Calcium sensitizer agents: A new class of inotropic agents in the treatment of decompensated heart failure

Perrone, Sergio V.; Kaplinsky, Edgardo

doi:10.1016/j.ijcard.2004.12.012

Cited by 40 publications

(28 citation statements)

References 63 publications

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“…This effect is an essential limitation for the use of the particular drugs in a clinical level. In contrast, levosimendan is a selective inhibitor of phosphodiesterase III at high doses, but at therapeutic level its inotropic effects are independent of phosphodiesterase metabolism and cyclic AMP production [20,21].…”

Section: Calcium Sensitizing Agentsmentioning

confidence: 99%

“…Classification and mechanisms of action Calcium sensitizing agents are a unique class of positive inotropic drugs that include levosimendan, pimobendan, senazodan, EMD-53998, and its enantiomer, ED-57033 [20]. These drugs seem to exert a dose-dependent calcium sensitizing mechanical enhancement on the failing heart via a variety of biochemical mechanisms, including the enhancement of troponin-C affinity for calcium, the direct stabilization of the calcium-induced conformation of troponin-C, or the action distal to the troponin-C molecule [21].…”

Section: Calcium Sensitizing Agentsmentioning

confidence: 99%

“…A loading dose of drug should be avoided in patients with systolic blood pressure less than 90 mmHg. Due to the accumulation of OR-1896, a drug infusion for time interval longer than 24 h is not recommended [20][21][22][23].…”

Section: Biologic and Pharmacologic Effects Of Levosimendanmentioning

confidence: 99%

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Classical inotropes and new cardiac enhancers

2007

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Acute heat failure syndromes are a heterogenous group of conditions. Chronic heart failure exacerbations represent the vast majority of cases. Pathophysiologic mechanisms, such as hypotension with peripheral tissue hypoperfusion, renal function impairment and myocardial ischemia and injury, adversely affect patients' clinical outcome. Classical inotropes, such as beta-agonists (dobutamine, dopamine) and phosphodiesterase inhibitors (milrinone), seem to improve clinical symptoms and hemodynamics of acutely decompensated chronic heat failure patients, but they have been associated with increased long-term mortality. Thus, on the basis of the available evidence, these agents can be used only as a temporary treatment of acute heart failure exacerbations with stringent criteria (ESC AHF guidelines), resistant to intravenous vasodilators and/or diuretics when systolic blood pressure (SBP) is >100 mmHg or as a first-line treatment in patients with worsening of chronic cardiac failure and low SBP (<100 mmHg). The calcium sensitizer levosimendan is a new cardiac enhancer that seems to be more effective than classical inotropes in improving cardiac mechanical efficiency and reducing congestion, without causing cardiomyocyte death or increasing myocardial oxygen uptake. Recent randomized trials showed that levosimendan is not superior to placebo or dobutamine in improving 1- and 6-month mortality, although it caused a greater reduction of neurohormonal response. More data are needed regarding patient selection and the optimum regimen and dosing of levosimendan before this treatment modality become the first line therapy of acutely decompensated chronic heart failure patients.

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Section: Calcium Sensitizing Agentsmentioning

confidence: 99%

Section: Calcium Sensitizing Agentsmentioning

confidence: 99%

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Classical inotropes and new cardiac enhancers

2007

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“…Inotropic agents have been indicated for the treatment of congestive heart failure (CHF) with reduced cardiac output and peripheral hypo-perfusion (1,2). Classic inotropic agents, including cardiac glycosides, catecholamines, and phosphodiesterase (PDE) III inhibitors, improve impaired cardiac pump function by elevating intracellular calcium concentration in myocardial cells to directly improve the myocardial contractility (2 -4).…”

Section: Introductionmentioning

confidence: 99%

Comparative Evaluation of Calcium-Sensitizing Agents, Pimobendan and SCH00013, on the Myocardial Function of Canine Pacing–Induced Model of Heart Failure

et al. 2014

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Abstract. Pimobendan and SCH00013 are calcium sensitizers that possess dual action of calcium sensitization and phosphodiesterase-III inhibition. This study was conducted to comparatively evaluate the effect of these medications on the myocardial function of the canine pacing-induced heart failure model using echocardiography. Heart failure was induced in 20 dogs, to which pimobendan and two different doses of SCH00013 were administered orally to 15 dogs for 3 weeks, and the remaining 5 dogs served as the control. Cardiac evaluations were performed at baseline, week 1, week 2, and week 3. Significant thinning and dilation of the left ventricles, with systolic dysfunction, indicated by reduction of fractional shortening (FS) and strain values, were observed with a low dose of SCH00013. Whereas, although systolic dysfunction was observed with reduction of FS and radial strain, significant dilation and thinning of the left ventricles and reduction of circumferential strain were not observed with pimobendan. Pimobendan had a potent positive inotropic effect, with little effect on synchronicity, while low-dose SCH00013 had a weaker positive inotropic effect but was able to sustain synchronicity. Although, it failed to show significant statistical differences, the results of this study allow speculations that administration of pimobendan and SCH00013 may have differing effect on the myocardial function in the canine pacing-induced heart failure model.

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“…[3][4][5] Calcium sensitizers are novel drugs acting by combination of the upstream and central/downstream mechanisms. 3,[5][6][7] Calcium sensitizers seem advantageous for treating acute decompensated heart failure and acute lowoutput heart failure, compared with clinically available inotropes, which act primarily by increasing intracellular calcium mobilization in cardiac myocytes. [5][6][7] Although evidence supports the idea that Ca 2+ sensitivity is decreased during acute cardiac hypoxia or ischemia, 8,9 data from subacute and chronic heart failure experiments showed that Ca 2+ sensitivity may even be increased because of a decrease in troponin I phosphorylation caused by the downregulation of b1-adrenoceptor-mediated signaling.…”

Section: Introductionmentioning

confidence: 99%

Levosimendan improves cardiac function and survival in rats with angiotensin II-induced hypertensive heart failure

et al. 2010

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Calcium-sensitizing agents improve cardiac function in acute heart failure; however, their long-term effects on cardiovascular mortality are unknown. We tested the hypothesis that levosimendan, an inodilator that acts through calcium sensitization, opening of ATP-dependent potassium channels and phosphodiesterase III inhibition, improves cardiac function and survival in double transgenic rats harboring human renin and angiotensinogen genes (dTGRs), a model of angiotensin II (Ang II)-induced hypertensive heart failure. Levosimendan (1 mg kg À1 ) was administered orally to 4-week-old dTGRs and normotensive Sprague-Dawley rats for 4 weeks. Untreated dTGRs developed severe hypertension, cardiac hypertrophy, heart failure with impaired diastolic relaxation, and exhibited a high mortality rate at the age of 8 weeks. Levosimendan did not decrease blood pressure and did not prevent cardiac hypertrophy. However, levosimendan improved systolic function, decreased cardiac atrial natriuretic peptide mRNA expression, ameliorated Ang II-induced cardiac damage and decreased mortality. Levosimendan did not correct Ang II-induced diastolic dysfunction and did not influence heart rate. In a separate survival study, levosimendan increased dTGR survival by 58% and median survival time by 27% (P¼0.004). Our findings suggest that levosimendan ameliorates Ang II-induced hypertensive heart failure and reduces mortality. The results also support the notion that the effects of levosimendan in dTGRs are mediated by blood pressure-independent mechanisms and include improved systolic function and amelioration of Ang II-induced coronary and cardiomyocyte damage.

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Calcium sensitizer agents: A new class of inotropic agents in the treatment of decompensated heart failure

Cited by 40 publications

References 63 publications

Classical inotropes and new cardiac enhancers

Classical inotropes and new cardiac enhancers

Comparative Evaluation of Calcium-Sensitizing Agents, Pimobendan and SCH00013, on the Myocardial Function of Canine Pacing–Induced Model of Heart Failure

Levosimendan improves cardiac function and survival in rats with angiotensin II-induced hypertensive heart failure

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