Kalsifik Aort Darlığı Patogenezinde Barsak Mikrobiyotasının Rolünün Araştırılması

Abstract

Calcific aortic valve disease (CAVD) is the most prevalent valvular heart disease. However, its pathogenesis has not been elucidated clearly. Gut microbiota has recently shown to be associated with atherosclerosis and several degenerative diseases. In this study, we aimed to investigate the role of gut microbiota in the pathogenesis of CAVD. We recruited eligible subjects with calcific aortic stenosis (CAS) (n= 60), aortic sclerosis (ASc) (n= 49) and age- and gender- matched control subjects (n= 48). Besides routine cardiovascular (CV) examination; arterial stiffness and 2D speckle tracking echocardiography were performed. Coronary artery, aortic valve and mitral annular calcium scores from computed tomographic (CT) scans were recorded. Besides routine laboratory tests, plasma levels of gut microbiota metabolites, namely choline, betaine and trimethylamine N- oxide (TMAO), and serum levels of biomarkers related to calcification (osteopontin [OPN]) and tissue remodeling (tissue inhibitor of matrix metalloproteinase- 1 [TIMP- 1], matrix metalloproteinase- 9 [MMP- 9]) were measured. Histopathological examinations were performed in aortic valves excised during aortic valve surgery due to either severe CAS or any other non- stenotic disease of the aortic valve. Prevalence of traditional CV risk factors, co- morbidities or medications did not differ among groups. The study population had normal levels of calcium- phosphorus product, alkaline phosphatase, parathyroid hormone and 25- hydroxyvitamin D. Reflective of systemic inflammation, C- reactive protein levels were also similar among patient groups. Patients with moderate- severe CAS had significantly higher plasma levels of choline, a marker of gut microbiota metabolism, when compared to both ASc (p=0.006) and control (p<0.001) groups. Plasma betaine/ choline ratio, which is another marker of gut microbiota metabolism, was significantly lower in patients with moderate- severe CAS compared to both ASc (p= 0.009) and control (p= 0.002) groups. Plasma TMAO levels did not statistically differ between groups (p=0.509). Plasma choline levels were significantly correlated with determinants of CAS severity, namely aortic peak flow velocity (p< 0.001) and aortic valve calcium score (p< 0.001). Plasma choline levels were also independently associated with aortic peak flow velocity (p= 0.009). There was a significant negative correlation between betaine/ choline ratio and aortic peak flow velocity (p< 0.001). In histopathological examinations, plasma choline levels were significantly elevated in patients who had aortic valves with denser lymphocyte infiltration (p< 0.001), more severe tissue remodeling (p= 0.002) and calcification (p= 0.002), neovascularization (p= 0.011), and osteoid metaplasia (p=0.004). These valves also demonstrated significantly higher CD11c+ dendritic cell and plasma cell infiltration, reflecting the chronic inflammatory nature of the disease. Our study hereby demonstrates a significant association between gut microbiota metabolites and CAVD presence and severity evaluated with echocardiography, computed tomography and histopathological examinations for the first time in the literature.