Robert C. Boerth

Mechanism of adriamycin cardiotoxicity: Evidence for oxidative stress

Abstract Adriamycin is a widely used anticancer agent but the cumulative dose-dependent cardiotoxicity severely limits the use of Adriamycin in the treatment of neoplastic diseases. Recent evidence suggests that Adriamycin forms reactive free radical species which may oxidize cellular components and produce the cardiomyopathy. Sulfhydryl donors and antioxidants have been effective in preventing acute Adriamycin cardiotoxicity in animal models presumably by scavenging the free radicals generated by Adriamycin. The sulfhydryl donors, namely cysteamine and N-acetyl cysteine, do not interfere with Adriamycins antitumor activity. The results from these studies give considerable hope that the chronic cardiotoxicity from Adriamycin may be attenuated in people, thereby givinh additional therapeutic benefit from this antitumor agent.

Assessment of ventricular size and function in congenitally corrected transposition of the great arteries

Twenty-four quantitative cineangiographic studies were performed in 19 patients with congenitally corrected transposition of the great arteries to assess right and left ventricular size and function. Ages ranged from 7 days to 44 years and associated lesions included ventricular septal defect (13 of 19), pulmonary stenosis (9 of 19), and systemic (tricuspid) valvular insufficiency (7 of 19). Systemic (anatomically right) ventricular end-diastolic volume was within normal limits in most patients and averaged 119% of predicted normal. Pulmonary (anatomically left) ventricular end-diastolic volume also was normal in most patients, averaged 112% of predicted, and was not different from systemic (right) ventricular end-diastolic volume. Systemic ventricular ejection fraction (RVEF) averaged 0.61 +/- 0.02 and was not different from pulmonary ventricular ejection fraction (LVEF) (0.65 +/- 0.02), but important differences were apparent when age was considered. With exclusion of 2 patients with hypoplastic systemic ventricles and 2 studies performed less than 6 months after open heart surgery, all 12 patients aged less than 10 years had a normal RVEF, whereas 2 of 5 patients aged greater than 17 years had a definitely low RVEF and 1 of 5 had a value at the lower limit of normal. In children, systemic and pulmonary ventricular pump function is usually normal in congenitally corrected transposition of the great arteries and any deviation from normal should suggest ventricular hypoplasia or an increase in afterload. After childhood, systemic ventricular dysfunction is more common and may reflect the inability of the anatomic right ventricle to function as the systemic pumping chamber over a normal lifetime in most patients with congenitally corrected transposition of the great arteries.

Time Required for Complete Recovery from Chronic Propranolol Therapy

Abstract Propranolol could not be detected in samples of plasma and left atrium obtained from eight patients during coronary bypass surgery 36 to 48 hours after withdrawal from chronic therapy. The norepinephrine sensitivity of strips of left atria obtained from four similar patients was not different from that in six control patients who had not previously received propranolol. In three ambulant patients, serial estimates of the chronotropic and inotropic responses to isoproterenol were made at daily intervals during withdrawal from propranolol. Isoproterenol sensitivity became stable or returned to control levels within 48 hours. These findings were confirmed by experiments in the rat. A withdrawal time of 48 hours thus appears sufficient for complete recovery from the cardiac effects of propranolol and any possibly active metabolites, and coronary bypass surgery should present no additional hazard. (N Engl J Med 289:607–609, 1973)

Right ventricular volume characteristics before and after palliative and reparative operation in tetralogy of Fallot.

SUMMARY Right heart volume data were obtained in 63 patients with tetralogy of Fallot. The patients were divided into three groups: 1) preoperative tetralogy (N = 34); 2) post shunt procedure (N = 14); 3A) post repair without outflow patch (N = 10); 3B) post repair with an outflow patch (N = 8). In Group 1 right ventricular end-diastolic volume (RVEDV), RV ejection fraction (EF), and RV systolic output (SO) were all mildly depressed. In post shunt patients, RVEDV was normal but RVEF remained depressed. RVEDV and RVSO increased following a shunt procedure, and these variables were larger in patients with a large versus a small shunt. In Group 3A RVEDV, RVEF, and RVSO were normal. In contrast in patients in Group 3B, RVEDV was increased averaging 177 ± 15% of normal, RVEF was depressed averaging 0.45 ± 0.04, and RVSO was normal. RV size and pump function are abnormal in patients whose operation requires an outflow tract patch and the factors which may contribute to these abnormalities include a higher RV peak pressure, pulmonary incompetence, and a larger noncontractile outflow tract. Longitudinal studies relating these variables to clinical performance and exercise testing will be important in assessment of the importance of these abnormalities.

Toxicologic enhancement by a combination of drugs which deplete hepatic glutathione: Acetaminophen and doxorubicin (Adriamycin)

Abstract A number of chemicals are metabolized to reactive and toxic intermediates. Some reactive metabolites are detoxified by conjugation with glutathione (GSH). When endogenous GSH levels are low, or when excessive quantities of reactive metabolites are produced, the metabolite can bind to essential cellular macromolecules causing toxicity. Since both acetaminophen and doxorubicin (Adriamycin) deplete hepatic GSH, it was hypothesized that under certain conditions, doxorubicin might potentiate the hepatic centralobular necrosis characteristically induced by high doses or chronic administration of acetaminophen. Such an interaction could have clinical significance since acetaminophen is used in high doses as an analgesic for cancer patients being treated with doxorubicin. In male Swiss ICR mice, doxorubicin 20 mg/kg ip enhanced the toxicity of acetaminophen in doses of 250 to 500 mg/kg. Compared with acetaminophen alone, combination treatment produced a 15-fold increase in lethality, a dose-dependent, 90-fold increase in SGPT concentration, and an increase in the incidence and severity of hepatic centralobular necrosis. Dororubicin pretreatment caused both a 66% increase in the covalent binding of acetaminophen to hepatic protein at 4 hr, and a further depletion of hepatic GSH, 18% below that induced by acetaminophen alone. The timing of treatments to allow congruence of peak hepatic GSH depletion was necessary for toxicologic enhancement, suggesting a crucial protective role for GSH, although contributions from other toxicologic mechanisms cannot be excluded. Under certain clinical circumstances, this interaction could occur in cancer patients being treated with doxorubicin and acetaminophen.

Myocardial dysfunction in children with acute meningococcemia

Acute meningococcemia is frequently associated with cardiovascular collapse of uncertain cause. Review of the records of 12 consecutive children revealed clinical evidence of myocardial dysfunction in six (50%). Subsequently myocardial function was prospectively assessed clinically and echocardiographically in 12 children. Seven (58%) of the 12 children had echocardiographic evidence of myocardial dysfunction as defined by a depressed left ventricular shortening fraction (LVSF). The mean LVSF in these seven children was 0.25 +/- 0.03, as compared with the mean LVSF of 0.39 +/- 0.7 in the remaining children. The LVSF estimate of myocardial function strongly correlated with cardiac output as measured by standard thermodilution (r = 0.98, P less than 0.01). Acute meningococcemia was not fatal in those children without evidence of myocardial dysfunction. In contrast, three of the seven children with evidence of myocardial dysfunction died. In four children, echocardiographic evidence of left ventricular dysfunction preceded cardiovascular collapse and clinical recognition of myocardial dysfunction. In children with an initially low LVSF, recovery of LVSF was associated with survival. Children with acute meningococcemia may have impaired myocardial function as indicated by depressed LVSF, resulting in low cardiac output despite normal intravascular volume. Thus, in addition to restoring intravascular volume, knowledge of the status of myocardial function may help direct therapy toward optimizing myocardial contractility.

Effect of sulfhydryl-containing compounds on the antitumor effects of adriamycin.

Abstract The lethality of single doses of adriamycin (ADR) in male mice has been reported to be antagonized by concurrent administration of the sulfhydryl compounds cysteamine (CYS) or N -acetylcysteine (NAC). The present investigation was undertaken to determine whether CYS and NAC also have an effect on the antitumor activity of ADR. The life span of male mice bearing a transplantable Ehrlich ascites carcinoma was significantly increased by ADR administered intraperitoneally for 4 successive days at sublethal dosages of 1.5 or 2.5 mg/kg/day. CYS or NAC (50 and 100 mg/kg ip, respectively) administered 1 hr before and 7 hr after ADR treatment did not inhibit the antitumor activity of ADR and further increased the life span of these tumorbearing animals. The uptake of ADR by Ehrlich ascites cells in vitro was not affected by CYS or NAC. ADR-induced inhibition of [ 3 H]thymidine incorporation into DNA of Ehrlich ascites cells in vitro was also not affected by CYS or NAC. The mechanism of sulfhydryl-induced protection against the cardiotoxicity of ADR appears not to interfere with the antitumor activity of ADR.

Myocardial injury in infants with congenital heart disease: Evaluation by creatine kinase MB isoenzyme analysis☆

Total creatine kinase (CK) and the myocardial isoenzyme CK MB activity were prospectively determined in 282 children hospitalized for cardiac catheterization and evaluation for suspected congenital cardiac abnormalities and compared with a hospitalized control group of children without such abnormalities. The percent CK MB and CK MB activity were abnormally elevated in symptomatic children with a large left to right shunt due either to a large ventricular septal defect (n = 22; p less than 0.001) or to complete atrioventricular canal (n = 10; p less than 0.001). Serum CK MB activity and percent CK MB were significantly related to the size of the shunt and the age of presentation with clinical symptoms of congestive heart failure in infants with a ventricular septal defect. CK MB activity was abnormally elevated in infants with symptomatic coarctation of the aorta, either with or without a ventricular septal defect (n = 15; p less than 0.001), and in infants with symptomatic aortic stenosis (n = 4; p less than 0.02). In contrast, CK MB activity was normal in asymptomatic children with coarctation of the aorta (n = 14) or aortic stenosis (n = 8) despite comparable systolic pressure gradients. CK MB activity and percent CK MB were abnormally elevated in those children with the cyanotic congenital cardiac abnormalities of either transposition of the great arteries (n = 32; p less than 0.001) or right ventricular outflow tract obstruction (n = 31; p less than 0.001). These results suggest that children with congenital cardiac abnormalities may have significant myocardial cell injury and release of CK MB that may be detected by the determination of serum CK MB activity. Cell injury may be secondary to arterial desaturation or acute pressure-volume overload, or both, as manifested by clinical symptoms of heart failure and measured hemodynamic variables.

Right and left heart size and function in infants with symptomatic coarctation.

Right and left heart volumes, ejection fractions and entricular outputs were determined from biplane cineangiocardiograms in infants with symptomatic coarctation of the aorta and correlated with clinical and hemodynamic alterations. Patients were divided into two age groups: group 1, ages 3.5 to 14 days and group 2, 5 weeks to 71/2 months. Infants in group 1 had severe depressions of left ventricular ejection fraction and output associated with normal left ventricular size. The massive cardiomegaly in these infants results from right heart enlargement secondary to left-to-right atrial shunting, and pulmonary hypertensive right heart failure, and possibly amore distensible right than left ventricle. Infants in group 2 also have right, and to a lesser degree, left heart enlargement. Group 2 patients differ from group 1 infants in having less impairment of left heart pump function and significant left ventricular myocardial hypertrophy. Echocardiographic measurements of left ventricular pump function are normal or increased inpostoperative patients. Thus alterations of left ventricular function in infants with symptomatic coarctation appear to be largely afterload related and do not indicate permanent impairment of left ventricular contractile function.

Left heart volume characteristics following ventricular septal defect closure in infancy.

SUMMARY Left ventricular and left atrial volume, left ventricular ejection fraction, and left ventricular muscle mass were determined preoperatively and postoperatively in 13 patients who underwent surgical closure of ventricular septal defects in the first two years of life. Left ventricular end-diastolic volume and systolic output averaged 255 ± 19% (± SEM) and 240 ± 19% of normal, respectively, before operation but fell to within normal limits postoperatively. Left ventricular ejection fraction was normal preoperatively (100 ± 4% of normal) and remained so after correction (106 ± 3%, NS). Left ventricular mass was mildly elevated at the preoperative catheterization (271 ± 21%) and decreased significantly following repair (P < 0.001). However, the postoperative left atrial volume (147 ± 14%) remained abnormal (P > 0.05). These data suggest that when early surgical closure of a ventricular septal defect is necessary because of failure of medical management, good results with regard to postoperative left ventricular size and function can be expected.