Heart failure (HF) is a complex and heterogeneous condition that results in an insufficient pumping of blood to meet the body’s needs and/or an impaired filling of the ventricle, often associated with symptoms like dyspnea and fatigue (Santulli et al., 2022). The diagnosis of HF is based on clinical assessment, which includes the patient’s symptoms, physical examination, and diagnostic tests. HF is a growing public health problem, leading to significant morbidity and mortality. Despite the wide spread of drugs and therapeutic approaches, and considerable advances in the care of patients, a high number of patients still suffer from functional impairment, poor quality of life, and early death due to HF; these issues can most likely be attributed to unrecognized molecular mechanisms of HF, ineffective current treatments, or adverse effects of the most valuable treatment options.

Calcium (Ca²⁺) is an essential player in the processes of cardiac contractility and relaxation, and alterations in its handling can facilitate arrhythmias and contribute to detrimental myocardial remodeling (Santulli et al., 2015; Gambardella et al., 2018; Kansakar et al., 2021). Indeed, one of the hallmarks of HF is the downregulation of sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2a (SERCA2a), eliciting an abnormal distribution of Ca²⁺ (Roe et al., 2015). Several studies have shown that an impaired SERCA2a activity may result from excessive inhibition by phospholamban (PLN), a 52-amino acid integral membrane protein that regulates SERCA in cardiac muscle cells: in its dephosphorylated form, PLN inhibits SERCA2a, whereas when PLN is phosphorylated by Protein kinase A (PKA), its ability to inhibit SERCA2a is lost (Periasamy et al., 2008; Zhang et al., 2008; Vafiadaki et al., 2022).

In an attempt to cope with these problems, treatments modulating myocyte Ca²⁺ handling by SERCA2a stimulation have been generated, harboring both inotropic and lusitropic properties. Istaroxime (PST2744) is the paramount example of SERCA2a enhancers; istaroxime has a dual mechanism of action (i.e., it activates SERCA2a but also inhibits the Na⁺/K⁺ ATPase pump) and therefore cannot be considered selective for SERCA2a (Micheletti et al., 2002; Rocchetti et al., 2003, 2005).

Confirming preclinical tests, the HORIZON-HF (Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent: A Randomized Control Trial in Patients Hospitalized with Heart Failure) trial demonstrated that istaroxime shortens the QT_C interval and decreases heart rate (unlike dobutamine or milrinone), can acutely lower filling pressures, and, at least at higher doses (1.5 μg/kg per min for 6 hours), can improve both cardiac output and lusitropic function, assessed by measuring the mitral deceleration time (Gheorghiade et al., 2008; Shah et al., 2009). Other recent trials yielded promising results when testing a 24-hour infusion of istaroxime in patients hospitalized for acute HF (Carubelli et al., 2020; Metra et al., 2022).

Nevertheless, istaroxime applications to the clinical scenario are greatly limited by its plasma half-life of less than 1 hour, due to an extensive hepatic metabolism; moreover, istaroxime is not selective for SERCA2a and often induces adverse side effects, including gastrointestinal distress and pain at the infusion site (Gheorghiade et al., 2008; Aditya and Rattan, 2012; Metra et al., 2022).

The work of Arici et al. (2022), published in this issue of JPET, elegantly investigated whether a metabolite of istaroxime, PST3093, could be harnessed for HF treatment, comparing its pharmacological activity with istaroxime and digoxin. The authors studied the effects of PST3093 at the molecular and cellular level, as well as in vivo.

At the molecular level, they report a first critical difference between istaroxime and PST3093, given that PST3093 does not inhibit the Na⁺/K⁺ ATPase pump but only stimulates SERCA2a, thus qualifying PST3093 as a selective activator (Arici et al., 2022). In addition, they revealed that PST3093 acts by weakening the SERCA-PLN interaction, a mechanism that had been previously confirmed, although not in an exclusive manner (Racioppi et al., 2021), also for istaroxime (Ferrandi et al., 2013; Kamel et al., 2021). Importantly, the authors were able to assess the pharmacokinetics of PST3093 in patients with HF, measuring a half-life of approximately 9 hours, substantially longer than that of istaroxime (Arici et al., 2022).

The in vivo study of PST3093 treatment was performed in a rat model of streptozotocin-induced diabetic cardiomyopathy, in which the association between reduced SERCA2a function and diastolic dysfunction had been previously reported (Jankauskas et al., 2021; Torre et al., 2022). Strikingly, PST3093 significantly ameliorated intracellular Ca²⁺ abnormalities induced by streptozotocin. Specifically, the observed reduction of Ca²⁺ at rest suggests that PST3093 might modulate other parameters of the Ca²⁺ cycle to ultimately maintain lower cytosolic Ca²⁺ levels. Eventually, the improved Ca²⁺ distribution is just what is expected from a specific activation of SERCA2a, leading to an improved cardiac performance. Indeed, the infusion of PST3093 improved cardiac function, as supported by robust echocardiographic data, and was beneficial in terms of both systolic and diastolic indexes (Arici et al., 2022). Another significant finding is that PST3093 is considerably less toxic than istaroxime, most likely because of its lack of effect on the Na⁺/K⁺ ATPase pump (Fig. 1). The authors provide a comprehensive ultrasound analysis, consistently supported by biochemical and electrophysiology data. Although the study represents a critical step forward in HF therapy, there are still some moot points to be elucidated. For instance, it is not fully clear why in rat microsomal preparations, PST3093 did not decrease K_dCa, which is expected to substantiate an increased Ca²⁺ affinity and enhanced SERCA function; such decrease was instead observed in guinea pig preparations. Notwithstanding, the authors were able to show in rat preparations an increased SERCA maximal hydrolytic velocity in response to PST3093. Further experimental evidence will be needed to assess in vivo how long the favorable lusitropic response is sustained. The authors did not measure the actual intracellular Ca²⁺ leak through the Ryanodine receptors (Santulli et al., 2017; Gambardella et al., 2022); this limitation is noteworthy because when evaluating SERCA2a gene therapy, several (albeit mostly theoretical) concerns were raised on the possibility of proarrhythmogenic effects of enhanced SERCA activity, most likely due to an indirect induction of Ca²⁺ leak from the sarcoplasmic reticulum (Sikkel et al., 2014; Sardu et al., 2020). Another limit is given by having used exclusively male animals.

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Fig. 1.

Schematic representation of the main differences between istaroxime and PST3093. Both compounds activate SERCA2a, but whereas PST3093 is a selective activator, istaroxime also inhibits Na⁺/K⁺ ATPase. Moreover, istaroxime has a relatively short half-life (∼1 hour), whereas PST3093 has a ∼9-hour half-life.

In general, the availability of suitable ino-lusitropic agents with a favorable profile would be certainly beneficial for the treatment of HF (Gambardella et al., 2020). Considering the numerous promising advantages presented in this study by Arici et al. (2022), PST3093 could be an excellent prototype to establish a forthcoming pharmacodynamic class with robust ino-lusitropic effects to treat HF (Mone et al., 2022). Potential future directions include 1) investigate in detail the mechanisms underlying the lower toxicity of PST3093 compared with istaroxime and validate the hypothesis that this aspect depends on its different inhibitory capabilities, 2) evaluate the actions of PST3093 on other SERCA isoforms in other cell types (Stammers et al., 2015), and 3) test the effects of PST3093 in types of HF in which the diastolic dysfunction is prevalent (Mone et al., 2022; Santulli et al., 2022), such as HF with preserved ejection fraction.

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