A stable ovine congestive heart failure model. A suitable substrate for left ventricular assist device assessment.

Similarities in coronary circulation and heart size of sheep to that of humans are specific advantages of a sheep model of congestive heart failure (CHF). CHF was created in 11 sheep (51 +/- 4 kg) by selective sequential intracoronary injection of 90 microns microspheres under 1.5% isoflurane anesthesia. Hemodynamic characteristics were assessed at baseline, 4 weeks after establishment of CHF (ejection fraction [EF] < 35%, n = 11), and 26 weeks (n = 7) later. Baseline echocardiographic EF was 59 +/- 5% and fell to 26 +/- 5% after 5 +/- 2 embolizations. The left ventricular (LV) pressure-volume relationship showed stable decreases in LV end-systolic elastance (Ees) and preload recruitable stroke work. Intravenous infusion of dobutamine increased Ees from 2.8 +/- 1.7 to 4.3 +/- 2.2 and 4.5 +/- 1.4 mmHg/ml at heart rates of 140 and 160/min, respectively, at baseline. Increases of Ees (from 1.3 +/- 0.5 to 2.3 +/- 0.7 and 1.9 +/- 0.5 mmHg/ml at heart rates of 140 and 160/min, respectively) with dobutamine under CHF conditions did not exceed Ees values at baseline without dobutamine. This response to dobutamine infusion did not change 26 weeks after establishment of CHF. This stable ovine CHF model is proposed for studies on the long-term effects of cardiac assist devices.

Animal models of heart failure for pharmacological studies.

1. Animals for the study of congestive heart failure (HF) should have chronic, stable disease produced by methods which allow controllable damage and hence predictable disease severity. 2. Pressure and volume loading have commonly been used in the past but these methods are limited by the difficulty of controlling the disease severity. 3. HF induced by cardiotoxic agents, particularly doxorubicin, has been widely used for experimental purposes, but again, control of the degree of damage may be difficult. 4. Coronary artery ligation or occlusion produces heart failure in experimental animals, with clear clinical relevance. Disadvantages of such techniques include fatal arrhythmias and collateral vessel growth that prevents or slows the onset of HF. 5. A minimally invasive model of HF which is relatively controllable can be produced by repeated or single DC shocks across the left ventricle. 6. Chronic rapid ventricular pacing produces a technically simple, predictable, stable and controllable preparation of HF with neurohumoral and haemodynamic changes which mimic the clinical pattern. These changes are reversible in the short term but after pacing for 1 year or longer complete recovery does not occur after cessation of pacing. 7. It has recently been suggested that a single DC shock, three to seven times the threshold defibrillating current, administered to the left ventricle, might provide the basis for the development of a model of heart failure which is technically simple and controllable.

Effect of enalapril in dogs with pacing-induced heart failure.

A repeated-measures study was conducted on 5 dogs to clinically, radiographically, and echocardiographically characterize the actions of the angiotensin-converting enzyme inhibitor, enalapril, before and after development of experimentally induced heart failure. Heart failure was artificially induced, using a surgically implanted programmable ventricular pacemaker, which stimulated the heart at a rate of 245 beats/min until a low-output cardiomyopathic state developed. This condition was then stabilized by decreasing the pacing rate to 190 beats/min. Pacing-induced heart failure was successfully induced in a mean +/- SD 4.2 +/- 1.95 weeks. The condition closely resembled the clinical, radiographic, and echocardiographic features of naturally acquired idiopathic dilated cardiomyopathy in dogs. Enalapril was well tolerated by dogs, and clinical adverse reactions did not develop. Results of echocardiographic studies indicated that enalapril treatment during the control period resulted in a significant (P < 0.05) increase in velocity of circumferential fiber shortening and a significant (P < 0.05) decrease in left ventricular ejection time. Therapeutic responses to enalapril were evident after development of heart failure. These included reduced severity of clinical signs of disease, evidence of decreased radiographically determined cardiac size (2 of 5 dogs), radiographic evidence of a reduction in pulmonary edema and congestion (4 of 5 dogs), significant (P < 0.05) reductions in left atrial and ventricular chamber dimensions (left atrial dimension, diastolic left ventricular internal dimension as determined echocardiographically), and improvement in some echocardiographic indices of left ventricular performance (velocity of circumferential fiber shortening and left ventricular ejection time).

Cardiovascular actions of dopexamine in anaesthetized and conscious dogs.

1. Arterial blood pressure, heart rate and cardiac contractility were measured in pentobarbitone-anaesthetized mongrel dogs and in conscious, instrumented dogs. 2. In anaesthetized dogs (n = 5), dose-response curves were obtained by intravenous infusion of increasing doses of dopexamine (5-20 micrograms kg-1 min-1). Infusions were administered three times to each animal to determine whether the responses were reproducible. Dopexamine increased heart rate and myocardial contractility and decreased blood pressure. The dose-response curves for dopexamine did not differ significantly over time. 3. In a second group of dogs (n = 6), dose-response curves (5-20 mg kg-1 min-1) were obtained as above and repeated after the administration of amitriptyline (2 mg kg-1, i.v.). Amitriptyline caused a non-significant reduction in the inotropic and chronotropic responses to dopexamine. 4. Control dose-response curves for dopexamine (5-50 micrograms kg-1 min-1) were similarly obtained in a third group of dogs (n = 6), and repeated after bilateral vagotomy and sympathetic denervation of the heart. In these animals, a third dose-response curve for dopexamine was obtained after the administration of ICI 118551 (0.2 mg kg-1, followed by 0.2 mg kg-1 h-1). The chronotropic response to dopexamine was significantly reduced after cardiac denervation. There was a small, non-significant reduction in the inotropic and depressor responses after denervation. Administration of ICI 115881 significantly reduced both the inotropic and chronotropic response to dopexamine and caused a non-significant reduction in the depressor response. 5. The effect of raclopride (0.2 mumol kg-1, p.o.) was investigated by comparison of the dose-response curves for dopexamine in a control group of dogs (n = 6) to those obtained in dogs which had been pretreated with raclopride (n = 5). Raclopride had no significant effect on the cardiovascular responses to dopexamine. 6. In conscious, instrumented dogs (n = 5), pretreated with raclopride, dose-related positive inotropic and chronotropic and depressor responses to dopexamine infusions were recorded. The chronotropic responses in conscious animals were significantly greater than those in the anaesthetized animals.7. The results of this study indicate that both the positive inotropic and chronotropic actions of dopamine are due to a combination of direct, Beta2-adrenoceptor-mediated effects and the baroreceptor reflex response to the depressor action of the drug.

Digoxin-stimulated calcium transport across rat diaphragm interactions with aminophylline and verapamil.

1. The effect of digoxin on calcium transport across muscle strips isolated from rat diaphragms was investigated. 2. Digoxin at concentrations ranging between 0.2-5.0 ng/ml in the incubation solution increased significantly (P less than 0.5) intracellular calcium in the diaphragm muscle strips in a dose-dependent pattern. 3. The inclusion of digoxin (2 ng/ml) and aminophylline (18.75 micrograms/ml) in the incubation medium showed a significant increase (P less than 0.001) in calcium uptake suggesting a synergistic effect on intracellular calcium accumulation. 4. The presence of digoxin with verapamil in the incubation medium showed a partial alleviation of the inhibitory effect of verapamil on calcium transport. 5. The effect of increasing calcium concentration in the presence of digoxin and digoxin plus aminophylline in the incubation medium, showed a nonsaturable linear relationship between calcium concentration and intracellular calcium accumulation.