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Pathophysiology of Heart Failure with Reduced Ejection Fraction
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Jacob Cao, John O'Sullivan, Sean Lal
As described previously, the sustained hyperadrenergic state that characterizes HF results in desensitization of cardiomyocytes to further adrenergic stimulation. As a result, there is increased phospholamban-dependent inhibition of SERCA-2a. Indeed, both phospholamban ablation and β blockade have been shown to improve excitation-contraction coupling and calcium handling in both animal and human studies. Upregulation of SERCA-2a function and expression have been trialed with varying success. Istaroxime, a direct SERCA-2a stimulator, has been shown to increase sarcoplasmic reticulum calcium reuptake during diastole and release during systole. In a randomized placebo-controlled trial of 120 patients with acute decompensated HF, istaroxime infusion was shown to improve left heart hemodynamics without any increase in adverse events.12 There are currently no studies examining istaroxime in chronic HFrEF. Post-translational protein modification has recently emerged as another area of research into improving SERCA-2a function. The conjugation of small ubiquitin-like modifiers (SUMO) to SERCA-2a has been shown to be essential in preserving SERCA-2a ATPase activity, and that HF is associated with a reduction in the extent of conjugation. Additionally, animal studies have demonstrated that restoration of SUMO1 via gene therapy improves cardiac function, with evidence in humans still pending.
The current and future status of inotropes in heart failure management
Published in Expert Review of Cardiovascular Therapy, 2023
Angelos Arfaras-Melainis, Ioannis Ventoulis, Effie Polyzogopoulou, Antonios Boultadakis, John Parissis
Istaroxime operates on the cardiac myocyte through a dual mechanism: Firstly, by blocking the sarcolemmal sodium-potassium ATPase, and secondly, by activating the sarcoendoplasmic reticulum calcium adenosine triphosphatase isoform 2a (SERCA2a). The first leads to improved contractility by raising the levels of intracellular Ca2+, while the second leads to enhanced lusitropy by promoting the absorption of free Ca2+into the sarcoplasmic reticulum during diastole [63]. In HORIZON-HF (Hemodynamic, Echocardiographic and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent, in Patients Hospitalized with Worsening Heart Failure and a Reduced Left Ventricular Systolic Function), a double-blind phase II study, the use of istaroxime was associated with an improvement in the hemodynamic profile (decreased PCWP, increased mean arterial pressure), without causing myocardial damage/necrosis [32,64]. More recently in 2022, in the SEISMiC (The Safety and Efficacy of Istaroxime for Pre-Cardiogenic Shock) trial, a phase IIa study in patients with pre-cardiogenic shock defined as stage B according to the classification by the Society for Cardiovascular Angiography and Interventions (SCAI), Metra et al reported that istaroxime improved blood pressure along with several echocardiographic parameters [33]. Consequently, istaroxime seems to emerge as a promising inotropic agent that is currently being further investigated for patients with HF.
Update on the effects of the sodium pump α1 subunit on human glioblastoma: from the laboratory to the clinic
Published in Expert Opinion on Investigational Drugs, 2018
Yu-Long Lan, Zhen-Long Yu, Jia-Cheng Lou, Xiao-Chi Ma, Bo Zhang
Istaroxime and/or its derivatives as well as well-known nonsugar-containing potent sodium pump inhibitors [84–87] are promising candidates for anticancer drug development. Importantly, these inhibitors are mostly selective for the α1 isoform of the sodium pump [71]. In addition, these compounds lack the ability to bind steroid hormone receptors, which is a property of interest [87], as it potentially allows pathway interference to be avoided, as shown for the estrogen receptor [88]. Furthermore, istaroxime is less prone to induce arrhythmia due to its favorable safety profile [89]. As mentioned earlier, nonsugar-containing sodium pump inhibitors as well as istaroxime and its derivatives, such as 3-RPOD [86], which exhibits outstanding potency in multiple cancer cell lines, are selectively cytotoxic in cancer cells versus normal cells [71] and may be more promising anticancer development candidates than CTS [71]. However, data regarding the pharmacokinetics and BBB transversability of these drugs are not currently available.
Targeting calcium-mediated inter-organellar crosstalk in cardiac diseases
Published in Expert Opinion on Therapeutic Targets, 2022
Mohit M. Hulsurkar, Satadru K. Lahiri, Jason Karch, Meng C. Wang, Xander H.T. Wehrens
Istaroxime, a pharmacological agent that increases SERCA2a activity by reducing PLN inhibition, is in the advanced stages of FDA approval [65]. However, this drug also inhibits other transporters including the Na+/K+-ATPase, which might contribute to potential therapeutic effects [66]. Different groups are exploring genetic alteration therapies to restore SERCA2a activity by inhibiting PLN [67,68]. Other PLN like micro peptides sarcolipin (SLN) and myoregulin (MLN) also inhibit SERCA2a activity [69,70]. Downregulation of SLN expression using RNA interference delivered by AAV is effective against Duchenne muscular dystrophy and associated cardiomyopathy [71].