Index Of Cardiac Contractility Research Articles

Computer software for the on-line measurement of the left ventricular end-systolic pressure-dimension relationship

A microcomputer system was designed to measure the end-systolic pressure-dimension relationship (ESPDR), an index of cardiac contractility that is independent of preload, afterload, and heart rate. To test the system, pressure-dimension data were obtained from swine left ventricles and from a mathematical model of the heart. Algorithms for filtering, location of end-systole, selection of the measurement interval, and calculation of the ESPDR were evaluated on the basis of speed, precision, accuracy, and robustness. The resulting program runs on an IBM-AT and measures ESPDR on-line within 60 seconds of the start of data acquisition. By reducing the time spent in data analysis and providing rapid feedback of information, the on-line software has increased productivity and facilitated improvements in experimental technique. This is a US government work. There are no restrictions on on its use.

Influence of endothelin on cardiovascular function, oxygen free radicals, and blood chemistry

Endothelin, a peptide that is derived from vascular endothelial cells, is a potent constrictor of mammalian blood vessels in in vitro studies. Various clinical conditions have been reported to be associated with an increase in the blood and tissue levels of endothelin. In the present study, the effects of two doses (2.059 and 4.118 μg/kg, intravenously) of endothelin on cardiac function and contractility; blood lactate, gases, and pH levels; blood and cardiac tissue MDA levels; PMN leukocyte chemiluminescence activity; and total WBC and PMN leukocyte counts were investigated in anesthetized dogs. Hemodynamic measurements and collection of blood samples for various biochemical measurements were made before and at various intervals up to 2 hours after endothelin administration. Endothelin in the large dose (4.118 μg/kg) produced a prolonged decrease in the indices of cardiac contractility and cardiac function and increases in TSVR, PVR, and mean right atrial pressure. The changes in the hemodynamic parameters with the smaller dose (2.059 μg/kg) were similar but of smaller magnitude. Significant decreases in dp/dt at CPIP:PAW and CI and increases in TSVR and PVR were observed with the smaller dose of endothelin. There were decreases in the bloodHCO3− and pH levels and an increase in H+ and blood lactate concentration and CK activity with the high dose of endothelin. No changes were observed in blood Po2 and Pco2 with either dose of endothelin. Circulating WBCs and PMN leukocytes decreased significantly with both doses of endothelin. There were no changes in the oxygen free radical-producing activity of PMN leukocytes and in the blood and cardiac tissue MDA levels. These results suggest that endothelin decreased cardiac function and cardiac contractility and increased SVR and PVR. The decrease in cardiac function and contractility may be due to ischemia from constriction of coronary arteries. The hemodynamic changes are unlikely be due to oxygen free radicals since there was no increase in the blood and cardiac tissue MDA levels and no change in the PMN chemiluminescence. These studies suggest that increases in endothelin levels in certain clinical conditions might cause added deleterious effects on cardiovascular function.

Cardiovascular effects of doxorubicin

1. Doxorubicin dose-dependently increased the cardiac contractility of isolated frog heart within the dose-range of 1.0 to 10.0 × 10 −7 M and dose-dependently increased the cardiac output of frog heart in situ with a dose-range between 10 −7 and 10 −5 M. 2. The results of the in situ investigation, using cardiac output as the index of cardiac contractility, were in agreement with the in vitro results. The positive inotropic effects of doxorubicin climaxed around 10 −5 M beyond which there was a dose-dependent decreased in contractility. 3. Haloperidol (10 −6 M), a dopaminergic receptor blocker, and propranolol (10 −8 M), a β-adrenergic blocker, did not block the positive inotropic effects of doxorubicin. 4. These results provide sufficient basis to suggest that doxorubicin is acting on the isolated amphibian heart through a mechanism which is not associated with β-adrenergic and/or dopaminergic receptors.

Nonsteroidal cardiotonics. 2. The inotropic activity of linear, tricyclic 5-6-5 fused heterocycles

We previously reported the structure-activity relationships (SAR) of adibendan (1), a potent and long-acting cardiotonic. This paper describes the synthesis of a novel series of linear, tricyclic fused heterocycles of the 5-6-5 type. The compounds were evaluated for positive inotropic activity in anesthetized rats, cats, and dogs. Changes in left ventricular dP/dt were measured as an index of cardiac contractility. The increase in contractility was not mediated via stimulation of beta-adrenergic receptors. The data revealed the intrinsic positive inotropic activity of the parent compound of this series, 5,7-dihydro-7,7-dimethylpyrrolo[2,3-f]benzimidazol-6(1H)-one (2). The structural features that impart optimal inotropic activity are presented and compared with those of the 4,5-dihydro-3(2H)-pyridazinone series. The most potent compounds were evaluated orally in conscious dogs with implanted Konigsberg pressure transducers to measure ventricular pressures, and their effect on left ventricular dP/dt was compared with that of 1, pimobendan, and indolidan. After administration of 1 mg/kg, 1, 3, 7, 19, 22, 24, 31, 54, pimobendan, and indolidan were equipotent, but only with 1, 31, pimobendan, and indolidan, durations of action exceeded 6 h.

Effect of oxygen free radicals on cardiovascular function at organ and cellular levels

Oxygen free radicals (OFR) have been implicated as a causative factor of cell damage in several pathologic conditions. It is possible that OFR could have effects on cardiac function and contractility. The present investigation deals with the effects of OFR in the absence and in the presence of scavangers of OFR (superoxide dismutase and catalase) on cardiac function, index of cardiac contractility, serum creatine kinase (CK), and blood lactate, Po 2 and pH in the anesthetized dogs. The hemodynamic measurements and collection of blood samples for measurement of CK, lactate, Po 2 and pH were made before and at various intervals after administration of OFR for 1 hour. Xanthine and xanthine oxidase were used to generate OFR. OFR produced a decrease in cardiac function and indices of myocardial contracility and an increase in the serum CK. OFR produced an increase in the systemic and pulmonary vascular resistance. Although there was a tendency for an increase in the blood lactate, the increase was not significant. The blood Po 2 and pH were not affected. Superoxide dismutase (SOD), alone or in combination with catalase, tended to protect cardiac function against the deleterious effects of OFR. Scavangers of OFR prevented the OFR-induced rise in serum CK. Although the protective effect of SOD plus catalase was slightly better than SOD alone, the results were not significantly different from each other. These results suggest that OFR are cardiac depressant and increase the peripheral vascular resistance besides causing cellular damage. Scavangers of OFR may be beneficial in counteracting the deleterious effects of OFR on hemodynamic parameters and cellular integrity.

Myocardial toxic effects during recombinant interleukin-2 therapy.

Arterial and pulmonary artery catheters were used to monitor the cardiopulmonary effects of recombinant interleukin-2 (rIL-2) given iv at a dose of 100,000 U/kg every 8 hours on days 1-5 to 10 patients with metastatic solid tumors. As anticipated, a severe capillary leak syndrome developed in all patients. Myocardial infarction (MI) occurred unexpectedly in three patients, as evidenced by a focal injury pattern on ECG and elevations of creatinine phosphokinase myocardial band fractions. All patients receiving rIL-2 exhibited major reductions in their left ventricular stroke work index (47 +/- 11 g.m/m2 to 29 +/- g.m/m2), an index of cardiac contractility. It remains uncertain whether the MIs were a byproduct of the capillary leak syndrome in patients with underlying coronary artery disease or whether rIL-2 directly or indirectly damages cardiac muscle.

Comparison between the cardiovascular effects of 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT) and clonidine in the conscious sino‐aortic denervated rat

1. The purpose of this study was to investigate the role of an intact baroreceptor reflex mechanism in the expression of the cardiovascular response to 8-OH-DPAT and to determine whether there are any differences between the activation of central alpha 2-adrenoreceptors and 5-HT1A receptors in this respect. To this end, the effects of 8-OH-DPAT and clonidine have been assessed on blood pressure, heart rate, ECG and cardiac contractility indices in conscious sino-aortic baroreceptor denervated (SAD) rats and their sham-operated controls. 2. In both sham-operated and SAD rats, intravenous (i.v.) administration of 8-OH-DPAT (32 micrograms kg-1) and clonidine (8 micrograms kg-1) produced falls in systemic blood pressure, left ventricular systolic pressure and dP/dtmax. 3. 8-OH-DPAT produced similar bradycardia in each group of rats; in contrast, clonidine had a greater effect in the SAD animals. Increases of the PQ interval mirrored the heart-rate changes with both compounds. 4. No significant changes in end diastolic blood pressure or in the myocardial contractility indices dP/dtmax/P and Vmax were evident. 5. This study provides support for the view that i.v. 8-OH-DPAT lowers blood pressure and heart rate through a central mechanism. The effects occur independently of an intact baroreceptor reflex and are not associated with effects on myocardial contractility. 8-OH-DPAT shows close qualitative similarities to clonidine in this model.

Efficiencies from consumed O2 and pressure-volume area to work of in situ dog heart.

We studied the efficiencies from oxygen consumption (VO2) to external mechanical work (EW), from VO2 to the systolic pressure-volume area (PVA), and from PVA to EW, and the effects of cardiac output and contractility index (Emax) on these efficiencies in the left ventricle of open-chest, right-heart-bypassed dogs. PVA is an intermediate form of energy between VO2 and EW. PVA, EW, and Emax were determined by an abrupt occlusion of the ascending aorta. The right-heart bypass allowed us to collect all coronary venous return for VO2 measurement. The EW/VO2 efficiency ranged between 4 and 21%, the PVA/VO2 efficiency ranged between 5 and 27%, and the EW/PVA efficiency ranged between 60 and 95%. At a given Emax, EW/PVA efficiency was independent of cardiac output, but PVA/VO2 and EW/VO2 efficiencies increased with cardiac output. An increase in Emax by dobutamine increased EW/PVA efficiency, but decreased PVA/VO2 and EW/VO2 efficiencies. We could theoretically account for these changes in EW/PVA, PVA/VO2, and EW/VO2 efficiencies of the in situ heart by the VO2-PVA relation and its dependence on Emax that we had observed.

Comparison Between the Effects of MDL 72567 and Nifedipine on Various Cardiovascular Parameters in Conscious Sinoaortic-Denervated Rats and Sham-Operated Controls

In this study the effects of a new calcium entry blocking agent, 2,6-dimethyl-3-methoxycarbonyl-4-(2-nitrophenyl)-5-(2-furoyl)-1, 4-dihydropyridine (MDL 72567), were compared with those of nifedipine on blood pressure, heart rate, ECG, and cardiac contractility indices in conscious sinoaortic baroreceptor-denervated (SA-denervated) rats and their sham-operated controls. In sham-operated rats, the calcium-entry blocking agents (0.1-2 mg/kg i.v.) produced equivalent falls in blood pressure. However, nifedipine caused a much greater reflex tachycardia which was accompanied by a negative inotropic effect, and with the highest dose (2 mg/kg), a prolongation of the PQ interval. MDL 72567 induced an increase in myocardial contractility. In SA-denervated rats, both drugs produced an enhanced fall in blood pressure accompanied by a negative inotropic effect. Nifedipine did not change heart rate in SA-denervated rats, whereas MDL 72567 caused bradycardia. Thus, in these experiments, MDL 72567 caused less reflex tachycardia for a given fall in blood pressure than nifedipine and was less likely to cause myocardial depression. These effects of MDL 72567 may represent valuable, clinically relevant advantages over nifedipine.

Evaluation of the QA interval as an index of cardiac contractility in anaesthetised dogs: responses to changes in cardiac loading and heart rate.

The response of a simple systolic time interval, the interval between the Q wave and the onset of the aortic blood pressure pulse (the QA interval), to changes in cardiac contractility, cardiac loading, and heart rate was evaluated in anaesthetised open chest dogs. The QA interval was found to be sensitive to increases in cardiac contractility, being reduced (maximum reduction 33.7(1.5) ms) in a dose related manner by infusions of isoprenaline, but was unaffected by reductions in cardiac loading (maximum reduction in diastolic blood pressure 39.7(5.9) mmHg), induced by infusion of sodium nitroprusside, or changes in heart rate (125 to 275 beats X min-1), induced by cardiac pacing. This contrasted with the response of a simultaneous alternative measurement of cardiac contractility, the maximum rate of rise of left ventricular pressure (LVdP/dtmax). Like the QA interval, LVdP/dtmax was also found to be sensitive to increased cardiac contractility (maximum increase 3583(401) mmHg X s-1) and was unaffected by changes in heart rate. Unlike the QA interval, however, LVdP/dtmax was consistently reduced (maximum reduction 1146(200) mmHg X s-1), in a dose related manner, by reductions in cardiac loading. The simplicity of the QA interval and its apparently selective response to changes in cardiac contractility suggests that this index could find a wider application in experimental and clinical settings.

Change in pulmonary and systemic circulation in acute ventricular septal defect.

The correlation between left to right ventricular (L-R) shunt flow and other hemodynamic changes was studied in 16 dogs with an acute ventricular septal defect (VSD) and normal pulmonary vascular bed. The interventricular shunt flow was measured directly with a specially designed electromagnetic flowmeter probe, where the area of the VSD was constant. The sudden presentation of VSD increased pulmonary arterial pressure, pulmonary flow and left ventricular end-diastolic pressure. L-R shunt flow was not changed significantly by atrial pacing except when the rate was increased to over 200/min. Dogs with a VSD were treated with isoproterenol and dextran to vary the shunt flow and hemodynamic parameters. L-R shunt flow was decreased by isoproterenol and increased by dextran loading. The percentage changes of L-R shunt flow from pre-drug values correlated well with the change in left ventricular end-diastolic pressure (r = 0.75) and the ratio of pulmonary to systemic vascular resistance (r = -0.73). Change in total pulmonary vascular resistance had a greater effect on L-R shunt flow than did a change in systemic vascular resistance, whereas a change in aortic flow had less effect (r = 0.35) on L-R shunt flow than did a change in preload and afterload. The time to peak LV dP/dt, as an index of cardiac contractility, and heart rate were not correlated with the relative change in L-R shunt flow. These results indicate that L-R shunt flow induced by the sudden presentation of a VSD varied with changes in the pulmonary and systemic circulation.

Defining end systole for end-systolic pressure-volume ratio

The end-systolic pressure-volume (ESPV) ratio ( E max) has recently been accepted as a valid cardiac contractility index. However, in vivo, it is difficult to define end systole (ES) precisely. This study was designed to analyze the effects of eight different ES definitions on E max. Nine chronically instrumented dogs were studied prior to and during the sequential infusions of phenylephrine (0.2 mg/min), epinephrine (2.0 μg/min), and dobutamine (10 μg/kg/min). Left ventricular (LV) dimensions and pressure were measured with sonomicrometers and micromanometer. ES was defined at peak LV pressure (PLVP), end-ejection, dp/dt min, 10, 20, 30 msec before dp/dt min, minimum volume before dp/dt min, and left-upper-corner of pressure volume loop (LUC). Although ESPV relationship from each definition was linear (mean r 0.89 ± 0.3, range 0.76 to 0.99) and sensitive to inotropic changes, the E max's were not all the same. The r was highest with LUC (mean 0.94 ± .02, range 0.90 to 0.99) and lowest with PLVP (mean 0.85 ± 0.03, range 0.76 to 0.92). E max from PLVP was least sensitive to epinephrine and dobutamine infusions. Thus, in order to compare different values of E max, the definition of ES must be precise and consistent. Although all the above eight definitions of ES appeared to produce reasonable ESPV relationship, PLVP appeared to be the worst while LUC appeared to be the best ES definition for determining E max.

Noninvasive index of cardiac contractility during stress testing: a collaborative study.

The present study was conducted in parallel in three different institutions with a similar purpose but using different technical setups. Based on the experimental demonstration that the external phonocardiogram is similar to the rate of acceleration (d3P/d3t) of the left ventricular pressure, and that catecholamines in a similar way increase the early positive wave of the left ventricular pressure and the first heart sound (S1) of the external phonocardiogram; knowing that exercise causes secretion of catecholamines and sympathetic reflexes, we have studied the S1 changes as a result of exertion in 34 normal young subjects. Blood pressure, heart rate, electrocardiograph, and phonocardiograph recordings of each subject were taken. In 10 subjects, cardiac output was also recorded by impedance cardiography. The result of the study was that the first heart sound increased routinely 4-5 times the normal amplitude; in a few subjects the increase was up to 15 times greater. While the extent of increase of S1 was proportional to the severity and duration of the effort and was usually proportional to the increase of other parameters, exceptions were noted as having marked increase of S1 with moderate increase of either blood pressure or heart rate. This was explained by the different receptors activated by the catecholamines and by the complexity of hormonal and neural influences acting on various organs in a stress test. The amplitude of S1 was found to be a reasonably reliable index for following changes of cardiac contractility during exercise, and the suggestion was made that this parameter should be studied in parallel with the others in routine stress tests.

Comparative studies of cardiovascular effects of a new dopamine agonist (SK&F 38393A) and dopamine

1. 1. SK&F 38393A (DAA) dose-dependently decreased the contractility of isolated frog hearts with an ED 50 of 6.60 ± 0.28 × 10 −5 M, while, dopamine (DA) elicited a dose-dependent increase in the contractility of the preparation with an ED 50 of 5.13 ± 0.36 × 10 −5 M. 2. 2. The results of in situ investigation, using cardiac output as the index of cardiac contractility, were in agreement with the in vitro results. 3. 3. Haloperidol (10 −6 M), a dopaminergic receptor blocker, did not block the cardiovascular effects of DAA and DA. However, propranolol (10 −8 M), a β-adrenergic receptor blocker, prevented the positive inotropic effects of DA but had no effects on the negative inotropic effects of DAA. 4. 4. The results suggest that DAA might be acting on this preparation through a mechanism which is probably not associated with β-adrenergic and/or dopaminergic receptors.

Cardiovascular studies during controlled baroreflex activation in the dog: II. Effects of metoprolol and enflurane.

An experimental model was designed to study circulatory drug effects with or without barostatic reflex influences. In dogs anaesthetized with chloralose, both carotid sinuses were perfused from a femoral by-pass either with systemic arterial pressure or with a pump in order to control the sinus pressure. Cardiac and aortic baroreceptors were denervated. I.v. metoprolol (240 micrograms X kg-1 + 102 micrograms X kg-1 X h-1) with constant carotid sinus pressure and thereby constant baroreceptor activation reduced cardiac output, heart rate, cardiac contractility and left ventricular stroke work index. Systemic vascular resistance increased. This response was independent of the degree of baroreflex activation. During the combined administration of enflurane (1.6% end-tidal concentration) and metoprolol, cardiac performance (cardiac output, stroke volume, heart rate, cardiac contractility and left ventricular stroke work index) was depressed independent of the degree of baroreflex activation. Barostatic reflexes, however, counteracted an observed decrease in systemic vascular resistance. This reflex vascular response was, during metoprolol-enflurane administration, associated with an increased left ventricular end-diastolic pressure.

Can sympathomimetic agents be classified by their action on the force-interval relationship?

The use of the force-interval relationship, the dependence of cardiac contractility on the rate and pattern of stimulation, has been suggested as an index of cardiac contractility, e g. it differentiates among normal, hypertrophied and failing myocardium. In this paper, we describe the effects of sympathomimetic agents on the force-interval relationship and show that this relationship is useful in differentiating the actions of these drugs on the myocardium. Rabbit right ventricular papillary muscles were exposed to isoproterenol, norepinephrine, methoxamine and phenylephrine during a standard two-stage pacing experiment. The force-interval relationship is characterized by force-interval curves which describe how contractility, i.e. the maximum rate of rise of force (Ḟ max), changes between contractions. In the control solution the curves were monotonic and the force-interval ratio (FIR), a measure of post-extrasystolic potentiation, was always greater than unity. Isoproterenol and norepinephrine had similar actions on the force-interval relationship: F max was potentiated, FIR reduced and the curves became biphasic. Methoxamine had the same effect on FIR and the curves. Practolol or propranolol competitively inhibited these changes whereas phentolamine did not inhibit but accentuated them. Phenylephrine increased F max, but unlike the other agonists it increased FIR and the curves remained monophasic. These effects were inhibited competitively by phentolamine. Based upon the action of the competitive inhibitors, these patterns are separable into those produced by α- and β-agonists. The results suggest that the force-interval relationship may be used as a new basis for distinguishing the actions of sympathomimetic agents.

Systolic time intervals during spironolactone treatment of digitalized and non-digitalized patients with ischaemic heart disease

The effect of spironolactone on cardiac contractility indices was studied by externally recording systolic time intervals in four digitalized and four non-digitalized patients with ischaemic heart disease. A negative inotropic effect was found after spironolactone 100mg b.i.d. in all eight patients, as measured by an increase in pre-ejection period index PEPI (p less than 0.01), and the ratio between pre-ejection period and left ventricular ejection time PEP/LVET (p less than 0.001), while pre- and afterload remained constant. As expected, digoxin exerted a positive inotropic effect, as a decrease was observed in PEPI (p less than 0.01), and PEP/LVET (p less than 0.001). It was not possible to ascertain whether the observed effect was caused by a pharmacological interaction at receptor level between spironolactone and digoxin, or indirectly to changes in endogenous substances e.g. aldosterone. The results suggest that spironolactone may have unintended side effects in patients with severe heart failure and that its use be reevaluated.

Elastase 長期使用時の循環動態, 特に非観血的動脈硬化度指標の変化について

We observed the hemodynamic and antisclerotic effects of Elastase (10800 E. S. units daily, orally) in 16 patients having arteriosclerotic disease for a period of 6 to 12 months.As the indices of arteriosclerosis, we used the pulse wave velocity and the volume elasticity in the Windkessel system, and got those indices and other hemodynamic parameters by Wezler's and Blumberger-Holldack's methods non-invasively and mechanocardiographicaphically. The data were analysed at 4 stages, that is, before administation, within 3 months, from 3 to 6 months and over 6 months after administration of Elastase.At each stage, the values of pulse wave velocity were 918±170, 784±186, 803±131, 781±102cm/sec, and volume elasticity, 2355±602, 1926± 557, 1984±462, 1950±343dyne/cm2 respectively, and the decrease of the indices was statistically significant (p<0.025-0.05). Total serum cholesterol and triglyceride were almost within normal limits at each stage (208±82, 261±112, 212±41, 186±40mg/dl; 150±89, 142±86, 172±102, 148± 99mg/dl, respectively).Total peripheral resistance was slightly decreased, consequently cardiac output was slightly increased. Blood pressure, heart rate, systolic time intervals, and the indices of cardiac function or cardiac contractility, that is, ET/PEP, SV/ET and A wave ratio of apexcardiogram, were not changed and remained within normal limits at all stages.We conclude that Elastase has a good influence upon the arteriosclerotic patients whose levels of total serum cholesterol and triglyceride are within normal limits as the agent did in the patients with hypercholesterinemia and hypertriglyceridemia, and the ameliorating effect on the pre-existing arteriosclerosis. This conclusion in clinical study is in agreement with many reports in animal experiments.

Effects of physical training and thyroxine on rodent cardiac functional and biochemical properties.

The effects of 8 weeks of interval running and of 14 days of thyroxine treatment were studied on selected cardiac functional and biochemical parameters of contraction in both female guinea pigs and rats. Relative to their respective sendentary-control groups, both trained groups demonstrated typical exercise adaptations of resting bradycardia and of increases in skeletal muscle oxidative enzymes and relative heart mass (P less than 0.05). Myosin ATPase, Ca2+ regulated myofibril ATPase, and + dP/dt max were at least two-fold higher in rats compared to guinea pigs (P less than 0.001). Physical training did not augment any of these parameters in either species under the experimental conditions studied. However, biochemical and functional indices of intrinsic cardiac contractility in guinea pigs were increased by injections of thyroxine; whereas, the same treatment regimen was without effect on the rats. These findings suggest that chronic running does not alter the intrinsic cardiac contractility state in either species. Also, exercise doesn't change the thyroid state of the guinea pig to a level sufficient to affect cardiac function.

Biophysics of the developing heart: II. The interaction of the force-interval relationship with inotropic state and muscle length (preload)

The interaction of the force-interval relationship, muscle length (ventricular volume), and inotropy was evaluated in isolated fetal myocardial preparations and in the in utero chronically instrumented fetal lamb. In the isolated muscle, 93 to 141 days' gestation, a change in muscle length strengthened all contractions equally (multiplicatively) but produced no other changes in either the quantitative or the qualitative characteristics of the force-interval relationship; it was significantly altered by isoproterenol. Similarly, in the intact fetal lamb the qualitative and quantitative features of the relationship did not depend on ventricular volume, e.g., postextrasystolic potentiation was constant over a wide range of volumes. But isoproterenol produced a decrease in postextrasystolic potentiation. These results demonstrate that the force-interval relationship satisfies two major criteria for an index of cardiac contractility and suggest that the relationship may provide a basis for the evaluation of changes in contractility with development and birth.