High CVH protection against new-onset pulmonary hypertension mediated by proteomic signatures

High levels of cardiovascular health (CVH), as defined by Life’s Essential 8 (LE8), is associated with a lower risk of developing pulmonary hypertension (PH), suggests a study. Proteomic signatures mediate this protective effect.

A total of 279,220 participants without PH at enrolment, identified using the UK Biobank, were included in the study. The association between CVH and incident PH was explored using Cox regression.

The investigators identified protein mediators using proteome-wide association, mediation, and functional enrichment analyses. They also validated key hub proteins at the transcriptional level through quantitative polymerase chain reaction (qPCR) in an animal model of PH, as well as at the protein level, and by macrophage-specific knockdown of interleukin (IL)-6 and CCL4 to evaluate its impact on rat pulmonary artery smooth muscle cell (PASMC) migration and proliferation.

More than 1,300 PH cases occurred over a median follow-up of 13.2 years. Participants with moderate CVH had 59-percent lower risk of PH (hazard ratio [HR], 0.41, 95 percent confidence interval [CI], 0.33‒0.49), and those with high CVH had an 82-percent reduced PH risk (HR, 0.18, 95 percent CI, 0.14‒0.23) than those with the lowest CVH.

In proteomic analyses, a distinct plasma protein signature significantly mediated the association between CVH and PH risk. In pathway enrichment analysis, proteins were enriched in inflammatory or immune pathways, and key hub proteins were found to play a role in the central mechanism pathway.

Notably, the mRNA and protein expression levels of IL-6 and C‒C motif chemokine ligand 4 (CCL4) were significantly increased in the lung tissue of PH rat models. In functional assays, knockdown of IL-6 or CCL4 macrophages led to a significant decrease in the migration and proliferation of rat PASMCs in vitro.

“[The] protective effect [of CVH] is primarily mediated by a proteomic signature, revealing the role of signalling pathways such as cytokine-cytokine receptor interaction in the prevention of PH,” the investigators said.