stroke in high-risk patients undergoing coronary artery bypass grafting. Whether the reduction of the neurologic risk outweighs the benefits of complete revascularization remains to be determined.

Use of the radial artery for myocardial revascularization.

BACKGROUND: The radial artery was first used as a coronary graft by Carpentier and associates in 1973 but, due to the disappointing results, it was abandoned. In 1992 its revival coincided with the widespread use of calcium-channel blockers in cardiovascular surgery, in the belief they could prevent spasm. METHODS: From January 1993 to October 1995 we operated on 109 patients for myocardial revascularization employing the radial artery with two different surgical techniques: in 95 patients (group 1) it was "pretreated" by opening its fascia after a gentle hydrostatic dilation and then anastomosed to the aorta; in 14 patients (group 2) it was branched to another conduit. We had two operative deaths (1.82%). RESULTS: At a mean interval of 532.42 days 105 patients are still alive, 2 (1.86%) having died of abdominal tumors. Fifty-six patients (52.33%) underwent angiography at a mean interval of 334.42 days: the patency of the radial artery was 88.88% in group 1 and 62.50% in group 2. Indications and contraindications are discussed. CONCLUSIONS: The radial artery is an easily manageable conduit whose early patency is very promising, although a longer follow-up is mandatory.

Biochemical changes in extracorporeal circulation in patients.

The effect of priming extracorporeal perfusion pumps with 50% and 80% diluted homologous blood on the serum electrolytes, acid-base status and plasma osmolality has been investigated in 103 patients undergoing open-heart surgery for congenital and acquired heart disease. The value in prognosis of plasma osmolality is discussed.

Changes of serum pyruvate and lactate in open-heart surgery.

In 20 patients under extracorporeal bypass, a study was undertaken of the changes in plasma of lactate and pyruvate, the lactate/pyruvate ratio and the lactate excess. A decrease has been found in the pyruvate and an increase in the other values lasting for the first days of the post-operative period. The causes may be many, such as changes in the oxidation potential, blood transfusions and liver function, and these may be manifested in an increase in the serum glutamic oxalacetic transaminase, glutamic pyruvic transaminase, lactic dehydrogenase, and gamma-glutamyl transpeptidase.

Changes of serum magnesium ions in open heart surgery.

The changes of magnesium in the serum were studied in 20 patients undergoing cardiac valve substitution procedures in extracorporeal circulation. The serum magnesium ions were determined before the onset of the anesthesia, at the beginning and at the end of the extracorporeal circulation, at the end of surgery and during the first post-operative day. A slight magnesium ion deficiency was observed even in the initial serum levels, probably due to the pre-operative diuretic therapy. The hypomagnesemia observed during the bypass was related to haemodilution and urinary losses. A limited increase in magnesemia, probably caused by the diffusion of the ion towards the vascular compartment, was observed at the end of the extracorporeal circulation. A new decrease was found during the post-operative stage, perhaps caused by the action of diuretics, which were administered.

Rheological and biochemical changes in open heart surgery with extracorporeal circulation and moderate hypothermia.

The plasma enzymes, glucose, urea nitrogen, total and conjugated bilirubin, osmolality, acid--base balance and rheological data have been studied in a group of patients who underwent open heart surgery to replace the stenotic or insufficient aortic valve. The aim of this study was to assess our operative conditions and to compare results with those obtained by other authors.

Plasma cortisol in open-heart surgery.

In view of disagreements about changes in plasma cortisol, during and after open-heart surgery, a group of patients was studied with both unconjugated plasma cortisol, and anaesthetic, surgical and pharmacological factors that could interfere with the response, being analysed.

Magnesium metabolism in open-heart surgery.

The levels of magnesium in serum, urine and erythrocytes were studied in 22 patients undergoing cardiac surgery for valvular prosthesis. Magnesium values were correlated with serum albumin and non-esterified fatty acids (NEFA). Data were collected before anesthesia, 10 min after sternotomy, heparinization and declamping of the aorta and in the 1st postoperative day. A slight decrease in magnesemia was observed before extracorporeal circulation (ECC) and was mainly due to haemodilution. The correlation of magnesium with NEFA was significant only after heparinization. The use of the St Thomas solution as cardioplegia fully corrected the hypomagnesemia previously reported during ECC as well as in the 1st postoperative day. A moderate hypermagnesemia was observed at the end of ECC, but no patient reached dangerous levels of serum magnesium. Urinary losses increased during and after ECC. Red blood cell magnesium showed a slight increase before ECC, followed by a significant reduction at the end of ECC.

Haemodynamic and metabolic effects of surface rewarming after coronary revascularization.

Cardiac surgery is often associated with a postoperative increase in the patient's metabolic rate; surface rewarming has been suggested to decrease the energy expenditure by preventing hypothermia. Thirty patients, undergoing coronary revascularization, were randomly divided into two groups; after surgery group A was rewarmed by a new device that acts by both conduction and convection, while group B was just covered with cotton blankets. Blood, oesophagus and skin (thigh and foot) temperatures were recorded on admission to the intensive care unit (ICU) and 30, 60, 90, 180, 270, and 450 min later. Haemodynamic parameters, oxygen delivery, calculated oxygen consumption, and plasma lactate concentration were assessed as well. Group A warmed up quicker than group B as far as the skin was concerned while the core temperature was unaffected. Group A was also characterized by lower cardiac indices and oxygen consumption. As the occurrence of a dependence of oxygen consumption on delivery could be reasonably ruled out in warmed patients because blood lactate levels were lower than in the controls, we conclude that surface rewarming might have some positive effect in decreasing metabolic demand after cardiac surgery even if the patient's core temperature is little affected. The inhibition of skin temperature receptors could possibly explain this finding.

Red blood cell energy metabolism during cardiopulmonary bypass.

BACKGROUND: During cardiopulmonary bypass (CPB) an intracellular ATP deficit could theoretically play a role in changes of erythrocyte shape and deformability caused by mechanical trauma. We therefore studied erythrocyte energy metabolism in 12 patients undergoing normothermic CPB for myocardial revascularization. METHODS: Blood samples were collected prior to and 45 minutes after CPB beginning and analyzed for erythrocyte ATP, ADP, and AMP and their metabolites, erythrocyte NAD and NADP, plasma and whole blood lactate (Lact(p) and Lact(b) respectively), and whole blood pyruvate (Pyr(b)). RESULTS: Values were expressed as mean +/- standard deviation or median (lower and higher quartiles) on the ground of a test for normality. During CPB erythrocyte nucleotides and their metabolites did not change significantly (ATP: 60.2+/-12.1 vs. 68.3+/-13.0; ADP: 12.2+/-3.6 vs. 12.0+/-3.1; AMP: 0.43+/-24 vs. 0.44+/-0.26; adenosine: 0.063 (0.034-0.203) vs. 0.77 (0.032-0.221); inosine: 0.064 (0.023-0.072) vs. 0.075 (0.025-0.111); hypoxanthine: 0.330+/-0.272 vs. 0.367+/-0.223; xanthine: 0.193+/-0.090 vs. 0.220+/-0.095; NAD: 3.149+/-0.743 vs. 3.358+/-0.851; values in microM/mM packed red blood cell hemoglobin) while NADP increased (2.110+/-0.390 vs. 2.433+/-0.288 microM/mM packed red blood cell hemoglobin; p<0.05). Ringer lactate, with which the extracorporeal circuit was primed, caused Lact(p) to increase (1.87+/-0.81 vs. 3.27+/-1.15 mM/l; p<0.01). Some lactate entered erythrocytes since Lact(p)/Lact(b) ratio did not change (1.09+/-0.25 vs. 1.07+/-0.23) and some was transformed into pyruvate since Pyr(b) increased [62.9 (30.3-73.3) vs. 100.5 (61.0-146.9) microM/l; p<0.01]. Lact(b)/Pyr(b) ratio did not change significantly [22.6 (16.1-40.5) vs. 27.9 (17.5-35.2)] so that NAD/NADH ratio and, consequently, the rate of glycolysis were unlikely to change too. CONCLUSIONS: Erythrocyte energy metabolism is not affected by CPB, at least during the period of time taken into account in this study.

Somatomedin-C plasma levels after coronary revascularization.

The decrease of Somatomedin-C (SM-C) plasma levels has been recently proposed as an index of acute malnutrition in critically ill patients. In this study SM-C values were determined before surgery for coronary revascularization, on the 2nd and 5th postoperative day. Twenty-four patients were admitted to the study; most of them (16 cases; 66%) presented with an increase of SM-C levels after surgery unlike 8 patients who showed unchanged or decreased levels. Multivariated analysis was applied to the factors that may affect SM-C values. SM-C significantly related to the Modified Predictive Nutritional Index, which was calculated prior to surgery, while no significant relationship was observed with patient age and type of oxygenator. No sign of liver damage was observed, so we concluded that decreased and, perhaps, unchanged SM-C levels after coronary revascularization were probably caused by acute nutritional deficiency. The incidence of this finding was remarkably high (33%) in spite of the absence of apparent malnutrition before surgery.

Perioperative management of a patient with Werlhof disease undergoing myocardial revascularization.

We herein report the case of a patient with idiopathic thrombocytopenic purpura (Werlhof disease) and coronary artery disease undergoing myocardial revascularization. The use of monomeric immunoglobulins, corticosteroids, platelets transfusion, use of a cell saver, normothermic cardiopulmonary bypass, aprotinine and homologous blood transfusion were combined in order to minimize the risk of bleeding complications in the postoperative period.

Creatine-kinase isoenzyme pattern in colonic infarction consequent to acute aortic dissection. A case report.

Bowel infarction can complicate acute aortic dissection (AAD); in that case early diagnosis, which decreases the high mortality, is often difficult. We report the case of one patient who underwent surgery for AAD and developed a colonic infarction, which was clinically manifest on the 4th postoperative day. However, bowel ischemia was suspected already 48 hours after surgery, on the basis of the suggestive CK pattern and the absence of myoglobin in plasma. Total CK activity reached the highest level only 48 hours after surgery (92,800 U/l); the peak was coincident with LDH, which increased proportionally less; CK-MM constituted 100% of total CK activity. The absence of myoglobin in plasma excluded the presence of rhabdomyolysis. We conclude that such laboratory findings suggest the occurrence of severe bowel ischemia.