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Purpose of Review To review the spectrum of cardiac manifestations and treatments of multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). Recent Findings Studies demonstrate that up to 80% of children with MIS-C may have cardiac involvement on a spectrum of severity. Cardiac manifestations include myocarditis, coronary artery aneurysms, conduction abnormalities, and arrhythmias. Current treatments, including inotropic support, immunomodulatory therapy, and anti-coagulation, have been effective at resolving these cardiac findings in the majority of patients. COVID-19 can also cause myocarditis in the acute stage of illness and recent descriptions of COVID-19 vaccine myocarditis have occurred. Summary Cardiac manifestations are common in MIS-C and should be assessed for at presentation and during the clinical course as indicated.

Catecholamines have been suggested to modulate innate immune responses in experimental settings. The significance hereof in the treatment of human septic shock is unknown. We therefore sought if and how vasopressor/inotropic doses relate to pro-inflammatory mediators during treatment of septic shock. We prospectively studied 20 consecutive septic shock patients. For 3 days after admission, hemodynamic variables, lactate and plasma levels of interleukins (IL)-6 and 8, tumor necrosis factor (TNF)-α, and elastase-α(1)-antitrypsin were measured six hourly. Doses of vasoactive drugs were recorded. Of the 20 patients, nine died in the intensive care unit. Dobutamine doses were positively associated and related to TNF-α plasma levels, independently of disease severity, hemodynamics, and outcome, in multivariable models. Dopamine doses were positively associated with IL-6, and norepinephrine was inversely associated with IL-8 and TNF-α levels. Our observations suggest that catecholamines used in the treatment of human septic shock differ in their potential modulation of the innate immune response to sepsis in vivo. Dobutamine treatment may contribute to circulating TNF-α and dopamine to IL-6, independently of activated neutrophils. Conversely, norepinephrine may lack pro-inflammatory actions.

The endothelium regulates the tone of vascular smooth muscle cells at rest and during exercise, and the thrombotic and adhesive properties of the vascular wall. Endothelial cells are also responsible for vessel growth (angiogenesis) and inhibition of the positive inotropic and chronotropic responses of catecholamines in cardiomyocytes. Regulation occurs by releasing of relaxing factors and among them nitric oxide is the most important modulator of myocardial function. A comprehensive analysis of the ­signaling pathways network that regulates endothelium structure and function will be presented in this chapter.

Maintaining hemodynamic stability is the primary goal of clinicians who care for critically ill patients. This requires knowledge of the anatomy and physiology of the autonomic nervous system, the cardiovascular system, and their interactions. This chapter reviews the autonomic innervation of the heart and peripheral circulation and the cardiovascular effects of the vasoactive amines and various inotropes.

Metabolic and non-metabolic actions of taurine provide its physiological functions in various tissues and organs (Huxtable, 1992). Phenomena associated with taurine include different cardiotropic effects. It has antiarrhythmic, positive inotropic and hypotensive action (Birdsall, 1998). There is considerable evidence that taurine modulates several processes involved in the pathogenesis of different pathological states of the heart. The most important ones are the modulation of oxygen paradox (Franconi et al., 1985) and a-dependent abnormalities (Kramer et al., 1981; Roysommuti et al., 2003). It also influences the membrane structure and function (Hamaguchi et al., 1991) and osmoregulation (Rasmusson et al., 1993). It is assumed that the cytoprotective properties underlie the antiarrhythmic and ischemia-reperfusion injury protection effects of taurine (Wang et al., 1992; Li et al., 1996; Chahine and Feng, 1998; Takahashi et al., 2003). Thus, the taurine molecule may be available for derivative synthesis on purpose of developing new cardioprotective drugs. We have synthesized a new taurine amide derivative 2-(1-methyl-2-phenylethyl)aminoethanesulphonic acid isopropylamide hydrochloride named Taurhythman. Previously, it was found that it influences systemic hemodynamics. It produced the dosedependent, moderately short-term cardiopulmonary reflex in cats (Sapronov et al., 1998) and induced depressive changes in arterial pressure, heartbeats rate, and peripheral resistance. These effects were accompanied by an increase in stroke volume, cardiac output and venous blood return. In the isolated perfused rabbit heart Taurhythman reduced the power and rate of heartbeats and decreased the resistance of coronary arterial vessels (unpublished data). Intravenous administration in rats induced short-term

Endothelin-1 (ET-1) and the muscarinic agonist carbachol do not affect the basal force of contraction, but induce a pronounced negative inotropic effect in the presence of β-adrenoceptor stimulation in the canine ventricular myocardium. We studied the influence of the phosphatase inhibitor cantharidin on the negative inotropic effect of ET-1 and carbachol in isolated canine right ventricular trabeculae and single ventricular myocytes. In the presence of 100 nM norepinephrine (NE), 10nM ET-1 and 30 nM carbachol induced a negative inotropic effect of an identical extent. Cantharidin at 10 μM did not affect the basal force of contraction and the positive inotropic effect of NE mediated by β-adrenoceptor stimulation. Cantharidin (10 μM) markedly attenuated the negative inotropic effect of ET-1, but it did not affect the negative inotropic effect of carbachol. At 30 μM, cantharidin induced a positive inotropic effect and enhanced the positive inotropic effect of NE. Cantharidin (30 μM) suppressed significantly the negative inotropic effect of carbachol (30 nM and 100 nM). In canine single ventricular myocytes, ET-1 (10nM) or carbachol (30nM) did not affect the baseline level of cell shortening and the amplitude of intracellular Ca2+ transients, while they inhibited the NE (30 μM)-induced increases in cell shortening and Ca2+ transients. Cantharidin (10 μM) attenuated the inhibitory action of ET-1, but did not affect the effects of carbachol in the presence of NE. These results indicate that the activation of phosphatase that is susceptible to cantharidin is involved in the negative inotropic effect of both ET-1 and carbachol. The extent of contribution of phosphatase activation appears to be greater in the ET-1-induced negative inotropic effect than in the effect of the muscarinic receptor agonist carbachol in the canine ventricular myocardium.

In clinical heart transplantation, the heart of a brain dead donor is used. The quality of the donor heart is one of the key factors for a succesful transplantation. A hemodynamically unstable brain dead donor is often rejected because survival of the recipient is reduced.1–3 The precise mechanisms of brain death-related hemodynamic instability remain unknown. One of the reported contributing factors is myocardial injury resulting from the acutely increased discharge of endogenous catecholamines during the onset of brain death.4,5 This injury has been supposed to change aerobic to anaerobic energy metabolism, causing depletion of myocardial high-energy phosphates and contractile dysfunction.6–8 Energy depletion appeared to be even more pronounced when high dosages of inotropic agents were used to treat contractile dysfunction of the canine donor heart.9 Notwithstanding these results, the presence of anaerobic metabolism is disputed by others.10-13

Plasma levels of proinflammatory cytokines, especially tumor necrosis factor (TNF)-α, are elevated in a variety of cardiovascular diseases, including myocarditis, myocardial infarction, and congestive heart failure. Recent studies have demonstrated that the heart itself is a source of cytokines in these disorders. To investigate the role of proinflammatory cytokines in myocardium, we created a model of transgenic mice (TG) that overexpress TNF-α specifically in the heart. These mice developed myocardial inflammation with extracellular matrix remodeling, ventricular hypertrophy with four-chamber dilatation, impaired contractility with diminished β-adrenergic responsiveness, reactivation of the fetal gene program with downregulation of calcium handling genes, and premature death with congestive heart failure. TG also demonstrated a substantial amount of myocardial apoptosis that was, however, mostly isolated to the interstitial cells. Both nitric oxide (NO) and reactive oxygen species were increased in TG. These results indicate that the myocardial production of TNF-α may play an important role in the pathogenesis of myocardial dysfunction. To determine the pathophysiologic importance of NO in TG myocardium, we crossed TG with iNOS knockout mice. Disruption of iNOS gene significantly improved β-adrenergic inotropic responsiveness in TG. However, it did not improve the survival. Thus, although myocardial expression of iNOS plays a key role in the attenuation of β-adrenergic inotropic responsiveness, NO-independent mechanisms may be more important in the development of congestive heart failure. In summary, TNF-α transgenic mice provide a unique model to study the inflammatory myocardial damage and explore new therapeutic strategies for congestive heart failure.

Diabetic cardiomyopathy is characterized by delayed cardiac relaxation. Delayed relaxation is suggested to be associated with sarcoplasmic reticulum (SR) dysfunction and/or increase in myofilament sensitivity to Ca2+. Although MCC-135, an intracellular Ca2+-handling modulator, accelerates the delayed relaxation without inotropic effect in the ventricular muscle isolated from rats with diabetic cardiomyopathy, the underlying mechanism has not been fully understood. We tested the hypotheses that MCC-135 modulates Ca2+ uptake by SR and myofilament sensitivity to Ca2+. Wistar rats were made diabetic by a single injection of streptozotocin (40 mg/kg i.v.). Seven months later, the left ventricular papillary muscle was isolated and skinned fibers with and without functional SR were prepared by treatment of the papillary muscle with saponin to study SR Ca2+ uptake and myofilament sensitivity to Ca2+, respectively. In diabetic rats, SR Ca2+ uptake was decreased, which was related to decrease in protein level of SR Ca2+-ATPase determined by western blot analysis. MCC-135 enhanced SR Ca2+ uptake in diabetic rats, but not in normal rats. In diabetic rats, maximum force was decreased but force at diastolic level of Ca2+ was increased, without significant change in myofilament sensitivity to Ca2+ compared with normal rats. MCC-135 decreased force at any pCa tested (pCa 7.0-4.4), but had no significant effect on myofilament sensitivity to Ca2+ in diabetic rats. These results suggest that MCC-135 enhances SR Ca2+ uptake and shifts force-pCa curve downward without modulating myofilament sensitivity to Ca2+. These effects may contribute to positive lusitropic effect without inotropic effect of MCC-135 observed in the ventricular muscle of diabetic cardiomyopathy.

Taurine, 2-aminoethanesulfonic acid, is a sulfur amino acid that is widely distributed in the body and is involved in many physiological processes1,2. Although taurine is classified as an α-amino acid, it is not incorporated into proteins or membranes. Taurine is present in high concentration (around 10 mM) within myocardial cells, but is found in relatively low levels in the plasma3. It has been found to exert many electrical and mechanical actions on cardiac muscle cells4–7including a positive inotropic effect8,9 and protective action against cellular calcium overload and cardiomyopathy10. Thus, there are many electropharmacological effects of taurine on cardiac muscle cells, but the underlying mechanisms still remain unclear. In the sino-atrial (SA) node, taurine might be a potent modulator of spontaneous activity. The actions of taurine on cardiac pacemaker currents of the SA node are discussed here.

The rate of mortality from acute respiratory distress syndrome (ARDS) has reportedly reached as high as 50–75%.1−3 The risk of ARDS development increases after severe blunt thoracic trauma (BTT) because of a higher likelihood for lung contusion4 and acute depression of cardiac function.5, 6 Monitoring of oxygen transport in patients with ARDS has shown that oxygen delivery and consumption were significantly higher in the survivors compared to nonsurvivors.7 This suggests that maintenance of oxygen delivery at optimal levels can potentially enable the reversal of ARDS.8 In cases of severe BTT, these oxygen transport variables may be induced by early cardiorespiratory dysfunction6, 9 which requires inotropic support.6, 8, 10 On the strength of these data, it is reasonable to conclude that the prevention and correction of oxygen deficiency are basic to intensive care during ARDS.

Congestive heart failure has traditionally been thought of as a hemodynamic problem wherein impaired left ventricular function leads to decreased peripheral perfusion, sodium retention, increased ventricular afterload, and progressively deteriorating left ventricular pumping capacity. In new or decompensated heart failure, this hemodynamic paradigm predicts acute clinical improvement. Chronically, however, treatment based fundamentally on inotropic support or vasodilation has proved either unsuccessful or counterproductive in most instances. It has subsequently been recognized that left ventricular dysfunction and heart failure are characterized by a number of neurohormonal imbalances, especially enhanced activity of the sympathetic nervous system and the renin-angiotensin-aldosterone axis. Acutely, interfering with these systems may have little effect, or even a negative effect, on hemodynamics and clinical status. Yet when applied chronically, treatments based on interfering with these systems improve ventricular function, quality of life, and improve survival. The reasons for the success of this therapy lie more in the cellular and biochemical consequences of reducing adrenergic stimulation and the effects of angiotensin II and aldosterone than in the direct manipulation of contractility or ventricular loading conditions. Nonetheless, controlling inappropriate diastolic and systolic wall stress is necessary for clinical stability and to prevent deteriorating neurohormonal imbalance. It therefore seems that while normalizing hemodynamics is important in the acute setting, and maintaining appropriate cardiac loading conditions chronically is necessary, hemodynamic manipulation does not in itself hold the key to improving outcomes in heart failure. The effect of treatment on adrenergic signaling, the activity of the renin-angiotensin-aldosterone axis, and left ventricular size, all are critical variables in predicting outcome. Treatment for heart failure therefore must not aggravate neurohormonal imbalance if it is to be successful in altering the natural history of the syndrome. Combining appropriate hemodynamic measures with agents that reduce adrenergic signaling, activity of the renin-angiotensin-aldosterone axis, and myocyte hypertrophy holds the key to successful long-term therapy The next generation of therapy in heart failure will need to respect these principles if it is to provide additional benefit beyond our current neurohormonally based regimens.

Glyburide, also known as glibenclamide, was shown to have positive inotropic effect in human and animal hearts. The objectives of the present study was to investigate the effects of glyburide on developed left ventricular pressure (DLVP), coronary flow (CF), and heart rate (HR), in isolated rabbit heart as well as its effects on myocardial contractility and L-type calcium current, iCa in guinea pig myocytes. Rabbit hearts were mounted on Langendorff apparatus and perfused with an oxygenated Krebs for 30 min until reaching steady state to be followed by 20 min of experimental perfusion divided into 5 min of control perfusion and 15 min of perfusion with Glyburide (10 µM). Ventricular myocytes were isolated by enzymatic dispersion technique and superfused in an oxygenated Tyrode solution. Cells were voltage-clamped at holding potential −40 mV to inactivate Na current and a step depolarizations, 200 msec duration, to 0 mV was applied to elicit iCa. The contractions of the myocytes were measured by optical methods. Glyburide significantly increased DLVP by 30% and CF by 36% but had no effect on HR. Glyburide increased cell contractility by 7 ± 6, 18 ± 7, 28 ± 9 and 54 ± 15% for 0.1, 1, 10 and 100 µM respectively, p < 0.001. Meanwhile it depressed iCa by 9 ± 6 and 19 ± 8% for 1 and 10 µM respectively. In conclusion, glyburide increased contractility of guinea pig single myocytes and of isolated rabbit heart, as indicated by increased developed left ventricular pressure while it depressed iCa. It is hypothesized that an elevation in intracellular calcium, which caused increased myocardial contractility, could be attributed to an increase in intracellular Na+ that could increase intracellular calcium via Na+/Ca2+ exchange. (Mol Cell Biochem 242: 81–87, 2003)

One might argue that the best way to study myocardial energetics is to measure the myocardial oxygen consumption of patients and healthy subjects in vivo — possibly before and after an acute or chronic pharmacological intervention. Although this idea is intriguing, there is a number of limitations for such a procedure. (1) Such a kind of procedure is invasive and time-consuming, and therefore some ethical considerations come into play (see below). (2) In the whole organism, any inotropic or vasodilating pharmacological intervention is necessarily followed by reflex neuroendocrine mechanisms which make interpretations of altered myocardial oxygen consumption invalid or at least complicated. In order to overcome this problem, myocardial oxygen consumption must be considered in relation to the respective hemodynamic variables, i.e., stress-time integral, peak systolic stress, pressure-volume area, contraction velocity and others (see below). (3) Measurements of myocardial oxygen consumption — in contrast to hemodynamic measurements — need long periods of steady state conditions.

Investigation on the contractile performance of non-failing and diseased myocardium was always in the center of interest in research for heart failure. For some experimental protocols it is of importance to exclude all factors, which could change the inotropic response of the examined myocardial structures. Endothelial cells and fibroblasts, which are present in large numbers in multicellular preparations like muscle strips or papillary muscles, may be responsible for these unpredictable changes of contractility. Therefore, big effort was made to develop a method, which concentrates on the contractile behaviour of one single cardiomyocyte.

Despite a series of elegant studies performed by Beznak in the fifties clearly demonstrating Growth Hormone (GH)’s role in maintaining a normal hypertrophie response following experimental aortic constriction (1-3), the cardiovascular role of the GH/IGF-1 axis was largely overlooked. In fact, until few years ago, GH was classically regarded as the principal mediator of bone linear growth, in addition to its well known actions on glucose homeostasis and skeletal muscle mass, and the heart was not generally considered as a target tissue (4). It is now well established that not only does GH play an essential role in maintaining a normal cardiac muscle mass and function, but also that its growth-promoting and positive inotropic actions may be beneficial in the setting of heart failure and ischemic syndromes.

The American College of Chest Physicians & Society of Critical Care Medicine Consensus [1] defines sepsis as the systemic inflammatory response syndrome (SIRS) as a result of infection. Septic shock is defined as sepsis-induced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities. These abnormalities may include, but are not limited to, lactic acidosis, oliguria or an acute alteration in mental status. Patients who are receiving inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured. From the years 1950–1991 mortality has soared by 13-fold [2]. Alone sepsis carries a 30–40% lethality [2] but when aggravated by shock, it has a 40–60% mortality [3]. Recently the effectiveness of invasive hemodynamic monitoring in septic shock has undergone intense scrutiny.

Recent evidence has implicated lipid-mediated second messengers such as 1,2diacylgjycerol (DAG)-protein protein kinase C (PKC) pathway as an important mediator underling multiple aspects of myocardial function (1). For example, PKC is involved in Ca2+ -induced inotropy, in mediating myocardial preconditioning by diverse stimuli both in animals and humans, and in the signaling processes which lead to the production of proinflammatory mediators. Hyperglycemia and diabetes have been shown to be associated with PKC activities (2). The changes in DAG-PKC pathway are significant in causing cardiovascular dysfunctions and pathologies.

Left ventricular hypertrophy occurs as an adaptation prior to chronic congestive heart failure caused by pressure or volume overload. We examined the modulation of the effects of Ca2+ sensitizers, namely, Org 30029 [N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximidamide hydrochloride] and JTV-704 (EGIS-9377) [2-(l-methylthio)-5-(2-mor-pholinoethylamino)-8,9-dihydro-7H-thiopyrano[3,2-d][l,2,4]triazolo[l,5-a]pyrimidine dihydrochloride], in comparison with those of β-adrenoceptor agonists in cardiomyocytes isolated from volume-overloaded rabbits. We isolated ventricular cardiomyocytes by means of collagenase perfusion 12 weeks after the shunt formation, when ventricular weight, aortic flow, left ventricular pressure, and diastolic pressure had been increased significantly. Cell shortening and Ca2+ transients were measured in cardiomyocytes loaded with indo-1. In cardiomyocytes isolated from the volume-overloaded heart, cell length and width were increased proportionally. The duration of Ca2+ transients and cell shortening was significandy prolonged in volume-overloaded cardiomyocytes compared with that in normal (isolated from sham-operated rabbit) cardiomyocytes. The response of Ca2+ transients and cell shortening to the Ca2+ sensitizers, namely, Org 30029 and JTV-704, was unaltered in volume-overloaded cardiomyocytes. By contrast, the response to dobutamine and isoproterenol was significandy attenuated in volume-overloaded cardiomyocytes compared with the response in normal cardiomyocytes. These results indicate that in volume-overloaded rabbit cardiomyocytes, the response to the Ca2+ sensitizers was maintained when the responsiveness to β-adrenoceptor stimulation had been reduced, an indication that the Ca2+ sensitizer may be beneficial for improvement of contractile dysfunction even when β-agonists lose their effectiveness in volume-overloaded cardiomyocytes with hypertrophy.

This paper discusses the mechanisms of two basic effects of thyroid hormones on atrial responses to β-adrenergic agonists, i.e. increased inotropic sensitivity and decreased maximal contractile responsiveness. The increased sensitivity of atria to β; adrenergic agonists under thyroid hormones appears to be related to increases in β-adrenoceptor density and Gs/Gi. protein ratio, leading to activation of Gs-mediated pathway, but suppression of Gi.-mediated pathway of adenylate cyclase regulation. Therefore, the i/c concentrations of cAMP and corresponding inotropic responses achieve their maximums at lower doses of β-adrenergic agonist. Thyroid hormones also decrease the expression of phospholamban, but increase the expression of sarcoplasmic reticulum Ca2+-pump. As a result, the basal activity of sarcoplasmic reticulum Ca2+-pump increases, but its β-adrenergic activation through phosphorylation of phospholamban decreases. It is suggested that these changes are causal for decreased maximal inotropic and lusitropic responses of atria to β-adrenergic agonists.(Mol Cell Biochem 184: 419–426, 1998)

The role of nitric oxide (NO) in heart failure is unknown. Studies of isolated blood vessels from patients with heart failure demonstrate impaired NO-dependent relaxation to acetylcholine. On the other hand, endomyocardial biopsy specimens from patients with dilated cardiomyopathy show increased activity of the inducible isoform of nitric oxide synthase (iNOS). Plasma levels of TNF-α, an activator of iNOS, are increased in heart failure, and TNF-α has been shown to have negative inotropic effects in hamster papillary muscle through an NO-dependent mechanism.

We have isolated an endogenous positive inotropic factor (EPIF) from porcine left heart ventricular tissue, which demonstrated to have only weak digitalis-like properties including the inhibition of myocardial Na+,K+-ATPase. EPIF completely lacks digitalis-like toxicity such as after-contractions in larger doses. In our recent studies, we have demonstrated that EPIF produces a decrease in the amplitude of the post-rest rapid cooling contracture which indicated that EPIF may release Ca2+from the sarcoplasmic reticulum. In the present study, the effects of EPIF were investigated on the Ca2+uptake and release properties of SR enriched membrane vesicles from rat heart. At pH 6.8 and in the presence of oxalate, EPIF dose-dependently inhibited the ATPdependent uptake of Ca2+by SR vesicles. Concentrations as low as 25 ul (in 1 mL uptake medium) of EPIF caused a 45-47% reduction in the uptake of Ca2+within 3-4 min. Increases in EPIF concentration to 50 ul/mL caused additional reduction of only 15-20% in the uptake of Ca2+. Concentrations of 25 ul/mL of EPIF had little or no effects on passive release of actively loaded Ca2+in SR vesicles. On doubling the concentrations to 50 ul/mL EPIF, however, enhanced the release of Ca2+by 25-28% during 1-2 min. and 44-48% after 4 min of incubation of Ca2+loaded vesicles in the release medium. Relatively smaller effects of EPIF on Ca2+release implies that EPIF may mainly lower the uptake of Ca2+in SR. This reduced uptake of Ca2+may be explained by the EPIF-induced inhibition of Ca2+pump.

Prostaglandin effects on the heart include changes in the functional and metabolic state, as well as a reduction of ischemia-induced myocardial injury1 and arrhythmias2. The cellular targets of these effects, however, have not been unambiguously defined. Since prostaglandins act via G protein coupled receptors, it is likely that cardiac tissues express one or several of the five classes of prostaglandin receptors, i. e. EP, IP, DP, FP and TP receptors. We here report a direct inhibitory action of PGE1 on myocardial contractility during β-adrenergic inotropic stimulation, that is likely to be mediated by an E-type prostaglandin receptor (EP3 subtype) leading to inhibition of adenylate cyclase.

Taurine has been reported to produce (i) a positive inotropic effect in heart muscle15, 20, (ii) beneficial effects against treatment of congestive heart failure1, and (iii) protective effects against Ca2+ overload27, 28. Compared to cardiac muscle, little is known on the action of taurine on vascular smooth muscle.

Intensive search into the presence of endogenous digitalis-like factor (EDLF) started shortly after identification of the alpha subunit of the Na,K,-ATPase as being receptor for digitalis glycosides. After years of skepticism, present data testify EDLF really exists. Most probably, the EDLF has chemical structure of either ouabain or of one of its isomers. It is secreted by the adrenal cortex, and, under conditions of stress, it’s secretion is regulated differently from the secretion of both gluco- and mineralocorticoids. The physiological role of the EDLF has not been fully understood yet. In the newborn’s kidneys, the inhibition of the Na,K-ATPase may assist to increase elimination of surplus sodum from the organism. In individuals of any age, the inhibitory influence of EDLF upon Na,K-ATPase in the arterial wall smooth muscle cells increases peripheral vascular resistance and thus, blood pressure. In the tissue culture, direct positive inotropic influences of EDLF upon rat cardiomyocytes was observed. However, the importance of positive inotropic effect of the EDLF upon the heart in clinical medicine remains to be elucidated. (Mol Cell Biochem 160/161:111–115, 1996)

The membrane-bound Na, K-ATPase, which by deriving energy from ATP performs the active transport of Na and K across the cell membrane, is of major importance to excitable tissues. By adjusting the translocation of Na and K across the cell membrane, it plays an important role in generating and maintaining the membrane potential. Furthermore the Na,K-pump is of major importance for interstitial K homeostasis following depolarization [1–3]. Additionally, there is a general consensus that the inotropic effect of cardiac glycosides is achieved through binding to left ventricular Na,K-ATPase. Thus, occupancy of Na,K-ATPase with cardiac glycoside inhibits its active cation transport and therefore, indirectly increases intracellular Ca availability by the Na-Ca exchanger, which in turn activates contractile proteins [4].

Of the amino acids that exist freely in the cytoplasm of myocardial cells, taurine is in highest concentration. While the precise physiological function of taurine in the myocardium has not be defined, taurine may have antioxidant properties8, 9, 29, modulating effects on myocardial calcium23, or a positive inotropic effect3, 32. In hearts isolated from taurine-de-pleted and control rats, Schaffer et al. 29 observed a significantly lower% recovery of mechanical performance in the depleted group than controls following ischemic-reperfusion injury. More recently, we24, 25 and others17 have reported that depletion of myocardial taurine results in cardiac dysfunction characterized by decreased left ventricular (LV) contractility, suggesting that taurine is essential to the maintenance of normal myocardial contractile function. Because taurine is an essential dietary amino acid in the domestic cat, a taurine-deficient state can be achieved in this species through restriction of dietary taurine14. In the cat dietary taurine deficiency leads to a spectrum of changes in myocardial function associated with decreased contractility24, 25. Dilated cardiomyopathy (DCM) appears to be one consequence of taurine deficiency in this species. However, not all cats maintained on taurine-deficient diets develop DCM24, 27, 30.

Heart failure represents the final common pathway for most forms of heart disease. Current therapy for the failing heart is directed primarily at symptoms and ventricular function; however, mortality continues to be high [1]. More recently, several cellular and molecular alterations have been identified in the failing heart that support the concept of progressive myocardial overload contributing to a chronic energy deficit and setting up a vicious cycle. In this condition long-term administration of inotropic agents that increase cyclic AMP and energy demand may be detrimental [2]. On the other hand, the improved survival observed with vasodilator [3,4] and proposed with beta-blockers [5,6] may be in part related to energy-sparing effects of these agents [7]. This concept has prompted interest in the evaluation of left ventricular performance in relation to myocardial oxygen consumption, so-called mechanical efficiency [8–24].

The sulfur amino acid taurine has been reported: (i) to be a positive inotropic (cardiotonic) agent in failing hearts, in both animals and human; (ii) to be depleted in myocardial cells in ischemic heart disease; and (iii) to cause heart failure when deficient in diet of animals (e. g., cats) that cannot synthesize taurine. The taurine content of the heart is elevated in patients and animals with congestive heart failure1. Taurine has been used as a treatment for patients with congestive heart failure (e. g., 3 g per day) by Dr. Azuma et al. In Japan and Korea, soft drinks (e. g., soda pop and fruit drinks) that contain taurine (e. g., 1 g) as an additive are widely available.

For the treatment of heart failure, inotropic agents yield short-term hemodynamic improvement. However, inotropic therapy is still an unfilled promise for the treatment of chronic heart failure (1). This may partly result from the fact that inotropic interventions increase myocardial oxygen consumption (VO2). Therefore, the investigation of myocardial energetics in relation to inotropic agents in patients with heart disease has clinical and therapeutic relevance. Recently, the concept of left ventricular (LV) elastance (Emax) and systolic pressure-volume area (PVA) has been proposed by Suga and his colleagues (2,3,4,5). Experimental studies have shown that the relation between VO2 and PVA is linear under a variety of loading conditions. This linear relation has been used to partition VO2 into non-mechanical and mechanical portions. Experimental studies have shown that positive inotropic interventions, which enhance Emax, shift the VO2-PVA relation line upward in a parallel manner. The resultant increase in VO2 intercept of the relation has been considered to be VO2 for non-mechanical work. The relation between Emax and PVA-independent VO2 has been reported to be linear; the slope represents “oxygen cost of contractility” under various inotropic interventions. The aim of this study was to examine the effects of various inotropic agents on human cardiac mechanoenergetics by utilizing the concept of Emax and the VO2-PVA relation. To this end, we compared the effects of the newly developed phosphodiesterase inhibitor E-1020 and a novel Ca++ sensitizing agent, MCI-154, with dobutamine in patients with heart disease.

β-adrcnergic receptor (βAR) stimulation increases the rate and force of myocardial contraction and enables the heart to respond appropriately to increased peripheral demands. While there are several different types of βARs, those in the heart were formerly thought to be primarily the β1AR. However, evidence from radioligand binding and functional studies [1–5] indicates that β1ARs and β2ARS coexist in the hearts of various mammalian species, and that both β1AR and β2AR stimulation play a significant role in the regulation of inotropic or chronotropic activities of the heart [6–8]. Since the β1AR pathway is down-regulated in human heart failure [9–11], the potential role of β2AR stimulation for improving cardiac performance has received considerable attention.

The effects of the vasoactive peptide angiotensin II (AII) on contractility and excitation-contraction coupling in isolated adult rabbit ventricular myocytes were investigated. In most ventricular myocytes, AII (10-8 M) induced a significant increase in fractional shortening which was not associated with an increase in the calcium transient measured with indo-1. AII did increase the intracellular pH by approximately 0.2 5 pH units coincident with the positive inotropic effect. Effects of AII on pH and contractility were blocked by inhibitors of Na+/H+ exchange. AII also increased the rate of pHi recovery from intracellular acidosis at pHi values above 6.9. AII was shown not to affect the L-type inward calcium current. However, in an occasional cell, AII was observed to cause a slight increase in the calcium transient. We hypothesize that this response may reflect an increase of calcium influx on the sodium calcium exchanger, as a consequence of an increase in subsarcolemmal sodium concentration resulting from enhanced Na+-H+ exchange.

The Huatuo reconstruction pill (HTRP) is a Chinese traditional herbal preparation which has been used for hundreds of years with remarkable effect on the cerebral palsy. The significant increase in both the common and internal carotid blood flow and the positive inotropic action on the heart were observed in anesthetized cat, dog and rabbit experiments following intravenous (iv) injection of HTRP extract 0.125 to 1.0 ml per kilogram body weight. 1.0 nl of which is equivalent to 0.2067 gm crude drugs. The carotid blood flow was selectively increased without change in vascular resistance of the hind limb. The internal carotid blood flow reached the maximal efficacy as high as 173% of the control level. Neither the action of potassium ion in the drug nor the histamine release was excluded. The positive inotropic action was demonstrated by the increase in LVP, dP/dtmax, Vmax, CO, TTI and dP/dt-LVP vectogram. Yet HR, BP, EEG, ECG and respiration remained unchanged. All these results may provide a theoretical explanation to HTRP therapeutic effect on neurological sequelae of cerebral vascular accident.

The bioactivc phospholipids of the cardiac cell membrane (sarcolemma) and their signaling pathways are emerging as important mediators of the myocardial response to external stimuli, including catecholamines [1]. It is known that the activity of the sympathetic nervous system is increased in congestive heart failure; this results in elevated levels of plasma catecholamines, which downregulate the β-adrenoceptors in failing hearts, leading to subsensitivity of the β-agonist-mediated biochemical and mechanical responses [2]. The α1-adrenoceptors, which are associated with the positive inotropic effect of catecholamines via activation of the membranal phosphoinositide-phospholipase C (PLC) [1], were found to remain unchanged [3] or to increase [4,5] in heart failure. In view of the downregulation of the β-adrenoceptors, the α1 type reflects a greater proportion of the total adrenoceptor population in the failing ventricle [3–5]. Thus α1-adrenoceptors can be seen to play a dominant role in eliciting the positive inotropic action of catecholamines in failing heart [6].

The course of research in cardiovascular physiology has been influenced greatly by the time-varying elastance [E(t)] theory of ventricular contraction which was introduced in the early 1970’s (1). In principle, the E(t) function describes the time variations in instantaneous ventricular volume-elastance during a beat and was proposed as a load-independent characterization of dynamic ventricular pump properties. Additionally, the value of E(t) at end systole (Ees), which is the slope of the end-systolic pressure-volume relationship (ESPVR), varies directly with inotropic background and it was therefore proposed that Ees could serve as a load-independent index of ventricular contractility. Evaluation of the energetics of the E(t) theory also led to the notion of a load-independent relationship between energy consumption (in the form of oxygen, mVO2) and mechanical energy liberation indexed by the pressure-volume area (PVA) (2).

Idiopathic dilated cardiomyopathy (DCM) is one of the fatal heart diseases which severely compromises cardiac performance. Various aspects of this disease have been analyzed and reported (1–7) including the pathophysiology, hemodynamics, and mortality, but many problems remain unresolved. One problem is that this disease is extremely resistant to therapy and no cardiotonic agent has been reported to decrease its mortality (8–11).

Taurine, a sulfur-containing amino acid, is present in myocardial cells at high concentration (around 10 mM) (13). Taurine produces many functions on the ion fluxes across cell membrane and the contractile force (13,31,33,34). It has already been reported that taurine produces a positive inotropic effect in heart muscles (3,7,8,10), that it has beneficial effects in treatment of congestive heart failure (2,36), and that is is protective against Ca2+ overload and cardiomyopathy (1,19,37). Taurine levels in the cells are lowered in ischemic heart failure (17,18).

Many investigations have shown the superiority of cold blood cardioplegia (BCP) to crystalloid cadioplegic solutions (CCP) in myocardial protection, especially in cardiac operations with a long ischemic time, in order to perform the distal coronary anastomoses on a quiescient, bloodless heart. In animal experiments, parameters of myocardial protection with BCP have been the left ventricular contractile function, the myocardial contents of high energy phosphates and the histological integrity of the myocardial cells1,2,3,4. Clinical investigations have shown the advantages of BCP with respect to operative mortality, perioperative infarction, incidence of heart rhythm disturbances and need for positive inotropic substances5,6,7.

In cardiac muscle, the high energy demands of contractile processes are primarily met by the oxidative synthesis of adenosine triphosphate (ATP). It is well recognized that this energy demand and, consequently, the myocardial oxygen consumption rate (MVO2)1, can vary over a large range. In the experimental setting, MVO2 can be be markedly increased by means of inotropic and/or chronotropic interventions. In the intact organism, such changes occur in response to increased circulatory demands as encountered, for example, in the transition from rest to a high level of exercise.

Relationships between cytosolic phosphorylation potential, low-flow ischemic purine release and post-ischemic left ventricular developed pressure were examined in perfused working guinea-pig heart. During moderate ischemic acidification, metabolic intervention by pyruvate attenuated cytosolic NADH accumulation and (ATP+ADP+AMP) degradation. In reperfusion, spontaneously developed ventricular pressure increased in parallel with the phosphorylation potential (R2 = 0.71), but forced restoration of function by inotropic measures occurred at the expense of the phosphorylation potential.

Taurine exerted a protective effect against the decline in the Ca2+- dependent slow action potentials (APs) caused by hypoxia (Sawamura et al., 1986a), but did not induce Ca2+-dependent slow APs (Sawamura et al., 1986b) and did not elevate cAMP level (Sawamura et al., 1983). Taurine also exerted a positive inotropic effect (in perfused embryonic (20-day-old) chick heart) without affecting the slow APs, and it was suggested that the positive inotropic effect was not mediated through an increase in slow Ca2+ current (Sawamura et al., 1986b). The effects of taurine on the Ca2+ slow current in guinea pig myocytes depended on the external Ca2+ concentration (Sawamura et al., 1990).

Experimental data clearly indicate that significant ontogenetic differences exist in cardiovascular sensitivity to inotropic agents, both under “in vitro” and “in vivo” conditions (1). It seems likely that despite significant interspecies differences developmental changes may exist in all mammals depending on the degree of maturation of systems involved in the regulation of contractile function (2). This field of investigation was stimulated in recent years by an increasing clinical use of positive and negative inotropic drugs (e.g. catecholamines, calcium antagonists) during early phases of ontogenetic development, particularly during pregnancy in order to prevent premature labor or to treat acute intrapartum fetal distress (3, 4) or in pediatric cardiology (5, 6).

Myocardial ischemia has been characterized as an imbalance between energy supply and demand. In the initial seconds after a sudden reduction of coronary blood flow, the energy demand (determined by contractile function) of the myocardium most certainly exceeds the reduced energy supply (determined by coronary blood flow). This temporary mismatch between regional contractile function and reduced blood flow, however, is an inherently unstable condition because regional contractile dysfunction ensues. The mechanisms responsible for the rapid reduction in contractile function in the acutely ischemic myocardium are still poorly understood. If some residual blood flow exists, a state of “perfusion-contraction matching” can be maintained without the development of irreversible damage, and the metabolic status of such hypoperfused myocardium improves as myocardial lactate production is attenuated and creatine phosphate, after an initial reduction, returns towards control values. Despite the decrease in baseline contractile function, the hypoperfused myocardium can respond to inotropic stimulation by dobutamine. The recruitment of an inotropic reserve implies increased energy utilization. In fact, during inotropic stimulation myocardial glycogen is further reduced and the partially normalized lactate production is again increased. Creatine phosphate is also decreased again, indicating that this energy reservoir is utilized more rapidly than it is being replenished. Apparently, the inotropic challenge once again precipitates a supply—demand imbalance, which had been at least partially corrected by the ischemia-induced decrease of regional contractile function. A chronic reduction in contractile function which normalizes upon reperfusion has been termed “hibernation.”