Epirubicin cardiotoxicity: a study of 135 patients with advanced breast cancer.

The cardiotoxicity of epirubicin (EPI) was evaluated clinically, radiologically, with ECG, and with multiple ECG-gated radionuclide determination of the left ventricular ejection fraction (LVEF) during rest in 135 patients with advanced breast cancer. The EPI doses were 60 mg/m2 on days 1 and 8 every 4 weeks or 45 mg/m2 plus vindesine 3 mg/m2 on the same schedule. The median cumulative dose of EPI was 500 mg/m2 (range, 47 to 1,563). Eight of the 135 patients developed congestive heart failure (CHF). Of 67 patients treated with EPI less than 500 mg/m2, none developed CHF. Among 48 patients treated with doses between 500 and 1,000 mg/m2, one had CHF (2%; 95% confidence limits, 0.1 to 11.1). Among 20 patients who received EPI from 1,000 to 1,563 mg/m2, seven developed CHF (35%; 95% confidence limits, 15.4 to 59.2). Four patients died due to cardiotoxicity. The risk of EPI cardiotoxicity at the present schedule is considerable at doses above 1,000 mg/m2. At doses between 500 and 1,000 mg/m2 the risk of CHF decreases, and at doses below 500 mg/m2, it is negligible. For all patients, the prevalence of CHF was 6% and the sensitivity of LVEF high (95%), mainly due to the low incidence of CHF. Among the 20 patients who received EPI at more than 1,000 mg/m2, the prevalence of CHF was 35% and the sensitivity only 64%. The specificity was maximally 62%. Our results suggest that LVEF is of no value as a predictor for CHF.

Acute effects of alcohol on left ventricular function in healthy subjects at rest and during upright exercise.

Six healthy men, aged 23 to 30 years, were studied by radionuclide angiocardiography at rest and at 2 submaximal exercise levels in the upright position during increasing alcohol intoxication. At light intoxication (serum ethanol 23 mmol/liter), the median value of left ventricular (LV) ejection fraction (EF) at rest decreased by 5%. At heavy intoxication (serum ethanol 45 mmol/liter), the median LVEF decreased at rest by 11% and during 75% submaximal exercise by 6%, heart rate at rest increased (median 81 vs 62 beats/min), and systolic blood pressure decreased during 50% submaximal exercise (median 145 vs 163 mm Hg). No significant changes of plasma epinephrine concentrations were recorded, whereas plasma norepinephrine concentrations were increased by 24% at rest during light intoxication and by 30 to 38% during heavy intoxication. No changes of LVEF and plasma catecholamine levels were recorded after ingestion of isovolumic, isocaloric drinks as compared with values obtained before intake. Thus, influences of ingestion per se and repeated investigations of LV function were excluded. These findings suggest that in healthy subjects alcohol intoxication causes a dose-dependent impairment of cardiac contractility. Compensatory mechanisms may account for a reduced influence during exercise.

Cardiac performance in patients with asymptomatic alcoholic cirrhosis of the liver.

Twenty patients with biopsy-proved alcoholic cirrhosis of the liver and no cardiac symptoms entered a noninvasive investigation program in which cardiac performance was evaluated. One patient was excluded from the study because of a significant ethanol content in the serum at the time of investigation and 4 patients were excluded because of significant electrocardiographic ST-segment changes during exercise testing. Fifteen patients (12 men, 3 women, median age 47 years) who had abstained from alcohol drinking for at least 2 months were studied by exercise testing, echocardiography, measurement of systolic time intervals and left ventricular (LV) radionuclide ejection fraction (EF) at rest and during submaximal exercise. Twelve healthy persons of the same age served as control subjects. Heart rate at rest was significantly elevated in the patient group, median 90 beats/min (range 62 to 128) vs 73 beats/min (range 61 to 89) (p less than 0.02). No significant differences were found in physical work capacity and systolic time intervals, and echocardiographic parameters did not differ with the exception of left atrial dimension (median 36 mm [range 22 to 47] in the patient group and 31 mm [range 17 to 38] in the control subjects, p less than 0.05). No significant difference was found in LVEF at rest. During exercise, however, the median LVEF increased only 6% in the patients versus 14% in the control subjects (p less than 0.05). The results of this study suggest that patients with alcoholic liver cirrhosis, although free of cardiac symptoms, may have a latent or preclinical cardiomyopathy that is manifest during physical stress.

Prospective evaluation of chronic cardiotoxicity due to high-dose epirubicin or combination chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil.

In a prospective study the left ventricular ejection fraction (LVEF), right ventricular ejection fraction (RVEF), systolic blood pressure, ECG, and heart rate were recorded at rest and during submaximal work to compare the cardiotoxic effect of epirubicin with a combination chemotherapy without known cardiotoxicity. A total of 14 females with advanced breast cancer were treated with epirubicin at a median cumulative dose of 827 mg/m2 (range, 550-1244). These patients had previously received cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or cyclophosphamide alone as adjuvant treatment, or CMF for advanced disease. The control group consisted of 11 females with advanced breast cancer given CMF only. The systolic blood pressure at rest as well as during submaximal work was significantly lower (P less than 0.05) after treatment in the epirubicin group than in the CMF controls. With regard to LVEF, the median value of 54% at rest was significantly lower after treatment in the epirubicin group than in the controls (59%). There was a significant fall in LVEF at rest and during exercise in the epirubicin group, whereas no such changes were found in the CMF controls after treatment. The RVEF was unaffected. In the epirubicin-treated group one patient developed fatal congestive heart failure, and in the remaining 13 patients treatment was discontinued due to progression of the cancer and not to cardiotoxicity. Thus, the cardiotoxicity of epirubicin changed the clinical outcome in only 1 of 14 patients with advanced breast cancer.

Right ventricular ejection fraction determined in three projections.

The right ventricular ejection fraction (RVEF) was successively determined in three projections in ten healthy volunteers aged 28-53, mean 37 years, with a first-pass technique using 99Tcm-labelled red blood cells and a gamma camera coupled to a computer. In the anterior-posterior projection (AP) the mean RVEF was 39.3%, range 26-49%, in the left anterior oblique (LAO) 43.7% (36-58), and in the right anterior oblique (RAO) 44.5% (36-54). These mean values do not differ significantly (P = 10%). The results from one of the subjects were withdrawn, as they deviated markedly from the general pattern, and the data were reanalysed from the remaining 9 subjects. Now the mean RVEF in the AP projection was 38.2%, which is significantly lower (P = 1%) than the corresponding RVEF of 44.3% in the LAO projection and of 45.2% in the RAO projection. Our results suggest that when using the classic first-pass technique, the right ventricle histograms will in any projection be influenced by the activity in the right atrium and the large vessels.

The effects of dopamine and noradrenaline on cardiovascular function in patients with acute respiratory failure.

The short-term haemodynamic effects of terminating dopamine and/or a combination of noradrenaline and nitroglycerin infusions were studied in 21 patients in acute respiratory failure. Patients were studied during treatment and 10 min after infusions were stopped. Off treatment, stroke index and cardiac index decreased significantly from 40.2 to 36.9 ml m-2 (P < 0.02) and from 3.80 to 3.42 litres m-2 (P < 0.02), respectively. Cardiac filling pressures decreased significantly and systemic vascular resistance increased, when infusions were stopped. As to heart rate, mean arterial pressure, mean pulmonary arterial pressure, right and left ventricular ejection fraction there were no significant changes between the data obtained during and off treatment. Although the haemodynamic status was significantly better during treatment with dopamine and/or noradrenaline-nitroglycerin in some respects, the overall beneficial effects of inotropic support were much less than anticipated.

Measurement of right and left ventricular ejection fraction in dogs.

Three techniques for measurement of right (RVEF) and two techniques for left (LVEF) ventricular ejection fraction were evaluated in five dogs. RVEF was measured with a first-pass radionuclide technique using erythrocytes labelled in vitro with Technetium-99m methylene disphosphonate (MDP) and compared with RVEF measured with a thermodilution technique. Thermodilution-determined RVEF was compared with RVEF values measured with cine angiocardiography. LVEF was measured with a radionuclide ECG-gated equilibrium technique and compared with cine angiocardiography. Measurements were performed before and during a continuous infusion of dopamine. There was an excellent correlation between RVEF measured with the first-pass and the thermodilution technique, rs being 0.86, n = 9, P less than 0.01. When RVEF measured with the thermodilution technique was compared with cine angiocardiography rs was 0.75, n = 10, P less than 0.01. LVEF measured with the ECG-gated equilibrium technique correlated well with cine angiocardiography (rs = 0.91, n = 10, P less than 0.01).

Effects of prenalterol on cardiac performance and transmural myocardial perfusion in patients with chronic renal failure.

The acute haemodynamic effects of the beta-adrenoreceptor agonist, prenalterol, were studied in six patients with chronic end-stage renal failure. Prenalterol 0.8 mg, 1.6 mg, and 3.2 mg was administered i.v. as a bolus, and after the last dose the selective adrenergic beta-1-receptor antagonist metoprolol was administered i.v. in doses of 5 and 10 mg. The haemodynamic effects of the drugs were investigated using impedance cardiography and radionuclide angiocardiography. The main haemodynamic effects were a dose-related chronotropic effect, demonstrated by an increase in heart rate (26%; less than 0.05), and an inotropic effect, shown by an increase in stroke volume index (20%; p less than 0.05) and left ventricular ejection time (12%; p less than 0.05); the cardiac index was increased by 47% (p less than 0.05). Transmural myocardial perfusion (DPTI/SPTI ratio) was decreased by 22% (p less than 0.05) after prenalterol. It is concluded that prenalterol has positive inotropic and chronotropic effects in patients with chronic renal failure, that the improvement in left ventricular performance is at the expense of a decreased transmural myocardial perfusion, and that metoprolol is a specific antidote.

The effect of continuous subcutaneous insulin infusion on cardiac performance during exercise in insulin-dependent diabetics.

To assess the effects of improved glycaemic control on the right and left ventricular ejection fraction (RVEF and LVEF), we performed radionuclide angiocardiography at rest and during exercise in nine insulin-dependent diabetics with a diabetes duration between 2 and 35 years (mean 12 years) and in 10 control subjects. The diabetics were investigated before and after 7 days' treatment with continuous subcutaneous insulin infusion (CSII). The diabetics had a significantly smaller rise in exercise-induced LVEF during normoglycaemia than in the hyperglycaemic state. In contrast to the control subjects, the diabetics, independent of glycaemic control, did not increase the end-diastolic volume and did not decrease the end-systolic volume during exercise. Our data indicate a preclinical abnormal left ventricular function in young diabetics without long-term diabetic complications. The dysfunction seems unrelated to changes in the loading of the heart and appears to be caused by decreased contractile reserve of the myocardium.

Right and left ventricular ejection fraction and left ventricular volume changes at rest and during exercise in normal subjects.

The effect of exercise upon right and left ventricular ejection fractions (RVEF and LVEF) as well as the changes upon left ventricular end-diastolic and end-systolic volume indices (LVEDVI and LVESVI) were investigated. Twenty-two normal subjects were studied at rest and during upright submaximal exercise. RVEF was determined using a first-pass method. LVEF was measured using multiple gated blood pool imaging. During the exercise test ECGs remained normal. HR and BP increased significantly (P less than 0.01). RVEF increased from 44% +/- 4 (mean +/- SD) to 60% +/- 6 (P less than 0.001). LVEF increased from 62% +/- 6 to 76 +/- 5 (P less than 0.001). A wider scatter was observed in delta RVEF than in delta LVEF. There was a 14% increase in LVEDV-index and a 14% decrease in LVESV-index (P less than 0.001). A multiple regression analysis with delta RVEF as the dependent variable and delta HR, delta systolic BP, delta LVEF, delta LVEDV-index and LVESV-index as independent variables showed a significant correlation between delta RVEF and delta LVEF and delta systolic BP (P less than 0.05). Our data provide insight into the mechanisms by which the pump performance is increased in normal subjects. The central mechanisms observed are the Starling effect and an increase in contractility of the myocardium. This is connected in the general circulation to an increase in afterload, indicating a redistribution of blood from the vascular beds to the muscles and to the heart.

Haemodynamic response to exercise in patients with alcoholic liver cirrhosis.

Physical work capacity was evaluated by a multistage bicycle exercise test in 29 patients, 22 men and seven women aged 35-61 years (mean 49) with alcoholic liver cirrhosis and in a sex- and age-matched control group. The maximal work load was reduced in the patient group, mean 122 vs. 186 watts in men (P less than 0.001), and 60 vs. 119 watts in women (P less than 0.005). Resting heart rate was higher in patients (91 vs. 78 beats X min-1, P less than 0.005), and the maximal heart rate was lower (159 vs. 170 beats X min-1, P less than 0.001) compared with controls. Thirteen of 29 (45%) patients compared with 5 of 29 (17%) control subjects had an increase in left ventricular ejection fraction of less than or equal to 5% during exercise (P less than 0.05). The present results suggest that an impaired capacity of the cardiac function to respond adequately to physical stress may at times contribute to the reduced physical work capacity seen in patients with alcoholic liver cirrhosis.

The predictive value of preoperative perfusion/ventilation scintigraphy, spirometry and x-ray of the lungs on postoperative pulmonary complications. A prospective study.

Prospectively, 125 patients were examined with 99mTc-perfusion scintigraphy, 89mKr- or 127Xe-ventilation scintigraphy and chest radiogram prior to major surgery. Postoperative therapy-demanding pulmonary complications occurred in 18% of the patients. A statistical association could be demonstrated between all the preoperative tests except ventilation scintigraphy and the frequency of complications. However, the predictive values of each of the tests, or even the combined results, were not significantly different from the frequency of complications among all the patients. It is concluded that the predictive values of perfusion- and ventilation scintigraphy, spirometry and radiogram of the chest are too low to be of any practical use.