Circulating exosome microRNA associated with heart failure secondary to myxomatous mitral valve disease in a naturally occurring canine model

Abstract

Myxomatous mitral valve disease (MMVD) is functionally and histologically identical to mitral valve prolapse (MVP) in humans. Currently, there are no medical treatments that can delay the progression of this valvular disease or associated cardiac remodelling. Therefore, there is a need to understand the molecular pathology associated with MMVD and MVP better, and thus identify potential therapeutic targets. Circulating exosomes contain small RNA, including miRNA, which reflect cell physiology and pathology. This study explored the association between circulating exosomal miRNA (ex-miRNA) content and MMVD, heart failure due to MMVD (MMVD-CHF) and ageing, which is strongly associated with MMVD. Ex-miRNA was isolated from old normal/healthy dogs (n = 6), young normal dogs (n = 7), dogs with MMVD (n = 7) and dogs with MMVD-CHF (n = 7). Separately, total plasma miRNA was isolated from normal dogs (n = 8), dogs with MMVD (n = 8) and dogs with MMVD-CHF (n = 11). Using reverse transcription quantitative polymerase chain reaction, exosomal miR-181c (p = 0.003) and miR-495 (p = 0.0001) significantly increased in dogs with MMVD-CHF compared to the other three groups. Exosomal miR-9 (p = 0.002) increased in dogs with MMVD and MMVD-CHF compared to age-matched (old) normal dogs. Exosomal miR-599 (p = 0.002) decreased in dogs with MMVD compared to old normal dogs. In total plasma, 58 miRNA were deemed significantly different (p < 0.04) between normal dogs, dogs with MMVD and dogs with MMVD-CHF. However, in contrast to ex-miRNA, none of the miRNA in total plasma remained statistically significant if the false discovery rate was <15%. Changes in ex-miRNA are observed in dogs as they age (miR-9, miR-495 and miR-599), develop MMVD (miR-9 and miR-599) and progress from MMVD to CHF (miR-181c and miR-495). Ex-miRNA expression-level changes appear to be more specific to disease states than total plasma miRNA.RESPONSIBLE EDITOR Elena Aikawa, Harvard Medical School, USA

ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs

“…Dysregulation of the extracellular matrix appears to be central to these changes. Valvular interstitial cells, possibly with post‐transcriptional regulation from microsatellite ribonucleic acids, acquire properties of activated myofibroblasts, and activated myofibroblasts increase proteolytic enzymes, including matrix metalloproteinases, which degrade collagen and elastin faster than they can be produced by unactivated valvular interstitial cells …”

“…Systemic or local metabolic, neurohormonal, or inflammatory mediators (eg, endogenous catecholamines, inflammatory cytokines) also may influence progression of the valve lesion or the subsequent myocardial remodeling and ventricular dysfunction that accompany long‐standing, hemodynamically important valvular regurgitation. The interactions of these factors, as well as the impact of changes in mitral valve annular geometry and mechanical stress on the pathogenesis and progression of MMVD, are incompletely understood …”

“…Valvular interstitial cells, possibly with posttranscriptional regulation from microsatellite ribonucleic acids, acquire properties of activated myofibroblasts, and activated myofibroblasts increase proteolytic enzymes, including matrix metalloproteinases, which degrade collagen and elastin faster than they can be produced by unactivated valvular interstitial cells. [13][14][15] Endothelial cell changes and subendothelial thickening also occur, [16][17][18] but these changes do not appear to put dogs with MMVD at increased risk for either arterial thromboembolism or infective endocarditis. Mitral valve prolapse is a common finding in dogs with myxomatous valve degeneration and represents a prominent echocardiographic feature of MMVD in some breeds.…”

“…The interactions of these factors, as well as the impact of changes in mitral valve annular geometry and mechanical stress on the pathogenesis and progression of MMVD, are incompletely understood. [11][12][13]24 The prevalence of MMVD increases markedly with age in small breed dogs, with up to 85% showing evidence of the valve lesion by 13 years of age. 25 The presence of the pathologic lesion of MMVD in an individual does not necessarily identify a dog that will develop clinically relevant valve regurgitation or signs of heart failure.…”

Exosomes, the message transporters in vascular calcification

“…Exosomes are also suggested to deliver intracellular contents such as proteins and RNAs, functioning as message transporters to promote VC . Emerging evidences revealed that exosomal miRs were significant in diagnosis, prognosis or even therapeutic target selection in patients with cancer and heart failure . Selective enrichments of miRs in exosomes were due to the alterations in parental or donor cells, from which exosomes are secreted or originated .…”