Charakterisierung des Darmmikrobioms bei Patienten mit hochgradiger, symptomatischer Aortenklappenstenose

Aortic valve stenosis (AS) is the most common valvular heart disease in the Western world and is associated with a high mortality rate, if left untreated. Echocardiographic parameters can be used to distinguish between different phenotypes, which show varying degrees of cardiac fibrosis in the sense of maladaptive cardiac remodeling and divergent survival rates after valve replacement. The gut microbiome is highly important for the human body due to the enormous number of microbiota and the numerous functions it performs in the body. Gut bacteria are able to affect systemic inflammation and organ fibrosis via their metabolites or through direct interaction with the immune system. Animal studies have demonstrated a protective effect of short chain fatty acids (SCFA)-producing bacteria in cardiovascular diseases. The aim of this study was to analyze the composition and diversity of the gut microbiota as well as the concentrations of SCFA as metabolites of the microbiota in the four AS phenotypes. This should expand the characterization of the individual phenotypes and identify possible pathophysiological relationships between the gut microbiome and cardiac remodeling, fibrosis, inflammation, and hemodynamic parameters. This prospective study included 81 patients who underwent valve replacement due to high-grade, symptomatic AS. Based on echocardiographic parameters, the patients were classified into the following four phenotypes: normal ejection fraction, high-gradient AS (Vmax ≥ 4 m/s, Pmean ≥ 40 mmHg, LVEF ≥50%), low ejection fraction, high-gradient AS (Vmax ≥ 4 m/s, Pmean ≥ 40 mmHg, LVEF < 50%), low ejection fraction, low-gradient AS (Vmax < 4 m/s, Pmean < 40 mmHg, aortic valve area ≤ 1 cm2, stroke volume index ≤ 35 ml/min2, LVEF < 50%), paradoxical low-flow, low-gradient AS (Vmax < 4 m/s, Pmean < 40 mmHg, aortic valve area ≤ 1 cm2, stroke volume index ≤ 35 ml/m2, LVEF ≥50%). Findings that were obtained during routine clinical examinations (e.g., medical history, physical examination, transthoracic echocardiography, and laboratory tests) were also used for the study. In addition, a rectal swab was taken from all patients and analyzed using 16S rRNA sequencing. Plasma concentrations of SCFA were quantified from EDTA blood using liquid chromatography coupled with mass spectrometry. To assess the degree of cardiac fibrosis, myocardial biopsies were taken from some patients during valve replacement surgery and cardiac MRI examinations were performed on some patients. The majority of patients belonged to phenotype 1 (40 patients). The prevalence of the other phenotypes was roughly the same: phenotype 2 comprised 11 patients, while phenotypes 3 and 4 each included 12 patients. Overall, no differences in alpha or beta diversity were found between the four phenotypes. When comparing the composition of the microbiome, five taxa were observed that differed significantly in their relative abundance between the AS phenotypes: The Erysipelotrichaceae family and the genera Tyzzerella, Cloacibacillus, Negativicoccus, and Erysipelatoclostridiaceae_UCG-004. The plasma concentrations of the three most important SCFAs (acetate, butyrate, and propionate) showed no significant differences between the four phenotypes. The plasma concentrations of hexanoic acid and isobutyrate were significantly higher in patients with phenotype 3 than in those with phenotype 2. A small number of weak correlations were found between patient characteristics and some plasma concentrations of SCFA. In this study, all four AS phenotypes showed similar diversity of the gut microbiome. However, the analysis of the relative abundance of individual taxa showed that the Erysipelotrichaceae family was more common in patients with phenotype 3 than in the other phenotypes – a group of bacteria associated with pathological conditions. For the well-studied and cardioprotective SCFAs butyrate and propionate, an association with concentric hypertrophy was found – a form of cardiac remodeling that is considered more favorable in the context of AS compared to eccentric hypertrophy. The remaining SCFAs showed partly inconsistent correlations with cardiac parameters, which corresponds to the current, inconsistent evidence on their effects. The results suggest that larger studies investigating the gut microbiome in connection with the characterization of inflammatory and fibrotic processes of the myocardium could be promising.