Role of hypoxia inducible factor HIF-1α in heart valves

The 2016 Albert Lasker Basic Medical Research Award and subsequently the 2019 Nobel Prize in Physiology or Medicine were awarded to William Kaelin, Jr., Sir Peter Ratcliffe, and Gregg Semenza for their work on how cells sense and adapt to hypoxic conditions. Their work showed that the changes in gene expression, cell metabolism, and tissue remodelling that occur in response to low oxygen concentrations are orchestrated by the transcription factor, hypoxia inducible factor-1α (HIF-1α). While the effects mediated by HIF-1α have been widely studied, its role in heart valves has only recently been investigated. These studies have shown that HIF-1α expression is evident in mechanisms that regulate the structure and function of heart valves. These include embryonic development, the regulation of the extracellular matrix, angiogenesis and the initiation of the calcification process. This review provides a background on the role and function of HIF-1α in response to hypoxia and a discussion of the available evidence of its involvement in the regulation of heart valves in health and disease

Candidate plasma biomarkers for predicting ascending aortic aneurysm in bicuspid aortic valve disease.

BACKGROUND: Bicuspid aortic valve (BAV) disease is the most common congenital cardiac abnormality affecting 1-2% of the population and is associated with a significantly increased risk of ascending aortic aneurysm. However, predicting which patients will develop aneurysms remains a challenge. This pilot study aimed to identify candidate plasma biomarkers for monitoring ascending aortic diameter and predicting risk of future aneurysm in BAV patients. METHODS: Plasma samples were collected pre-operatively from BAV patients undergoing aortic valve surgery. Maximum ascending aortic diameter was measured on pre-operative transoesophageal echocardiography. Maximum diameter ≥ 45 mm was classified as aneurysmal. Sequential Window Acquisition of all THeoretical Mass Spectra (SWATH-MS), an advanced mass spectrometry technique, was used to identify and quantify all proteins within the samples. Protein abundance and aortic diameter were correlated using logistic regression. Levene's test was used to identify proteins demonstrating low abundance variability in the aneurysmal patients (consistent expression in disease), and high variability in the non-aneurysmal patients (differential expression between 'at risk' and not 'at risk' patients). RESULTS: Fifteen plasma samples were collected (seven non-aneurysmal and 8 aneurysmal BAV patients). The mean age of the patients was 55.5 years and the majority were female (10/15, 67%). Four proteins (haemoglobin subunits alpha, beta and delta and mannan-binding lectin serine protease) correlated significantly with maximal ascending aortic diameter (p < 0.05, r = 0.5-0.6). Five plasma proteins demonstrated significantly lower variability in the aneurysmal group and may indicate increased risk of aneurysm in non-aneurysmal patients (DNA-dependent protein kinase catalytic subunit, lumican, tetranectin, gelsolin and cartilage acidic protein 1). A further 7 proteins were identified only in the aneurysmal group (matrin-3, glucose-6-phosphate isomerase, coactosin-like protein, peptidyl-prolyl cis-trans isomerase A, golgin subfamily B member 1, myeloperoxidase and 2'-deoxynucleoside 5'-phosphate N-hydrolase 1). CONCLUSIONS: This study is the first to identify candidate plasma biomarkers for predicting aortic diameter and risk of future aneurysm in BAV patients. It provides valuable pilot data and proof of principle that could be used to design a large-scale prospective investigation. Ultimately, a more affordable 'off-the-shelf' follow-on blood assay could then be developed in place of SWATH-MS, for use in the healthcare setting

The role of hypoxia on interstitial mitral valve cells

Mitral valve disease is a multifactorial process. The valve is a complex structure that contains an amalgam of extracellular proteins, cellular components, nerves and blood vessels. It is predicted that some of the central portions of the valve leaflets could exist under hypoxic conditions. Hypoxia could play a role in initiating the structural changes in the valve that lead to dysfunction of the valve. It is known to cause the up-regulation of hypoxia-induced factor (HIF) that can regulate the differentiation of cells, the production of extracellular matrix (ECM) and expression of matrix remodelling enzymes, all of which are characteristic changes seen in one or more forms of the disease. This study aimed to investigate the effect of hypoxia on the basic behaviour and phenotypic profile of mitral valve interstitial cells (MVICs), and their functional response to produce and control the ECM components. The expression of HIF-1α and its role in mediating the effects induced by hypoxia were also investigated, and also the characteristics of blood vessels in the mitral valve leaflet in porcine as well as normal and diseased human valves. MVICs incubated under hypoxia remained viable and continued to grow, while retaining their morphology and phenotype. On the other hand, severe hypoxia resulted in reduced production of the ECM components sulphated glycosaminoglycan (sGAG) and collagen, while it induced matrix metabolism through up-regulating the gene expression of matrix metalloproteases and their tissue inhibitors. Human rheumatic valves had more evident expression of HIF-1α compared with normal or myxomatous degeneration valves. Porcine MVICs (pMVICs) expressed HIF-1α under hypoxia. Stimulating HIF-1α chemically causes a reduction in the amount of GAG produced, similar to the effect observed under severe hypoxia. The study also confirmed the presence of vascular supply to the normal mitral valve leaflets and showed that there was increased vascularisation in rheumatic valves, while there was a loss of vessels in myxomatous degenerative ones. In conclusion, normal mitral valve leaflets are vascular structures of variable pattern. Diseased valves are associated with changes in leaflet vascularity either by neovascularisation in rheumatic disease, or by loss of vascularisation in myxomatous degeneration. Hypoxia affects the production of certain ECM proteins and remodelling enzymes by MVICs. These effects appear to be mediated by the induction of HIF-1α. This study highlights an important process and mechanism in heart valve in health and disease and helps improve the understanding of its complex biology. This could have future implications on the treatment of valve disease and the future applications in heart valve tissue engineering.Open Acces

Knife in the superior mediastinum: Amazing escape

This text describe through images, how a knife is retrieved from the superior mediastinum

Hypoxia-mediated regulation of the secretory properties of mitral valve interstitial cells

The sophisticated function of the mitral valve depends to a large extent on its extracellular matrix (ECM) and specific cellular components. These are tightly regulated by a repertoire of mechanical stimuli and biological pathways. One potentially important stimulus is hypoxia. The purpose of this investigation is to determine the effect of hypoxia on the regulation of mitral valve interstitial cells (MVICs) with respect to the synthesis and secretion of extracellular matrix proteins. Hypoxia resulted in reduced production of total collagen and sulfated glycosaminoglycans (sGAG) in cultured porcine MVICs. Increased gene expression of matrix metalloproteinases-1 and -9 and their tissue inhibitors 1 and 2 was also observed after incubation under hypoxic conditions for up to 24 h. Hypoxia had no effect on MVIC viability, morphology, or phenotype. MVICs expressed hypoxia-inducible factor (HIF)-1α under hypoxia. Stimulating HIF-1α chemically caused a reduction in the amount of sGAG produced, similar to the effect observed under hypoxia. Human rheumatic valves had greater expression of HIF-1α compared with normal or myxomatous degenerated valves. In conclusion, hypoxia affects the production of certain ECM proteins and expression of matrix remodeling enzymes by MVICs. The effects of hypoxia appear to correlate with the induction of HIF-1α. This study highlights a potential role of hypoxia and HIF-1α in regulating the mitral valve, which could be important in health and disease.NEW & NOTEWORTHY This study demonstrates that hypoxia regulates extracellular matrix secretion and the remodeling potential of heart valve interstitial cells. Expression of hypoxia-induced factor-1α plays a role in these effects. These data highlight the potential role of hypoxia as a physiological mediator of the complex function of heart valve cells

Feasibility of a novel, synthetic, self-assembling peptide for suture-line haemostasis in cardiac surgery

Abstract Backgroud To assess the feasibility and efficacy of PuraStat®, a novel haemostatic agent, in achieving suture line haemostasis in a wide range of cardiac surgical procedures and surgery of the thoracic aorta. Methods A prospective, non-randomised study was conducted at our institution. Operative data on fifty consecutive patients undergoing cardiac surgery where PuraStat® was utilised in cases of intraoperative suture line bleeding was prospectively collected. Questionnaires encompassing multiple aspects of the ease of use and efficacy of PuraStat® were completed by ten surgeons (five consultants and five senior registrars) and analysed to gauge the performance of the product. Results No major adverse cardiac events were reported in this cohort. Complications such as atrial fibrillation, pacemaker requirement and pleural effusions were comparable to the national average. Mean blood product use of packed red cells, platelets, fresh-frozen plasma (FFP) and cryoprecipitate was below the national average. There was one incidence of re-exploration, however this was due to pericardial constriction rather than bleeding. Analysis of questionnaire responses revealed that surgeons consistently rated PuraStat® highly (between a score of 7 and 10 in the various subcategories). The transparent nature or PuraStat® allowed unobscured visualisation of suture sites and possessed excellent qualities in terms of adherence to site of application. The application of PuraStat® did not interfere with the use of other haemostatic agents or manipulation of the suture site by the surgeon. Conclusion PuraStat® is an easy-to-use and effective haemostatic agent in a wide range of cardiac and aortic surgical procedures