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)

HMG CoA reductase inhibitors (statins) have an established place in the treatment of coronary artery disease. However, their role in the treatment of heart failure (HF), including HF due to coronary artery disease, has been controversial since beneficial as well as possible harmful effects may occur. Several recent studies lend support for a beneficial effect of the statins in HF. These include: (i) post hoc subgroup analyses of prospective randomized clinical trials of statin therapy among patients with stable coronary artery disease where statins reduce the incidence of new HF; (ii) subgroup analysis of the evidence of statin use in large HF trails with different medication and medical devices; (iii) retrospective observational studies of statin use in HF; and (iv) prospective randomized clinical trials of statins in non-ischemic. Beneficial effects include attenuation of cardiac hypertrophy, improvement in endothelial function, anti-inflammatory effects, reduction in the activity of matrix metalloproteinases, reduction in apoptosis, interference with neurohormones, and improved homeostasis. However, there are also theoretical concerns about statins in HF, and existing literature for their safety and efficacy in HF patients has been limited by the retrospective or observational nature of these analyses, examination of incompletely validated surrogate endpoints and small prospective studies in subgroups of HF subjects. In contrast with the normal population, low concentrations of LDL and total cholesterol are associated with a worse prognosis in HF patients and a possible mechanism is reduction in ubiquinone (coenzyme Q10) levels, which is required for oxidative phosphorylation in cells. The safety aspect of these drugs in HF patients needs to be answered before statins can be recommended as a routine drug. For the moment there are several large-scale prospective outcome studies in HF which probably will give us more definitive answers.
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PMID:The role of statins in heart failure. 1800 20

Both primary and secondary prevention studies have provided a wealth of evidence that statin therapy effectively reduces cardiovascular events. However, this general statement on the efficacy and safety of statin treatment has not been validated in patients with chronic heart failure (CHF). Recently, numerous statin trials have reported analysis on CHF parameters and numerous CHF trials have performed analysis on baseline statin use. In this article, we will review the currently available evidence from a pathophysiological as well as clinical perspective, building a case for and against the use of statins in CHF. From a pathophysiological perspective, we will discuss the known association of cholesterol and mortality, the ubiquinone, and the endotoxin-lipoprotein hypothesis. From a clinical perspective, we will discuss the observational studies, subgroup analysis of large randomized controlled trials, prospective randomized trials in CHF patients, and the future perspectives of the large European statin studies focussing on the statin therapy in CHF.
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PMID:The case for statin therapy in chronic heart failure. 1806 Mar 76

Chronic hemodynamic overload on the heart results in pathological myocardial hypertrophy, eventually followed by heart failure. Phosphatase calcineurin is a crucial mediator of this response. Little is known, however, about the role of calcineurin in response to acute alterations in loading conditions of the heart, where it could be mediating beneficial adaptational processes. We therefore analyzed proteome changes following a short-term increase in preload in rabbit myocardium in the absence or presence of the calcineurin inhibitor cyclosporine A. Rabbit right ventricular isolated papillary muscles were cultivated in a muscle chamber system under physiological conditions and remained either completely unloaded or were stretched to a preload of 3 mN/mm(2), while performing isotonic contractions (zero afterload). After 6 h, proteome changes were detected by two-dimensional gel electrophoresis and ESI-MS/MS. We identified 28 proteins that were upregulated by preload compared to the unloaded group (at least 1.75-fold regulation, all P < 0.05). Specifically, mechanical load upregulated a variety of enzymes involved in energy metabolism (i.e., aconitase, pyruvate kinase, fructose bisphosphate aldolase, ATP synthase alpha chain, acetyl-CoA acetyltransferase, NADH ubiquinone oxidoreductase, ubiquinol cytochrome c reductase, hydroxyacyl-CoA dehydrogenase). Cyclosporine A treatment (1 micromol/l) abolished the preload-induced upregulation of these proteins. We demonstrate for the first time that an acute increase in the myocardial preload causes upregulation of metabolic enzymes, thereby increasing the capacity of the myocardium to generate ATP production. This short-term adaptation to enhanced mechanical load appears to critically depend on calcineurin phosphatase activity.
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PMID:Myocardial adaptation of energy metabolism to elevated preload depends on calcineurin activity : a proteomic approach. 1827 99

Coenzyme Q(10) (CoQ(10)) has been used as a drug for chronic heart failure. Furthermore, various biological effects of CoQ(10) have also been applied for food supplements and cosmetics. However, CoQ(10) was found to be poorly soluble in water, so that its bioavailability was low and variable depending on food intake. In the present investigation, a novel liquid (nano-emulsion, NE) and water-soluble powder formulations, including cyclodextrin-Q10 complex (CoQ(10)-CD) and dry-emulsion (DE), were prepared. The physicochemical properties of each formulation were characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM), powder X-ray diffractometry (PXRD), and differential scanning calorimetry (DSC). In all powder formulations prepared, CoQ(10) existed mainly as an amorphous form as determined by PXRD and DSC, and each powder formulation exhibited high solubility and dispersibility in water resulting in the formation of a nano-sized emulsion (NE; 60nm) and micron sized particles (DEs and CoQ(10)-CD; 0.77-2.4microm). The pharmacokinetic study of each dosage form, in comparison to a CoQ(10) crystal suspension, was also carried out in rats after a single oral dose. Although similar kinetic values were seen with T(max) of 1.5 and 1.7h, respectively, for NE and crystalline CoQ(10), NE exhibited ca 1.7-fold higher AUC and C(max) than the crystalline CoQ(10).
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PMID:Physicochemical and pharmacokinetic characterization of water-soluble Coenzyme Q(10) formulations. 1870 89

Coenzyme Q(10) (CoQ(10)) is an essential cofactor in the mitochondrial electron transport pathway, and is also a lipid-soluble antioxidant. It is endogenously synthesised via the mevalonate pathway, and some is obtained from the diet. CoQ(10) supplements are available over the counter from health food shops and pharmacies. CoQ(10) deficiency has been implicated in several clinical disorders, including but not confined to heart failure, hypertension, Parkinson's disease and malignancy. Statin, 3-hydroxy-3- methyl-glutaryl (HMG)-CoA reductase inhibitor therapy inhibits conversion of HMG-CoA to mevalonate and lowers plasma CoQ(10) concentrations. The case for measurement of plasma CoQ(10) is based on the relationship between levels and outcomes, as in chronic heart failure, where it may identify individuals most likely to benefit from supplementation therapy. During CoQ(10) supplementation plasma CoQ(10) levels should be monitored to ensure efficacy, given that there is variable bioavailability between commercial formulations, and known inter-individual variation in CoQ(10) absorption. Knowledge of biological variation and reference change values is important to determine whether a significant change in plasma CoQ(10) has occurred, whether a reduction for example following statin therapy or an increase following supplementation. Emerging evidence will determine whether CoQ(10) does indeed have an important clinical role and in particular, whether there is a case for measurement.
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PMID:Coenzyme Q10: is there a clinical role and a case for measurement? 1878 45

Patients with CHF, NYHA class IV, often fail to achieve adequate plasma CoQ10 levels on supplemental ubiquinone at dosages up to 900 mg/day. These patients often have plasma total CoQ10 levels of less than 2.5 microg/ml and have limited clinical improvement. It is postulated that the intestinal edema in these critically ill patients may impair CoQ10 absorption. We identified seven patients with advanced CHF (mean EF 22%) with sub-therapeutic plasma CoQ10 levels with mean level of 1.6 microg/ml on an average dose of 450 mg of ubiquinone daily (150-600 mg/day). All seven of these patients were changed to an average of 580 mg/day of ubiquinol (450-900 mg/day) with follow-up plasma CoQ10 levels, clinical status, and EF measurements by echocardiography. Mean plasma CoQ10 levels increased from 1.6 microg/ml (0.9-2.0 microg/ml) up to 6.5 microg/ml (2.6-9.3 microg/ml). Mean EF improved from 22% (10-35%) up to 39% (10-60%) and clinical improvement has been remarkable with NYHA class improving from a mean of IV to a mean of II (I to III). Ubiquinol has dramatically improved absorption in patients with severe heart failure and the improvement in plasma CoQ10 levels is correlated with both clinical improvement and improvement in measurement of left ventricular function.
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PMID:Supplemental ubiquinol in patients with advanced congestive heart failure. 1909 7

Coenzyme Q10 (ubiquinone) is a mitochondrial coenzyme which is essential for the production of ATP. Being at the core of cellular energy processes it assumes importance in cells with high energy requirements like the cardiac cells which are extremely sensitive to CoQ10 deficiency produced by cardiac diseases. CoQ10 has thus a potential role for prevention and treatment of heart ailments by improving cellular bioenergetics. In addition it has an antioxidant, a free radical scavenging and a vasodilator effect which may be helpful in these conditions. It inhibits LDL oxidation and thus the progression of atherosclerosis. It decreases proinflammatory cytokines and decreases blood viscosity which is helpful in patients of heart failure and coronary artery disease. It also improves ischemia and reperfusion injury of coronary revascularisation. Significant improvement has been observed in clinical and hemodynamic parameters and in exercise tolerance in patients given adjunctive CoQ10 in doses from 60 to 200 mg daily in the various trials conducted in patients of heart failure, hypertension, ischemic heart disease and other cardiac illnesses. Recently it has been found to be an independent predictor of mortality in congestive heart failure. It has also been found to be helpful in vertigo and Meniere-like syndrome by improving the immune system. Further research is going on to establish firmly its role in the therapy of cardiovascular diseases.
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PMID:Role of coenzyme Q10 (CoQ10) in cardiac disease, hypertension and Meniere-like syndrome. 1963 84

The role of a secondary respiratory chain deficiency as an additional mechanism to intoxication, leading to development of long-term energy-dependent complications, has been recently suggested in patients with propionic acidemia (PA). We show for the first time a coenzyme Q(10) (CoQ(10)) functional defect accompanied by a multiple organ oxidative phosphorylation (OXPHOS) deficiency in a child who succumbed to acute heart failure in the absence of metabolic stress. Quinone-dependent activities in the liver (complex I+III, complex II+III) were reduced, suggesting a decrease in electron transfer related to the quinone pool. The restoration of complex II+III activity after addition of exogenous ubiquinone to the assay system suggests CoQ(10) deficiency. Nevertheless, we disposed of insufficient material to perform direct measurement of CoQ(10) content in the patient's liver. Death occurred before biochemical diagnosis of OXPHOS deficiency could be made. However, this case highlights the usefulness of rapidly identifying CoQ(10) defects secondary to PA since this OXPHOS disorder has a good treatment response which could improve heart complications or prevent their appearance. Nevertheless, further studies will be necessary to determine whether CoQ(10) treatment can be useful in PA complications linked to CoQ(10) deficiency.
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PMID:Fatal heart failure associated with CoQ10 and multiple OXPHOS deficiency in a child with propionic acidemia. 2132 67

Coenzyme Q(10) (CoQ(10)), also known as ubiquinone for its presence in all body cells, is an essential part of the cell energy-producing system. However, it is also a powerful lipophilic antioxidant protecting lipoproteins and cell membranes. Due to these two actions, CoQ(10) is commonly used in clinical practice in chronic heart failure, male infertility, and neurodegenerative disease. However, it is also taken as an anti-aging substance by healthy people aiming for long-term neuroprotection and by sportsmen to improve endurance. Many hormones are known to be involved in body energy regulation, in terms of production, consumption and dissipation, and their influence on CoQ(10) body content or blood values may represent an important pathophysiological mechanism. We summarize the main findings of the literature about the link between hormonal systems and circulating CoQ(10) levels. In particular the role of thyroid hormones, directly involved in the regulation of energy homeostasis, is discussed. There is also a link with gonadal and adrenal hormones, partially due to the common biosynthetic pathway with CoQ(10), but also to the increased oxidative stress found in hypogonadism and hypoadrenalism.
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PMID:Hormonal influence on coenzyme Q(10) levels in blood plasma. 2227 29

Recent experimental evidence has replaced the random diffusion model of electron transfer with a model of supramolecular organisation based on specific interactions between individual respiratory complexes. These supercomplexes are detected by blue-native electrophoresis and are found to be functionally relevant by flux control analysis; moreover, they have been isolated and characterised by single-particle electron microscopy. The supramolecular association of individual complexes strongly depends on membrane lipid amount and composition and is affected by lipid peroxidation; it also seems to be modulated by membrane potential and protein phosphorylation. Supercomplex association confers several new properties with respect to the non-associated respiratory complexes to the respiratory chain: the most obvious is substrate channelling, specifically addressing Coenzyme Q and cytochrome c to interact directly with the partner enzymes without the need of a less efficient random diffusion step; in addition, supramolecular association may provide a further rate advantage by conferring long-range conformational changes to the individual complexes. Additional properties are stabilisation of Complex I, as evidenced by the destabilising effect on Complex I of mutations in either Complex III or Complex IV, and prevention of excessive generation of reactive oxygen species. On the basis of the properties described above, we hypothesise that an oxidative stress acts primarily by disassembling supercomplex associations thereby establishing a vicious circle of oxidative stress and energy failure, ultimately leading to cell damage and disease. We provide evidence that in physiological ageing and in some disease states, characterised by oxidative stress and mitochondrial damage, such as heart failure, neurodegenerative disorders and cancer, a loss of supercomplex association occurs, in line with our working hypothesis.
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PMID:Supramolecular organisation of the mitochondrial respiratory chain: a new challenge for the mechanism and control of oxidative phosphorylation. 2272 56


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