Pulmonary arterial hypertension (PAH) has been extensively identified as a disease condition that affects small pulmonary arteries by causing progressive vascular narrowing, resulting in increased pulmonary arterial resistance and eventual right ventricular failure (1). During the course of their condition, patients with PAH may develop acute right heart failure (RHF) (2). Acute decompensated RHF is distinguished by a rapid exacerbation of the pathological signs of RHF followed by congestion and systemic circulatory inefficiency, which could result in multisystem organ failure (3, 4). The short-term prognosis of acute decompensated RHF is extremely poor, and it continues to remain the leading cause of death among PAH patients (5, 6). Treatment of triggering factors, careful fluid management, and measures to restore cardiac function and minimize right ventricular afterload are the foundations of intensive care for acute decompensated PAH (7).

Therapeutic interventions for patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) are usually more complicated than those for idiopathic PAH. In individuals with PAH linked to systemic lupus erythematosus or mixed CTD in the chronic phase, immunosuppressive treatment that combines cyclophosphamide and glucocorticoids might yield positive clinical outcomes (8), which could result in a therapeutic process similar to idiopathic PAH (9). Thus, the benefit from traditional medical therapies is somewhat lacking, stressing the importance of alternative therapeutic strategies in patients who are unable to undergo timely urgent lung transplantation and right ventricle assistance devices.

Levosimendan, a myocardial calcium sensitizer and vasodilator, which is usually utilized in left heart failure, might be effective in acute pulmonary embolism-induced right ventricular failure treatment, owing to its pharmacological profile with combined pulmonary vasodilation and increased right ventricular contractility (10). Nevertheless, there are currently insufficient data for levosimendan therapy in PAH and even acute decompensated RHF, and it is incorrect to generalize findings from trials utilizing levosimendan on the left ventricle (LV) to the RV. The focus of this study was to assess the effect of levosimendan on acute decompensated RHF in patients with CTD-PAH.

Our findings indicate that in the present treatment period, acute decompensated RHF is still a severe life-threatening disease. Our data demonstrated that levosimendan could improve clinical indices and survival rates during hospitalization, but had no significant effect on medium-and long-term outcomes at follow-up.

It is widely established that people with CTD are more likely to develop group 1 PAH (9). Preclinical research supports the idea that PAH may be caused by immunological dysfunction (20). CTD-PAH is typified by vasoconstriction and modification of small-to-medium-sized pulmonary arterioles, as well as significant interstitial inflammation and fibrotic alterations (21). Patients with CTD-PAH have a worse overall survival rate than patients diagnosed with other forms of PAH. Greater awareness of PAH morbidity and death in CTDs has resulted in a growing number of research studies investigating disease burden, pathophysiology, and risk factors related to the development of PAH in CTDs. Current therapeutic guidelines and updates mainly focus on generalized treatment for all group 1 PAH without any specific guidelines for managing CTD-PAH (22, 23). The current treatment algorithm may be divided into three main areas: (1) general measures, supportive therapy, referral strategy, acute vasoreactivity testing, and chronic treatment with calcium channel blockers; (2) initial therapy with approved PAH drugs; and (3) clinical response to the initial therapy, combination therapy, balloon atrial septostomy, and lung transplantation (22). Therefore, it is worth exploring alternative therapies for acute decompensated RHF in patients with CTD-PAH (23).

Levosimendan is recognized as a calcium-sensitizing agent comprising cardioprotective, pulmonary vasodilatory, and inotropic characteristics. In contrast to other inotropes, levosimendan's positive inotropic effects do not occur at the cost of elevated myocardial oxygen demand or calcium overload (24, 25). As previous studies have shown, levosimendan has slightly distinct effects on the left and right ventricular hemodynamic parameters. In the systemic vasculature, the vasodilator response is greater than the response in the pulmonary circulation (26). On the other hand, the positive inotropic impact is larger on the right than on the left ventricles, as indirectly evaluated by the percentage increase in stroke index (18). This could imply that an increase in right contractility instead of a reduction in afterload is the main mechanism of action of levosimendan in right ventricular dysfunction. This may lead to the emergence of a particularly high-risk group of patients requiring additional vasopressor treatment. We cannot rule out that the vasodilating effects of levosimendan in these high-risk individuals may worsen the detrimental consequences of hypotension and the toxic effects of vasopressor treatment. Thus, caution should be exercised while administering levosimendan, and a loading dosage should be prevented.

It is worth noting that our study showed no significant differences in the RHC characteristics at follow-up. Some studies indicated that levosimendan could enhance RV function, enhance RV mechanical efficiency, improve clinical symptoms, and reduce pulmonary arterial pressure in treating patients with acute decompensated RHF due to PAH. However, the improved clinical effect caused by levosimendan may disappear when exceeding the time of hemodynamic persistent effects, 7–9 days as reported (18). Further research in future trials with a larger patient population and a longer follow-up period is required.

Right hemodynamic monitoring by RHC has been identified as the most efficient tool for evaluating cardiac function, right ventricular preload, and right ventricle afterload in pulmonary hypertension. The primary modified parameters in acute decompensation are right atrial pressure and cardiac output, which have been shown to be significant prognostic indicators of PAH (27). Nevertheless, invasive hemodynamic monitoring may be hazardous in severely unstable PAH patients, which poses a risk of arrhythmia and infection. Studies have shown that echocardiography may be a safe method for obtaining essential data on systolic pulmonary arterial pressure and cardiac index as an appropriate reflection of right ventricular preload (28, 29). After analyzing the benefit-to-risk ratio, RHC is recommended in severe and complicated cases (3). Meanwhile, the central venous line might be beneficial in monitoring the central venous pressure to estimate the development of right ventricular preload and improve fluid balance management with diuretics. Furthermore, central venous oxygen saturation measurements are advised to assess tissue oxygenation (3).

In our study, NT-proBNP, troponin I, and CRP levels in the levosimendan cohort were significantly reduced at discharge compared with the control group. Several studies have verified the prognostic significance of biomarkers such as troponin and BNP (5, 30). In individuals with acute decompensated pulmonary hypertension, CRP levels are helpful in screening for inflammatory processes (5), probably indicating a systemic inflammatory reaction syndrome due to acute right cardiac decompensation. Numerous studies have confirmed the inflammatory reaction in acute RHF and indicated the probable diagnostic and prognostic values of these inflammatory markers in such cases (31). It has also been shown to have prognostic significance when coupled with RV dysfunction, a predictor of poor PAH results (32). Inflammatory activation is directly related to the extent of impairment of cardiac function and neurohormonal activation. Inflammatory pathways emphasize that additional research on stable and decompensated PAH is necessary to discover new treatment targets. There have been increasing efforts to understand the relationship between autoimmunity, inflammation, and the evolution of PAH (32). In the latest research, Immunosuppressive therapy of rituximab in patients with systemic sclerosis-pulmonary arterial hypertension (SSc-PAH) was associated with inflammatory resolution following B-cell depletion (33).

Our results further indicate that patients with acute decompensated RHF should preferably be treated in specialist facilities that can access all interventional, medical, and surgical alternatives, including lung transplantation, ECMO, and medical therapies. Identifying alternative treatment strategies in patients with PAH and acute decompensated RHF is essential for improving outcomes.

Our results show that levosimendan treatment is practicable and enhances hemodynamic parameters during hospitalization in individuals with decompensated RHF. The increase in the right ventricular stroke index, as well as the leftward shift of the association between the right ventricular preload and cardiac output, illustrated that the surge in the contractility of the right ventricle instead of the reduction of the afterload is the key underlying mechanism. To validate this notion, further research involving a larger number of patients is required.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: https://pan.baidu.com/s/1tsHlgG0RLcm8AZfhitJCHw.

The studies involving human participants were reviewed and approved by Ethics Committee for the First Affiliated Hospital of Harbin Medical University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

CQ, WF, RZ, and XQ conceived and designed the experiments. CQ, WF, QZ, XL, GW, ZY, YS, and SH performed the experiments. CQ, WF, MS, QL, CZ, and RZ analyzed the data. CQ, WF, and RZ wrote the manuscript. All authors contributed to the manuscript and approved the submitted version.

This work was supported by the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, Heilongjiang Province, China [Grant Number KF201823 (to CQ)].

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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