Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The biguanide, metformin, sensitizes the liver to the effect of insulin, suppressing hepatic glucose output. Thiazolidinediones such as rosiglitazone and pioglitazone enhance insulin-mediated glucose disposal, leading to reduced plasma insulin concentrations. These classes of drugs may also have varying beneficial effects on features of insulin resistance such as lipid levels, blood pressure and body weight. Metformin in combination with insulin has been shown to significantly improve blood glucose levels while lowering total daily insulin dose and body weight. The thiazolidinediones in combination with insulin have also been effective in lowering blood glucose levels and total daily insulin dose. Triple combination therapy using insulin, metformin and a thiazolidinedione improves glycaemic control to a greater degree than dual therapy using insulin and metformin or insulin and a thiazolidinedione. There is insufficient evidence to recommend the use of metformin or thiazolidinediones in type 1 diabetic patients. Although these agents are largely well tolerated, some subjects experience significant gastrointestinal problems while using metformin. Metformin is associated with a low risk of lactic acidosis, but should not be used in patients with elevated serum creatinine or those being treated for congestive heart failure. The thiazolidinediones are associated with an increase in body weight, although this can be avoided with careful lifestyle management. Thiazolidinediones may also lead to oedema and are associated with a low incidence of hepatocellular injury. Thiazolidinediones are contraindicated in patients with underlying heart disease who are at risk of congestive heart failure and in patients who have abnormal hepatic function. The desired blood glucose-lowering effect and adverse event profiles of these agents should be considered when recommending these agents to diabetic patients. The potential for metformin or the thiazolidinediones to impact long-term cardiovascular outcomes remains under investigation.
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PMID:Combination therapy using metformin or thiazolidinediones and insulin in the treatment of diabetes mellitus. 1621 7

Classical non-insulin antihyperglycemic drugs currently approved for the treatment of type 2 diabetes mellitus (T2DM) comprise five groups: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. Novel compounds are represented by the incretin mimetic drugs like glucagon like peptide-1 (GLP-1), the dipeptidyl peptidase 4 (DPP-4) inhibitors, dual peroxisome proliferator-activated receptors (PPAR) agonists (glitazars) and amylin mimetic drugs. We review the cardiovascular effects of these drugs in an attempt to improve knowledge regarding their potential risks when treating T2DM in cardiac patients. Metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as recent myocardial infarction, heart or renal failure. Sulfonylureas exert their effect by closing the ATP-dependent potassium channels. This prevents the opening of these channels during myocardial ischemia, impeding the necessary hyperpolarization that protects the cell. The combined sulfonylurea/metformin therapy reveals additive effects on mortality in patients with coronary artery disease (CAD). Meglitinides effects are similar to those of sulfonylureas, due to their almost analogous mechanism of action. Glitazones lower leptin levels, leading to weight gain and are unsafe in NYHA class III or IV. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates is yet unknown. The incretin GLP-1 is associated with reductions in body weight and appears to present positive inotropic effects. DPP-4 inhibitors influences on the cardiovascular system seem to be neutral and patients do not gain weight. The future of glitazars is presently uncertain following concerns about their safety. The amylin mimetic drug paramlintide, while a satisfactory adjuvant medication in insulin-dependent diabetes, is unlikely to play a major role in the management of T2DM. Summarizing the present information it can be stated that 1. Four out the five classical oral antidiabetic drug groups present proven or potential cardiac hazards; 2. These hazards are not mere 'side effects', but biochemical phenomena which are deeply rooted in the drugs' mechanism of action; 3. Current data indicate that the combined glibenclamide/metformin therapy seems to present special risk and should be avoided in the long-term management of T2DM with proven CAD; 4. Glitazones should be avoided in patients with overt heart failure; 5, The novel incretin mimetic drugs and DPP-4 inhibitors--while usually inadequate as monotherapy--appear to be satisfactory adjuvant drugs due to the lack of known undesirable cardiovascular effects; 6. Customized antihyperglycemic pharmacological approaches should be implemented for the achievement of optimal treatment of T2DM patients with heart disease. In this context, it should be carefully taken into consideration whether the leading clinical status is CAD or heart failure.
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PMID:A cardiologic approach to non-insulin antidiabetic pharmacotherapy in patients with heart disease. 1961 27

Endoplasmic reticulum stress signaling (ERSS) plays an important role in the pathogenesis of diabetes and heart disease. The latter is a common comorbidity of diabetes and worsens patient outcome. Results from clinical studies suggest beneficial effects of metformin - a widely used oral drug for the treatment of type 2 diabetes - on the heart of diabetic patients with heart failure. We therefore analyzed the effect of metformin on ERSS in primary rat cardiomyocytes. We found that metformin activates the PERK-ATF4 but not the ATF6 or IRE1-XBP1 branch in ERSS and leads to a strong upregulation of CHOP mRNA and protein. Surprisingly, long-term induction of CHOP by metformin is not accompanied by apoptosis even though CHOP is regarded to be a mediator of ER-stress-induced apoptosis. In conclusion, metformin induces distinct ER stress pathways in cardiomyocytes and our results indicate that CHOP is not necessarily a mediator of apoptosis. Metformin might exert its cardioprotective effect through selective activation of ERSS pathways in the cardiomyocyte.
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PMID:Metformin differentially activates ER stress signaling pathways without inducing apoptosis. 2210 72

Metformin is a common medication used for the treatment of type 2 diabetes, especially in obese subjects. Clinical studies show that, in addition to the lowering effect of blood glucose, metformin reduces cardiovascular risk, does not induce weight gain and additionally, provides a unique safety strategy and efficacy in patients with diabetes and heart disease. However, this treatment is not without risks. The most feared metabolic complication is lactic acidosis that often occurs with complex and severe clinical symptoms and is associated with a high mortality risk. We detail our experience, during one year, regarding four patients with diabetes treated with metformin who developed such acute renal failure and lactic acidosis as to require hemodialysis treatment. The patients selected had previous normal renal function but a history of serious cardiovascular disease (hypertensive cardiomiopathy, ischemic revascularized and/or dilated, chronic obstructive arterial disease). We observed in all four of our patients an onset of non-related symptoms (fever, fatigue, vomiting and gastrointestinal disorders), a rapid deterioration in renal function, anuria and very high levels of lactic acid. In two patients we found acute pancreatitis. In addition to rehydration therapy, hemodialysis was started instantly with progressive rebalancing of the biohumoral status, effective recovery of spontaneous diuresis and improvement of the clinical status in three patients. Unfortunately, we had a failure during the initial hours of ward admittance, with an important clinical situation complicated by acute cardiac ischemia, abnormal heart rhythm, ending in death. Our experience provides us with elements to reflect on. Lactic acidosis is a serious metabolic disorder because it is associated with a high mortality risk. So a rapid diagnosis and a complete recognition of all the fundamental elements are important for its management. Starting hemodialysis early and prolonged treatment can solve complicated clinical status, correct acidosis and restore kidney function in patients with serious comorbidity.
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PMID:[Lactic acidosis, acute renal failure and heart failure during treatment with metformin: what do we know?]. 2648 Feb 56

Chronic chagasic cardiomyopathy (CCC) develops years after acute infection by Trypanosoma cruzi and does not improve after trypanocidal therapy, despite reduction of parasite burden. During disease, the heart undergoes oxidative stress, a potential causative factor for arrhythmias and contractile dysfunction. Here we tested whether antioxidants/ cardioprotective drugs could improve cardiac function in established Chagas heart disease. We chose a model that resembles B1-B2 stage of human CCC, treated mice with resveratrol and performed electrocardiography and echocardiography studies. Resveratrol reduced the prolonged PR and QTc intervals, increased heart rates and reversed sinus arrhythmia, atrial and atrioventricular conduction disorders; restored a normal left ventricular ejection fraction, improved stroke volume and cardiac output. Resveratrol activated the AMPK-pathway and reduced both ROS production and heart parasite burden, without interfering with vascularization or myocarditis intensity. Resveratrol was even capable of improving heart function of infected mice when treatment was started late after infection, while trypanocidal drug benznidazole failed. We attempted to mimic resveratrol's actions using metformin (AMPK-activator) or tempol (SOD-mimetic). Metformin and tempol mimicked the beneficial effects of resveratrol on heart function and decreased lipid peroxidation, but did not alter parasite burden. These results indicate that AMPK activation and ROS neutralization are key strategies to induce tolerance to Chagas heart disease. Despite all tissue damage observed in established Chagas heart disease, we found that a physiological dysfunction can still be reversed by treatment with resveratrol, metformin and tempol, resulting in improved heart function and representing a starting point to develop innovative therapies in CCC.
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PMID:Resveratrol Reverses Functional Chagas Heart Disease in Mice. 2778 62

The incidence and mortality of cardiovascular disease in diabetic patients are 2-3 times higher than those in non-diabetic patients. Abnormal function of the L-type calcium channel in myocardial tissue might result in multiple cardiac disorders such as a prolonged QT interval. Therefore, QT prolongation is an independent risk factor of cardiovascular disease in patients with diabetes mellitus. Metformin, a hypoglycemic agent, is widely known to effectively reduce the occurrence of macrovascular diseases. The aim of the present study was to evaluate the effect of metformin on prolonged QT interval and to explore potential ionic mechanisms induced by diabetes. Diabetic mouse models were established with streptozotocin and an electrocardiogram was used to monitor the QT interval after 4 weeks of metformin treatment in each group. Action potential duration (APD) and L-type calcium current (I Ca-L) were detected by patch-clamp in isolated mice ventricular cardiomyocytes and neonatal cardiomyocytes of mice. The expression levels of CACNA1C mRNA and Cav1.2 were measured by real-time PCR, western blot and immunofluorescence. A shortened QT interval was observed after 4 weeks of metformin treatment in diabetic mice. Patch-clamp results revealed that both APD and I Ca-L were shortened in mouse cardiomyocytes. Furthermore, the expression levels of CACNA1C mRNA and Cav1.2 were decreased in the metformin group. The same results were also obtained in cultured neonatal mice cardiomyocytes. Overall, these results verify that metformin could shorten a prolonged QT interval by inhibiting the calcium current, suggesting that metformin may play a role in the electrophysiology underlying diabetic cardiopathy.
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PMID:Metformin Shortens Prolonged QT Interval in Diabetic Mice by Inhibiting L-Type Calcium Current: A Possible Therapeutic Approach. 3259 91

Metformin is ubiquitously used in the management of Type II Diabetes Mellitus (DMII). Over the years, our growing knowledge of its therapeutic potential has broadened its use to the treatment of infertility in polycystic ovarian syndrome, gestational diabetes, and even obesity. Recently, it has been suggested as a novel therapy in cardiovascular disease (CVD). Given that CVD is the leading cause of death in patients with DMII, with ~ 75% dying from a cardiovascular event, the intersection of DMII and CVD provides a unique therapeutic target. In particular, pulmonary hypertension (PH) related to CVD (Group II PH) may be an optimal target for metformin therapy. The objective of this review article is to provide an overview of the pathophysiology of PH related to left heart disease (PH-LHD), outline the proposed pathophysiologic mechanism of insulin resistance in heart failure and PH-LHD, and evaluate the role metformin may have in heart failure and PH-LHD.
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PMID:Metformin in Pulmonary Hypertension in Left Heart Disease. 3297 59