Reduction In Myocardial Contractility Research Articles

Calcium antagonists: An overview

Calcium antagonists reduce the influx of calcium ions through the calcium channels. This causes a reduction in myocardial contractility or a fall in vascular resistance because of a lowering of vascular smooth muscle tone. Therefore, the net effect is a fall in blood pressure. The three major classes of calcium antagonists, the dihydropyridines, papaverine derivatives, and benzothiazepines, differ in molecular structure and their binding characteristics to the calcium channels. Furthermore, newer antagonists, particularly the dihydropyridines such as nicardipine, have a high affinity for vascular tissue and are highly selective for vascular smooth muscle. These compounds also have a favorable effect on hypertension mainly because of lowering of vascular resistance. In addition, they do not cause potentially negative metabolic effects on glucose or lipid levels and are generally well tolerated. Based on these findings, the Joint National Committee in the United States and the World Health Organization/International Society of hypertension Committee on the Management of Mild Hypertension recommended the use of calcium antagonists as first-line treatment in hypertension.

Effect of graded reductions of coronary pressure and flow on myocardial metabolism and performance: A model of “hibernating” myocardium

The term “hibernating” myocardium has been applied to chronic left ventricular dysfunction without angina or ischemic electrocardiographic changes in patients with coronary artery disease that is reversed by therapy that increases myocardial blood flow. To investigate the relation between coronary blood flow and ventricular function experimentally, graded reductions in coronary artery pressure were produced in isolated perfused rat hearts as contractile performance (peak systolic pressure and its first derivative [dp/dt]) and metabolic variables were measured using phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy.As coronary pressure and flow were reduced, significant reductions in myocardial oxygen consumption and contractile performance were observed, which returned to control levels when coronary artery pressure and flow were restored to baseline values. Two phases of metabolic abnormality were observed. With modest reductions in coronary perfusion, proportionate reductions in myocardial oxygen consumption and contractile behavior were accompanied by a slight reduction in creatine phosphate but no significant lactate production. With greater reductions in coronary artery pressure and flow, creatine phosphate decreased more, adenosine triphosphate levels and myocardial pH decreased significantly and myocardial lactate production increased. The balanced reductions in myocardial contractility and oxygen consumption without metabolic abnormalities traditionally associated with “ischemia” observed in the first phase provides evidence in normal hearts for resetting of the myocardial contractile behavior and oxygen consumption in the presence of reduced coronary flow (that is, hibernating myocardium). The data suggest that reductions in adenosine diphosphate and the index of the reduced form of nicotinamide adenine dinucleotide (NADH) (lactate formation) do not explain the coupling between coronary artery pressure and flow and myocardial oxygen consumption as contractile performance decreases.

Activated human polymorphonuclear leucocytes reduce rabbit papillary muscle function: role of the CD 18 glycoprotein adhesion complex

The aim was to determine if human polymorphonuclear leucocytes activated by human recombinant C5a (hrC5a) reduce the contractile function of the isolated papillary muscle and if this response depends upon the functional integrity of the CD18 glycoprotein adhesion complex. Human neutrophils with or without pretreatment with monoclonal antibodies to the CD18 adhesion complex were added to organ baths containing isolated papillary muscles of the rabbit and activated with hrC5a. Changes in papillary muscle function were measured. 52 right ventricular papillary muscles isolated from rabbit and neutrophils isolated from human whole blood were used. Neither neutrophils nor hrC5a alone reduced papillary muscle function, but activation of neutrophils with hrC5a provoked reduction in myocardial contractility. This correlated with the degree of neutrophil stimulation, assessed by cell aggregation. Pretreatment of neutrophils with antibodies to the CD18 adhesion complex significantly attenuated the neutrophil induced contractile impairment. Activated human neutrophils can impair contractile function of papillary muscles, which is dependent upon adhesion of the leucocytes to the muscle via the CD18 complex.

Plasma atrial natriuretic factor in patients with acute myocardial infarction

Plasma atrial natriuretic factor (ANF), renin activity (PRA), aldosterone and antidiuretic hormone (ADH) were determined in 16 patients with uncomplicated acute myocardial infarction (AMI) for 7 days in all patients and in six patients for 8 more days. Echocardiograms were performed and central venous pressure (CVP) was measured on the 2nd, 7th and 15th days. On admission, plasma ANF was higher in patients with AMI (129.8 +/- 70.6 pg ml-1, mean +/- SD) than in healthy volunteers (50.6 +/- 10.0 pg ml-1) (P less than 0.05). Arterial pressure, heart rate, CVP were normal. Left atrial (LAD) and left ventricular diameters (LVDD) were increased in six patients. Ejection fraction (EF) was reduced in all. A significant inverse relationship between ANF and EF was observed. Patients with EF less than or equal to 45%, high LAD and LVDD had the highest plasma ANF and showed steady high plasma ANF for 15 days. Patients with EF greater than 45%, normal LAD and LVDD had elevated plasma levels only for 10 days, rising significantly on days 3-7 after admission. PRA and ADH values were normal throughout the study, whereas aldosterone was above the normal range only on admission. These findings suggest that the reduction in myocardial contractility induced by the infarction may account for the rise in ANF secretion via increased left atrial pressure or left atrial dilatation.

RETRACTED: Efficacy of the Phosphodiesterase Inhibitor Enoximone in Complicated Cardiac Surgery

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the request of the editor. In 2018, CHEST published a notice1 that all articles authored by Joachim Boldt be read with caution due to expressions of concern about falsified data. In 2020, CHEST received additional evidence of research misconduct and breaches of scientific integrity that were discovered following an investigation by the author's former institution, the University of Giessen2. In light of this new evidence, this article has been retracted by CHEST. 1. Irwin, R.S., MD, Master FCCP. Notice From the Editor in Chief. CHEST 153(3), p. 767. 2. Mukherjee, J. Statement on the scientific credibility of articles published by Joachim Boldt, formerly professor at Justus Liebig University (JLU), Giessen, Germany. https://ars.els-cdn.com/content/image/1-s2.0-S000709122030163X-mmc3.pdf.

The myocardium in congestive heart failure

It is now apparent that the myocardium in patients with congestive heart failure (CHF) is not normal, because important structural and molecular changes modify function in these hearts. It appears likely that the myocardium in these patients with CHF becomes unable to provide enough chemical energy to meet its mechanical requirements. If this interpretation is correct, the resulting condition of “energy starvation” would have several important implications for therapy. For example, inotropic stimulation, by increasing energy expenditure, could contribute to the progressive myocardial cell death that characterizes end-stage cardiac hypertrophy. Conversely, the reduction in myocardial contractility that develops in the chronically overloaded heart reduces myocardial energy expenditure, and changes in the expression of myosin isoforms improve cardiac efficiency. Therefore, an important goal of therapy in the patient with CHF is to reduce energy expenditure by unloading the failing heart and, in some cases, by administration of negative inotropic drugs.

Hemodynamic profiles of antianginal agents.

The 3 main classes of antianginal drugs are nitrates, beta blockers, and calcium channel blockers. Nitrates have been viewed classically as affecting myocardial demand by reducing intraventricular volume and lowering the filling pressure of the left ventricle. They have been used increasingly to improve oxygen supply in myocardial ischemia by increasing coronary blood flow and actually causing coronary vasodilatation, and by having an effect on endothelial competence. Beta blockers are used to decrease myocardial blood flow by reducing myocardial demand, with reduction of myocardial contractility, afterload, and heart rate. No major improvement of oxygen supply is seen with this class of medication, and in fact, there is some potential for augmenting coronary vasoconstriction. Calcium channel blockers not only reduce myocardial demand by reducing afterload and, in some cases, heart rate, but similar to nitrates, they enhance myocardial oxygen supply.

Effects of bepridil on regional myocardial ischemia and comparison with verapamil

This study was designed to assess the efficacy of bepridil in reducing regional myocardial ischemia and to compare its efficacy with that of verapamil. Forty-five anesthetized, open-chest dogs were subjected to three 5-minute occlusions of the left anterior descending coronary artery (LAD), each followed by 45 minutes of reperfusion. Eleven dogs (group 1) served as controls. In 10 dogs, bepridil, 5 mg/kg, was administered before the third occlusion (group 2). In 11 dogs, verapamil was administered before the third occlusion (group 3). In each dog, on-line intramyocardial hydrogen ion concentration and carbon dioxide tension were measured in the myocardial segment supplied by the LAD. Regional myocardial contractility was assessed in this area with 2 pairs of ultrasonic crystals inserted to determine percent segmental shortening. Regional myocardial blood flow was determined during each occlusion by washout of xenon-127. The increase in hydrogen ion concentration and carbon dioxide tension did not change from occlusion 2 to occlusion 3 in the control group. Both bepridil and verapamil elicited a significant reduction in the extent of regional ischemia, evidenced by a reduction in the accumulation of hydrogen ions, in occlusion 3 vs occlusion 2. Systolic bulging occurred during all occlusions and the periods of reperfusion were not sufficient to allow complete recovery of regional function. Bepridil and verapamil each caused a significant increase in percent segmental shortening (both p < 0.025), and verapamil effected a significant improvement of function during occlusion 3 compared with occlusion 2. Neither bepridil nor verapamil affected regional myocardial blood flow. These data show that bepridil's salutary effect on regional myocardial ischemia is similar to, but less potent than, that of verapamil. This salutary effect is achieved neither through a reduction in myocardial contractility nor through an increase in myocardial oxygen supply. It is probably a result of a reduction in the rate-pressure product and prevention of the deleterious effect of calcium overload on the mitochondria.

Calcium interferes with the cardiodepressive effects of beta-blocker overdose in isolated rat hearts.

Propranolol, timolol and sotalol were compared with respect to their cardiotoxic properties in isolated, spontaneously beating rat hearts. Propranolol and timolol induced a dose-dependent decrease in myocardial contractility. A high dose of sotalol had only modest negative inotropic effects. Similar reductions in myocardial contractility were observed in isolated, ventricle-stimulated rat hearts. These observations were similar to those in a previous study in which spontaneously beating and ventricle-stimulated reserpinized rat hearts were investigated. Spontaneously beating rat hearts were perfused with a high-, a normal- and a low-Ca++ medium, each with and without propranolol, timolol and sotalol. Addition of each beta-blocker to a normal-Ca++ medium induced a decrease of myocardial contractility and of heart rate and an increase of AV-conduction time when compared with the drug-free medium. In a high-Ca++ medium containing the same concentration of each beta-blocker, a less pronounced decrease of myocardial contractility was observed. Heart rate decreased and AV-conduction time increased to the same extent as after perfusion with the drug containing normal-Ca++ medium. With respect to the corresponding drug-free medium perfusion with a low-Ca++ medium with each beta-blocker enhanced the decline in myocardial contractility, most pronounced in propranolol and timolol containing media. For propranolol and sotalol the decrease in heart rate and increase in AV-conduction time were similar to the results after administration of the same beta-blocker in a high- and a normal-Ca++ perfusion media. Timolol caused an electromechanical dissociation. It was concluded that in beta-blocker intoxication the negative-inotropic phenomena cannot be explained by an action of the drugs on the beta-receptor since the results in reserpinized and non-reserpinized rat hearts were similar. Other effects have to be responsible for the observed cardiotoxic phenomena. The present results indicate that these phenomena can be influenced by Ca++ and or can be attributed to differences in lipophilicity.

Electrophysiologic and hemodynamic effects of slow-channel blocking drugs

T HE last decade has witnessed an intense clinical and experimental investigation of the pharmacologic properties and the therapeutic applications of the class of drugs which now have come to be known as “calcium antagonists, ” “slow-channel inhibitors”, or “calcium influx blockers.“i-3 Although the prototype agent of such compounds, verapamil, has been known since 1 962,4 it is only recently that the concept of the selective slow-channel inhibition has been clearly delineated and has gained widespread recognition.5,6 Such an appreciation has followed closely in the wake of numerous developments which have provided a rational basis for the use of slow-channel inhibitors in a very large and increasing number of cardiocirculatory disorders.‘x7 An important advance was made when it was found that the inward depolarizing current in heart muscle had two components, one having fast kinetics and the other slow, each capable of being blocked selectively by specific antagonists.8-‘0 It was aIso found that certain fibers in the normal heart were dependent almost exclusively on slow-channel potentials.” For example, the selective inhibition of such potentials in the middle of the AV node provided a highly effective and predictable method for terminating reentrant paroxysmal supraventricular tachycardias which utilize anterograde conduction through the AV node as part of the re-entrant circuit.‘2,13 Although not all slow-channel antagonists block AV conduction in this manner, the selective inhibition of the slow-channel in cardiac muscle in general has become the main basis for identifying slow-channel inhibitors.236,‘4 The fact that the transport of calcium through the slowchannel during an action potential is responsible for excitation-contraction coupling in heart muscle, a major consequence of the inhibition of this process is a reduction in myocardial contractility, most clearly evident15*16 in isolated cardiac muscle. However, if such a negative inotropic propensity of this class of agents were not modulated favorably by their associated extracardiac effects, it is unlikely that they could be employed “safely” in clinical therapeutics. It so happens that slow-channel blocking compounds also inhibit calcium movements in smooth muscle;‘7*‘8 in so doing they reduce contraction thereby producing vasodilatation in the peripheral vessels and in the coronary circulation.4”7”9-2’ The peripheral vasodilator effect is of particular significance insofar as it may reflexly increase heart rate, AV conduction, and myocardial contractility while improving ventricular performance indirectly by reducing ventricular afterload. In this atricle, the electrophysiologic and hemodynamic effects of slow-channel blockade are discussed relative to the overall pharmacologic properties of the most significant compounds (Fig. 1). Since the precise delineation of their cardiocirculatory and electrophysiologic actions in intact animals and man is critically dependent on their fundamental effects on isolated cardiac and smooth muscle cells, the role of the slow channel in excitation-contraction coupling in these tissues will first be discussed in brief.

Computerized study of the time course of adaptive reserves of the heart in alcoholics treated with nonachlazine

One of the clinical manifestations of alcoholic cardiomyopathy is pain of anginal character, accompanied by a reduction in myocardial contractility. Accordingly it was decided to investigate the effectiveness of treatment of such patients with the original Soviet drug nonachlazine, which combines antianginal properties with a potentiating effect on the contractile function of the heart [3]. Despite numerous investigations into the mechanism of action of nonachlazine, its effect on the adaptive reserves of the heart has not hitherto been studied.

Salient metabolic features in the myocardial cell

Myocardial energy balance strictly depends on oxydative substrate metabolism. In a fasting state FFA are the main energy source and in a fed state the heart uses mainly carbohydrates. The metabolic pattern is largely influenced by myocardial ischemia. Lactate production is the most important marker of the ischemic heart but its venous release in coronary sinus is strongly dependent on the degree of ischemia. During severe ischemia lactate production and release by the ischemic cell are inhibited; during mild ischemia, myocardial lactate production and coronary venous release are enhanced. FFA metabolism is also influenced by the various degrees of myocardial ischemia; their storage in the cell may contribute to arrhytmias, which often complicate myocardial infarction. During hypertrophy, the metabolic pattern does not differ substantially from normal. Hypertrophy is however the first step towards heart failure. Impaired calcium turnover, nucleic acids and protein synthesis, catecholamine deficiency and defects during the phases of the energy cycle, contribute to a progressive reduction in myocardial contractility. Ischemia-dependent heart failure is strongly connected to intracellular acidosis, by specific competition between H + and Ca ++ ions at the troponin level. The metabolic disorder is negatively influenced by digitalis, which enhances myocardial oxygen consumption, lactate production and, consequently, intracellular acidosis.

The effect of the short-acting barbiturate enibomal (Narcodorm) on systolic time intervals.

The systolic time intervals were studied in 16 surgical patients without heart disease between 29 and 75 years of age by a non-invasive technique before and after an induction dose of enibomal (Narcodorm). The pre-injection period/left ventricular ejection time-ratio (PEP/LVET-ratio) increased between 8 and 60% and (1/PEP-2) decreased between 3 and 50%, indicating a reduction of myocardial contractility under the influence of enibomal. Factors responsible for circulatory depression during barbiturate anaesthesia are discussed.

Influence of autonomic blockade on the reduction in myocardial performance produced by clonidine

Clonidine (15 μg/kg, i.v.) induced an increase followed by a long-lasting decrease in blood pressure and reduced heart rate and cardiac output of dogs. All the indices of myocardial performance were decreased: maximal rate of rise in left ventricular pressure, max dP/dt/I.P. (I.P. = ventricular pressure at max dP/dt), pressure time index. The left ventricular end diastolic pressure was increased even when stroke work was decreased. The curve relating dP/dt to the developed pressure was flattened. These facts indicate that clonidine decreased myocardial contractility. Ventricular volumes were not altered. Pacing of the heart after clonidine did not lead to a recovery of cardiac output and myocardial contractility. To analyze the role of the sympathetic and vagal tones on these factors, 5 groups of dogs were used: (1) reserpinized, (2) reserpinized with both vagus nerves cut, (3) with β-adrenoceptor (S 2395, 50 μg/kg) and muscarinic receptor (atropine, 50 μg/kg) blockade, (4) with both vagus nerves cut, and (5)_with both carotid sinus nerves cut. Heart rate was markedly reduced in group 1 but not change in group 2 and 3 3; in groups 4 and 5, heart rate was decreased but to a smaller extent than in control dogs. Therefore the decrease in sympathetic tone and the increase in vagal tone were responsible for the bradycardia. The increase in the vagal tone was apparently due to potentiation of the influence of baroreceptor impulses. The maximal rate of rise in left ventricular pressure did not change in groups 1,2, and 3, but was decreased in groups 4 and 5, indicating that the loss of the sympathetic tone was responsible for the reduction in myocardial contractility. Cardiac output was not changed significantly in groups 2,3 and 4, but decreased in groups 1,3 and 5. The loss of the sympathetic tone and the bradycardia when very marked appear to reduce cardiac output. Left ventricular end diastolic pressure rose in groups 1 and 2, and was increased only transiently in groups 4 and 5. The decrease in myocardial contractility, the changes in blood pressure, the bradycardia and possibly the reduced venous return appear to be the factors influencing this parameter. Blood pressure shows the usual biphasic changes, an increase followed by a decrease in groups 3,4 and 5, did not change in group 1, and was only increased in group 2. The loss of the sympathetic tone was therefore responsible for this effect.

Reduction of myocardial contractility by 100 percent oxygen in patients with coronary disease.

SummaryChanges in contractility indices for left ventricular muscle were calculated during air and oxygen breathing in 19 studies on 14 patients with coronary artery disease. The following significant changes were observed on oxygen breathing: rises in pO2 of arterial blood, in left ventricular systolic pressure, and in tension-time index, and a fall in the velocity of the shortening of the contractile element of the left ventricular muscle at zero load (Vmax). The fall in Vmax was similar even when heart rate was maintained constant. These observations suggest that oxygen breathing diminishes myocardial contractility and consequently may reduce myocardial oxygen demand. It is recognized that the reduction in myocardial contractility may be only one of the factors responsible for the decrease in myocardial oxygen demand induced by oxygen administration.

Anti-toxic action of methylprednisolone in hemorrhagic shock

The potential beneficial effects of the synthetic glucocorticoid, methylprednisolone, in shock were assessed in cats subjected to hemorrhagic shock. A threefold increase in survival time was obtained using methylprednisolone (20 mg/kg) which correlated with low plasma levels of a myocardial depressant factor (MDF) and of the lysosomal enzymes, β-glucuronidase and plasma cathepsin-like activity (PCLA). These data suggest that methylprednisolone exerts a protective effect in hemorrhagic shock by preventing the release of lysosomal enzymes which may be responsible for the formation of MDF, a peptide implicated in the reduction of myocardial contractility during postoligemic shock.

Relation between plasma lignocaine levels and induced haemodynamic changes.

Intravenous lignocaine (1 mg./kg. body weight) was found to produce insignificant haemodynamic changes, and in particular no reduction in myocardial contractility. A rate of 2 mg./minute infused intravenously is suggested for therapeutic purposes.In anaesthetized dogs an infusion of 13.5 mg./minute caused moderate haemodynamic depression and a maximum plasma level of 7 mug./ml. Massive injections of 200 and 400 mg. of lignocaine produced a maximum plasma level of 13.8 and 27.8 mug./ml., respectively, and in the latter failure of myocardial contraction in the presence of a normal E.C.G. ensued ("pump failure"). Lignocaine appears to alter the uptake of calcium by myocardial sarcoplasmic reticulum, and this may explain the negative inotropic effect of large doses.

Lignocaine for acute ventricular arrhythmias

Lignocaine is a stable local anaesthetic which rapidly diffuses through tissues. Like quinidine and procainamide it reduces ventricular irritability.1 2 Clinical studies indicate that it can readily control ventricular arrhythmias without important lowering of blood pressure or reduction of myocardial contractility,3–9which are common after procainamide3 and quinidine. Intravenous lignocaine has therefore become the preferred drug for treating most types of acute ventricular arrhythmias. The treatment seems to have spread rapidly because clinicians are impressed by experience with it; numerous reports of clinical series have been published, but no controlled trials.

Pathophysiology and biochemistry of end-stage hypertensive heart disease

Sustained hypertension is accompanied by certain physiologic and biochemical changes in the heart which may lead to an eventual reduction in myocardial contractility and the onset of circulatory congestion. The early mechanical stress of the hypertensive state evokes cardiac hyperfunction and concentric left ventricular hypertrophy through stimulation of protein synthesis. At some point in the course of the disease one or more rate-limiting processes, in either energy metabolism, excitation-contraction coupling, or the mechanical function of the sarcomere, prevent a normal response to further stress. The small chambered, concentrically hypertrophied ventricle gives way to a large chambered, eccentrically hypertrophied one which must develop a greater wall tension to perform the same or lesser amounts of stroke work. Structural changes in mitochondria, myofibrils, and the coronary circulation occur along with abnormalities in enzyme activity and catecholamine content of the myocardium. The sequence and relative significance of these changes are currently being investigated to elucidate the underlying cause of intrinsic myocardial failure in hypertensive heart disease.