Oxidative stress initiates hemodynamic change in CKD-induced heart disease.

Chronic kidney disease (CKD) predisposes to cardiac remodeling and coronary microvascular dysfunction. Studies in swine identified changes in microvascular structure and function, as well as changes in mitochondrial structure and oxidative stress. However, CKD was combined with metabolic derangement, thereby obscuring the contribution of CKD alone. Therefore, we studied the impact of CKD on the heart and combined proteome studies with measurement of cardiac function and perfusion to identify processes involved in cardiac remodeling in CKD. CKD was induced in swine at 10-12 weeks of age while sham-operated swine served as controls. 5-6 months later, left ventricular (LV) function and coronary flow reserve were measured. LC-MS-MS-based proteomic analysis of LV tissue was performed. LV myocardium and kidneys were histologically examined for interstitial fibrosis and oxidative stress. Renal embolization resulted in mild chronic kidney injury (increased fibrosis and urinary NGAL). PV loops showed LV dilation and increased wall stress, while preload recruitable stroke work was impaired in CKD. Quantitative proteomic analysis of LV myocardium and STRING pre-ranked functional analysis showed enrichments in pathways related to contractile function, reactive oxygen species, and extracellular matrix (ECM) remodeling, which were confirmed histologically and associated with impaired total anti-oxidant capacity. H2O2 exposure of myocardial slices from CKD, but not normal swine, impaired contractile function. Furthermore, in CKD, mitochondrial proteins were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow. Thus, mild CKD induces alterations in mitochondrial proteins along with contractile proteins, oxidative stress and ECM remodeling, that were associated with changes in cardiac function and perfusion.

The gut commensal Blautia maintains colonic mucus function under low-fiber consumption through secretion of short-chain fatty acids.

Beneficial gut bacteria are indispensable for developing colonic mucus and fully establishing its protective function against intestinal microorganisms. Low-fiber diet consumption alters the gut bacterial configuration and disturbs this microbe-mucus interaction, but the specific bacteria and microbial metabolites responsible for maintaining mucus function remain poorly understood. By using human-to-mouse microbiota transplantation and ex vivo analysis of colonic mucus function, we here show as a proof-of-concept that individuals who increase their daily dietary fiber intake can improve the capacity of their gut microbiota to prevent diet-mediated mucus defects. Mucus growth, a critical feature of intact colonic mucus, correlated with the abundance of the gut commensal Blautia, and supplementation of Blautia coccoides to mice confirmed its mucus-stimulating capacity. Mechanistically, B. coccoides stimulated mucus growth through the production of the short-chain fatty acids propionate and acetate via activation of the short-chain fatty acid receptor Ffar2, which could serve as a new target to restore mucus growth during mucus-associated lifestyle diseases.

The right ventricle in tetralogy of Fallot: adaptation to sequential loading.

Right ventricular dysfunction is a major determinant of outcome in patients with complex congenital heart disease, as in tetralogy of Fallot. In these patients, right ventricular dysfunction emerges after initial pressure overload and hypoxemia, which is followed by chronic volume overload due to pulmonary regurgitation after corrective surgery. Myocardial adaptation and the transition to right ventricular failure remain poorly understood. Combining insights from clinical and experimental physiology and myocardial (tissue) data has identified a disease phenotype with important distinctions from other types of heart failure. This phenotype of the right ventricle in tetralogy of Fallot can be described as a syndrome of dysfunctional characteristics affecting both contraction and filling. These characteristics are the end result of several adaptation pathways of the cardiomyocytes, myocardial vasculature and extracellular matrix. As long as the long-term outcome of surgical correction of tetralogy of Fallot remains suboptimal, other treatment strategies need to be explored. Novel insights in failure of adaptation and the role of cardiomyocyte proliferation might provide targets for treatment of the (dysfunctional) right ventricle under stress.