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Inotropes and inodilators for acute heart failure: sarcomere active drugs in focus.

Nagy L, Pollesello P, Papp Z - J. Cardiovasc. Pharmacol. (2014)

Bottom Line: Traditionally inotropic agents, referred to as Ca mobilizers load the cardiomyocyte with Ca and thereby increase oxygen consumption and risk for arrhythmias.Direct activation of the cardiac sarcomere may be achieved by either sensitizing the cardiac myofilaments to Ca or activating directly the cardiac myosin.In this review, we focus on sarcomere targeted inotropic agents, emphasizing their mechanisms of action and overview the most relevant clinical considerations.

View Article: PubMed Central - PubMed

Affiliation: *Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; and †Critical Care, Proprietary Products Division, Orion Pharma, Orion Corporation, Espoo, Finland.

ABSTRACT
Acute heart failure (AHF) emerges as a major and growing epidemiological concern with high morbidity and mortality rates. Current therapies in patients with acute heart failure rely on different strategies. Patients with hypotension, hypoperfusion, or shock require inotropic support, whereas diuretics and vasodilators are recommended in patients with systemic or pulmonary congestion. Traditionally inotropic agents, referred to as Ca mobilizers load the cardiomyocyte with Ca and thereby increase oxygen consumption and risk for arrhythmias. These limitations of traditional inotropes may be avoided by sarcomere targeted agents. Direct activation of the cardiac sarcomere may be achieved by either sensitizing the cardiac myofilaments to Ca or activating directly the cardiac myosin. In this review, we focus on sarcomere targeted inotropic agents, emphasizing their mechanisms of action and overview the most relevant clinical considerations.

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Related in: MedlinePlus

Actin–myosin cycling involves coupled biochemical and mechanical events. ATP binding to the myosin heads results in a dissociation from the actin filaments. Then, ATP is hydrolyzed to ADP + Pi. In the presence of Ca2+, the myosin head binds to the actin filament forming a weakly attached conformation. Thereafter, Pi dissociates from the myosin heads resulting in a high affinity cross-bridge accompanied by the force producing power stroke step. Omecamtiv mecarbil interferes with the rate-limiting step of the actin–myosin cycle by accelerating Pi release from the myosin heads. Consequently, omecamtiv mecarbil increases the number of force-generating myosin heads contributing to enhanced cardiac contractility.
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Figure 3: Actin–myosin cycling involves coupled biochemical and mechanical events. ATP binding to the myosin heads results in a dissociation from the actin filaments. Then, ATP is hydrolyzed to ADP + Pi. In the presence of Ca2+, the myosin head binds to the actin filament forming a weakly attached conformation. Thereafter, Pi dissociates from the myosin heads resulting in a high affinity cross-bridge accompanied by the force producing power stroke step. Omecamtiv mecarbil interferes with the rate-limiting step of the actin–myosin cycle by accelerating Pi release from the myosin heads. Consequently, omecamtiv mecarbil increases the number of force-generating myosin heads contributing to enhanced cardiac contractility.

Mentions: Omecamtiv mecarbil, previously referred as CK-1827452, exerts a positive inotropy through its selective binding to the S1 domain of the cardiac myosin where the relay helix and converter domain converge at the base of the force-producing lever arm. The mechanism of action evokes a conformational change in the nucleotide-binding domain of the cardiac myosin head contributing to the allosteric activation of its mechanical and enzymatic properties (Fig. 3).86 Importantly, myosin activation does not occur when fast skeletal and smooth muscle myosin is present instead of the cardiac isoform implying a cardioselective manner of the omecamtiv mecarbil binding.87,88


Inotropes and inodilators for acute heart failure: sarcomere active drugs in focus.

Nagy L, Pollesello P, Papp Z - J. Cardiovasc. Pharmacol. (2014)

Actin–myosin cycling involves coupled biochemical and mechanical events. ATP binding to the myosin heads results in a dissociation from the actin filaments. Then, ATP is hydrolyzed to ADP + Pi. In the presence of Ca2+, the myosin head binds to the actin filament forming a weakly attached conformation. Thereafter, Pi dissociates from the myosin heads resulting in a high affinity cross-bridge accompanied by the force producing power stroke step. Omecamtiv mecarbil interferes with the rate-limiting step of the actin–myosin cycle by accelerating Pi release from the myosin heads. Consequently, omecamtiv mecarbil increases the number of force-generating myosin heads contributing to enhanced cardiac contractility.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4232335&req=5

Figure 3: Actin–myosin cycling involves coupled biochemical and mechanical events. ATP binding to the myosin heads results in a dissociation from the actin filaments. Then, ATP is hydrolyzed to ADP + Pi. In the presence of Ca2+, the myosin head binds to the actin filament forming a weakly attached conformation. Thereafter, Pi dissociates from the myosin heads resulting in a high affinity cross-bridge accompanied by the force producing power stroke step. Omecamtiv mecarbil interferes with the rate-limiting step of the actin–myosin cycle by accelerating Pi release from the myosin heads. Consequently, omecamtiv mecarbil increases the number of force-generating myosin heads contributing to enhanced cardiac contractility.
Mentions: Omecamtiv mecarbil, previously referred as CK-1827452, exerts a positive inotropy through its selective binding to the S1 domain of the cardiac myosin where the relay helix and converter domain converge at the base of the force-producing lever arm. The mechanism of action evokes a conformational change in the nucleotide-binding domain of the cardiac myosin head contributing to the allosteric activation of its mechanical and enzymatic properties (Fig. 3).86 Importantly, myosin activation does not occur when fast skeletal and smooth muscle myosin is present instead of the cardiac isoform implying a cardioselective manner of the omecamtiv mecarbil binding.87,88

Bottom Line: Traditionally inotropic agents, referred to as Ca mobilizers load the cardiomyocyte with Ca and thereby increase oxygen consumption and risk for arrhythmias.Direct activation of the cardiac sarcomere may be achieved by either sensitizing the cardiac myofilaments to Ca or activating directly the cardiac myosin.In this review, we focus on sarcomere targeted inotropic agents, emphasizing their mechanisms of action and overview the most relevant clinical considerations.

View Article: PubMed Central - PubMed

Affiliation: *Division of Clinical Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; and †Critical Care, Proprietary Products Division, Orion Pharma, Orion Corporation, Espoo, Finland.

ABSTRACT
Acute heart failure (AHF) emerges as a major and growing epidemiological concern with high morbidity and mortality rates. Current therapies in patients with acute heart failure rely on different strategies. Patients with hypotension, hypoperfusion, or shock require inotropic support, whereas diuretics and vasodilators are recommended in patients with systemic or pulmonary congestion. Traditionally inotropic agents, referred to as Ca mobilizers load the cardiomyocyte with Ca and thereby increase oxygen consumption and risk for arrhythmias. These limitations of traditional inotropes may be avoided by sarcomere targeted agents. Direct activation of the cardiac sarcomere may be achieved by either sensitizing the cardiac myofilaments to Ca or activating directly the cardiac myosin. In this review, we focus on sarcomere targeted inotropic agents, emphasizing their mechanisms of action and overview the most relevant clinical considerations.

Show MeSH
Related in: MedlinePlus