Identifying novel biomarkers and therapeutic targets for heart failure and associated pulmonary hypertension

Background: Pulmonary hypertension (PH) often complicates heart failure (HF) but can hardly be addressed therapeutically. Whether sodium-glucose cotransporter 2 inhibitors (SGLT2i) positively impact on HF-associated PH is unknown. Omics may lead to the discovery of novel therapeutic targets for HF and PH. Aims: To evaluate the impact of SGLT2i compared to conventional anti-HF therapy on mid-term clinical and echocardiographic outcomes and to assess potential biological effects, including changes in oxidative stress markers (telomere length, mitochondrial DNA), proteomic and miRNA expression profiles. Methods: In an observational series of seventy-four patients with HF and reduced ejection fraction (HFrEF) patients were divided into two groups receiving (T=0) either 10 mg/day the SGLT2i dapagliflozin or empagliflozin on top of conventional anti-HF therapy (gliflozin group G), or a no-gliflozin anti-HF therapy (no-gliflozin group). Plasma samples from the gliflozin and the no-gliflozin groups were profiled by untargeted proteomics. Results: Compared to the no-gliflozin group, the gliflozin group at follow-up had better World Health Organization functional class (WHO-FC Δ 0.03±1,5 vs 1.1±1, p=0.001), lesser clinical signs of right heart failure (odds ratio OR 3.46; 95% CI 1.2-9.8; p=0.023) and a lower echocardiographic probability of PH (1.88±0.89 vs 1.4±0.62, p=0.017). In the gliflozin group, several biological pathways were triggered (p-value <10-3), such as those related to the T-lymphocyte immune response, chemotaxis of monocytes, leukocytes and phagocytes. Importantly, the gliflozin group featured a downregulation of the activin and miR-1306-5p signaling pathways, which are now emerging as novel therapeutic targets in pulmonary arterial hypertension (PAH). Conclusions: In HF patients, SGLT2i improve functional capacity and right heart failure and reduce the echocardiographic probability of PH. The activin and miR-1306-5p are overactivated in HF patients and serum levels of such biomarkers are reduced by SGLT2i. SGLT2i may be an additional therapeutic tool in patients with HF-associated PH.