Biomedical subjects

K Jane Grande-Allen

Publications and source records attributed to K Jane Grande-Allen.

14 recordsLinked to original sources

PubMed2026

Cardiovascular Disease and Androgens: Clinical Trends, Potential Mechanisms, and Considerations for Engineering Solutions.

This review summarizes the current understanding of androgen physiology, relationships between androgens and cardiovascular (CV) diseases, and novel engineering approaches to study the effect of androgens on CV system. Testosterone (T), the primary sex hormone in biological males and a potent sex hormone in females, is the androgen of focus for this review. In the cardiovascular system, T signaling is seen through varying genomic and non-genomic mechanisms, which are further detailed in this review. Varying androgen levels in aging adults can significantly impact CVD outcomes, particularly for males. We also consider the implication of exogenous T treatment and androgen deprivation treatments on CVD. Furthermore, androgen-related trends in different CVD processes such as cardiac hypertrophy, congestive heart failure, atherosclerosis, calcific aortic valve disease, and aneurysms are explored. To that end, we present opportunities for novel tissue engineered approaches to discovering mechanisms and potential therapeutic pathways for androgen-related CV conditions.

Androgen deprivation↗

PubMed2006

Effects of static and cyclic loading in regulating extracellular matrix synthesis by cardiovascular cells.

Extracellular matrix (ECM) provides several structural and functional characteristics to tissues including cell support, mechanical integrity and biological signaling. In cardiovascular tissues, cells produce various ECM components such as collagen, elastin, proteoglycans, matrix metalloproteinases, growth factors and signaling molecules. The cardiovascular cells (cardiac fibroblasts, cardiomyocytes, endothelial cells, and vascular smooth muscle cells) sense the changes in mechanical strains applied to them, through cell-surface receptors such as integrins and ion channels, and adjust their expression and synthesis of ECM molecules in order to adapt their environment to these changes. ECM changes due to altered mechanics are evident in numerous pathological situations including hypertension, cardiac hypertrophy, myocardial infarction, myxomatous heart valve disease, and atherosclerosis. In hypertrophic conditions, for example, increased mechanical loading is involved with enhanced collagen synthesis, whereas in myxomatous and atherosclerotic conditions reduced mechanical strains are accompanied by an accumulation of proteoglycans. Therefore, investigating the effects of various strain patterns on cardiovascular cells can enhance our understanding of ECM regulation and pathologies. This review focuses on the in vitro modulation of the synthesis of various ECM molecules through static or cyclic stretching of cardiovascular cells.

Animals↗

PubMed2006

Review. Hyaluronan: a powerful tissue engineering tool.

Hyaluronan (HA) is a versatile molecular tool with considerable potential for tissue engineering applications. The inclusion of HA has created biocompatible biomaterials and engineered tissues that can be crosslinked or degraded controllably and can facilitate angiogenesis, osteointegration, and cell phenotype preservation. The utility of HA in tissue engineering has been broadened further by the recently identified HA synthases, which can be manipulated to stimulate the endogenous production of HA by cells seeded within biomaterial scaffolds. Overall, HA shows great promise in the development of engineered tissues and biomaterials for a variety of biomedical needs including orthopedic, cardiovascular, pharmacologic, and oncologic applications.

Animals↗

PubMed2006

Phenotypic characterization of isolated valvular interstitial cell subpopulations.

BACKGROUND AND AIM OF THE STUDY: Valvular interstitial cells (VICs) demonstrate a heterogeneous range of phenotypes such as variable expression of smooth muscle alpha-actin (SMalphaA). Myofibroblast-like VICs, expressing high levels of SMalphaA, are thought to be involved in myxomatous degeneration of mitral valves. The inability to isolate specific cell types has restricted potential investigations of valvular disease mechanisms. Thus, investigations were conducted into methods of isolating different cell subpopulations from primary VICs as a preparatory step for cell type-specific evaluations of heart valve disease. METHODS: VICs were isolated from porcine valves, cultured to 80% confluency, and subdivided using differential detachment or adhesion. The subdivided cells were further cultured and analyzed phenotypically by immunocytochemistry and flow cytometry to characterize SMalphaA expression. Roundness and growth rates were also analyzed. RESULTS: VICs that were relatively sensitive to trypsinization expressed low and heterogeneous levels of SMalphaA (15-35%), whereas more-adherent VICs expressed higher and homogeneous levels (>98%) suggestive of a myofibroblast-like phenotype. The more-adherent cells also had lower growth potential and were less round than less-adhesive VICs. Separated cell subtypes were found to maintain their phenotype through several cell passages. CONCLUSION: VICs are a mixed population of cells, many of which express high levels of SMalphaA. Differential detachment and adhesion can effectively separate cell subpopulations from primary cultures of VICs. The ability to study valve cell subpopulations has substantial implications for future analyses of valvular biology, disease, and tissue engineering.

Actins↗

PubMed2005

Apparently normal mitral valves in patients with heart failure demonstrate biochemical and structural derangements: an extracellular matrix and echocardiographic study.

OBJECTIVES: This study assessed apparently normal mitral valves from patients with congestive heart failure (CHF) using biochemical and echocardiographic measures of extracellular matrix (ECM) and anatomy. BACKGROUND: Mitral regurgitation (MR) is frequently found in patients with CHF. This MR is considered purely functional, yet animal studies suggest that altered left ventricular (LV) function leads to increased cellularity and fibrosis of the mitral valve. Therefore, we hypothesized that patients with CHF might have partly organic MR, via dysfunctional valvular remodeling. METHODS: Mitral valves from transplant recipient hearts of patients with CHF (23 dilated, 14 ischemic) were analyzed for deoxyribonucleic acid (DNA), collagen, glycosaminoglycan (GAG), and water concentrations and compared with autopsy controls. Cardiac dimensions and functional parameters (measured from recent echocardiograms) were compared with biochemical parameters using a repeated measures generalized linear model. RESULTS: The mitral valves in CHF had up to 78% more DNA (p <0.03), 59% more GAGs (p <0.02), and 15% more collagen (p <0.007), but 7% less water (p <0.05) than normal. The absence of anterior leaflet redundancy was associated with these deranged biochemical measures (p <0.03). Associations were found between leaflet thickness and DNA concentration (+, p=0.003), annular diameter and chordal collagen (+, p=0.03), and water concentration and both left atrial diameter (-, p=0.008) and LV collagen concentration (-, p=0.04). CONCLUSIONS: Mitral valves in CHF are biochemically different from normal, with ECM changes that are influenced by the altered cardiac dimensions. This remodeling suggests that MR in patients with CHF may not be purely functional, and that these valves are not "normal."

Adult↗

PubMed2005

Mitral valve stiffening in end-stage heart failure: evidence of an organic contribution to functional mitral regurgitation.

OBJECTIVE: Mitral regurgitation is a complication for many patients with congestive heart failure. Although this regurgitation is considered purely functional, we hypothesize that the alterations in cardiac geometry and function induce dysfunctional remodeling of the mitral valve, which can be demonstrated by alterations in the material behavior of the leaflets and chordae. METHODS: Mitral leaflets and chordae from 23 valves from transplant recipient hearts (11 with dilated and 12 with ischemic cardiomyopathy) and from 21 normal valves (from autopsy) were mechanically tested. RESULTS: Radially oriented anterior mitral leaflet strips from failing hearts were 61% stiffer and 23% less viscous on average than those from autopsy control hearts. The mean stiffness of circumferentially oriented anterior leaflet strips was 50% higher than that of control hearts. Leaflet extensibility was reduced 35% overall. Likewise, the failing heart chordae were an average of 16% stiffer (all P < or = .05). CONCLUSIONS: Mitral valves in congestive heart failure have significantly altered mechanics that suggest that the tissue is permanently distended and fibrotic and might be unable to stretch sufficiently to cover the valve orifice. These material changes in the valve tissues accompany the biochemical alterations in extracellular matrix composition that we have previously reported. Our finding of leaflet and chordal remodeling suggests that mitral regurgitation in patients experiencing heart failure might not be purely functional and that these mitral valves should not be considered normal. Moreover, there are implications for strategies of mitral valve surgery or percutaneous approaches in this patient population.

Chordae Tendineae↗

PubMed2004

Glycosaminoglycans and proteoglycans in normal mitral valve leaflets and chordae: association with regions of tensile and compressive loading.

This study was designed to identify the specific proteoglycans and glycosaminoglycans (GAGs) in the leaflets and chordae of the mitral valve and to interpret their presence in relation to the tensile and compressive loads borne by these tissues. Leaflets and chordae from normal human mitral valves (n = 31, obtained at autopsy) were weighed and selected portions digested using proteinase K, hyaluronidase, and chondroitinases. After fluorescent derivatization, fluorophore-assisted carbohydrate electrophoresis was used to separate and quantify the derivatized saccharides specific for each GAG type. In addition, the lengths of the chondroitin/dermatan sulfate chains were determined. Proteoglycans were identified by western blotting. The regions of the valve that experience tension, such as the chordae and the central portion of the anterior leaflet, contained less water, less hyaluronan, and mainly iduronate and 4-sulfated N-acetylgalactosamine with chain lengths of 50-70 disaccharides. These GAGs are likely associated with the small proteoglycans decorin and biglycan, which were found in abundance in the tensile regions. The valve regions that experience compression, such as the posterior leaflet and the free edge of the anterior leaflet, contained significantly more water, hyaluronan, and glucuronate and 6-sulfated N-acetylgalactosamine with chain lengths of 80-90 disaccharides. These GAGs are likely components of water-binding versican aggregates, which were abundant in the compressive loading regions. The relative amounts and distributions of these GAGs are therefore consistent with the tensile and compressive loads that these tissues bear. Finally, the concentrations of total GAGs and many different chondroitin/dermatan sulfate subclasses were significantly decreased with advancing age.

Acetylgalactosamine↗

PubMed2004

Cell viability mapping within long-term heart valve organ cultures.

BACKGROUND AND AIM OF THE STUDY: Organ cultures maintain cells within their native microstructural environment, and thus offer greater potential for studying tissue disease and remodeling than do monolayer cell cultures or pathological examinations of diseased tissue. To validate an in-vitro heart valve organ culture model, cell viability was examined within valve tissues over sustained culture periods. METHODS: Following culture of blocks of valve tissue for 1 to 49 days, cross-sections were cut with a vibratome, stained with a LIVE/DEAD kit, and imaged with confocal microscopy to quantify the number of live and dead cells present. RESULTS: In numerous organ cultures, valvular interstitial cells were found to be viable beyond 30 days. Live cells were abundant in the central region of the valve, but more sparse in the deepest central regions. Dead cells were found mainly on the surface of both fresh tissues and tissues after prolonged culture, with few dead cells occurring centrally. CONCLUSION: This is the first reported mapping of cell viability within heart valve organ cultures, and results suggest that extended organ culture of valve leaflets is indeed possible. The derived viability staining methods have wide applicability for organ cultures of other tissues as well as tissue-engineered matrices.

Animals↗

PubMed2003

Glycosaminoglycan profiles of myxomatous mitral leaflets and chordae parallel the severity of mechanical alterations.

OBJECTIVES: This biochemical study compared the extracellular matrix of normal mitral valves and myxomatous mitral valves with either unileaflet prolapse (ULP) or bileaflet prolapse (BLP). BACKGROUND: Myxomatous mitral valves are weaker and more extensible than normal valves, and myxomatous chordae are more mechanically compromised than leaflets. Despite histological evidence that glycosaminoglycans (GAGs) accumulate in myxomatous valves, previous biochemical analyses have not adequately examined the different GAG classes. METHODS: Leaflets and chordae from myxomatous valves (n = 41 ULP, 31 BLP) and normal valves (n = 27) were dried, dissolved, and assayed for deoxyribonucleic acid, collagen, and total GAGs. Specific GAG classes were analyzed with selective enzyme digestions and fluorophore-assisted carbohydrate electrophoresis. RESULTS: Biochemical changes were more pronounced in chordae than in leaflets. Myxomatous leaflets and chordae had 3% to 9% more water content and 30% to 150% higher GAG concentrations than normal. Collagen concentration was slightly elevated in the myxomatous valves. Chordae from ULP had 62% more GAGs than those from BLP, primarily from elevated levels of hyaluronan and chondroitin-6-sulfate. CONCLUSIONS: The GAG classes elevated in the myxomatous chordae are associated with matrix microstructure and elastic fiber deficiencies and may influence the hydration-related "floppy" nature of these tissues. These abnormalities may be related to the reported mechanical weakness of myxomatous chordae. The biochemical differences between ULP and BLP confirm previous mechanical and echocardiographic distinctions.

Adult↗

PubMed2003

Loss of chondroitin 6-sulfate and hyaluronan from failed porcine bioprosthetic valves.

Explanted porcine bioprosthetic valves have a thinned spongiosa, partially because of an overall loss of glycosaminoglycans (GAGs). We measured the concentrations of specific GAG classes in explanted bioprosthetic valves (n = 14, implanted 12.0 +/- 4.7 years) compared with glutaraldehyde-fixed porcine controls. After extraction with NaOH, GAGs were analyzed using either a hexuronic acid assay or fluorophore-assisted carbohydrate electrophoresis to quantify the individual GAG classes. The total GAG concentration in explants was 198 +/- 95 pmol/mg wet weight-93% less than freshly fixed controls. Explants also contained altered proportions of the different GAG classes relative to controls. The proportions of hyaluronan and chondroitin/dermatan-6-sulfate were reduced from 39 to 7% and 34 to 18% of total GAGs, respectively. The predominant explant GAG class was chondroitin/dermatan-4-sulfate (proportion elevated from 14 to 70%). This GAG is commonly found in the collagen-associated proteoglycan decorin, which is likely well crosslinked by glutaraldehyde. Chondroitin-6-sulfate is commonly found in the water- and hyaluronan-binding proteoglycan versican, which is likely poorly crosslinked. The loss of versican and its associated water-binding capacity is consistent with the thinned spongiosa. The resultant compromise of hydration, compressive resistance, and viscoelasticity may be responsible for the deterioration of the bioprosthesis in vivo.

Animals↗

PubMed2003

3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro.

Recent findings have implicated the 5-hydroxytryptamine 2B (5-HT2B) serotonin receptor in mediating the heart valve fibroplasia [valvular heart disease (VHD)] and primary pulmonary hypertension observed in patients taking the now-banned appetite suppressant fenfluramine (Pondimin, Redux). Via large-scale, random screening of a portion of the receptorome, we have discovered that the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") and its N-demethylated metabolite 3,4-methylenedioxyamphetamine (MDA) each preferentially bind to and activate human recombinant 5-HT2B receptors. We also demonstrate that MDMA and MDA, like fenfluramine and its N-deethylated metabolite norfenfluramine, elicit prolonged mitogenic responses in human valvular interstitial cells via activation of 5-HT2B receptors. We also report that pergolide and dihydroergotamine, two drugs recently demonstrated to induce VHD in humans, potently activate 5-HT2B receptors, thus validating this assay system for its ability to predict medications that might induce VHD. Our discovery that MDMA and a major metabolite, MDA, induce prolonged mitogenic responses in vitro similar to those induced by fenfluramine and norfenfluramine in vivo (i.e., valvular interstitial cell fibroplasia) predict that long-term MDMA use could lead to the development of fenfluramine-like VHD. Because of the widespread abuse of MDMA, these findings have major public health implications. These findings also underscore the necessity of screening current and future drugs at h5-HT2B receptors for agonist actions before their use in humans.

3,4-Methylenedioxyamphetamine↗

PubMed2002

Core protein dependence of epimerization of glucuronosyl residues in galactosaminoglycans.

Chondroitin sulfate and dermatan sulfate proteoglycans are distinguished by differences in their proportion of d-glucuronosyl and l-iduronosyl residues, the latter being formed by chondroitin-glucuronate 5-epimerase during or after glycosaminoglycan chain polymerization. To investigate the influence of the core protein on the extent of epimerization, we expressed chimeric proteins in 293 HEK cells constructed from intact or modified Met(1)-Gln(153) of decorin (DCN), which normally has a single dermatan sulfate chain at Ser(34), in combination with intact or modified Leu(241)-Ser(353) of CSF-1, which has a chondroitin sulfate attachment site at Ser(309). Transfected DCN(M1-Q153), like full-length DCN, contained approximately 20% l-iduronate. Conversely, transfected CSF-1(L241-S353), attached C-terminally on the DCN prepropeptide, contained almost exclusively d-glucuronate. Transfected intact chimeric DCN(M1-Q153)-CSF-1(L241-S353), with two glycosaminoglycan chains, also contained almost exclusively d-glucuronate in chains at both sites, as did chimeras in which alanine was substituted for serine at either of the glycosaminoglycan attachment sites. Nevertheless, undersulfated intact chimeric proteoglycan was an effective substrate for epimerization of glucuronate to iduronate residues when incubated with microsomal proteins and 3'-phosphoadenylylphosphosulfate. C-terminal truncation constructs were prepared from the full-length chimera with an alanine substitution at the CSF-1 glycosaminoglycan attachment site. Transfected truncations retaining the alanine-blocked site contained chains with essentially only glucuronate, whereas those further truncated by 49 or more amino acids and missing the modified attachment site contained chains with approximately 15% iduronate. This 49-amino acid region contains a 7-amino acid motif that appears to be conserved in several chondroitin sulfate proteoglycans. The results are consistent with a model in which the core protein, possibly via this motif, is responsible for routing to subcellular compartments with or without sufficient access to chondroitin-glucuronate 5-epimerase for the addition of chains with or without iduronate residues, respectively.

Amino Acid Sequence↗

PubMed2002

Failure mechanics of mitral valve chordae tendineae.

BACKGROUND AND AIM OF THE STUDY: Rupture of chordae tendineae is the main cause of mitral valve insufficiency, and often requires corrective surgery. The precise mechanisms of chordal rupture, however, are unknown. METHODS: Failure mechanics were measured in porcine mitral valve chordae (37 anterior marginal, 40 anterior basal, 35 posterior marginal, and 38 posterior basal). Full-length chordae were weighed, measured, and stretched to failure in an Instron tensile testing machine. The ruptured ends were characterized under a dissecting microscope. RESULTS: Marginal chordae had 68% thinner cross-sectional areas and failed at 68% less load and 28% less strain than basal chordae. Chordae from the posterior leaflet were 35% thinner and failed at 43% less load and 22% less strain than anterior leaflet chordae. Failure strength was lowest for posterior marginal chordae. Chordae most frequently tore just below the leaflet insertion, in what was often their narrowest section. CONCLUSION: Overall, the marginal chordae and posterior leaflet chordae were thinner and required less strain and load to fail than basal chordae and anterior leaflet chordae, respectively. These results support previous reports of decreased extensibility in marginal chordae. The high incidence of ruptures in the posterior marginal chordae of diseased mitral valves may be due to an inherent weakness in these chordae.

Animals↗

PubMedDate not supplied

Age-related structural changes in cardiac valves: implications for tissue-engineered repairs.

Elderly patients would receive substantial benefits from tissue-engineered heart valves (TEHVs), but most TEHV research has not focused on applications for this growing patient population. There will be numerous technical challenges involved in developing TEHVs for the elderly, such as designing tissues to accommodate higher blood pressure and larger aortic roots that may be friable or calcified. Concomitant medications may also affect the biology of the TEHV. Due to the predominantly senescent behavior of cells from older persons, a nonautologous cell source may be required to develop the TEHV. Decellularized heart valve allografts from elderly donors may not be durable enough to use as a scaffold, but several polymer and natural biodegradable scaffolds may provide promising alternatives. The selection of cell sources, scaffolds, and mechanical/biologic conditioning will need to be precisely targeted to meet the diverse physiological, medical, and surgical requirements of elderly patients.

Aging↗