Ca2+ Sensitivity of Contractile Machinery and Ca2+ Handling Energy. Simulation.

Namba, Tatsuji; Takaki, Miyako; Araki, Junichi; Ishioka, Kazunari; Akashi, Takuji; Zhao, Ling; Matsushita, Takehiko; Itô, Haruo; Fujii, Wakako; Matsubara, Hiromi; Suga, Hiroyuki

doi:10.1536/ihj.34.601

Cited by 10 publications

(2 citation statements)

References 25 publications

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“…Myofilament Ca 2+ sensitivity remains decreased in post-ischemic or "stunned" myocardium even once the intracellular milieu is restored, likely because of modification of or proteolytic injury to contractile proteins [15, 16]. Myofilament Ca 2+ sensitization has been proposed as an attractive drug target to increase pump function in failing hearts without deleterious effects on energetic efficiency [17, 18]. In response several “Ca 2+ sensitizers” were developed and studied in the 1990s [19–21], but often impaired cardiac relaxation [22, 23] and only Levosimendan is currently in clinical use in Europe [24].…”

Section: Regulation Of Myofilament Ca2+ Sensitivitymentioning

confidence: 99%

Increased myofilament Ca2+-sensitivity and arrhythmia susceptibility

Huke

Knollmann

2010

Journal of Molecular and Cellular Cardiology

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Increased myofilament Ca 2+ sensitivity, a common attribute of inherited and acquired cardiomyopathies, is often associated with cardiac arrhythmias. Accumulating evidence supports that increased myofilament Ca 2+ sensitivity is an independent risk factor for arrhythmias, but the underlying molecular mechanism remains unclear. This review focuses on potential mechanisms how myofilament Ca 2+ sensitivity may affect cardiac excitation and leads to the generation of arrhythmias. We discuss in detail the downstream effects of increased myofilament Ca 2+ sensitivity, i.e. altered Ca 2+ buffering/handling, impaired energy metabolism and increased mechanical stretch, and how they may contribute to the proarrhythmic effect.Keywords sudden cardiac death; reentry arrhythmias; conduction velocity; Ca2+ handling; energetic deficit; mechanical stretch Regulation of myofilament Ca 2+ sensitivityIn heart muscle, cyclic interactions between thin (actin) filaments and thick (myosin) filaments result in muscle shortening and force production. Initiation of contraction occurs when Ca 2+ binds to troponin C in the troponin complex on the thin filament [1]. The troponin complex is comprised of troponin C (TnC or the Ca 2+ binding subunit), troponin I (TnI, involved in inhibition of actin-myosin interaction in the absence of Ca 2+ ), and troponin T (TnT which binds the troponin complex to tropomyosin, another thin filament protein) in a 1:1:1 stoichiometric ratio [2]. During diastole when cytosolic Ca 2+ levels are low, tropomyosin is positioned such that actin and myosin cannot interact. Once Ca 2+ binds to TnC, tropomyosin shifts and allows actin and myosin to form strong cross-bridges. The thin and thick filaments slide along each other driven by ATP hydrolysis and the heart contracts. Myofilament activation is directly dependent on the amount of activating Ca 2+ , but is also determined by the Ca 2+ dependence of force production (=myofilament Ca 2+ sensitivity), which can be regulated within certain limits. The Ca 2+ sensitivity of the myofilament is usually determined

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Section: Regulation Of Myofilament Ca2+ Sensitivitymentioning

confidence: 99%

Increased myofilament Ca2+-sensitivity and arrhythmia susceptibility

Huke

Knollmann

2010

Journal of Molecular and Cellular Cardiology

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“…Our data indicate that expression of the ssTnI isoform and associated increase in myofilament Ca 2ϩ sensitivity appears to improve the contractile efficiency, but whether this is due to an improvement in the efficiency of the contractile machinery or the energy in handling Ca 2ϩ , is not determined. Mathematical modeling of myocardial Ca 2ϩ handling suggests that Ca 2ϩ sensitization of the myofilaments reduces the total Ca 2ϩ handling energy of the sarcoplasmic reticulum required to maintain contractility (23). Thus, in the context of the infarcted heart, enhancing contractile efficiency may provide a means of lessening the overall cellular demand on energy production within the viable myocardium to slow progression of the decompensated stages.…”

Section: Discussionmentioning

confidence: 99%

Myofilament calcium sensitization delays decompensated hypertrophy differently between the sexes following myocardial infarction

Shioura¹,

Farjah

Geenen³

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Contractile dysfunction is common to many forms of cardiovascular disease. Approaches directed at enhancing cardiac contractility at the level of the myofilaments during heart failure (HF) may provide a means to improve overall cardiovascular function. We are interested in gender-based differences in cardiac function and the effect of sarcomere activation agents that increase contractility. Thus, we studied the effect of gender and time on integrated arterial-ventricular function (A-V relationship) following myocardial infarction (MI). In addition, transgenic mice that overexpress the slow skeletal troponin I isoform were used to determine the impact of increased myofilament Ca(2+) sensitivity following MI. Based on pressure-volume (P-V) loop measurements, we used derived parameters of cardiovascular function to reveal the effects of sex, time, and increased myofilament Ca(2+) sensitivity among groups of post-MI mice. Analysis of the A-V relationship revealed that the initial increase was similar between the sexes, but the vascular unloading of the heart served to delay the decompensated stage in females. Conversely, the vascular response at 6 and 10 wk post-MI in males contributed to the continuous decline in cardiovascular function. Increasing the myofilament Ca(2+) sensitivity appeared to provide sufficient contractile support to improve contractile function in both male and female transgenic mice. However, the improved contractile function was more beneficial in males as the concurrent vascular response contributed to a delayed decompensated stage in female transgenic mice post-MI. This study represents a quantitative approach to integrating the vascular-ventricular relationship to provide meaningful and diagnostic value following MI. Consequently, the data provide a basis for understanding how the A-V relationship is coupled between males and females and the enhanced ability of the cardiovascular system to tolerate pathophysiological stresses associated with HF in females.

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