Marie Guerraty

Endothelial Heterogeneity Associated with Regional Athero-Susceptibility and Adaptation to Disturbed Blood Flow in Vivo

Endothelial phenotypic heterogeneity plays an important role in the susceptibility of the cardiovascular system to disease. Arteries and heart valves are susceptible to chronic inflammatory disease in regions of blood flow disturbance that implicates hemodynamic forces and transport characteristics as prominent influences on endothelial phenotype. By combining in vivo high-throughput genomics (discovery science) and in vitro mechanistic approaches (reductionist science), we present endothelial patho-susceptibility as an imbalance of multiple interrelated pathways that sensitize the cells to pathological change. The recently identified association of endoplasmic reticulum stress with endothelium in regions of flow disturbance is outlined as an important example of susceptible phenotype linked to proinflammatory and oxidative stress pathways.

Hypercholesterolemia Induces Side-Specific Phenotypic Changes and Peroxisome Proliferator–Activated Receptor-γ Pathway Activation in Swine Aortic Valve Endothelium

Background—The endothelium of healthy aortic valves expresses different phenotypes on the aortic and ventricular sides. On the aortic side, which is susceptible to aortic valve sclerosis, there is a balanced coexpression of both propathological and protective pathways. Side-specific global gene expression can address endothelial phenotype balance in early aortic valve sclerosis. Methods and Results—Adult male swine were fed a hypercholesterolemic or an isocaloric normal diet for 2-week and 6-month periods. Hypercholesterolemia induced localized lipid insudation confined to the aortic side of the leaflet. Transcript profiling of valve endothelial populations showed that the susceptible aortic side was more sensitive to 2-week hypercholesterolemia than the ventricular side (1,325 vs 87 genes were differentially expressed). However, greater sensitivity was not evidence of a dysfunctional phenotype. Instead, pathway analyses identified differential expression of caspase 3–, peroxisome proliferator–activated receptor &ggr;–, TNF-&agr;–, and nuclear factor-&kgr;B–related pathways that were consistent with a protective endothelial phenotype. This was confirmed at the protein level at 2 weeks and persisted at 6 months. Conclusions—In a large animal model at high spatial resolution, endothelium on the pathosusceptible side of the aortic valve leaflet is responsive to hypercholesterolemia. Transcript profiles indicative of a protective phenotype were induced and persisted on the side prone to aortic valve sclerosis.

Models of Aortic Valve Calcification

Aortic valve stenosis is a complex inflammatory process, akin to arterial atherosclerosis, involving lymphocytic infiltrates, macrophages, foam cells, endothelial activation and dysfunction, increased cellularity and extracellular matrix deposition, and lipoprotein accumulation. A clonal population of aortic valve myofibroblasts spontaneously undergoes phenotypic transdifferentiation into osteoblast-like cells and forms calcific nodules in cell culture. Animal models complement these cell culture models by providing in vivo systems in which to study the complex molecular and cellular interactions that cause aortic valve disease in the native hemodynamic and biochemical environment. Whereas some species, such as swine, can develop spontaneous vascular and valvular atherosclerotic lesions, others, such as rabbits and mice, have not been shown to develop lesions naturally and require an inciting factor, such as hypercholesterolemia. In this article, we review the published cell culture and animal models available to study calcific aortic valve disease.

Relation of Aortic Valve Calcium to Chronic Kidney Disease (from the Chronic Renal Insufficiency Cohort Study)

Although subjects with chronic kidney disease (CKD) are at markedly increased risk for cardiovascular mortality, the relation between CKD and aortic valve calcification has not been fully elucidated. Also, few data are available on the relation of aortic valve calcification and earlier stages of CKD. We sought to assess the relation of aortic valve calcium (AVC) with estimated glomerular filtration rate (eGFR), traditional and novel cardiovascular risk factors, and markers of bone metabolism in the Chronic Renal Insufficiency Cohort (CRIC) Study. All patients who underwent aortic valve scanning in the CRIC study were included. The relation between AVC and eGFR, traditional and novel cardiovascular risk factors, and markers of calcium metabolism were analyzed using both unadjusted and adjusted regression models. A total of 1,964 CRIC participants underwent computed tomography for AVC quantification. Decreased renal function was independently associated with increased levels of AVC (eGFR 47.11, 44.17, and 39 ml/min/1.73 m2, respectively, p<0.001). This association persisted after adjusting for traditional, but not novel, AVC risk factors. Adjusted regression models identified several traditional and novel risk factors for AVC in patients with CKD. There was a difference in AVC risk factors between black and nonblack patients. In conclusion, our study shows that eGFR is associated in a dose-dependent manner with AVC in patients with CKD, and this association is independent of traditional cardiovascular risk factors.

Biomarkers of Calcific Aortic Valve DiseaseHighlights

Calcific aortic valve disease (CAVD) is a highly prevalent cardiovascular disorder accounting for a rising economic and social burden on aging populations. In spite of continuing study on the pathophysiology of disease, there remain no medical therapies to prevent the progression of CAVD. The discovery of biomarkers represents a potentially complementary approach in stratifying risk and timing of intervention in CAVD and has the advantage of providing insight into causal factors for the disease. Biomarkers have been studied extensively in atherosclerotic cardiovascular disease, with success as additive for clinical and scientific purposes. Similar research in CAVD is less robust; however, the available studies of biomarkers in CAVD show promise for enhanced clinical decision making and identification of causal factors for the disease. This comprehensive review summarizes available established and novel biomarkers in CAVD, their contributions toward an understanding of pathophysiology, their potential clinical utility, and provides an outline to direct future research in the field.

Getting Physical With the Aortic Valve

Mammalian cells and tissues rely on continuous interactions with the structural, physical, and soluble chemical environment to adapt to rapidly changing conditions. This ensures the continuation of proper physiological functions, accurate developmental cues during embryogenesis, containment of chronic pathological changes, and efficient repair of acute injuries. As part of cell regulation, the mechanical status of cells is constantly undergoing adjustment through coordinated responses to changes of intracellular tension imposed by internal and external forces and by encounters with extracellular matrices of varying stiffness.1,2 The role of extracellular proteins in mechanoregulated cell biology has emerged over the last decade in studies of fibrosis—the differentiation of myofibroblasts that express contractile α-smooth muscle actin (α-SMA) organized into stress fibers. Myofibroblast differentiation requires sustained mechanical tension that in turn is dependent on the stiffness of the extracellular matrix as sensed through integrin adhesion sites in the cell membrane.3 A critical soluble protein required for myofibroblast differentiation is transforming growth factor-β (TGF-β)4 that is secreted from myofibroblasts and, in an autocrine loop, can stimulate the cell via TGF-β receptors. However, secreted TGF-β binds to the extracellular matrix via a fibronectin splice variant (TGF-β latent complex), making it unavailable to the cell and preventing differentiation.5 In 2007, Wipff et al6 showed that TGF-β availability depends on the matrix …