**Author details**

Erik Fung1,2 and Masanori Aikawa3

1 Section of Cardiology, Heart & Vascular Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA

2 Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire, USA

3 Center for Excellence in Vascular Biology, Cardiovascular Division, Brigham and Wom‐ en's Hospital and Harvard Medical School, Boston, Massachusetts, USA

### **References**

**5. Clinical implications**

114 Calcific Aortic Valve Disease

al., 2011).

USA

**Author details**

Erik Fung1,2 and Masanori Aikawa3

Lebanon, New Hampshire, USA

Calcific aortic valve disease in individuals with severe aortic stenosis can progress quickly after presentation with symptoms, usually portending limited short-term survival (Turina et al., 1987). Clinical trials on medical therapy including statins have found little benefit and utility in forestalling disease progression, with no demonstrated impact on survival. Since the evidence suggests that inflammatory cells, particularly macrophages, play a crucial role in calcification, anti-inflammatory therapies may prevent development of arterial and valvular calcification. We and others have demonstrated that lipid lowering reduces inflammation (Aikawa et al., 1998; Aikawa et al., 2001; Chu et al., 2012; Libby and Aikawa, 2002; Libby et al., 2011). However, clinical trials (e.g. SALTIRE, SEAS, etc.) have failed to demonstrate that lipid lowering attenuates development of aortic stenosis. Preclinical findings suggest that macro‐ phage accumulation precedes calcific changes in arteries and valves while lesions with advanced calcification are often unassociated with macrophages (Aikawa et al., 2007a; Aikawa et al., 2007b). This may suggest that anti-inflammatory therapies need to be initiated early (Aikawa and Otto, 2012), and thus clinical trials involving patients who had been diagnosed with aortic stenosis due to advanced calcification did not show substantial benefits of lipid lowering therapy. To establish more effective therapies, it is crucial to better understand the complex mechanisms for aortic valve calcification. To identify individuals with subclinical aortic valve calcification and those with high probability or propensity of developing severe aortic valvular stenosis, methods for early detection of calcific changes (e.g., molecular imaging, biomarkers) need to be developed. National Institutes of Health of the United States of America has formed the Working Group of Calcific Aortic Valve Disease to facilitate basic research on this devastating global health threat and initiated federal funding (Rajamannan et

1 Section of Cardiology, Heart & Vascular Center, Dartmouth-Hitchcock Medical Center,

2 Geisel School of Medicine at Dartmouth, Dartmouth College, Hanover, New Hampshire,

3 Center for Excellence in Vascular Biology, Cardiovascular Division, Brigham and Wom‐

en's Hospital and Harvard Medical School, Boston, Massachusetts, USA


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**Chapter 5**

**Role of MicroRNAs in Cardiovascular Calcification**

With a growing older population, cardiovascular diseases are becoming an increasing economic and social burden in Western societies. Cardiovascular calcification is a major characteristic of chronic inflammatory disorders — such as chronic renal disease (CRD), type 2 diabetes (T2D), atherosclerosis and calcific aortic valve disease (CAVD) — that associate with significant morbidity and mortality. Cardiovascular calcification also associates with osteoporosis in humans and animal models [1, 2] — the so-called "calcifica‐ tion paradox" [3]. The concept that similar pathways control both bone remodeling and vascular calcification is currently widely accepted, but the precise mechanisms of calcifica‐ tion remain largely unknown. Osteogenic transition of vascular smooth muscle cells (SMCs), valvular interstitial cells (VIC) or stem cells is induced by bone morphogenetic proteins, inflammation, oxidative stress, or high phosphate levels, and leads to a unique molecular pattern marked by osteogenic transcription factors [4]. Loss of mineralization inhibitors, such as matrix γ-carboxyglutamic acid Gla protein (MGP) and fetuin-A also contribute to cardiovascular calcification. The physiological balance between induction and inhibition of calcification becomes dysregulated in CRD, T2D, atherosclerosis, and CAVD. Consequently, calcification may occur at several sites in the cardiovascular system,

The central role of miRNAs as fine-tune regulators in the cardiovascular system and bone biology has gained acceptance and has raised the possibility for novel therapeutic targets. Circulating miRNAs have been proposed as biomarkers for a wide range of cardiovascu‐ lar diseases, but knowledge of miRNA biology in cardiovascular calcification is very

and reproduction in any medium, provided the original work is properly cited.

© 2013 Goettsch and Aikawa; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

including the intima and media of vessels and cardiac valves [3].

Claudia Goettsch and Elena Aikawa

http://dx.doi.org/10.5772/55326

**1. Introduction**

limited.

Additional information is available at the end of the chapter

