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Positive inotropic agents are fundamental in the treatment of heart failure; however, their arrhythmogenic liability and the increased myocardial oxygen demand strongly limit their therapeutic utility. Pursuing our study on cardiovascular activities of lupin alkaloid derivatives, several 2-(4-substituted-phenyl)-2-dehydrosparteines and 2-(4-substituted-phenyl)sparteines were prepared and tested for inotropic and chronotropic activities on isolated guinea pig atria. Four compounds (6b, 6e, 7b, and 7f) exhibited significant inotropism that, at the higher concentrations, was followed by negative inotropism or toxicity. Compound 7e (2-(4-tolyl)sparteine) exhibited a steep dose-depending inotropic activity up to the highest concentration tested (300 µM) with an Emax of 116.5 ± 3.4% of basal force, proving less potent but much more active in comparison to the highest concentrations tested of digoxin and milrinone having Emax of 87.5 ± 3.1% and 52.2 ± 1.1%, respectively. Finally, docking studies suggested that the relevant sparteine derivatives could target the sigma-1 receptor, whose involvement in cardiac activity is well documented.

Positive inotropic agents are fundamental in the treatment of heart failure; however, their arrhythmogenic liability and the increased myocardial oxygen demand strongly limit their therapeutic utility. Pursuing our study on cardiovascular activities of lupin alkaloid derivatives, several 2-(4-substituted-phenyl)-2-dehydrosparteines and 2-(4-substituted-phenyl)sparteines were prepared and tested for inotropic and chronotropic activities on isolated guinea pig atria. Four compounds (6b,6e,7b, and7f) exhibited significant inotropism that, at the higher concentrations, was followed by negative inotropism or toxicity. Compound7e(2-(4-tolyl)sparteine) exhibited a steep dose-depending inotropic activity up to the highest concentration tested (300 µM) with anEmaxof 116.5 ± 3.4% of basal force, proving less potent but much more active in comparison to the highest concentrations tested of digoxin and milrinone havingEmaxof 87.5 ± 3.1% and 52.2 ± 1.1%, respectively. Finally, docking studies suggested that the relevant sparteine derivatives could target the sigma-1 receptor, whose involvement in cardiac activity is well documented. [ABSTRACT FROM PUBLISHER]

Intravenous positive inotropic agents are commonly used to treat the patients with acute decompensated heart failure due to left ventricular systolic dysfunction. Although these agents seem to be beneficial for improving symptoms of heart failure in the short-term; it has been reported that they are associated with increased mortality and morbidity. Levosimendan is a new calcium sensitizer and K-ATP channel opener, has emerged as an alternative option of pharmacologic inotropic support in patients with decompensated heart failure. Recent reports on levosimendan's use in severe heart failure demonstrated that this agent is more favorable drug compared with conventional inotropic agents, though its better profile in terms of myocardial efficiency has not been completely understood. This review summarizes the evidence from current scientific literature including our recent trials regarding the mechanism of action, efficiency and the use of levosimendan. [ABSTRACT FROM AUTHOR]

Abstract: Background: Previous studies in patients and in dogs with experimentally induced heart failure (HF) showed that electrical signals applied to the failing myocardium during the absolute refractory period improved left ventricular (LV) function. We examined the effects these same cardiac contractility modulating (CCM) electrical signals on myocardial oxygen consumption (MVO2) in both patients and dogs with chronic HF. Methods and Results: Six dogs with microembolizations-induced HF and 9 HF patients underwent CCM leads and generator (OPTIMIZER II) implantation. After baseline measurements, CCM signals were delivered continuously for 2 hours in dogs and for 30 minutes in patients. MVO2 was measured before and after CCM therapy. In dogs, CCM therapy increased LV ejection fraction at 2 hours (26 ± 1 versus 31 ± 2 %, P = .001) without increasing MVO2 (257 ± 41 versus 180 ± 34 μmol/min). In patients, CCM therapy increased LV peak +dP/dt by 10.1 ± 1.5 %. As with dogs, the increase in LV function after 30 minutes of CCM therapy was not associated with increased MVO2 (13.6 ± 9.7 versus 12.5 ± 7.2 mL O2/min). Conclusions: The study results suggest that unlike cAMP-dependent positive inotropic drugs, the increase in LV function during CCM therapy is elicited without increasing MVO2. [Copyright &y& Elsevier]

Abstract: Sea anemone toxins, whose biological function is the capture of marine prey, are invaluable tools for studying the structure and function of mammalian voltage-gated sodium channels. Their high degree of specificity and selectivity have allowed for detailed analysis of inactivation gating and assignment of molecular entities responsible for this process. Because of their ability to discriminate among channel isoforms, and their high degree of structural conservation, these toxins could serve as important lead compounds for future pharmaceutical design. [Copyright &y& Elsevier]

The central haemodynamic effects of pindolol and xamoterol have been investigated in patients with postural hypotension. Pindolol is a non-selective beta-adrenoceptor partial agonist, whereas xamoterol is β-selective and possesses a higher degree of agonist activity. The study comprised 16 patients with postural hypotension of different aetiologies. Blood pressure, heart rate and stroke volume were measured in the supine and head-up tilted positions. Left ventricular ejection fraction (LVEF) was measured in the supine position, and vascular resistance, left ventricular volume, and left ventricular contractility were derived. Pindolol and xamoterol were administered intravenously in incremental doses to reach total doses of 0.02 and 0.20 mg · kg, respectively. Pindolol showed β-adrenoceptor antagonistic effects in the supine position through decrements in heart rate from 70 to 66 beats · min and LVEF from 0.57 to 0.52, and reduced mean arterial blood pressure from 103 mm Hg to 93 mm Hg. Xamoterol showed beta-adrenoceptor agonistic effects in the supine position through increments in heart rate from 72 to 90 beats · min and LVEF from 0.58 to 0.66, and raised mean arterial blood pressure from 108 to 123 mm Hg. It is concluded that the degree of agonist activity of a beta-adrenergic agent is of importance if it is given to a patient with postural hypotension. [ABSTRACT FROM AUTHOR]

In isolated papillary muscle strips from nonfailing donor hearts (NF) and from the hearts of patients with dilated cardiomyopathy with severe heart failure (NYHA IV), the force-frequency relationship was studied. Experiments were performed under basal conditions and in the presence of 0.01 μ M or 0.1 μ M isoprenaline and 0.02 μ M ouabain. In NF, there was a positive inotropic effect following an increase of the stimulating frequency, whereas in NYHA IV, the force gradually declined under these conditions. Low concentrations (0.01) μ M of isoprenaline prevented the negative inotropic effect in NYHA IV, whereas at 0.1 μ M the mechanical function deteriorated in NF and NYHA IV. Ouabain had no effect on the force-frequency relationship compared to basal conditions. It is concluded that a reduction of high frequencies does improve the contractility in the failing myocardium. It is not unreasonable to speculate that this mechanism might be involved in the beneficial effects of drugs which reduce the heart rate, such as β-adrenoceptor antagonists and cardiac glycosides, in the condition of congestive heart failure in which the sympathetic tone is high. [ABSTRACT FROM AUTHOR]

The effect of EMD 53998 (EMD) (0.1-100 μmol/l), chemically a racemic thiadiazinone derivative, suggested to be a potent Ca-sensitizer, was studied in human failing and nonfailing left ventricular myocardium. For comparison, the effects of the pyridazinone derivative pimobendan (0,1-300 μmol/l), isoprenaline (Iso) (0.001-3 μmol/l) as well as CaCl (1.8-1.5 mmol/l Ca) were investigated. The positive inotropic response were examined in electrically driven (1 Hz, 37°C) human left ventricular papillary muscle strips from terminally failing hearts (NYHA IV, n=24) and nonfailing donor hearts (NF, n=9). The effect of EMD on the Ca-sensitivity of skinned fiber preparations from the very same human failing hearts were studied as well. EMD and pimobendan increased force of contraction (FOC) in a concentration-dependent manner. As judged from the EC-values, EMD increased FOC more potently than pimobendan. EMD was significantly more effective than pimobendan to increase FOC in papillary muscle strips from NYHA IV (EMD: +2.5±0.1 mN; pimobendan: +0.8±0.2 mN) as well as from nonfailing hearts (EMD: +3.1±0.5 mN; pimobendan: +1.2±0.2 mN). Only in terminally failing myocardium, EMD increased FOC as effectively as Iso. After inotropic stimulation with EMD, pimobendan, or Iso, carbachol (1000 μmol/l) reduced FOC in left ventricular papillary muscle strips, indicating a cAMP dependent mode of action. In skinned fiber experiments, EMD increased Ca-sensitivity significantly more (p<0.01) than pimobendan. In conclusion: EMD increases FOC in human myocardium via sensitizing of the contractile proteins towards Ca and by inhibition of phosphodiesterase III-isoenzymes. EMD is a potent calcium sensitizing agent in human myocardium. Thiadiazinone derivatives could be one step in the evolution to more potent and selective calcium-sensitizers. [ABSTRACT FROM AUTHOR]

The hemodynamic effects of the dihydropyridine derivative Bay k 8644, a new calcium agonist with positive inotropic actions, were studied in instrumented conscious dogs before and after beta adrenergic blockade with propranolol. Intravenous Bay k 8644 (2, 4, 8 and 20 μg/kg/min) produced dose-related increases in arterial and left ventricular systolic pressures and myocardial contractility (+dP/dt; % segment shortening). Coronary blood flow velocity was increased at higher doses. Prior administration of propranolol produced no significant alteration of the hemodynamic effects of Bay k 8644. Increases in arterial and left ventricular pressures produced by Bay k 8644 were controlled by intravenous infusion of sodium nitroprusside with resulting enhancement of positive inotropic effects. The results demonstrate that the hemodynamic responses to this novel calcium agonist with positive inotropic properties are not mediated via beta adrenergic mechanisms and control of increases in arterial pressure lead to enhanced regional contractility. [ABSTRACT FROM AUTHOR]

The cardiac and coronary vasodilator effects of milrinone and amrinone were compared in isolated, blood-perfused papillary muscle and sinoatrial (SA) node and atrioventricular (AV) node preparations of dogs. Milrinone (0.3-100 nmol) and amrinone (0.01-3 µmol) were administered intraarterially. Both drugs increased the force of contraction of paced and unpaced papillary muscles and the rate of automaticity of the latter; they increased sinus rate and accelerated AV nodal conduction. However, both drugs were not homogeneously effective on cardiac variables but affected them in the following order: The force of contraction of the ventricular muscle > SA nodal automaticity ÷ AV nodal conduction>ventricular automaticity. In producing these cardiac effects, milrinone was 30-60 times more potent than amrinone. Both drugs increased (coronary) blood flow in all preparations. In this respect milrinone was about ten times more potent than amrinone. As a result, milrinone can be characterized as having almost equal cardiotonic and coronary vasodilatory effects, whereas amrinone is more coronary vasodilatory than cardiotonic. These differences in cardiovascular profile may contribute to their differential salutary mechanisms in the treatment of heart failure. Both drugs induced neither AV nodal tachycardia nor ventricular arrhythmia. [ABSTRACT FROM AUTHOR]

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DPI 201-106 (DPI), a novel and potent cardiotonic agent, exhibits its effects by prolonging the open state of Na channels, resulting in an increase in action potential duration, and thus, is supposed to share the class III antiarrhythmic activity. The effects of DPI on the hemodynamics, intraventricular conduction and refractoriness of heart, and the incidence of arrhythmias induced by programmed electrical ventricular stimulation (PES) were compared with (±)-dobutamine. Dogs which survived for 5 to 7 days after the induction of myocardial infarction were used as the model. The presence of sub-acute myocardial infarction caused by occluding the left anterior descending coronary artery elicited a mild left ventricular dysfunction represented by a significant decrease in peak LV dp/dt by about 20%. Both i.v. bolus injection of DPI (1, 3 and 5 mg/kg) and i. v. continuous infusion of dobutamine (3, 5 and 10 μg/kg/min), which were administered in a cumulative manner, dose-dependently improved the hemodynamic parameters. At the higher doses of both DPI (3 and 5 mg/kg) and dobutamine (5 and 10 μg/kg/min) the control values were reached or even exceeded. DPI dose-dependently increased the effective refractory period (ERP) of both non-infarcted and infarcted ventricular myocardia to a similar degree, but the conduction time showed a frequency-dependent increase in the infarcted myocardium to a greater degree than in the non-infarcted myocardium after DPI. In contrast, dobutamine decreased the ERP in both non-infarcted and infarcted myocardia, and slightly increased the difference of refractoriness between the non-infarcted and infarcted zones with no effect on the intraventricular conduction. In the PES study, DPI (3 and 5 mg/kg) produced a significant decrease in the incidence of ventricular tachycardia, whereas dobutamine (5 and 10 μg/kg/min) tended to worsen the arrhythmias. These findings suggest that cardiotonic agents with a class III antiarrhythmic property such as DPI may be potentially useful for the management of heart failure accompanied by ischemic heart disease. [ABSTRACT FROM AUTHOR]

The effects of the new inotropic agents saterinone, sulmazole, UD-CG 212.C1 and milrinone at A adenosine receptors and m-cholinoceptors were evaluated in human myocardium from patients with heart failure. At A adenosine receptors, all compounds inhibited H-DPCPX-binding to ventricular membrane preparations at micromolar concentrations. As judged from the K-values, the rank order of potency was saterinone > sulmazole > UD-CG 212.C1 > milrinone. The new inotropic agents also displaced the binding of H-QNB at m-cholinoceptors. Except for saterinone, the concentration ranges of mean K-values were considerably higher at m-cholinoceptors than at A adenosine receptors. The rank order of potency was saterinone > sulmazole > UD-CG 212.Cl > milrinone. Competition of the A adenosine receptor agonist R-PIA to H-DPCPX-binding showed a biphasic curve with a shallow slope (Hill coefficient n = 0.63) and revealed two affinity states of the A adenosine receptor. In the presence of guanine nucleotides [Gpp(NH)p], the competition curve showed one low affinity class of binding sites and was shifted to the right. In contrast, the competition curves of the new inotropic agents were characterized by a monophasic, steeper slope (mean Hill coefficient n = 0.98). Guanine nucleotides had no effect. Similar results were obtained with saterinone and carbachol at m-cholinoceptors. Competition with carbachol revealed three affinity states of the m-cholinoceptor, the superhigh affinity binding was reversed by Gpp(NH)p. Competition with saterinone revealed one class of binding sites which was not influenced by Gpp(NH)p. Accordingly, in isolated, electrically driven human atrial trabeculae, the negative inotropic effect of adenosine was antagonized concentration-dependently by saterinone, sulmazole and UD-CG 212.Cl. Similarly the negative inotropic effect of carbachol was antagonized concentration-dependently by saterinone. It is concluded that the new inotropic agents bind to A adenosine receptors and that their interaction is of antagonist nature. This mechanism might contribute to their capacity to enhance force of contraction by stimulation of cAMP-formation in addition to phosphodiesterase inhibition. The effects of saterinone may be partially due to antagonism at m-cholinoceptors. This is presumably not the case with the other inotropic agents studied given their low affinity for this receptor. [ABSTRACT FROM AUTHOR]

The bipyridine derivative, milrinone, produced positive inotropic effects in isolated, contracting right ventricular papillary muscles and left atria from guinea pigs as well as in human papillary muscle strips. The inotropic effect was biphasic in guinea pig papillary muscles (EC, high affinity, 1.5×10 mol/l, about 35% of maximal effect; apparent EC, 3×10 mol/l with a maximal effect at 2×10 mol/l) but monophasic in guinea pig left atria (EC, 6×10 mol/l) and in human papillary muscle strips (EC, 5.8×10 mol/l). In guinea pig papillary muscles, reserpine pretreatment or l-practolol preincubation reduced the low concentration effect only. In the presence of l-practolol, carbachol reduced the low concentration effect only. In the presence of l-practolol, carbachol reduced but not abolished the inotropic effects of milrinone (3×10 mol/l, 1×10 mol/l) in both guinea pig and human myocardium. This antagonism was prevented by atropine preincubation. The maximum inotropic effect of milrinone was similar to that of ouabain and calcium in guinea pig myocardium but markedly less than either calcium or ouabain in human myocardium. Milrinone inhibited crude guinea pig and human cardiac phosphodiesterase activity in vitro but did not inhibit H-ouabain binding to partially purified human cardiac (Na+K)-ATPase-containing membranes. We conclude that the primary mode of action of milrinone in both guinea pig and human myocardium is through inhibition of phosphodiesterase. The reduced maximal inotropic effect of milrinone compared with calcium in human but not in guinea pig myocardium indicates basic differences between healthy animal and diseased human cardiac muscle. [ABSTRACT FROM AUTHOR]

Background: With the prevalence of cardiovascular diseases increasing worldwide, early prediction and accurate assessment of heart failure (HF) risk are crucial to meet the clinical demand. Objective: Our study objective was to develop machine learning (ML) models based on real-world electronic health records to predict 1-year in-hospital mortality, use of positive inotropic agents, and 1-year all-cause readmission rate. Methods: For this single-center study, we recruited patients with newly diagnosed HF hospitalized between December 2010 and August 2018 at the First Affiliated Hospital of Dalian Medical University (Liaoning Province, China). The models were constructed for a population set (90:10 split of data set into training and test sets) using 79 variables during the first hospitalization. Logistic regression, support vector machine, artificial neural network, random forest, and extreme gradient boosting models were investigated for outcome predictions. Results: Of the 13,602 patients with HF enrolled in the study, 537 (3.95%) died within 1 year and 2779 patients (20.43%) had a history of use of positive inotropic agents. ML algorithms improved the performance of predictive models for 1-year in-hospital mortality (areas under the curve [AUCs] 0.92-1.00), use of positive inotropic medication (AUCs 0.85-0.96), and 1-year readmission rates (AUCs 0.63-0.96). A decision tree of mortality risk was created and stratified by single variables at levels of high-sensitivity cardiac troponin I (<0.068 μg/L), followed by percentage of lymphocytes (<14.688%) and neutrophil count (4.870×109/L). Conclusions: ML techniques based on a large scale of clinical variables can improve outcome predictions for patients with HF. The mortality decision tree may contribute to guiding better clinical risk assessment and decision making. J Med Internet Res 2021;23(4):e24996 doi:10.2196/24996 [ABSTRACT FROM AUTHOR]

Background: With the prevalence of cardiovascular diseases increasing worldwide, early prediction and accurate assessment of heart failure (HF) risk are crucial to meet the clinical demand.Objective: Our study objective was to develop machine learning (ML) models based on real-world electronic health records to predict 1-year in-hospital mortality, use of positive inotropic agents, and 1-year all-cause readmission rate.Methods: For this single-center study, we recruited patients with newly diagnosed HF hospitalized between December 2010 and August 2018 at the First Affiliated Hospital of Dalian Medical University (Liaoning Province, China). The models were constructed for a population set (90:10 split of data set into training and test sets) using 79 variables during the first hospitalization. Logistic regression, support vector machine, artificial neural network, random forest, and extreme gradient boosting models were investigated for outcome predictions.Results: Of the 13,602 patients with HF enrolled in the study, 537 (3.95%) died within 1 year and 2779 patients (20.43%) had a history of use of positive inotropic agents. ML algorithms improved the performance of predictive models for 1-year in-hospital mortality (areas under the curve [AUCs] 0.92-1.00), use of positive inotropic medication (AUCs 0.85-0.96), and 1-year readmission rates (AUCs 0.63-0.96). A decision tree of mortality risk was created and stratified by single variables at levels of high-sensitivity cardiac troponin I (<0.068 μg/L), followed by percentage of lymphocytes (<14.688%) and neutrophil count (4.870×109/L).Conclusions: ML techniques based on a large scale of clinical variables can improve outcome predictions for patients with HF. The mortality decision tree may contribute to guiding better clinical risk assessment and decision making. [ABSTRACT FROM AUTHOR]