Biomarkers in Cardiovascular Dysautonomia: an Emerging Field

Sammanfattning: Background: Cardiovascular autonomic dysfunction is a multifactorial disorder manifested as orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS). OH has been associated with an increased risk of cardiovascular disease (CVD), and the underlying mechanisms are not fully understood and explored.Aims and methods: Project I: We aimed to discover protein biomarkers related to OH using an antibody-based proteomics technique measuring 92 cardiovascular biomarkers simultaneously, in 399 patients from the SYSTEMA cohort, who underwent head-up tilt testing.Project II: Our aim was to examine the association between classical OH and inflammatory protein biomarkers, by conducting a cross-sectional study, with 279 patients from the SYSTEMA cohort, measuring 57 inflammatory and cancer-related human protein biomarkers using the same technique as in paper II.Project III: We aimed to evaluate the role of four hemodynamically active cardiovascular protein biomarkers (CT-proAVP, CT-proET-1, MR-proADM and MR-proANP), in predicting the longitudinal association on fragility fractures. We investigated 5415 participants from the prospective MPP population-based cohort. Project IV: We aimed to investigate circulating growth hormone (GH) levels in POTS compared with healthy controls from the SYSTEMA cohort, by using a high-sensitivity chemiluminescence sandwich immunoassay, since low levels of GH have been linked to cardiovascular morbidity.Results:Project I: We found that OH-patients had elevated plasma concentrations of four cardiovascular biomarkers (MMP-7, TM, MB and TIM-1), that were related to atherosclerosis, thrombosis, endothelial dysfunction and vascular inflammation. Notably, both MMP-7 and TIM-1 were independently related with OH.Project II: We identified four inflammatory biomarkers (MK, ILT-3, REG-4 and TR-AP) that were increased in patients with classical OH, possibly indicating a multifactorial interaction between inflammation, autonomic dysfunction and atherothrombosis.Project III: Plasma concentrations of MR-proADM and MRproANP were elevated in participants with fractures, and the fracture risk across MR-proANP quartiles increased linearly. Notably, participants in the top quartile of all four biomarkers, had a two- to threefold greater risk of fractures at any site. Project IV: POTS patients had significantly higher composite OHQ score, supine heart rate and diastolic blood pressure than controls. Plasma levels of GH were significantly lower in POTS than in controls. GH levels were inversely related to daily activity scale in POTS, and inversely related to supine systolic blood pressure in both POTS and controls.Conclusions: Our findings expand the growing evidence that molecular biomarkers may considerably improve the understanding of pathophysiological mechanisms associated with cardiovascular autonomic dysfunction. We revealed new associations between biomarkers related to OH and POTS, possibly aiding in the development of predictive strategies targeted at early identification of individuals with disrupted cardiovascular homeostasis.