Role of calcium desensitization in the treatment of myocardial dysfunction after deep hypothermic circulatory arrest

Rungatscher, Alessio; Hallström, Seth; Giacomazzi, Alice; Linardi, Daniele; Milani, Elisabetta; Tessari, Maddalena; Luciani, Giovanni Battista; Scarabelli, Tiziano M.; Mazzucco, Alessandro; Faggian, Giuseppe

doi:10.1186/cc13071

Cited by 14 publications

(12 citation statements)

References 26 publications

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“…With respect to Ca 2ϩ sensitizers, we are unaware that any have been shown to unequivocally target TnI phosphorylation. In previous studies, we (6) and others (27) found that the Ca 2ϩ sensitizer levosimendan improves the pressure/volume relationship of the heart after H/R in an in vivo rat model. Most studies indicate that levosimendan exerts its positive inotropic effects by targeting Ca 2ϩ binding to cTnC or by inhibiting phosphodiesterase 3 (PDE3) breakdown of cAMP (9, 23).…”

Section: Discussionmentioning

confidence: 76%

“…Most studies indicate that levosimendan exerts its positive inotropic effects by targeting Ca 2ϩ binding to cTnC or by inhibiting phosphodiesterase 3 (PDE3) breakdown of cAMP (9, 23). Rungatscher and colleagues (27) reported that levosimendan mitigated the H/R-induced increase in cTnI phosphorylation and suggested that this was the underlying mechanism of enhanced contractility in their in vivo rat model. However, based on this result, we conducted experiments exploring the effects of levosimendan on cTnI phosphorylation in isolated cardiomyocytes, but could not confirm that levosimendan had any mitigating effect on the H/R-induced increase in cTnI phosphorylation.…”

Section: Discussionmentioning

confidence: 97%

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Hypothermia/rewarming disrupts excitation-contraction coupling in cardiomyocytes

Schaible

Han

Hoang

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Hypothermia/rewarming (H/R) is poorly tolerated by the myocardium; however, the underlying intracellular basis of H/R-induced cardiac dysfunction remains elusive. We hypothesized that in cardiomyocytes, H/R disrupts excitation-contraction coupling by reducing myofilament Ca(2+) sensitivity due to an increase in cardiac troponin I (cTnI) phosphorylation. To test this hypothesis, isolated rat cardiomyocytes (13-15 cells from 6 rats per group) were electrically stimulated to evoke both cytosolic Ca(2+) ([Ca(2+)]cyto) and contractile (sarcomere shortening) responses that were simultaneously measured using an IonOptix system. Cardiomyocytes were divided into two groups: 1) those exposed to hypothermia (15°C for 2 h) followed by rewarming (35°C; H/R); or 2) time-matched normothermic (35°C) controls (CTL). Contractile dysfunction after H/R was indicated by reduced velocity and extent of sarcomere length (SL) shortening compared with time-matched controls. Throughout hypothermia, basal [Ca(2+)]cyto increased and the duration of evoked [Ca(2+)]cyto transients was prolonged. Phase-loop plots of [Ca(2+)]cyto vs. contraction were shifted rightward in cardiomyocytes during hypothermia compared with CTL, indicating a decrease in Ca(2+) sensitivity. Using Western blot, we found that H/R increases cTnI phosphorylation. These results support our overall hypothesis and suggest that H/R disrupts excitation-contraction coupling of cardiomyocytes due to increased cTnI phosphorylation and reduced Ca(2+) sensitivity.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 97%

Hypothermia/rewarming disrupts excitation-contraction coupling in cardiomyocytes

Schaible

Han

Hoang

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…The latter is indeed an essential component of ECC circuits in clinical setting [ 19 ]. Both CPB and ECMO are based on the performance of oxygenator to support circulatory and respiratory functions during cardiac surgery operations or critical cardiorespiratory diseases, respectively [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Oxygenator Is the Main Responsible for Leukocyte Activation in Experimental Model of Extracorporeal Circulation: A Cautionary Tale

Rungatscher

Tessari

Stranieri

et al. 2015

Mediators of Inflammation

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In order to assess mechanisms underlying inflammatory activation during extracorporeal circulation (ECC), several small animal models of ECC have been proposed recently. The majority of them are based on home-made, nonstandardized, and hardly reproducible oxygenators. The present study has generated fundamental information on the role of oxygenator of ECC in activating inflammatory signaling pathways on leukocytes, leading to systemic inflammatory response, and organ dysfunction. The present results suggest that experimental animal models of ECC used in translational research on inflammatory response should be based on standardized, reproducible oxygenators with clinical characteristics.

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“…The inotropic and lusitropic effects of levosimendan at low concentrations (nM) have been attributed to Ca 2+ sensitization and phosphodiesterase3 inhibition mechanisms [8]. As it acts in a very specific manner, levosimendan has been found to achieve satisfactory preconditioning and positive inotropic effects without Ca 2+ overload, thereby improving survival rates among adult heart failure patients [9, 10].…”

Section: Introductionmentioning

confidence: 99%

Prophylactic use of levosimendan in pediatric patients undergoing cardiac surgery: a prospective randomized controlled trial

et al. 2019

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BackgroundThe administration of levosimendan prophylactically to patients undergoing cardiac surgery remains a controversial practice, and few studies have specifically assessed the value of this approach in pediatric patients. This study therefore sought to explore the safety and efficacy of prophylactic levosimendan administration to pediatric patients as a means of preventing low cardiac output syndrome (LCOS) based upon hemodynamic, biomarker, and pharmacokinetic readouts.MethodsThis was a single-center, double-blind, randomized, placebo-controlled trial. Patients ≤ 48 months old were enrolled between July 2018 and April 2019 and were randomly assigned to groups that received either placebo or levosimendan infusions for 48 h post-surgery, along with all other standard methods of care. LCOS incidence was the primary outcome of this study.ResultsA total of 187 patients were enrolled, of whom 94 and 93 received levosimendan and placebo, respectively. LCOS incidence did not differ significantly between the levosimendan and placebo groups (10 [10.6%] versus 18 [19.4%] patients, respectively; 95% confidence interval [CI] 0.19–1.13; p = 0.090) nor did 90-day mortality (3 [3.2%] versus 4 [4.3%] patients, CI 0.14–3.69, p = 0.693), duration of mechanical ventilation (median, 47.5 h and 39.5 h, respectively; p = 0.532), ICU stay (median, 114.5 h and 118 h, respectively; p = 0.442), and hospital stay (median, 20 days and 20 days, respectively; p = 0.806). The incidence of hypotension and cardiac arrhythmia did not differ significantly between the groups. Levels of levosimendan fell rapidly without any plateau in plasma concentrations during infusion. A multiple logistic regression indicated that randomization to the levosimendan group was a predictor of LCOS.ConclusionsProphylactic levosimendan administration was safe in pediatric patients and had some benefit to postoperative hemodynamic parameters, but failed to provide significant benefit with respect to LCOS or 90-day mortality relative to placebo.Trial registrationName of the registry: Safety evaluation and therapeutic effect of levosimendan on the low cardiac output syndrome in patients after cardiopulmonary bypass. Trial registration number: ChiCTR1800016594. Date of registration: 11 June 2018. URL of trial registry record: http://www.chictr.org.cn/index.aspx

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Role of calcium desensitization in the treatment of myocardial dysfunction after deep hypothermic circulatory arrest

Cited by 14 publications

References 26 publications

Hypothermia/rewarming disrupts excitation-contraction coupling in cardiomyocytes

Hypothermia/rewarming disrupts excitation-contraction coupling in cardiomyocytes

Oxygenator Is the Main Responsible for Leukocyte Activation in Experimental Model of Extracorporeal Circulation: A Cautionary Tale

Prophylactic use of levosimendan in pediatric patients undergoing cardiac surgery: a prospective randomized controlled trial

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