The tricuspid valve also maladapts: A multiscale study in sheep with biventricular heart failure

ObjectivesWe set out to determine the tricuspid valve’s propensity to (mal)adapt in disease.BackgroundTricuspid regurgitation (TR) is generally considered secondary to right and/or left ventricular disease without organic failure. Interestingly, we and others have previously shown the mitral valve (mal)adapts in functional mitral regurgitation, which may warrant reconsideration of its functional etiology. Whether the tricuspid valve similarly (mal)adapts is mostly unknown.MethodsWe evaluated the (mal)adaptive response of tricuspid valve anterior leaflets (TVALs) from an ovine model in which over-pacing (19 ± 6 days) induced biventricular heart failure and TR (tachycardia-induced cardiomyopathy, TIC, n=33) and compared findings to those from a control group (n=17). In both groups, we performed proteomics, immunohistochemistry, histology, two-photon microscopy, collagen assays, leaflet thickness and morphology measurements, and biaxial mechanical tests.ResultsWe found metabolically active resident valvular cells in TIC TVALs which expressed activation and turnover markers. In TIC TVALs, we observed a 140% increase in collagen content (p=0.016), increased collagen dispersion regionally (p=0.017), a 130% increase in leaflet area (p=0.002), a 140% increase in thickness (p=0.006), and a 130% increase in radial stiffness (p=0.006).ConclusionsOur data suggest that TVALs (mal)adapt during TIC on all scales. This response is likely initiated by activated valvular cells, resulting in collagen turnover, and ultimately leading to thickening, area increase, and stiffening. Our data motivates future studies on the exact pathways leading to tricuspid (mal)adaptation and pharmacological therapeutic strategies for TR.Condensed AbstractIn most cases, tricuspid regurgitation is presumed to originate from valve extrinsic factors. We challenge this paradigm and hypothesize that the tricuspid valve maladapts, rendering the valve at least partially culpable for its dysfunction. As such, we set out to demonstrate that the tricuspid valve, indeed, maladapts in an ovine model of heart disease. In the anterior leaflets, we found alterations on the protein and cell-level, leading to maladaptation in the form of tissue growth, thickening, and stiffening. Our findings may initially motivate mechanistic pathway studies, and in the future, leaflet-targeted pharmacological therapeutic options for tricuspid regurgitation.

New Insights into the Roles of Monocytes/Macrophages in Cardiovascular Calcification Associated with Chronic Kidney Disease

Cardiovascular disease (CVD) is an important cause of death in patients with chronic kidney disease (CKD), and cardiovascular calcification (CVC) is one of the strongest predictors of CVD in this population. Cardiovascular calcification results from complex cellular interactions involving the endothelium, vascular/valvular cells (i.e., vascular smooth muscle cells, valvular interstitial cells and resident fibroblasts), and monocyte-derived macrophages. Indeed, the production of pro-inflammatory cytokines and oxidative stress by monocyte-derived macrophages is responsible for the osteogenic transformation and mineralization of vascular/valvular cells. However, monocytes/macrophages show the ability to modify their phenotype, and consequently their functions, when facing environmental modifications. This plasticity complicates efforts to understand the pathogenesis of CVC—particularly in a CKD setting, where both uraemic toxins and CKD treatment may affect monocyte/macrophage functions and thereby influence CVC. Here, we review (i) the mechanisms by which each monocyte/macrophage subset either promotes or prevents CVC, and (ii) how both uraemic toxins and CKD therapies might affect these monocyte/macrophage functions.