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

Recent studies have been directed at modulating the heart failure process through inhibition of activated matrix metalloproteinases (MMPs). We hypothesized that a loss of MMP inhibitory control by tissue inhibitor of MMP (TIMP)-1 deficiency alters the course of postinfarction chamber remodeling and induced chronic myocardial infarction (MI) in wild-type (WT) and TIMP-1(-/-) mice. Left ventricular (LV) pressure-volume loops obtained from WT and TIMP-1(-/-) mice demonstrated that LV end-diastolic volume [52 +/- 4 (WT) vs. 71 +/- 6 (TIMP-1(-/-)) microl] and LV end-diastolic pressure [9.0 +/- 1.2 (WT) vs. 12.7 +/- 1.4 (TIMP-1(-/-)) mmHg] were significantly increased in the TIMP-1(-/-) mice 2 wk after MI. LV contractility was reduced to a similar degree in the WT and TIMP-1(-/-) groups after MI, as indicated by a significant fall in the LV end-systolic pressure-volume relationship. Ventricular weight and cross-sectional areas of LV myocytes were significantly increased in TIMP-1(-/-) mice, indicating that the hypertrophic response was more pronounced. The observed significant loss of fibrillar collagen in the TIMP-1(-/-) controls may have been an important contributory factor for the observed LV alterations in the TIMP-1(-/-) mice after MI. These findings demonstrate that TIMP-1 deficiency amplifies adverse LV remodeling after MI in mice and emphasizes the importance of local endogenous control of cardiac MMP activity by TIMP-1.
 ...
PMID:Deficiency of TIMP-1 exacerbates LV remodeling after myocardial infarction in mice. 1238 39

In the failing heart, an imbalance in matrix metalloproteinases (MMPs) and their biological regulators, the tissue inhibitors of MMPs (TIMPs), may result in cardiac dilatation from matrix degradation. We hypothesized that a reduction of myocardial TIMP-3 is associated with adverse matrix remodeling in both human and experimental heart failure. Cardiomyopathic hamsters at age 15 wk (normal), 25 wk (compensated stage), and 35 wk (overt failure) were compared with age-matched normal controls. MMP activity (gelatinase bioassay) was increased in cardiomyopathic hearts (P = 0.03) and peaked during the transition to overt heart failure. TIMP-3 content (immunoblot) was decreased compared with normal controls (74 +/- 5% at 25 wk, 69 +/- 10% at 35 wk; P = 0.001) and its reduction was associated with increased MMP activity (r = -0.6; P = 0.004). TIMP-1 increased progressively (P = 0.001), whereas TIMP-2, TIMP-4, and MMP protein levels were unchanged. Myocardial collagen (hydroxyproline content) increased with time during the progression to end-stage cardiac failure (P < 0.0001). Collagen synthesis ([(14)C]proline uptake) was elevated in cardiomyopathy at 15 and 25 wk (P < 0.05). The collagen cross-linking ratio (insoluble:soluble collagen) was reduced (P = 0.003) as the left ventricle dilated. By confocal microscopy restricted to viable myocardium, collagen content was reduced (P = 0.04) with fragmentation (P < 0.0001) and thinning (P = 0.003) of perimysial collagen fibers. Similarly, patients with end-stage congestive heart failure (n = 7) compared with nonfailing controls (n = 2) had elevated gelatinase MMP activity (P = 0.02) associated with isolated reductions in TIMP-3 (55 +/- 5% of normal; P = 0.003). Reductions of TIMP-3 parallel adverse matrix remodeling in the cardiomyopathic hamster and the failing human heart. TIMP-3 may contribute to the regulation of myocardial remodeling and its reduction may promote a transition from compensated to end-stage congestive heart failure.
 ...
PMID:Matrix remodeling in experimental and human heart failure: a possible regulatory role for TIMP-3. 1238 70

The cardiac extracellular matrix consists of a three-dimensional structural network of interstitial collagens to which other matrix components are attached. The main physiological functions of this network are to retain tissue integrity and cardiac pump function. Collagen deposition is controlled and can be modulated by hormonal factors, growth factors, cytokines, regulatory proteins and/or hemodynamic factors. Increased collagen deposition is a prerequisite to prevent dilatation of the infarcted area. Excessive accumulation of collagen leads to ventricular diastolic and systolic dysfunction and ultimately contributes to heart failure. An appropriate balance of extracellular matrix synthesis and degradation is required for normal morphogenesis and maintenance of tissue architecture. A disbalance in the extracellular matrix turnover either by decreased matrix synthesis and/or increased degradation leads to less than normal extracellular matrix in the myocardium which in its turn may lead to cardiac dilatation or even rupture. Extracellular matrix degrading enzymes expressed after myocardial infarction belong to the families of serine and matrix metalloproteinases (MMPs) and are secreted as latent proenzymes that have to be activated. It is crucial to keep the activity of these enzymes under tight control by either influencing the synthesis, activation or inhibition by tissue inhibitors of MMPs (TIMPs) or alpha2-macroglobulin. First studies using MMP inhibitors in experimental models of myocardial infarction seem to give attenuation of ventricular geometry but not always improvement of cardiac function. A central role in the activation of MMPs plays the plasminogen-plasmin system. Invasion of inflammatory cells and hitherto the rest of the wound healing cascade is inhibited in plasminogen or uPA deficient mice, most likely by the inhibition of MMP activity. Regulating the balance of extracellular matrix remodeling either by extracellular matrix synthesis or degradation might be one of the possible prevention mechanisms for heart failure. But also regeneration of the vascular and cardiomyocyte network might be potential new treatments for people with heart failure.
 ...
PMID:Integration of concepts: cardiac extracellular matrix remodeling after myocardial infarction. 1255 43

Accumulation of oxidized-matrix between the endothelium and myocytes is associated with endocardial endothelial (EE) dysfunction in diabetes and heart failure. High levels of circulating homocysteine (Hcy) have been demonstrated in diabetes mellitus (DM). These high levels of Hcy (hyperhomocysteinemia, HHcy) have a negative correlation with peroxisome proliferator activated receptor (PPAR) expression. Studies have demonstrated that Hcy decreases bioavailability of endothelial nitric oxide (eNO), generates nitrotyrosine, and activates latent matrix metalloproteinase (MMP), instigating EE dysfunction. PPAR ligands ameliorate endothelial dysfunction and DM. In addition Hcy competes with PPAR ligands. The understanding of molecular, cellular, and extracellular mechanisms by which Hcy amplifies DM will have therapeutic ramifications for diabetic cardiomyopathy.
 ...
PMID:Role of nitric oxide in matrix remodeling in diabetes and heart failure. 1265 56

In recent years, rapid growth in the understanding of the pathophysiology of chronic heart failure has allowed for insights into many potential new therapeutic strategies. Yet until now, despite sound biological basis for efficacy and success in early-Phase studies, novel agents have not stood up to the scrutiny of late-Phase clinical trials. Indeed, remarkably negative results have been observed for vasopeptidase inhibitors, endothelin receptor antagonists and agents which block immune activation. However, efficacy data from other novel agents are still awaited, including the selective aldosterone receptor antagonist eplerenone, arginine vasopressin inhibitors, erythropoietin and hydroxy-methyl-glutaryl coenzyme A reductase inhibitors. Other classes of drugs which may enter clinical development include cardiac metabolic agents, matrix metalloproteinase inhibitors and advanced glycation end product antagonists. That the mortality and morbidity of patients with chronic heart failure remain unacceptably high makes the ongoing commitment to exploration of new drug therapies for the condition critical.
 ...
PMID:New developments in the pharmacological treatment of chronic heart failure. 1272 Apr 87

The present study focuses on lesions of the pericardium commonly observed in fast growing broilers. These lesions are examined in the context of electrophysiological and functional changes associated with cardiac performance and patho-physiology in broilers succumbing to acute or chronic heart failure. Typical lesions involving the pericardium in fast growing broiler chickens included: (1) excessive pericardial effusion, (2) locally extensive or focal adhesions between parietal and visceral components of the pericardium, (3) fibrous deposits on visceral pericardium, and (4) thickened pericardium. Echocardiographic evidence indicated that severe pericardial effusion and/or adhesions may have a restrictive effect on heart pump function, where both diastolic and systolic function of the heart may be affected. Electrocardiographic data showed a strong trend indicating that pericardial adhesions may be associated with ventricular arrhythmia and increased risk of sudden death in fast growing broilers. Relatively high levels of matrix metalloproteinase MMP-2 activity have been found in pericardial effusions from affected chickens, suggesting a possible involvement of this enzyme in the aetiology of pericardial lesions. The present results indicate that pericardial lesions may be associated with biochemical, morphological, electrophysiological, and functional changes occurring in the hearts of broilers succumbing to acute or chronic heart failure and ascites.
 ...
PMID:Lesions of the pericardium and their significance in the aetiology of heart failure in broiler chickens. 1272 38

Although sympathoadrenal system has a pivotal role in maintaining homeostasis during stress, protracted activation adversely affects life expectancy in patients with heart failure. Detrimental effects of sympathoadrenal activation over time have been confirmed using transgenic mice overexpressing beta 1-adrenergic receptors, which showed that initial hypercontractility led to cardiac hypertrophy with failure, resulting in premature death. Mechanisms underlying such adverse effects involve multiple biological events including production of oxygen free radicals, cytokines, matrix metalloproteinase, apoptosis, cardiac hypertrophy, and chamber remodeling as well as energy expenditure. Desensitization phenomenon of the beta-adrenergic receptors is one of the predominant features characterizing congestive heart failure. Down-regulation of the receptors, increases in inhibitory guanine-nucleotide(G) protein and G-protein-coupled receptor kinases are responsible for the phenomenon.
 ...
PMID:[Alterations in sympathoadrenal system in congestive heart failure]. 1275 96

Congestive heart failure (CHF) is a leading cause of death in developed countries and its prevalence is increasing throughout the world. Progressive left ventricular dilation and contractile dysfunction cause most cases of CHF. Recent therapies have targeted the neurohumoral system, with few therapies directed toward the actual dilation process; however, emerging data indicate that certain members of the family of metalloenzymes, the matrix metalloproteinases, are not only associated with ventricular dilation, but may actually mediate the dilation process. Because these enzymes are extracellular and are pharmacologic targets, matrix metalloproteinase inhibition is a novel potential therapy for delaying or preventing heart failure.
 ...
PMID:MMP inhibition as a potential therapeutic strategy for CHF. 1293 56

Functional angiotensin II receptors have been documented in cardiac fibroblasts as well as an intracardiac aldosterone system that responds to short- and long-term physiological stimuli. In vitro, angiotensin II increased cardiac fibroblast-mediated collagen synthesis and mRNA levels of collagen type I, type III, pro-alpha1 (I) collagen, pro-alpha1 (III) collagen and fibronectin, and inhibited matrix metalloproteinase I activity. The angiotensin II-stimulated secretion and expression of collagen was completely abolished by AT1 receptor antagonism, but not affected by AT2 receptor antagonism. In vivo, chronic infusion of angiotensin II increased the collagen volume fraction in the ventricles. Angiotensin-converting enzyme (ACE) inhibition and AT1 receptor antagonism, but not AT2 receptor antagonism, reduced collagen deposition in the myocardium in spontaneously hypertensive rats and in rat myocardium following myocardial infarction. During chronic aldosterone infusion in uninephrectomized rats on a high-salt diet, a marked accumulation of interstitial and to a lesser extent perivascular collagen occurs in the heart in both ventricles. The cardiac fibrosis in this aldosterone model is prevented by spironolactone. During the continuous infusion of aldosterone in the rat, the appearance of fibrosis was delayed and started 4 weeks after the beginning of the infusion, which argues against a direct effect of aldosterone. The mechanism of aldosterone-salt-induced cardiac fibrosis possibly involves angiotensin II acting through upregulated AT1 receptors and the cardiac AT1 receptor is the target for aldosterone. An accumulation of collagen in the heart has also been found in patients with adrenal adenomas and during chronic activation of the renin-angiotensin-aldosterone system such as in surgically-induced unilateral renal ischemia, unilateral renal artery banding or renovascular hypertension. Spironolactone prevents aortic collagen accumulation in spontaneously hypertensive rats. In patients with stable chronic heart failure, spironolactone treatment in addition to diuretics and ACE inhibition reduced circulating levels of procollagen type III N-terminal aminopeptide. Also, in the Randomized Aldactone Evaluation Study, spironolactone coadministered with conventional therapy of ACE inhibitors, loop diuretics and digitalis in patients with symptomatic heart failure defined as NYHA classes III-IV, reduced total mortality by 30%.
 ...
PMID:Role of intracardiac renin-angiotensin-aldosterone system in extracellular matrix remodeling. 1457 Dec 85

Remodelling of extracellular matrix by activated matrix metalloproteinases is considered to contribute to progression of ventricle remodelling during chronic heart failure. The aim of this study was to associate two promoter polymorphisms, -790T/G and -735C/T, in the gene for matrix metalloproteinase (MMP)-2 (gelatinase A) with chronic heart failure (CHF). For this purpose, 164 patients (124 men, 40 women, median age 56 years, range 21-91 years) with CHF (functional class NYHA II-IV, ejection fraction median 25%, cardiothoracic index more than 50%) were compared with 196 control subjects without clinical signs of cardiovascular disease (131 men and 65 women, median age 56 years, range 27-84 years) in -790T/G and -735C/T MMP-2 genotype distributions and allelic frequencies. The genotypes were determined by polymerase chain reaction (PCR) with restriction analyses. A significant increase of the T allele of the -790T/G MMP-2 polymorphism (p = 0.04), as well as of the C allele of the -735C/T MMP-2 gene polymorphism, in patients with CHF was proven (p = 0.04). The heterozygote CT of the -735C/T MMP-2 polymorphism exhibits a 7 times higher odds ratio (OR) for the CHF patients with lower levels of total cholesterol (less than 5 mmol/l), especially for non-hypertensive CHF men (OR = 7.28, 95% confidence interval 1.51-35.03, p = 0.006). Determination of MMP polymorphisms in the regulatory area of the gene could help us to comprehend individual susceptibility of patients with CHF to MMP inhibitors based on known risks of MMP genotypes.
 ...
PMID:Two MMP-2 promoter polymorphisms (-790T/G and -735C/T) in chronic heart failure. 1458 Jan 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>