Ischemic Left Ventricular Failure Research Articles

Intracavitary filling pattern in the failing left ventricle assessed by color M-mode Doppler echocardiography

Objectives. The present study aimed to investigate the mechanism of intracavitary changes in filling pattern during acute ischemic left ventricular failure and during beta-adrenergic blockade.Background. Recent clinical studies with color M-mode Doppler imaging have shown abnormal intracavitary filling patterns in the diseased ventricle.Methods. In open chest anesthetized dogs with intracardiac micromanometers and myocardial segment-length crystals, global ischemic left ventricular failure was induced (n = 8) by coronary microembolization. In nonischemic ventricles inotropy was decreased (n = 6) by intravenous propranolol and increased (n = 6) by intravenous isoproterenol. From color M-mode Doppler images we calculated the time difference between peak early diastolic filling velocity at the mitral tip and apex using computer analysis. The time difference of peak velocity was used as an index of the timing of apical filling.Results. There was marked retardation of apical filling with microembolization and propranolol. Time difference of peak velocity increased from 20 ± 6 (mean ± SEM) to 101 ± 17 ms (p < 0.05) and from 21 ± 8 to 80 ± 18 ms (p < 0.05), respectively. Time constant of isovolumic relaxation increased from 34 ± 3 to 43 ± 5 ms (p < 0.05) and from 31 ± 1 to 39 ± 3 ms (p < 0.05) during microembolization and beta-blockade, respectively. Isoproterenol tended to cause the opposite changes. Time difference of peak velocity showed a positive correlation with time constant of isovolumic relaxation (r = 0.89, p < 0.01) and a negative correlation with peak early transmitral pressure gradient (r = 0.88, p < 0.01 ). In the intact left ventricle, peak apical filling velocity coincided with peak early transmitral pressure gradient. During ischemic failure, however, peak apical filling velocity occurred 53 ± 14 ms after peak early transmitral pressure gradient had decreased to zero and at a time when transmitral flow had ceased, suggesting a change in intraventricular flow distribution.Conclusions. Color M-mode Doppler imaging revealed retarded apical filling during depression of myocardial function by global myocardiai ischemia or beta-blockade. The abnormal filling pattern may be a sign of impaired left ventricular relaxation.

Hemodynamic Effects of Benazeprilat in the Anesthetized Dog with Acute Left Ventricular Failure.

To examine the hemodynamic effects of benazepril, an angiotensin converting enzyme inhibitor, in left ventricular failure, its active metabolite benazeprilat was administered during acute ischemic left ventricular failure in anesthetized open chest dog induced by repeated injections of plastic microspheres into the left coronary artery. The coronary embolization with microspheres resulted in a moderate and stable left ventricular pump failure characterized by increased left ventricular end-diastolic pressure (LVEDP) and decreased cardiac output (CO). Benazeprilat (30 micrograms/kg) administered intravenously after a stabilization period lowered LVEDP and maintained CO. The total peripheral resistance was reduced with benazeprilat. The oxygen consumption and the coronary blood flow were reduced with benazeprilat because of a decrease in wall tension and afterload. These results suggest that benazeprilat (benazepril) has beneficial effects for the treatment of acute left ventricular failure.

Ischaemic left ventricular failure: evidence of sustained benefit after 18 months' treatment with xamoterol.

The long term effects of treatment with xamoterol in 14 patients aged 44-73 with mild to moderate heart failure as a result of ischaemic heart disease are reported. After 18 months' treatment with xamoterol, patients were assessed in a randomised double blind crossover comparison of xamoterol (200 mg twice a day) and placebo, each given for one month. Compared with placebo, xamoterol significantly increased exercise duration and work done on a bicycle ergometer and reduced the maximum exercise heart rate. Assessment of symptoms and activities at 12 months by visual analogue and Likert scales showed a trend towards the relief of symptoms of breathlessness and tiredness and an improvement in activity. There was an improvement in the clinical signs of heart failure and no haemodynamic deterioration over a 12 month period as assessed by ejection fraction. The improvement in exercise tolerance, symptoms, and activities was sustained for 18 months without side effects or development of tolerance.

Class III antiarrhythmic activity of UK-68, 798 in acute ischaemic left ventricular failure in dogs

Class III antiarrhythmic activity of UK-68, 798 in acute ischaemic left ventricular failure in dogs

Haemodynamic effects of a new class III antiarrhythmic drug, [formula omitted], during acute ischaemic left ventricular failure in dogs

Haemodynamic effects of a new class III antiarrhythmic drug, [formula omitted], during acute ischaemic left ventricular failure in dogs

Effects of the Novel β-Adrenergic Partial Agonist Alifedrine on Cardiac Performance in Dogs with Acute Ischemic Left Ventricular Failure

Acute ischemic left ventricular failure was induced in dogs by coronary embolization with plastic microspheres, resulting in reduced cardiac output (CO), increased left ventricular end-diastolic pressure (LVEDP), pulmonary capillary pressure (PCP), and total peripheral resistance (TPR). Intravenous (i.v.) administration of alifedrine, a beta-adrenergic partial agonist (0.3 mg/kg as bolus and 0.3 mg/kg/h as infusion), significantly improved performance of the failing heart. Left ventricular contractility was increased up to 50%, heart rate (HR) up to 28%, and CO up to 30%. LVEDP, PCP, and TPR were markedly decreased. Myocardial oxygen consumption was increased only to a minor degree despite the positive inotropic effect; coronary flow was augmented up to 26%. Thus, alifedrine in this model markedly improved left ventricular function by balanced stimulation of the myocardium and reduction of pre- and afterload.

Plasma concentrations of atrial natriuretic factor in acute left ventricular failure in the dog.

Acute ischemic left ventricular failure was induced in anesthetized dogs by repeated coronary embolization with 50 microns microspheres. Plasma concentrations of atrial natriuretic factor (ANF) were measured by radioimmunoassay of arterial and venous samples before and after failure induction. Heart failure was accompanied by a doubling of arterial ANF concentration, whereas there were only insignificant changes on the venous side. The increase in arterial ANF correlated significantly to the increase in left ventricular end-diastolic pressure, but not to the increase in right atrial pressure. Measurements of pericardial pressure indicated that a pericardial constraint acted to reduce atrial distension and thereby cardiac ANF release during failure.

A Reappraisal of Nitrate Therapy

Nitroglycerin and the long-acting nitrates are beneficial in stable and unstable angina pectoris and acute myocardial infarction and as adjunctive therapy in congestive heart failure. Nitroglycerin compounds relax vascular smooth muscle, producing venous, arterial, and arteriolar dilatation. These actions are modulated by stimulation of intracellular cyclic guanosine monophosphate. Nitrate efficacy in ischemic heart disease is due to peripheral venous and arterial vasodilatation that results in decreased myocardial oxygen consumption. Nitrates also dilate coronary arteries and collaterals, reverse coronary vasoconstriction, and enlarge some coronary atherosclerotic lesions. Nitrates improve exercise performance in stable angina pectoris. Intravenous nitroglycerin should be used in the initial treatment of unstable angina. Nitrates may be beneficial in myocardial infarction for control of ischemic pain, acute hypertension, and left ventricular failure. In subjects with congestive heart failure, nitrates reduce symptoms and improve exercise tolerance. Nitrate tolerance is a problem with continuous nitrate therapy. Tolerance is most likely to occur with frequent dosing or the use of long-acting nitrates, particularly transdermal nitroglycerin disks, and can be prevented or reversed with intermittent-dosing regimens.

Cardiovascular properties of bemarinone: A new orally active quinazolinone cardiotonic agent

AbstractThe cardiovascular properties of bemarinone (5, 6‐dimethoxy‐4‐methyl‐2‐(1H)‐quinazolinone), a new chemical entity with positive inotropic and vasodilator activity, were investigated. Bemarinone (10−6−10−3M) selectively increased contractile force 144 ± 15% in electrically paced guinea pig left atria while marginally affecting sinus rate (16 ± 13%, peak effect) in spontaneously beating right atria. In anesthetized dogs, bemarinone (0.125–0.875 mg/kg, i.v.) increased myocardial contractile force (21–114%) and left ventricular dP/dtmax (7–45%) in a dose‐related manner. Selective inotropic activity was observed in vivo since no significant change in mean arterial pressure or heart rate occurred at a 50% increase in contractile force (ED50 = 0.23 mg/kg). In conscious instrumented dogs, oral administration of bemarinone (2.5–10 mg/kg) produced peak increases in left ventricular dP/dtmax ranging from 28% to 87% (ED50 = 3.7 mg/kg). The onset of positive inotropic activity after 10 mg/kg p.o. occurred within 5 min, and the duration exceeded 3 hr. Bemarinone decreased mean arterial blood pressure (0.4–16%) via a reduction in total peripheral resistance. Direct vascular effects were observed in vitro since bemarinone relaxed rabbit aortic strips contracted with phenylephrine or KCl. In an acute model of ischemic left ventricular failure, bemarinone increased cardiac output (41%) and stroke volume (34%) while reducing left ventricular end diastolic pressure (63%) and total peripheral resistance (29%) without significantly changing mean arterial pressure or heart rate. The positive inotropic effect of bemarinone was not antagonized by propranolol and atropine pretreatment. The compound selectively and competitively inhibited cyclic AMP phosphodiesterase fraction III from canine ventricle (Ki = 15.8.μM). In summary, bemari none is an orally active, positive inotropic and vasodilator agent with potential clinical utility in the management of congestive heart failure.

Total body oxygen consumption and haemodynamics during the treatment of acute ischaemic heart failure with dopamine and high doses of insulin in dogs.

Acute ischaemic left ventricular failure was induced in closed-chest anaesthetized dogs by injection of 50 microns plastic microspheres into the left main coronary artery. This effected a 33% decrease in cardiac output. Dopamine and high doses of insulin restored cardiac output, and these agents in combination raised cardiac output to 34% above pre-ischaemic levels. Total body oxygen consumption was calculated at the various levels of cardiac output, and was found to remain essentially unchanged. Inotropic agents, then, may result in overperfusion with respect to oxygen demand.

Increased left atrial myocardial blood flow during acute ischemic left ventricular failure

Increased left atrial myocardial blood flow during acute ischemic left ventricular failure

Enalapril in Experimental Hypertension and Acute Heart Failure

The hemodynamic effects of enalaprilat (MK-422) and lisinopril (MK-521) were compared with the calcium channel blocker felodipine in dogs with ischemic left ventricular (LV) failure. The combination of nitrendipine plus enalapril was also examined in ischemic failure and in rats with spontaneous hypertension. In anesthetized dogs coronary embolization with 50 micron plastic microspheres reduced cardiac output and LV dP/dt max by approximately 40%, and LV end-diastolic pressure increased to greater than 13 mm Hg. Enalaprilat and lisinopril reduced mean arterial pressure by a maximum of 20 mm Hg and total peripheral resistance by approximately 30%. Left ventricular dP/dt:LVP, which was substantially decreased by embolization, was slightly increased by both angiotensin converting enzyme (ACE) inhibitors. The calcium entry blockers felodipine and nitrendipine qualitatively produced many of the same hemodynamic effects as the ACE inhibitors, but, in addition, they markedly reduced coronary resistance, increased myocardial blood flow, and did not alter cardiac contractility (LV dP/dt max). In spontaneously hypertensive rats single doses of nitrendipine (1.25 to 5.0 mg/kg per os) and enalapril (0.3 and 3.0 mg/kg per os) reduced mean arterial pressure, but differences were observed in the onset (enalapril 2 h versus nitrendipine 0.5 h), the duration of action, and magnitude of effect. In terms of blood pressure lowering, nitrendipine, 5.0 mg/kg per os, was clearly additive to 3.0 mg/kg per os of enalapril, but other combinations (enalapril, 3 mg/kg per os plus 0.625 mg/kg of nitrendipine or enalapril, 0.3 mg/kg per os plus 0.625 mg/kg nitrendipine) were not.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of the converting enzyme inhibitor ramipril (HOE 498) in anesthetized dogs with acute ischemic left ventricular failure.

The non-sulfhydryl converting enzyme inhibitor Ramipril (HOE 498) is characterized by long lasting antihypertensive activity in man. To examine its cardiovascular potential in heart failure, ramipril was administered during acute ischemic left ventricular failure in pentobarbital anesthetized dogs, induced by repeated injections of plastic microspheres into the left main coronary artery. Repeated embolizations produced stable left ventricular (LV) pump failure characterized by LV enddiastolic pressure of 22 mmHg, reductions in LV dp/dt max and cardiac output. Blood pressure and heart rate were not changed while total peripheral resistance increased. After a stabilization period ramipril was administered in two doses at 30 or 100 micrograms/kg as an intravenous bolus followed by continuous infusion of 3 or 10 micrograms/kg/min for 150 min. Ramipril in the lower dose decreased LV enddiastolic pressure by 8 mmHg, mean pulmonary artery pressure by 4 mmHg, systemic blood pressure by 40 mmHg and total peripheral resistance by 1280 dyn x sec x cm-5. LV dp/dt max, heart rate and cardiac output remained unchanged during ramipril administration. More pronounced effects were obtained with the higher dose. In conclusion, the improvements of hemodynamics produced by ramipril during acute ischemic left ventricular failure in anesthetized dogs are best explained by a reduction in both preload and afterload.

Haemodynamic Dose–Response Effects of Intravenous Amrinone in Left Ventricular Failure Complicating Acute Myocardial Infarction

The haemodynamic dose-response effects of intravenous amrinone were measured in 16 male patients, aged 40-65 years, with radiographic and haemodynamic evidence of left ventricular failure 4-18 h after acute myocardial infarction. After a l-h control period to confirm stable haemodynamic baseline variables, patients were randomised to either low-dose (200-400-800 micrograms/kg/h) or high-dose (800-1600-3200 micrograms/kg/h) intravenous amrinone. Each of the three infusions was given consecutively over 30 min (total infusion time 90 min) in each group, and haemodynamic measurements were made at the end of each infusion step. No arrhythmias or other untoward side effects, including haematological changes, were observed during the infusions. In both groups, intravenous amrinone reduced the pulmonary artery-occluded pressure (PAOP) (p less than 0.01), increased the cardiac output (p less than 0.05), and reduced the systemic vascular resistance (p less than 0.05). The reductions in PAOP and systemic arterial diastolic pressure and the increase in heart rate were directly dose-related, but the changes in cardiac output and systemic vascular resistance were not. These results suggest that peripheral vasodilation, particularly of venous capacitance vessels, as well as positive inotropic stimulation, may play a role in the haemodynamic changes induced by intravenous amrinone in acute ischaemic left ventricular failure.

Factors associated with pulmonary infarction. A discriminant analysis study.

To determine the relative importance of multiple interrelated factors that have been considered to contribute to pulmonary infarction, the authors performed a discriminant analysis on consecutively autopsied patients with pulmonary embolism. From the clinic records of 45 individuals, the authors tabulated the underlying illness, history of valvular or ischemic heart disease, right and left ventricular failure, sepsis, shock, malignancy, premortem functional status, and the clinician's suspicion of pulmonary embolism. At postmortem examination, the authors measured and recorded the extent of emphysema, pneumonia, neoplasia, pulmonary vascular atherosclerosis; thickness and dilatation of both cardiac ventricles; the presence of valvular heart disease; the number, diameter, and amount of occlusion of the pulmonary arteries that contained thromboemboli; the extension of the clot, the size of the infarct; the Reid-Index; and the thickness of pulmonary and bronchial arterial wall. The major determinants of infarction were as follows: poor premortem functional status, the number of lobes having emboli, left ventricular failure, and the presence of lung cancer. The authors then tested the equation generated from these patients on 21 additional patients. The discriminant function correctly classified 81% of first group and predicted the occurrence of infarction in new patients with 70% accuracy. The size of the infarct was most correlated with the use of vasodilators and the embolic burden.

Comparative Effects of Dobutamine and Corwin, a β1-Adrenergic Partial Agonist, in Experimental Left Ventricular Failure

Corwin is a new, long-acting beta 1-adrenergic partial agonist for oral and intravenous (i.v.) use. The effects of corwin were compared with those of dobutamine in acute ischemic left ventricular failure in dogs. Failure was produced by embolization of the left main coronary artery with 50 micron plastic microspheres. This induced severe depression in left ventricular function, as evidenced by a marked increase in left ventricular end-diastolic pressure, reduction in left ventricular dP/dtmax, and cardiac output. After 45 min was allowed for stabilization, the 27 dogs were randomly assigned to three groups: control (n = 9), dobutamine-treated (5-10 micrograms/kg/min i.v., n = 9), and corwin-treated (0.025-0.10 mg/kg i.v., n = 9). The doses of dobutamine and corwin were adjusted to give an increase in left ventricular dP/dtmax of 50%. Both drugs similarly increased cardiac output (p less than 0.01), lowered left ventricular end-diastolic pressure (p less than 0.01) and total peripheral vascular resistance (p less than 0.01), but did not affect the heart rate. Only dobutamine increased the mean arterial pressure (p less than 0.01). Both drugs also increased the arterial concentrations and myocardial uptake of fatty acids (p less than 0.05) but caused only a small and nonsignificant increase in myocardial oxygen consumption. Our findings indicate that the hemodynamic and metabolic profiles of corwin and dobutamine are similar, and both drugs should be of special value in the treatment of congestive heart failure. Since corwin can be given orally and has a longer duration of action, it is potentially useful in the long-term treatment of heart failure.

Haemodynamic effects of high doses of insulin during acute left ventricular failure in dogs.

Haemodynamic effects of pharmacological doses of insulin during acute ischaemic heart failure were studied in 8 dogs. Severe depression of left ventricular function was induced by the injection of 50 micron plastic microspheres into the left main coronary artery. This was demonstrated by a significant increase in left ventricular end-diastolic pressure and a significant decrease in the maximum rate of left ventricular pressure rise (LVdP/dtmax), stroke volume and cardiac output. Eighty-five minutes after the embolization procedure, 300 IU of insulin free of glucagon and calcium was injected as a bolus. This was followed by infusion of glucose and potassium to maintain physiological levels of these factors. Five minutes after insulin administration, there was a significant improvement in left ventricular performance as shown by decreased left ventricular end-diastolic pressure (P less than 0.01) and increased LVdP/dtmax (P less than 0.01), stroke volume (P less than 0.05) and cardiac output (P less than 0.05). A significant reduction in heart rate occurred. A non-significant increase in mean aortic blood pressure and reduction in total peripheral resistance were seen. In conclusion, pharmacological doses of insulin significantly improve cardiac pump function during acute ischaemic left ventricular failure in dogs.

Metabolic effects of high doses of insulin during acute left ventricular failure in dogs.

Metabolic effects of pharmacological doses of insulin were studied during acute ischaemic heart failure in 7 dogs. Severe depression of left ventricular performance was induced by embolization of the left main coronary artery with 50 micron plastic microspheres. This was followed by a significant reduction in myocardial blood flow and oxygen consumption. After a period of stabilization of the haemodynamic and metabolic variables, 300 IU of insulin free of glucagon and calcium was injected as a bolus dose. Glucose and potassium were given to maintain their plasma concentrations. Insulin significantly improved performance of the failing left ventricle. Myocardial blood flow was significantly increased, whereas myocardial oxygen consumption was unchanged. Insulin significantly reduced arterial concentrations and myocardial uptake of free fatty acids, while myocardial uptake of glucose and lactate showed a non-significant increase. In conclusion, pharmacological doses of insulin significantly improve cardiac pump function without increasing myocardial oxygen consumption during acute ischaemic left ventricular failure in dogs. This may be partly related to reduced myocardial uptake of free fatty acids relative to that of glucose.

Haemodynamic and metabolic consequences of elevated plasma free fatty acids during acute ischaemic left ventricular failure in dogs.

Haemodynamic and metabolic effects of elevated plasma concentrations of free fatty acids (FFA) were studied during acute ischaemic left ventricular failure in closed-chest anaesthetized dogs. Embolization of the left main coronary artery with 50 micron plastic microspheres induced severe depression of left ventricular performance as indicated by a marked increase in left ventricular end-diastolic pressure (LVEDP), and marked reductions in LVdP/dtmax, cardiac output and myocardial oxygen consumption (MVO2). When stable conditions were reached, eight dogs received a triglyceride emulsion and heparin to raise plasma FFA. This was associated with increased MVO2 and further elevation of LVEDP. In two dogs receiving the triglyceride emulsion but no heparin, plasma FFA was not elevated, and MVO2 and LVEDP were unchanged. In conclusion, elevation of plasma FFA was associated with increased myocardial oxygen requirement and further depression of LV function in dogs with acute ischaemic LV failure.

Hemodynamic and myocardial metabolic effects of the beta-agonist prenalterol in ischemic left ventricular dysfunction.

Hemodynamic and myocardial metabolic parameters in ischemic left ventricular (LV) dysfunction were evaluated in response to the beta-agonist prenalterol. Twenty micrograms/kg intravenous prenalterol increased resting heart rate and cardiac output and decreased LV filling pressure, systemic vascular resistance, and pulmonary artery pressure. Resting coronary blood flow and myocardial oxygen consumption increased but net myocardial lactate and oxygen extraction did not change significantly. During pacing induced tachycardia (121 +/- 4 beats/min), prenalterol improved cardiac index and stroke work index; whereas, LV filling pressure, systemic vascular resistance, and pulmonary artery pressure decreased. Coronary blood flow and myocardial oxygen extraction did not change significantly. Net myocardial lactate extraction during pacing decreased insignificantly; one patient developed overt lactate production. Thus, prenalterol improves cardiovascular function at rest and during pacing-induced tachycardia in ischemic LV failure, but at the cost of higher resting myocardial oxygen consumption. The majority of subjects had no adverse metabolic response.