Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mast cells have been implicated as important in tissue remodeling and fibrosis. We investigated the effect of mechanical ventricular unloading upon myocardial fibrosis and cardiac mast cell density in patients undergoing left ventricular assist device (LVAD) implantation. Paired myocardial tissue samples were obtained from 30 patients with end-stage cardiomyopathy at the time of LVAD implantation and at the time of removal and were compared with samples taken from donor hearts. Tissue sections were stained and quantitated for mast cells and myocardial fibrosis. Mast cell density (tryptase positive cells) in cardiomyopathy was higher than that in donor hearts (33.5 +/- 3.6 SEM cells/10 fields vs.15.2 +/- 2.0 SEM cells/10 fields respectively, p = 0.04) and was lower than LVAD supported hearts (33.5 +/- 3.6 SEM cells/10 fields vs. 49.8 +/- 5.7 SEM cells/10 fields respectively, p = 0.01). Mast cells are primarily localized in areas of increased interstitial fibrosis adjacent to myocardial cells and not vessels. There was statistically significant correlation between mast cells and interstitial collagen (p = 0.03) in patients before LVAD implantation that did not persist after mechanical support (p = 0.18). These results suggest that mechanical support with left ventricular assist devices induces an increase in mast cell number in the myocardium and an associated decrease in myocardial fibrosis. We believe these data demonstrate a dual role for cardiac mast cells in the increase in fibrosis in heart failure and the decrease after LVAD and its associated cardiac improvement.
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PMID:Quantitative changes in mast cell populations after left ventricular assist device implantation. 1596 59

The chronic elevation in ventricular wall stress secondary to ventricular volume or pressure overload leads to structural remodeling of the muscular, vascular and extracellular matrix components of the myocardium. While initially a compensatory response, the progressive hypertrophy and ventricular dilatation induced by this condition ultimately have a detrimental effect on ventricular function, resulting in heart failure. Fibrillar collagen provides the skeletal framework which interconnects the cardiomyocytes, thereby maintaining ventricular shape and size and contributing to tissue stiffness. Accordingly, these myocardial collagen fibers must be disrupted for ventricular dilatation, sphericalization and wall thinning to occur. The presence of an abundant, latent matrix metalloproteinase (MMP) population which coexists with myocardial fibrillar collagen has been documented. Thus, the potential for collagen degradation to exceed synthesis exists should there be significant activation of this latent MMP system. Mast cells are known to store and release a variety of biologically active mediators including TNF-alpha and proteases such as tryptase and chymase, which can induce MMP activation. Increased cardiac mast cell density has been implicated in the pathophysiology of human end-stage cardiomyopathy and experimental myocardial infarction, hypertension and chronic volume overload secondary to mitral regurgitation and aorto-caval fistula. The potential role of cardiac mast cells in activating MMPs, which then results in fibrillar collagen degradation and adverse myocardial remodeling secondary to chronic volume and pressure overload will be the subject of this review.
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PMID:Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overload. 1637 24

Cardiac mast cells proliferate in cardiovascular diseases. In myocardial ischemia, mast cell mediators contribute to coronary vasoconstriction, arrhythmias, leukocyte recruitment, and tissue injury and repair. Arrhythmic dysfunction, coronary vasoconstriction, and contractile failure are also characteristic of cardiac anaphylaxis. In coronary atherosclerosis, mast cell mediators facilitate cholesterol accumulation and plaque destabilization. In cardiac failure, mast cell chymase causes myocyte apoptosis and fibroblast proliferation, leading to ventricular dysfunction. Chymase and tryptase also contribute to fibrosis in cardiomyopathies and myocarditis. In addition, mast cell tumor necrosis factor-alpha promotes myocardial remodeling. Cardiac remodeling and hypertrophy in end-stage hypertension are also induced by mast cell mediators and proteases. We recently discovered that cardiac mast cells contain and release renin, which initiates local angiotensin formation. Angiotensin causes coronary vasoconstriction, arrhythmias, fibrosis, apoptosis, and endothelin release, all demonstrated mechanisms of mast-cell-associated cardiac disease. The effects of angiotensin are further amplified by the release of norepinephrine from cardiac sympathetic nerves. Our discovery of renin in cardiac mast cells and its release in pathophysiological conditions uncovers an important new pathway in the development of mast-cell-associated heart diseases. Several steps in this novel pathway may constitute future therapeutic targets.
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PMID:Renin: at the heart of the mast cell. 1749 56

Chymase has been known as a local angiotensin II-generating enzyme in the cardiovascular system in dogs, monkeys, hamsters, and humans; however, recently it was reported that chymase also has various other functions. Therefore, we decided to examine whether the inhibition of chymase improves disease conditions associated with the pathophysiology of dilated cardiomyopathy in rats and its possible mechanism of action as rat chymase is unable to produce angiotensin II. We examined the effect of TY-51469, a novel chymase inhibitor (0.1 mg/kg/day [group CYI-0.1, n = 15] and 1 mg/kg/day [group CYI-1, n = 15]), in myosin-immunized postmyocarditis rats. Another group of myosin-immunized rats was treated with vehicle (group V, n = 15). Age-matched normal rats without immunization (group N, n = 10) were also included in the study. After 4 weeks of treatment, we evaluated cardiac function; area of fibrosis; fibrogenesis; levels of transforming growth factor (TGF)-beta1 and collagen III; hypertrophy and its marker, atrial natriuretic peptide (ANP); and mast cell activity. Survival rate and myocardial functions improved dose-dependently with chymase inhibitor treatment after myosin immunization. A reduction in the percent area of myocardial fibrosis, fibrogenesis, myocardial hypertrophy, and mast cell activity along with a reduction in TGF-beta1, collagen III, and ANP levels in the myocardium were noted in postmyocarditis rats that received chymase inhibitor treatment. The treatment also decreased myocardial aldosterone synthase levels in those animals. Inhibition of chymase reduces the pathogenesis of postmyocarditis dilated cardiomyopathy and progression to heart failure by preventing the pathological remodeling and residual inflammation in rats.
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PMID:Chymase inhibition reduces the progression to heart failure after autoimmune myocarditis in rats. 1789 29

The mast cell is a multipotent inflammatory cell that has been shown to participate in the pathogenesis of a variety of diseases, such as immediate hypersensitivity reactions, arthritis, atherosclerosis, and heart failure. Upon stimulation, mast cells exocytose cytoplasmic secretory granules into their extracellular microenvironment. These granules are modified lysosomes containing preformed mediators such as histamine, neutral proteases, cytokines, and growth factors embedded in a heparin proteoglycan matrix. When exposed to the extracellular fluid, the soluble components of the granules (e.g., histamine and cytokines) diffuse away, whereas the heparin proteoglycans and the mast cell-specific neutral proteases (e.g., chymase) remain tightly bound to each other, forming proteolytically active intra- and extracellular granule remnants. This unit describes a method to isolate rat serosa mast cell granule remnants in experiments aimed at determining the role of mast cell activation and degranulation in disease.
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PMID:Isolation of mast cell granules. 1822 84

Heart failure (HF) is a chronic syndrome in which pathological cardiac remodeling is an integral part of the disease and mast cell (MC) degranulation-derived mediators have been suggested to play a role in its progression. Protein kinase C (PKC) signaling is a key event in the signal transduction pathway of MC degranulation. We recently found that inhibition of epsilonPKC slows down the progression of hypertension-induced HF in salt-sensitive Dahl rats fed a high-salt diet. We therefore determined whether epsilonPKC inhibition affects MC degranulation in this model. Six week-old male Dahl rats were fed with a high-salt diet to induce systemic hypertension, which resulted in concentric left ventricular hypertrophy at the age of 11 weeks, followed by myocardial dilatation and HF at the age of 17 weeks. We administered epsilonV1-2, an epsilonPKC-selective inhibitor peptide (3 mg/kg/day), deltaV1-1, a deltaPKC-selective inhibitor peptide (3 mg/kg/day), TAT (negative control; at equimolar concentration; 1.6 mg/kg/day) or olmesartan (angiotensin receptor blocker [ARB] as a positive control; 3 mg/kg/day) between 11 weeks and 17 weeks. Treatment with epsilonV1-2 attenuated cardiac MC degranulation without affecting MC density, myocardial fibrosis, microvessel patency, vascular thickening and cardiac inflammation in comparison to TAT- or deltaV1-1-treatment. Treatment with ARB also attenuated MC degranulation and cardiac remodeling, but to a lesser extent when compared to epsilonV1-2. Finally, epsilonV1-2 treatment inhibited MC degranulation in isolated peritoneal MCs. Together, our data suggest that epsilonPKC inhibition attenuates pathological remodeling in hypertension-induced HF, at least in part, by preventing cardiac MC degranulation.
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PMID:Mast cells and epsilonPKC: a role in cardiac remodeling in hypertension-induced heart failure. 1880 78

Galectin-3 (Gal-3) is secreted by activated macrophages. In hypertension, Gal-3 is a marker for hypertrophic hearts prone to develop heart failure. Gal-3 infused in pericardial sac leads to cardiac inflammation, remodeling, and dysfunction. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a naturally occurring tetrapeptide, prevents and reverses inflammation and collagen deposition in the heart in hypertension and heart failure postmyocardial infarction. In the present study, we hypothesize that Ac-SDKP prevents Gal-3-induced cardiac inflammation, remodeling, and dysfunction, and these effects are mediated by the transforming growth factor (TGF)-beta/Smad3 signaling pathway. Adult male rats were divided into four groups and received the following intrapericardial infusion for 4 wk: 1) vehicle (saline, n = 8); 2) Ac-SDKP (800 microg x kg(-1) x day(-1), n = 8); 3) Gal-3 (12 microg/day, n = 7); and 4) Ac-SDKP + Gal-3 (n = 7). Left ventricular ejection fraction, cardiac output, and transmitral velocity were measured by echocardiography; inflammatory cell infiltration, cardiomyocyte hypertrophy, and collagen deposition in the heart by histological and immunohistochemical staining; and TGF-beta expression and Smad3 phosphorylation by Western blot. We found that, in the left ventricle, Gal-3 1) enhanced macrophage and mast cell infiltration, increased cardiac interstitial and perivascular fibrosis, and causes cardiac hypertrophy; 2) increased TGF-beta expression and Smad3 phosphorylation; and 3) decreased negative change in pressure over time response to isoproterenol challenge, ratio of early left ventricular filling phase to atrial contraction phase, and left ventricular ejection fraction. Ac-SDKP partially or completely prevented these effects. We conclude that Ac-SDKP prevents Gal-3-induced cardiac inflammation, fibrosis, hypertrophy, and dysfunction, possibly via inhibition of the TGF-beta/Smad3 signaling pathway.
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PMID:N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin. 1909 14

Dexamethasone (Dex), for prevention of chronic lung disease in preterm infants, showed potential negative long-term effects. Studies regarding long-term cardiovascular effects are lacking. We investigated possible histopathological myocardial changes after neonatal Dex in the young and adult rat heart. Rats were treated with Dex on d 1, 2, and 3 (0.5, 0.3, and 0.1 mg/kg) of life. Control-pups received saline. At 4, 8, and 50 wk after birth rats were killed and anatomic data collected. Heart tissue was stained with hematoxylin and eosin, Cadherin-periodic acid schiff, and sirius red for cardiomyocyte morphometry and collagen determination. Presence of macrophages and mast cells was analyzed. Cardiomyocyte length of the Dex-treated rats was increased in all three age groups, whereas ventricular weight was reduced. Cardiomyocyte volumes were increased at 50 wk indicating cellular hypertrophy. Collagen content gradually increased with age and was 62% higher in Dex rats at 50 wk. Macrophage focus score and mast cell count were also higher. Neonatal Dex affects normal heart growth resulting in cellular hypertrophy and increased collagen deposition in the adult rat heart. Because previous studies in rats showed premature death, suggesting cardiac failure, cardiovascular follow-up of preterm infants treated with glucocorticoids should be considered.
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PMID:Histopathological changes of the heart after neonatal dexamethasone treatment: studies in 4-, 8-, and 50-week-old rats. 1928 45

In the recent past, hyperhomocysteinemia (HHCY) has been linked to chronic heart failure. Folate and vitamin B12 deficiencies are the common causes of HHCY. The impact of these vitamins on cardiac function and morphology has scarcely been investigated. The aim of this study was to conduct an analysis of the cardiac effect of folate and vitamin B12 deficiency in vivo. Two groups of rats, a control (Co, n = 10) and a vitamin-deficient group (VitDef, n = 10), were fed for 12 weeks with a folate and vitamin B12-free diet or an equicaloric control diet. Plasma and tissue concentrations of HCY, S-adenosyl-homocysteine (SAH), S-adenosyl-methionine (SAM), and brain natriuretic peptide (BNP) were measured. Moreover, echocardiographic and histomorphometric analyses were performed. VitDef animals developed a significant HHCY (Co vs VitDef: 6.8 +/- 2.7 vs 61.1 +/- 12.8 micromol/l, P < 0.001). Fractional shortening, left ventricular dimension at end-diastole and end-systole, posterior wall thickness, perivascular collagen, mast cell number, and BNP tissue levels were comparable in VitDef and Co animals. Interstitial collagen (Co vs VitDef: 6.8 +/- 3.0 vs 4.5 +/- 2.1%, P < 0.05), plasma BNP (Co vs VitDef: 180 +/- 80 vs 70 +/- 60 ng/l, P < 0.05), and tissue HCY (Co vs VitDef: 0.13 +/- 0.07 vs 0.07 +/- 0.04 micromol/g protein, P < 0.05) were lower in VitDef animals. Folate and vitamin B12 deficiency do not affect cardiac function and morphology.
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PMID:The cardiac effects of prolonged vitamin B12 and folate deficiency in rats. 1939 44

Atrial fibrillation (AF) is a common arrhythmia that increases the risk of stroke and heart failure. Here, we have shown that mast cells, key mediators of allergic and immune responses, are critically involved in AF pathogenesis in stressed mouse hearts. Pressure overload induced mast cell infiltration and fibrosis in the atrium and enhanced AF susceptibility following atrial burst stimulation. Both atrial fibrosis and AF inducibility were attenuated by stabilization of mast cells with cromolyn and by BM reconstitution from mast cell-deficient WBB6F1-KitW/W-v mice. When cocultured with cardiac myocytes or fibroblasts, BM-derived mouse mast cells increased platelet-derived growth factor A (PDGF-A) synthesis and promoted cell proliferation and collagen expression in cardiac fibroblasts. These changes were abolished by treatment with a neutralizing antibody specific for PDGF alpha-receptor (PDGFR-alpha). Consistent with these data, upregulation of atrial Pdgfa expression in pressure-overloaded hearts was suppressed by BM reconstitution from WBB6F1-KitW/W-v mice. Furthermore, injection of the neutralizing PDGFR-alpha-specific antibody attenuated atrial fibrosis and AF inducibility in pressure-overloaded hearts, whereas administration of homodimer of PDGF-A (PDGF-AA) promoted atrial fibrosis and enhanced AF susceptibility in normal hearts. Our results suggest a crucial role for mast cells in AF and highlight a potential application of controlling the mast cell/PDGF-A axis to achieve upstream prevention of AF in stressed hearts.
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PMID:Cardiac mast cells cause atrial fibrillation through PDGF-A-mediated fibrosis in pressure-overloaded mouse hearts. 2003 2


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