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)

The process of cardiac remodeling in response to cardiac injury and/or persistent elevations in wall stress generally relates to the progressive changes that occur in ventricular chamber dimensions and the various components of the myocardium, in particular the cardiomyocytes and the extracellular matrix. Volume overload, pressure overload or myocardial injury produces a sustained abnormal elevation in myocardial wall stress which initiates cardiac remodeling that frequently results in ventricular decompensation and heart failure. Regardless of the inciting cause, there appear to be three distinct phases to this process. In the initial phase, fibrillar collagen is partially degraded secondary to increased matrix metalloproteinase (MMP) activity. Following this, there is a chronic compensatory phase during which MMP activity and collagen concentration return to normal while cardiomyocyte size continues to progressively increase. The final phase is attained once the compensatory hypertrophic mechanisms are exhausted and is characterized by elevated MMP activity, marked ventricular dilatation and prominent fibrosis. Details of this progressive, dynamic remodeling process and its effect on ventricular function during chronic volume overload, chronic pressure overload and following myocardial infarction will be the focus of this article.
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PMID:The dynamic interaction between matrix metalloproteinase activity and adverse myocardial remodeling. 1473 66

Collagen turnover is a slow process on a biologic timescale with a t$\\frac12$ of 20-27 days that is mediated primarily by the matrix metalloproteinases (MMPs). Low collagen metabolism is not due to an intrinsically low Km of MMPs, but rather due to a highly regulated system of activity. Despite the stability of collagen and MMPs, the articles in this special addition illustrate the importance of this enzyme family in the disease process leading to congestive heart failure. Like MMPs, drug development is a tightly regulated process, and the successful turnover of MMP inhibitors into a marketed drug has also been a slow process on a pharmaceutical timescale. Since the discovery of the archetypal MMP (type 1 collagenase) over four decades ago by Gross and Lapierre, most major pharmaceutical companies have had MMP inhibitor programs for a variety of indications. Despite decades of research, tens of thousands of compounds synthesized and screened, and billions of dollars spent in clinical studies-Periostat (doxycycline hyclate, CollaGenex Pharmaceuticals Inc.) is the only collagenase inhibitor to be successfully launched. In addition, Periostat's approval is currently limited to periodontal disease. This article focuses on some of the lessons to be learned from the failure of so many MMP inhibitors across so many indications, and what potential exists for MMP inhibitors as a drug class, especially for heart failure.
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PMID:Matrix metalloproteinase inhibitor development and the remodeling of drug discovery. 1473 69

Cardiac hypertrophy can lead to heart failure (HF), but it is unpredictable which hypertrophied myocardium will progress to HF. We surmised that apart from hypertrophy-related genes, failure-related genes are expressed before the onset of failure, permitting molecular prediction of HF. Hearts from hypertensive homozygous renin-overexpressing (Ren-2) rats that had progressed to early HF were compared by microarray analysis to Ren-2 rats that had remained compensated. To identify which HF-related genes preceded failure, cardiac biopsy specimens were taken during compensated hypertrophy and we then monitored whether the rat progressed to HF or remained compensated. Among 48 genes overexpressed in failing hearts, we focused on thrombospondin-2 (TSP2). TSP2 was selectively overexpressed only in biopsy specimens from rats that later progressed to HF. Moreover, expression of TSP2 was increased in human hypertrophied hearts with decreased (0.19+/-0.01) versus normal ejection fraction (0.11+/-0.03 [arbitrary units]; P<0.05). Angiotensin II induced fatal cardiac rupture in 70% of TSP2 knockout mice, with cardiac failure in the surviving mice; this was not seen in wild-type mice. In TSP2 knockout mice, angiotensin II increased matrix metalloproteinase (MMP)-2 and MMP-9 activity by 120% and 390% compared with wild-type mice (P<0.05). In conclusion, we identify TSP2 as a crucial regulator of the integrity of the cardiac matrix that is necessary for the myocardium to cope with increased loading and that may function by its regulation of MMP activity. This suggests that expression of TSP2 marks an early-stage molecular program that is activated uniquely in hypertrophied hearts that are prone to fail.
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PMID:Thrombospondin-2 is essential for myocardial matrix integrity: increased expression identifies failure-prone cardiac hypertrophy. 1534 66

We examined the hypothesis that oxidants generated nitroso derivatives, activated latent matrix metalloproteinase (MMP), and induced proteinase-activated receptor 1 (PAR-1), leading to disconnection between the endothelium and myocytes. Administration of cardiospecific tissue inhibitor of metalloproteinase-4 (TIMP-4/CIMP) ameliorated the oxidative-proteolytic stress and endothelial-myocyte uncoupling in chronic heart failure (CHF) in mice. Aortic-vena cava fistula (AVF) was created in 30 male mice (C57BL/6J) and studied at 0-, 2-, and 8-wk AVF. To reverse cardiac remodeling, as measured by MMP activation, purified CIMP was administered by an osmotic minipump subcutaneously after 8-wk AVF, and groups of mice (n = 6 mice/group) were examined after 12 and 16 wk. Levels of PAR-1 in the left ventricle (LV) were increased at 2 and 8 wk (compared with 0 wk of no CIMP treatment) but were normal at 12 and 16 wk after CIMP treatment, as measured by Western blot analysis. Similar results were obtained for LV levels of nitrotyrosine, MMP-2 and -9 activities, and TIMP-1 and -3. However, the levels of TIMP-4, endothelial cell density, and responses of cardiac rings to acetylcholine and bradykinin were attenuated at 2 and 8 wk and normalized after CIMP administration in AVF mice. CIMP induced nitric oxide in microvascular endocardial endothelial cells. The results suggest that nitro generation activated MMP and PAR-1, leading to endothelial-myocyte uncoupling. CIMP treatment normalized PAR-1 expression and ameliorated endothelial-myocyte uncoupling by decreasing oxidant-mediated proteolytic stress in CHF.
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PMID:Protease-activated receptor and endothelial-myocyte uncoupling in chronic heart failure. 1568 8

There are fundamental differences between males and females with regard to susceptibility to heart disease. Although numerous animal models of heart failure have demonstrated that premenopausal females are afforded cardioprotection and, therefore, fare better in the face of cardiac disease than their male counterparts, many questions as to how this occurs still exist. Recently, we showed that 1) increased mast cell density is associated with adverse ventricular remodeling and 2) chemically induced mast cell degranulation using compound 48/80 resulted in remarkable changes in matrix metalloproteinase (MMP) activity, cardiac collagen structure, and cardiac diastolic function in normal male rats. With the known gender differences in cardiac disease in mind, we sought to examine the effects of chemically induced cardiac mast cell degranulation in isolated, blood-perfused hearts of intact female rats, ovariectomized female rats, and ovariectomized female rats treated with 17beta-estradiol. In response to mast cell degranulation, no significant differences in cardiac function, MMP-2 activity, or collagen volume fraction were observed between intact female rats and ovariectomized female rats treated with estrogen. In the ovariectomized female group, a significant rightward shift in the left ventricular pressure-volume relation, accompanied by a marked 133% increase in active MMP-2 values over that in the intact female group, was noted after treatment with compound 48/80 (P < or = 0.05), along with a significant reduction in collagen volume fraction below control (0.46 +/- 0.23 vs. 0.73 +/- 0.13%, P < or = 0.05). These findings indicate that estrogen's cardioprotective role can be partially mediated by its effects on cardiac mast cells, MMPs, and the extracellular matrix.
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PMID:Modulation of cardiac mast cell-mediated extracellular matrix degradation by estrogen. 1572 8

Cardiac fibroblasts play a central role in the maintenance of extracellular matrix in the normal heart and as mediators of inflammatory and fibrotic myocardial remodeling in the injured and failing heart. In this review, we evaluate the cardiac fibroblast as a therapeutic target in heart disease. Unique features of cardiac fibroblast cell biology are discussed in relation to normal and pathophysiological cardiac function. The contribution of cardiac fibrosis as an independent risk factor in the outcome of heart failure is considered. Candidate drug therapies that derive benefit from actions on cardiac fibroblasts are summarized, including inhibitors of angiotensin-aldosterone systems, endothelin receptor antagonists, statins, anticytokine therapies, matrix metalloproteinase inhibitors, and novel antifibrotic/anti-inflammatory agents. These findings point the way to future challenges in cardiac fibroblast biology and pharmacotherapy.
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PMID:The cardiac fibroblast: therapeutic target in myocardial remodeling and failure. 1582 92

From experimental and clinical studies it is known that matrix conservation and degradation by matrix metalloproteinases (MMPs) plays a major role in plaque progression and destabilization with related onset of acute vascular events such as acute coronary syndromes or cerebrovascular accidents. Recently, extracellular MMPs inducer (EMMPRIN) has been reported to induce and activate the expression of MMPs in myocardium and plays an important role in the ventricular remodeling in human heart failure. Similarly to heart failure myocardium, EMMPRIN may be expressed in human atheroma and play a role in the extracellular matrix (ECM) remodeling and atherogenic cell differentiation. This study was designed to investigate the possible biological role of EMMPRIN in human atheroma. Immunohistochemical analysis for MMPs and EMMPRIN was performed on human carotid endarterectomy specimens and control aortas. EMMPRIN showed significant immunoreactivity in human atherosclerotic carotid lesions, and was colocalized with macrophage/monocyte infiltrates in atherosclerotic intima, plaque itself and vascular smooth muscle cells (VSMCs). Zymography and Western blot analysis revealed EMMPRIN expression in the carotid atheromas, but not in the control aortas. Human bone marrow monocytes, which were cultured with atherogenic proinflammatory cytokine stimulation revealed increased EMMPRIN and MMPs expressions. ECM remodeling is under the control of induction and inhibition of matrix degrading protease and the novel MMP inducer, EMMPRIN may play a role in influx and differentiation of monocytes and destabilizing atheroma.
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PMID:Upstream regulation of matrix metalloproteinase by EMMPRIN; extracellular matrix metalloproteinase inducer in advanced atherosclerotic plaque. 1582 73

Although multiple advancements have been made in the treatment of heart failure (HF), mortality rates remain alarmingly high. The accepted arsenal of therapeutics includes a diuretic, digitalis, a beta-blocking agent and an inhibitor of the renin-angiotensin-aldosterone system. Despite the employment of a vast array of agents, nearly 300,000 patients in the US die annually with HF as a primary or contributory cause of death. Additional molecular targets are being evaluated in preclinical and clinical settings including vasopeptidase inhibitors, endothelin-1 receptor antagonists, arginine vasopressin antagonists, selective aldosterone blockers, TNF-alpha blockers and matrix metalloproteinase inhibitors. Although these approaches hold promise as viable therapeutics, a thorough evaluation of clinical benefit from these agents requires additional trials. Future disease-modifying approaches will also undoubtedly include cell transplantation and gene therapy. It is likely that notable advances in HF treatment will come from agents that attenuate myocardial remodelling. Indeed, maintenance or improvement of cardiac structure can attenuate HF development and improve mortality.
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PMID:Emerging therapies for heart failure. 1598 48

The induction of T helper (TH) lymphocytes by distinct TH ligands results in a differentiation to TH1/TH2 subsets based on their unique pattern of cytokine secretion and effector functions. We hypothesized that the relative proportion of TH1/TH2 directly relates to cardiac fibroblast (CF) function and thereby cardiac extracellular matrix (ECM) composition and cardiac diastolic function in the absence of injury or altered wall stress. We compared the effect of selective TH1 with TH2 inducers on cardiac gene expression, ECM composition, and diastolic function in C57BL/J mice. Twelve weeks after immune modulation, the left ventricular stiffness (beta) was significantly increased in the TH1 group and decreased in the TH2 group (P < 0.01). The TH2 group also demonstrated significantly increased end-diastolic and end-systolic volumes (P < 0.01). Cardiac gene expression patterns for pro-matrix metalloproteinase (MMP)-9 and -13 were increased by greater than fivefold in the TH2 group and significantly decreased in the TH1 group (P < 0.05). The total cardiac collagen and cross-linked collagen were significantly increased in the TH1 group and decreased in the TH2 group (P < 0.01). Coculturing lymphocytes harvested from the treated mice with naive primary CF demonstrated a direct control of the lymphocytes on CF pro-collagen, pro-MMP gene expression, and MMP activity. These results suggest that the TH phenotype differentially affects diastolic function through modulating CF pro-collagen and pro-MMP gene expression, MMP activity, and cardiac collagen cross-linking, resulting in altered ECM composition. Thus modulation of TH lymphocyte function could promote adaptive remodeling in heart failure and postmyocardial infarction.
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PMID:A role for T lymphocytes in mediating cardiac diastolic function. 1601 17

This article provides information and a commentary on landmark trials presented at the American College of Cardiology meeting held in March 2005, relevant to the pathophysiology, prevention and treatment of heart failure. All reports should be considered as preliminary data, as analyses may change in the final publication. CARE-HF showed that Cardiac Re-synchronisation Therapy, administered in addition to expert pharmacological management, reduced all cause mortality and CV hospitalisation in patients with moderate or severe heart failure and cardiac dyssynchrony. The Women's Health Study showed no benefit of vitamin E supplementation or aspirin in the primary prevention of CV disease. The TNT study showed that reducing LDL cholesterol to levels lower than currently recommended, produced a 22% reduction in the incidence of major cardiovascular events. In COMPASS, an implantable device that continuously monitors intra-cardiac pressures was shown to be safe and to improve care in patients with chronic heart failure. Tezosentan failed to show benefit in patients with acute heart failure in the VERITAS study. The CANPAP study failed to show a benefit of continuous positive airway pressure on mortality and heart transplantation in heart failure patients with central sleep apnoea. EECP therapy improved exercise capacity but had no effect on peak VO2 in heart failure patients in the PEECH study. In the PREMIER study the matrix metalloproteinase inhibitor PG-116800 failed to prevent LV remodelling following myocardial infarction.
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PMID:Clinical trials update from the American College of Cardiology meeting: CARE-HF and the remission of heart failure, Women's Health Study, TNT, COMPASS-HF, VERITAS, CANPAP, PEECH and PREMIER. 1608 44


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