The microRNA profile of aortic stenosis

Abstract

Background Valvular heart disease (VHD), especially aortic stenosis (AS), is an important cause of morbidity and mortality, but no medical therapies currently exist for most forms of VHD. The only treatment available for severe AS is valve replacement, a procedure that often carries significant risks. There is little information available regarding how the disease burden due to VHD has changed over time

Calcific aortic valve disease (CAVD) is the process underlying AS. Early CAVD leads to thickening and/or calcification of the aortic valve without causing a significant pressure gradient– this is diagnosed as aortic sclerosis on cardiac imaging. Despite this lack of haemodynamic effect, aortic sclerosis has previously been associated with an increased risk of some cardiovascular events, but not stroke. The aims of this thesis were, firstly, to investigate the changing epidemiology of VHD by assessing VHD mortality rates, secondly, to more accurately define the risks associated with aortic sclerosis, and finally, to examine the molecular biology of CAVD, in an attempt to find new therapeutic avenues to explore in the future. Methods Cause of death information for New Zealand and the United States of America was used to assess trends in mortality rates due to VHD. A systematic review and meta-analysis of high-quality prospective observational studies was performed to accurately delineate the epidemiology and risks of aortic sclerosis. Micro-ribonucleic acid (microRNA) profiling was used to examine the molecular biology of CAVD. MicroRNAs are short sequences of nucleotides that are slow to degrade even after significant periods of time post-mortem. Post-mortem aortic valve specimens were therefore compared to diseased aortic valve tissue obtained at the time of aortic valve replacement. Circulating microRNA profiles were compared between participants with and without AS. Results Mortality rates due to VHD increased throughout the 1990’s until stabilising in the first part of the 21st century, with a similar trend seen in New Zealand and the United States. Most of the mortality was due to aortic valve disease. Population projections suggest that, unless mortality rates decrease in the future, there will be a dramatic increase in numbers dying of VHD over the next few decades, due to an ageing population. The prevalence of aortic sclerosis increases approximately linearly with the age of the population studied. It progresses slowly, and uncommonly leads to clinical AS. Despite this, on meta-analysis, aortic sclerosis was associated with an increased risk of all examined cardiovascular events, including stroke. MicroRNA tissue profiling showed clear differences between diseased and control aortic valves, with suppression of miR-122-5p and increased expression of miR-21-5p. Circulating microRNA profiles, while showing differences between those with and without AS, did not have favourable properties for use as a biomarker. Conclusions VHD, and in particular AS, is projected to be a major cause of death and disabililty over the foreseeable future. A number of new avenues of investigation have been raised by the microRNA studies undertaken, with the aim being to develop new medical therapies for AS.