Identification of Circulating Plasma Proteins as a Mediator of Hypertension-Driven Cardiac Remodeling: A Mediation Mendelian Randomization Study

BACKGROUND: This study focused on circulating plasma protein profiles to identify mediators of hypertension-driven myocardial remodeling and heart failure. METHODS: A Mendelian randomization design was used to investigate the causal impact of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure on 82 cardiac magnetic resonance traits and heart failure risk. Mediation analyses were also conducted to identify potential plasma proteins mediating these effects. RESULTS: Genetically proxied higher SBP, DBP, and pulse pressure were causally associated with increased left ventricular myocardial mass and alterations in global myocardial wall thickness at end diastole. Elevated SBP and DBP were linked to increased regional myocardial radial strain of the left ventricle (basal anterior, mid, and apical walls), while higher SBP was associated with reduced circumferential strain in specific left ventricular segments (apical, mid-anteroseptal, mid-inferoseptal, and mid-inferolateral walls). Specific plasma proteins mediated the impact of blood pressure on cardiac remodeling, with FGF5 (fibroblast growth factor 5) contributing 2.96% ( P =0.024) and 4.15% ( P =0.046) to the total effect of SBP and DBP on myocardial wall thickness at end diastole in the apical anterior segment and leptin explaining 15.21% ( P =0.042) and 23.24% ( P =0.022) of the total effect of SBP and DBP on radial strain in the mid-anteroseptal segment. Additionally, FGF5 was the only mediator, explaining 4.19% ( P =0.013) and 4.54% ( P =0.032) of the total effect of SBP and DBP on heart failure susceptibility. CONCLUSIONS: This mediation Mendelian randomization study provides evidence supporting specific circulating plasma proteins as mediators of hypertension-driven cardiac remodeling and heart failure.