Mechanisms of Action of Calcium-Sensitizing Drugs

Haikala, Heimo; Lindén, Inge‐Britt

doi:10.1097/00005344-199506261-00003

Cited by 113 publications

(26 citation statements)

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“…Thus it appears that these findings that we observed may also be indicative of a cAMP-dependent facilitation of relaxation by levosimendan (e.g., by a PDE inhibitory pharmacodynamic action) (12,17).…”

Section: Fig 2 Group Means Of Increasing Hrcaused Percent Changes Osupporting

confidence: 52%

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Levosimendan restores the positive force-frequency relation in heart failure

Masutani

Cheng

Tachibana

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Masutani S, Cheng HJ, Tachibana H, Little WC, Cheng CP. Levosimendan restores the positive force-frequency relation in heart failure. Am J Physiol Heart Circ Physiol 301: H488 -H496, 2011. First published May 13, 2011; doi:10.1152/ajpheart.01116.2010.-Frequency potentiation of contractile function is a major mechanism of the increase in myocardial performance during exercise. In heart failure (HF), this positive force-frequency relation is impaired, and the abnormal left ventricular (LV)-arterial coupling is exacerbated by tachycardia. A myofilament Ca 2ϩ sensitizer, levosimendan, has been shown to improve exercise tolerance in HF. This may be due to its beneficial actions on the force-frequency relation and LV-arterial coupling (end-systolic elastance/arterial elastance, EES/EA). We assessed the effects of therapeutic doses of levosimendan on the forcefrequency relation and EES/EA in nine conscious dogs after pacinginduced HF using pressure-volume analysis. Before HF, pacing tachycardia increased E ES, shortened , and did not impair EES/EA and mechanical efficiency (stroke work/pressure-volume area, SW/PVA). In contrast, after HF, pacing at 140, 160, 180, and 200 beat/min (bpm) produced smaller a increase of EES or less shortening of , whereas EES/EA (from 0.56 at baseline to 0.42 at 200 bpm) and SW/PVA (from 0.52 at baseline to 0.43 at 200 bpm) progressively decreased. With levosimendan, basal E ES increased 27% (6.2 mmHg/ml), decreased 11% (40.8 ms), EES/EA increased 34% (0.75), and SW/PVA improved by 15% (0.60). During tachycardia, E ES further increased by 23%, 37%, 68%, and 89%; decreased by 9%, 12%, 15%, and 17%; and EES/EA was augmented by 11%, 16%, 31%, and 33%, incrementally, with pacing rate. SW/PVA was improved (0.61 to 0.64). In conclusion, in HF, treatment with levosimendan restores the normal positive LV systolic and diastolic force-frequency relation and prevents tachycardia-induced adverse effect on LV-arterial coupling and mechanical efficiency.drugs; contractility; diastole; heart rate UNDER NORMAL CONDITIONS, an increase in heart rate (HR) augments myocardial contractility and the rate of relaxation (15,39,44). This force-frequency behavior is determined by both calcium handling and myofilament properties (26). It has been shown that the integrated dynamic balance of the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) is the primary cellular mechanism responsible for the force-frequency relation (FFR) and is determined by sarcoplasmic reticulum (SR) Ca 2ϩ load and Ca 2ϩ flux through the sarcolemma via L-type Ca 2ϩ channels and the Na ϩ -Ca 2ϩ exchanger (13). The positive FFR and relaxation-frequency relation (RFR) enhance cardiac performance during stress or exercise (7,36,39,44,52). In heart failure (HF), the positive FFR and RFR are impaired (16,24,28,29,44), and the abnormal left ventricular (LV)-arterial coupling is exacerbated by tachycardia. This contributes to exercise intolerance in HF (44, 52). The altered responses of LV contraction and relaxation to HR in HF may at least partially ...

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Section: Fig 2 Group Means Of Increasing Hrcaused Percent Changes Osupporting

confidence: 52%

“…troponin C during systole leading to sensitization of the contractile apparatus to calcium ions (17,18). This mode of action of levosimendan may lead to frequency-dependent Ca 2ϩ sensitization of the myofilaments, thereby reversing the abnormalities of the FFR in HF.…”

Section: Fig 2 Group Means Of Increasing Hrcaused Percent Changes Omentioning

confidence: 99%

Levosimendan restores the positive force-frequency relation in heart failure

Masutani

Cheng

Tachibana

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Positive inotropic drugs are added to the conventional treatment when peripheral hypoperfusion signs are present. Levosimendan does not distinctively potentiate intracellular cyclic adenosine monophosphate and calcium levels; in contrast to other inotropic drugs, levosimendan stabilizes cross-bonds between actin and myosin, leading to enhanced contractility (8)(9)(10). Levosimendan stimulates adenosine triphosphate-sensitive potassium channels on vascular smooth muscles, resulting in arterial and venous vasodilatation.…”

Section: Discussionmentioning

confidence: 94%

Predictive Value of Fragmented QRS in Response to Levosimendan Therapy in Patients with Heart Failure

Erkal¹,

Bayar²,

Esin³

et al. 2017

Cyprus J Med Sci

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BACKGROUNDData on the effect on re-hospitalization are limited when levosimendan is added to conventional treatment. We aimed to investigate the role of fragmented QRS (f QRS) on the surface electrocardiogram in predicting the response to levosimendan therapy in patients with acute systolic heart failure. MATERIAL and METHODSPatients with a left ventricular ejection fraction of <35% were enrolled in this retrospective observational study. They were administered a levosimendan therapy for 24 h, and the number of re-admissions due to decompensated heart failure annually were recorded. Patients were divided two groups: group 1, 0-7 admissions per year and group 2, >7 admissions per year. RESULTSThere were 42 patients in group 1 and 24 in group 2. The presence of fragmented QRS was seen in 41% of the patients in group 1 and in 92% of the patients in group 2 (p<0.001). The presence of fragmented QRS during the hospitalization of patients treated with levosimendan was found to be an independent predictor of the admission of more than 7 patients in the multivariate analysis. CONCLUSIONThe presence of fragmented QRS during hospitalization may predict a lower response to levosimendan therapy in patients with decompensated heart failure.

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“…den de bu me ka niz ma nın so rum lu ol du ğu dü şü -nül mek te dir. [3][4][5][6] Bi li nen inot ro pik ajan la ra ve in traa or tik ba lon pom pa sı uy gu la ma la rı na ce vap alı na ma yan dü şük kalp de bi li ol gu lar da do za bağım lı ola rak kalp de bi si ve atım vo lü mün de ar tışa, pul mo ner ka pil ler uç ba sınç ve sis te mik vas kü ler re zis tans ta azal ma ya yol aç tı ğı bil di ril miş tir. 7 Le vo si men da nın kalp trans plan tas yo nun da kul la nı mı na da ir ye ter li bil gi bu lun ma mak ta dır.…”

Section: Ortotopik Kalp Transplantasyonundaunclassified

“…Be ra be rin de kul la nı lan di ğer inot rop la rın do zu nu dü şür mek te yar dım cı oldu ğu için ge li şe bi le cek yan et ki le ri ni azalt ma ko nusun da da fay da sağ la ya bil mek te dir. [3][4][5] Le vo si men dan da mar du va rın da ki düz kas hüc re le rin de ATP ba ğım lı K + ka nal la rı nın ak ti ve ede rek va zo di la tas yo na ne den olur. Ko ro ner ar terler de va zo di la tas yo na ne den ola rak mi yo kar di yal kan akı mı nı art tı rır.…”

Section: 2unclassified