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 aim of our study was to analyze the long-term survival and cardiac function in 194 consecutive, thrombolysis-ineligible acute myocardial infarction (AMI) patients receiving 48-hour intravenous magnesium sulfate (22 g) - 96 patients, compared with placebo - 98 patients. After a mean 4.8-year follow-up, all-cause mortality and cardiac mortality were significantly lower in the magnesium compared to the placebo group [(18 vs. 33 patients, p < 0.01) and (12 vs. 30 patients, p < 0.001), respectively]. Rest radionuclide ventriculography tests for left-ventricular ejection fraction (LVEF) were assessed in surviving patients up to completion of follow-up. Magnesium-treated patients had a significantly higher LVEF (0.51 +/- 0.10 vs. 0.44 +/- 0.14, p < 0.05) and a lower incidence of heart failure compared to placebo-treated patients (12 vs. 3 patients, p = 0.02). Beneficial effects of intravenous magnesium therapy in thrombolysis-ineligible AMI patients appeared to last for at least 4.8 years, concomitant with preserved LVEF, suggesting a favorable role for acute magnesium treatment in these patients.
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PMID:Long-term outcome of intravenous magnesium therapy in thrombolysis-ineligible acute myocardial infarction patients. 1284 47

Phosphorylation of the skeletal muscle (RyR1) and cardiac muscle (RyR2) ryanodine receptors has been reported to modulate channel activity. Abnormally high phosphorylation levels (hyperphosphorylation) at Ser-2843 in RyR1 and Ser-2809 in RyR2 and dissociation of FK506-binding proteins from the receptors have been implicated as one of the causes of altered calcium homeostasis observed during human heart failure. Using site-directed mutagenesis, we prepared recombinant RyR1 and RyR2 mutant receptors mimicking constitutively phosphorylated and dephosphorylated channels carrying a Ser/Asp (RyR1-S2843D and RyR2-S2809D) and Ser/Ala (RyR1-S2843A and RyR2-S2809A) substitution, respectively. Following transient expression in human embryonic kidney 293 cells, the effects of Ca2+, Mg2+, and ATP on channel function were determined using single channel and [3H]ryanodine binding measurements. In both assays, neither the skeletal nor cardiac mutants showed significant differences compared with wild type. Similarly essentially identical caffeine responses were observed in Ca2+ imaging measurements. Co-immunoprecipitation and Western blot analysis showed comparable binding of FK506-binding proteins to wild type and mutant receptors. Finally metabolic labeling experiments showed that the cardiac ryanodine receptor was phosphorylated at additional sites. Taken together, the results did not support the view that phosphorylation of a single site (RyR1-Ser-2843 and RyR2-Ser-2809) substantially changes RyR1 and RyR2 channel function.
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PMID:Characterization of recombinant skeletal muscle (Ser-2843) and cardiac muscle (Ser-2809) ryanodine receptor phosphorylation mutants. 1453 76

Hypomagnesemia is common in hospitalized patients, especially in elderly patients with coronary artery disease (CAD) and/or those with chronic heart failure. Hypomagnesemia is associated with increased all cause mortality and mortality from CAD. Magnesium supplementation improves myocardial metabolism, inhibits calcium accumulation and myocardial cell death; it improves vascular tone, peripheral vascular resistance, afterload and cardiac output, reduces cardiac arrhythmias and improves lipid metabolism. Magnesium also reduces vulnerability to oxygen-derived free radicals, improves endothelial function and inhibits platelet function, including platelet aggregation and adhesion, which potentially confers upon magnesium physiologic and natural effects similar to adenosine-diphosphate inhibitors such as clopidogrel. However, data regarding the use of magnesium in patients with acute myocardial infarction (AMI) are conflicting. Although some previous relatively small randomized clinical trials demonstrated a remarkable reduction in mortality when intravenous magnesium was administered to relatively high risk AMI patients, two recently published large-scale randomized clinical trials (the Fourth International Study of Infarct Survival [ISIS 4] and Magnesium in Coronaries [MAGIC]) were unable to demonstrate any advantage of intravenous magnesium over placebo. Nevertheless, the theoretical benefits of magnesium supplementation as a cardio-protective agent in CAD patients, promising results from animal and human studies, its relatively low-cost and ease of handling requiring no special expertise, together with its excellent tolerability, gives magnesium a place in treating CAD patients, especially in those at high risk, such as CAD patients with heart failure, the elderly and hospitalized patients with hypomagnesemia. Furthermore, magnesium therapy is indicated in life-threatening ventricular arrhythmias such as torsades de pointes and intractable ventricular tachycardia.
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PMID:Does magnesium have a role in the treatment of patients with coronary artery disease? 1472 75

A novel technique, using energy dispersive X-ray microanalysis (EXAtm), for noninvasive intracellular (i.c.) measurement of magnesium [Mg2+]i has now been accomplished and proven to be a valuable tool in multiple aspects of normal as well as pathological magnesium metabolism. Since only 1% of total body Mg2+ is found in the intravascular space, serum levels of Mg2+ give little information about a patient's overall Mg2+ status with respect to this essential mineral. Using the EXAtm analysis it has shown been determined that Mg2+ levels are significantly reduced in many physiological states which may lead to serious pathological conditions [15]. Description of the methodology and examples of data as well as potential applications will focus on intracellular (i.c.) [Mg2+]i determinations obtained in cells from subjects with cardiovascular disease (CVD) syndromes related to Mg2+ deficiency. Examples of the application of EXAtm evaluation include examination of intracellular magnesium and other minerals in a wide spectrum of conditions which include cardiovascular conditions, arrhythmias, heart failure, myocardial infarction, and bypass surgery. Standardization of control values were performed at NASA.
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PMID:Development of cellular magnesium nano-analysis in treatment of clinical magnesium deficiency. 1563 23

Cardiac myocyte loss, regardless of insult, can trigger compensatory myocardial remodeling leading to heart failure. Identifying mediators of cardiac myocyte survival may advance clinical efforts toward myocardial preservation. Angiopoietin-1 limits ischemia-induced cardiac injury. This benefit is ascribed to angiogenesis because the receptor, tie2, is largely endothelial-specific. We propose that direct, non-tie2 interactions of angiopoietin-1 on cardiac myocytes contribute to this cardioprotection. We found that mouse C2C12 skeletal myocytes lack tie2, yet dose-dependently adhered to angiopoietin-1 and angiopoietin-2 similarly to laminin, fibronectin, vitronectin, and more than to collagen-I, -III, and -IV. Adhesion was divalent cation-mediated (Mn2+, Ca2+, not Mg2+), blocked with EDTA/EGTA, RGD-based peptides, and select integrin subunit antibodies. Similar findings were obtained with human skeletal myocytes (HSMs) and freshly isolated rat neonatal cardiac myocytes (NCMs). Furthermore, angiopoietin-1 conferred significant survival advantage exceeding that of most cell matrices, which was not fully explained by differences in cell adhesion. Angiopoietin-1 promoted survival of serum-starved C2C12, HSM, and NCM (MTT, trypan blue) and prevented taxol-induced apoptosis (caspase-3). Immobilized and soluble angiopoietin-1 phosphorylated Akt(S473) and MAPK(p42/44), (not FAK(Y397)) in C2C12 more than in endothelial cells and more than did angiopoietin-2 or cell matrices. EDTA, RGD-based peptides, and some integrin antibodies blocked these responses. Angiopoietin-1 activated HSM and NCM Akt(S473) and MAPK(p42/44) survival pathways. We propose that this novel function contributes to developmental and cardioprotective actions of angiopoietin-1 presently attributed to vascular effects alone. Angiopoietin-1 may prove therapeutically valuable in cardiac remodeling by supporting myocyte viability and preserving pump function. The full text of this article is available online at http://circres.ahajournals.org.
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PMID:Angiopoietin-1 promotes cardiac and skeletal myocyte survival through integrins. 1569 86

Cardiac excitation-contraction coupling occurs by a calcium ion-mediated mechanism in which the signal of action potential is converted into Ca2+ influx into the cardiomyocytes through the sarcolemmal L-type calcium channels. This is followed by Ca2+-induced release of additional Ca2+ ions from the lumen of the sarcoplasmic reticulum into the cytosol via type 2 ryanodine receptors (RyR2). RyR2 channels form large complexes with additional regulatory proteins, including FKBP12.6 and calsequestrin 2 (CASQ2). Catecholamines, released into the body fluids during emotional or physical stress, activate Ca2+-induced Ca2+ release by protein kinase A-mediated phosphorylation of RyR2. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an insidious, early-onset and highly malignant, inherited disorder characterized by effort-induced ventricular arrhythmias in the absence of structural alterations of the heart. At least some cases of sudden, unexplained death in young individuals may be ascribed to CPVT. Mutations of the RyR2 gene cause autosomal dominant CPVT, while mutations of the CASQ2 gene may cause an autosomal recessive or dominant form of CPVT. The steps of the molecular pathogenesis of CPVT are not entirely clear, but inappropriate "leakiness" of RyR2 channels is thought to play a role; the underlying mechanisms may involve an increase in the basal activity of the RyR2 channel, alterations in its phosphorylation status, a defective interaction of RyR2 with other molecules or ions, such as FKBP12.6, CASQ2, or Mg2+, or its abnormal activation by extra- or intraluminal Ca2+ ions. Beta-adrenergic antagonists have proven to be of value in prevention of arrhythmias in CPVT patients, but occasional treatment failures call for alternative measures. There is great interest at present for the development of novel antiarrhythmic drugs for CPVT, as the same approaches may be applied for treatment of more common forms of life-threatening arrhythmias, such as those arising during ischemia and heart failure.
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PMID:Catecholaminergic polymorphic ventricular tachycardia: recent mechanistic insights. 1591 75

Results of the Randomized Aldactone Evaluation Study and the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study indicate aldosterone receptor antagonism, together with angiotensin-converting enzyme inhibition and loop diuretics, is a most effective strategy in reducing risk for all-cause and cardiovascular-related mortality and morbidity in patients with symptomatic heart failure. Responsible mechanisms are likely multifactoral. As a circulating hormone, aldosterone has well-known endocrine properties that contribute to the pathophysiology of congestive heart failure. This includes Na+ resorption at the expense of K+ excretion in such tissues as kidneys, colon, sweat, and salivary glands. Mg2+ excretion at these sites is likewise enhanced by aldosterone, whereas adrenal aldosterone secretion is regulated by extracellular Mg2+. Other endocrine actions of aldosterone receptor-ligand binding include: a reduction in biologically active cytosolic-free Mg2+, with intracellular Ca2+ loading in nonepithelial cells such as peripheral blood mononuclear cells; its influence on endothelial cell function; and its central actions, including the choroid plexus, activity of the hypothalamic paraventricular nucleus, and autonomic nervous system. De novo generation of aldosterone within the cardiovasculature is recognized and findings suggest its auto/paracrine properties contribute to tissue repair. Each of these actions is interrupted by aldosterone receptor antagonism and therefore may contribute to its salutary response in heart failure.
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PMID:Efficacy of aldosterone receptor antagonism in heart failure: potential mechanisms. 1603 25

The data on magnesium supplementation in patients with acute myocardial infarction (AMI) is conflicting. Although a number of relatively small randomized clinical trials have demonstrated a remarkable reduction in mortality when administered to relatively high risk AMI patients, two recently published large-scale randomized clinical trials (the Fourth International Study of Infarct Survival and Magnesium in Coronaries) failed to show any superiority of intravenous magnesium over placebo. Nevertheless, the theoretical potential benefits of magnesium supplementation as a cardioprotective agent in coronary artery disease (CAD) patients, in conjunction with previous promising results from work in animal and humans, its relatively low cost, easy administration, with no need for special expertise, and relatively free of adverse effects, gives magnesium a place in treating CAD patients, especially high-risk groups such as CAD patients with heart failure, the elderly and hospitalized patients with hypomagnesemia.
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PMID:Magnesium and myocardial infarction. 1627 21

Metabolic therapy involves the administration of a substance normally found in the body to enhance a metabolic reaction within the cell. This may be achieved in two ways. First, for some systems, a substance can be given to achieve greater than normal levels in the body so as to drive an enzymic reaction in a preferred direction. Second, metabolic therapy may be used to correct an absolute or relative deficiency of a cellular component. Thus, metabolic therapy differs greatly from most standard cardiovascular pharmacologic therapy such as the use of ACE Inhibitors b-blockers, statins and calcium channel antagonists that are given to block rather than enhance cellular processes. In this review we highlight some metabolic substances that have potential benefit in treating heart disease or improving outcomes after cardiovascular interventions. Glucose-insulin-potassium therapy is protective against myocardial ischaemia by elevating myocardial glycogen levels. Coenzyme Q(10) is a lipid-soluble antioxidant that plays a crucial role in cellular ATP production. Magnesium orotate, a key intermediate in the biosynthetic pathway of glycogen, has been shown to improve the energy status of the cell and improve recovery from cardioplegic arrest. The amino acid aspartate plays an important role in providing energy substrates for oxidative phosphorylation in the myocyte. By improving cellular energy production, metabolic therapy has the potential to benefit cardiac function during the stress of cardiac surgery, myocardial infarction and cardiac failure.
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PMID:The principles of metabolic therapy for heart disease. 1635 48

Magnesium is a micronutrient essential for the normal functioning of the cardiovascular system, and Mg deficiency (MgD) is frequently associated in the clinical setting with chronic pathologies such as CHF, diabetes, hypertension, and other pathologies. Animal models of MgD have demonstrated a systemic pro-inflammatory/pro-oxidant state, involving multiple tissues/organs including neuronal, hematopoietic, cardiovascular, and gastrointestinal systems; during later stages of MgD, a cardiomyopathy develops which may result from a cascade of inflammatory events. In rodent models of dietary MgD, a significant rise in circulating levels of proinflammatory neuropeptides such as substance P (SP) and calcitonin gene-related peptide among others, was observed within days (1-7) of initiating the Mg-restricted diet, and implicated a neurogenic trigger for the subsequent inflammatory events; this early "neurogenic inflammation" phase may be mediated in part, by the Mg-gated N: -methyl-D-aspartate (NMDA) receptor/channel complex. Deregulation of the NMDA receptor may trigger the abrupt release of neuronal SP from the sensory-motor C-fibers to promote the subsequent pro-inflammatory changes: elevations in circulating inflammatory cells, inflammatory cytokines, histamine, and PGE(2) levels, as well as formation of nitric oxide, reactive oxygen species, lipid peroxidation products, and depletion of key endogenous antioxidants. Concurrent elevations of tissue CD14, a high affinity receptor for lipopolyssacharide, suggest that intestinal permeability may be compromised leading to endotoxemia. If exposure to these early (1-3 weeks MgD) inflammatory/pro-oxidant events becomes prolonged, this might lead to impaired cardiac function, and when co-existing with other pathologies, may enhance the risk of developing chronic heart failure.
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PMID:The nerve-heart connection in the pro-oxidant response to Mg-deficiency. 1681 76


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