Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however, upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the progression to heart failure. Despite the critical importance of fibrosis in cardiovascular disease, our limited understanding of the cardiac fibroblast impedes the development of potential therapies that effectively target this cell type and its pathological contribution to disease progression. This review summarizes current knowledge regarding the origins and roles of fibroblasts, mediators and signaling pathways known to influence fibroblast function after myocardial injury, as well as novel therapeutic strategies under investigation to attenuate cardiac fibrosis.

The mature heart valves are made up of highly organized extracellular matrix (ECM) and valve interstitial cells (VICs) surrounded by an endothelial cell layer. The ECM of the valves is stratified into elastin-, proteoglycan-, and collagen-rich layers that confer distinct biomechanical properties to the leaflets and supporting structures. Signaling pathways have critical functions in primary valvulogenesis as well as the maintenance of valve structure and function over time. Animal models provide powerful tools to study valve development and disease processes. Valve disease is a significant public health problem, and increasing evidence implicates aberrant developmental mechanisms underlying pathogenesis. Further studies are necessary to determine regulatory pathway interactions underlying valve pathogenesis in order to generate new avenues for novel therapeutics.

In recent years, significant advances have been made in the definition of regulatory pathways that control normal and abnormal cardiac valve development. Here, we review the cellular and molecular mechanisms underlying the early development of valve progenitors and establishment of normal valve structure and function. Regulatory hierarchies consisting of a variety of signaling pathways, transcription factors, and downstream structural genes are conserved during vertebrate valvulogenesis. Complex intersecting regulatory pathways are required for endocardial cushion formation, valve progenitor cell proliferation, valve cell lineage development, and establishment of extracellular matrix compartments in the stratified valve leaflets. There is increasing evidence that the regulatory mechanisms governing normal valve development also contribute to human valve pathology. In addition, congenital valve malformations are predominant among diseased valves replaced late in life. The understanding of valve developmental mechanisms has important implications in the diagnosis and management of congenital and adult valve disease.

In the heart, autophagy is required for normal cardiac function and also has been implicated in cardiovascular disease. FoxO transcription factors promote autophagy in skeletal muscle and have additional roles in regulation of cell size, proliferation, and metabolism. Here we investigate the role of FoxO transcription factors in regulating autophagy and cell size in cardiomyocytes. In cultured rat neonatal cardiomyocytes, glucose deprivation leads to decreased cell size and induction of autophagy pathway genes LC3, Gabarapl1, and Atg12. Likewise, overexpression of either FoxO1 or FoxO3 reduces cardiomyocyte cell size and induces expression of autophagy pathway genes. Moreover, inhibition of FoxO activity by dominant negative FoxO1 (Δ256) blocks cardiomyocyte cell size reduction upon starvation, suggesting the necessity of FoxO function in cardiomyocyte cell size regulation. Under starvation conditions, endogenous FoxO1 and FoxO3 are localized to the nucleus and bind to promoter sequences of Gabarapl1 and Atg12. In vivo studies show that cellular stress, such as starvation or ischemia/reperfusion in mice, results in induction of autophagy in the heart with concomitant dephosphorylation of FoxO, consistent with increased activity of nuclear FoxO transcription factors. Together these results provide evidence for an important role for FoxO1 and FoxO3 in regulating autophagy and cell size in cardiomyocytes.

Heart valve disease is an important cause of morbidity and mortality worldwide. Little is known about valve disease pathogenesis, but increasing evidence implicates a genetic basis for valve disease, suggesting a developmental origin. Although the cellular and molecular processes involved in early valvulogenesis have been well described, less is known about the regulation of valve extracellular matrix (ECM) organization and valvular interstitial cell (VIC) distribution that characterize the mature valve structure. Histochemistry, immunohistochemistry, and electron microscopy were used to examine ECM organization, VIC distribution, and cell proliferation during late valvulogenesis in chicken and mouse. In mature valves, ECM organization is conserved across species, and developmental studies demonstrate that ECM stratification begins during late embryonic cusp remodeling and continues into postnatal life. Cell proliferation decreases concomitant with ECM stratification and VIC compartmentalization. Explanted, stenotic bicuspid aortic valves (BAVs) from pediatric patients were also examined. The diseased valves exhibited disruption of the highly organized ECM and VIC distribution seen in normal valves. Cusps from diseased valves were thickened with increased and disorganized collagens and proteoglycans, decreased and fragmented elastic fibers, and cellular disarray without calcification or cell proliferation. Taken together, these studies show that normal valve development is characterized by spatiotemporal coordination of ECM organization and VIC compartmentalization and that these developmental processes are disrupted in pediatric patients with diseased BAVs.

Calcific aortic valve disease (CAVD) is increasingly prevalent worldwide with significant morbidity and mortality. Therapeutic options beyond surgical valve replacement are currently limited. In 2011, the National Heart Lung and Blood Institute assembled a working group on aortic stenosis. This group identified CAVD as an actively regulated disease process in need of further study. As a result, the Alliance of Investigators on CAVD was formed to coordinate and promote CAVD research, with the goals of identifying individuals at risk, developing new therapeutic approaches, and improving diagnostic methods. The group is composed of cardiologists, geneticists, imaging specialists, and basic science researchers. This report reviews the current status of CAVD research and treatment strategies with identification of areas in need of additional investigation for optimal management of this patient population.