Molecular dynamics provides new insights into the mechanism of calcium signal transduction and interdomain interactions in cardiac troponin.

Understanding the regulation of cardiac muscle contraction at a molecular level is crucial for the development of therapeutics for heart conditions. Despite the availability of atomic structures of the protein components of cardiac muscle thin filaments, detailed insights into their dynamics and response to calcium are yet to be fully depicted. In this study, we used molecular dynamics simulations of the core domains of the cardiac muscle protein troponin to characterize the equilibrium dynamics of its calcium-bound and calcium-free forms, with a focus on elements of cardiac muscle contraction activation and deactivation, that is, calcium binding to the cardiac troponin Ca2+ -binding subunit (TnC) and the release of the switch region of the troponin inhibitory subunit (TnI) from TnC. The process of calcium binding to the TnC binding site is described as a three-step process commencing with calcium capture by the binding site residues, followed by cooperative residue interplay bringing the calcium ion to the binding site, and finally, calcium-water exchange. Furthermore, we uncovered a set of TnC-TnI interdomain interactions that are critical for TnC N-lobe hydrophobic pocket dynamics. Absence of these interactions allows the closure of the TnC N-lobe hydrophobic pocket while the TnI switch region remains expelled, whereas if the interactions are maintained, the hydrophobic pocket remains open. Modification of these interactions may fine-tune the ability of the TnC N-lobe hydrophobic pocket to close or remain open, modulate cardiac contractility and present potential therapy-relevant targets.

Calcium Sensitizers in Cardiac Surgery: Who, When, How and Why?

Inodilators are a heterogeneous group of drugs with vasodilatory and inotropic effects. The cardioprotective effect of levosimendan is multifactorial, but now research on levosimendan is focused on the organ-protective properties of this drug in different settings, the regimen that seems to provide the greatest cardiologic and systemic benefits is early administration of levosimendan. We try to answer four questions in this review, which type of patients need this drug? what is the best time to start with it? and the best way that we could give it and finally the reasons for use it.

Newer treatments for decompensated heart failure: focus on levosimendan.

Acute heart failure (AHF) is a major cause of hospitalizations. Severe dyspnea, pulmonary congestion and low cardiac output with peripheral vasoconstriction and renal hypoperfusion is a main form of clinical presentation. Most patients with acute worsening have a pre-existing decompensated chronic heart failure (ADCHF), but AHF may also occur as a first manifestation of a previously unknown heart disease. Myocardial ischemia, cardiac arrhythmias, non-compliance with medication and infections are frequent precipitating factors. Management of AHF depends on the underlying heart disease and cause of decompensation. In patients with ADCHF vasodilators and iv diuretics are first-line drugs for rapid reduction of dyspnea and congestion. In patients with signs of low cardiac output and oliguria, inotropic agents are also often administered to prevent further deterioration. Beta-adrenergic agents and phosphodiesterase inhibitors correct the hemodynamic disturbance, but may also induce arrhythmias and worsen myocardial ischemia. Inotropic therapy therefore remains controversial. A novel class of drugs, the calcium sensitizers, represent a new therapeutic option. Levosimendan was shown to improve myocardial contractility without increasing oxygen requirements and to produce peripheral and coronary vasodilation. Its therapeutic effects and tolerance have been tested in several trials. The present review focuses on the clinical pharmacology and therapeutic utility of levosimendan in patients with ADCHF.

Levosimendan: Nueva estrategia en el manejo de la falla cardíaca / Levosimendan: A new strategy in the treatment of heart failure

La insuficiencia cardíaca congestiva se ha considerado como un grave problema de salud. De manera tradicional, la insuficiencia cardíaca ha sido manejada con diferentes fármacos, como son los diuréticos, digital, inotrópicos del tipo de las catecolaminas y no catecolaminas; sin embargo, el manejo de los mismos, también tienen efectos secundarios en donde se incluyen la génesis de las arritmias e incluso la muerte. Un nuevo grupo de drogas recientemente ha impactado en el manejo de los pacientes con insuficiencia cardíaca aguda y crónica, estos son los sensibilizadores de calcio, que actúan incrementando la contractilidad miocárdica, sin aumentar la liberación del calcio citosólico. El levosimendan, es un sensibilizador de calcio que además de aumentar la contractilidad, posee efecto vasodilatador por activación de los canales de K(ATP), siendo ambos mecanismos los que ofrecen una opción terapéutica en la falla cardíaca. Varios estudios han comprobado la eficacia y seguridad de la droga en diferentes estadios y poblaciones, por lo que se considera en la actualidad que el uso del levosimendan es una alternativa real y segura de tratamiento en aquellos pacientes con falla ventricular aguda o crónica que necesiten soporte farmacológico endovenoso.

Congestive heart failure is a long standing health issue. Traditionally, heart failure has been treated with a wide array of drugs such as diuretics, digitalis, catecholamine and non catecholamine inotropics, although treatment with these drugs bears adverse effects, such as the generation of arrhythmia and even death. A new class of drugs has recently exerted a positive impact on the treatment of patients with heart failure; these are the calcium sensitizers that enhance myocardial contractility without increasing cytosolic calcium. Levosimendan is a calcium sensitizer that, besides increasing contractility, has a vasodilating effect due to the activation of K(ATP) channels, being both mechanisms responsible for an advantageous therapeutic option. Different studies have proven the efficiency and safety profile of the drug on various scenarios and populations; thereby considering levosimendan a real and safe alternative treatment for patients with acute or chronic ventricular failure that need intravenous pharmacological support.