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)

Thiazolidinediones (TZDs) or glitazones are agents that are widely used for the treatment of type 2 diabetes mellitus. These drugs have a multitude of therapeutic effects including reduction in insulin resistance and hyperglycaemia, anti-inflammatory effects and amelioration of hypertension, microalbuminuria and hepatic steatosis. The TZD molecular target, peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear transcription factor, is expressed diffusely in humans, including many tissues comprising the cardiovascular and renal systems. This suggests a potential for TZDs to elicit perturbing effects on these systems, which are independent of their effects on glucose and lipid metabolism. One of the most common adverse effects of TZDs is fluid retention, which can result in, or exacerbate, oedema and congestive heart failure (CHF). The frequency of peripheral oedema is approximately 5% when TZDs are used in mono- or combination oral therapy, and about 15% when used with insulin. Patients with type 2 diabetes are at high risk of myriad morbid complications, including CHF. The development of CHF, particularly in the elderly, is a harbinger of premature mortality. TZD-induced oedema is largely peripheral, may have its origins in changes in haemodynamics, with some contribution from molecules, which regulate cell and tissue permeability (e.g. vascular endothelial growth factor and protein kinase Cbeta), and remains the preponderant manifestation of TZD-induced fluid retention even in those with existing heart failure. Preclinical and pilot clinical data attest to the fact that at least part of the fluid retention derives from a direct effect of TZDs on sodium reabsorption via the renal medullary collecting duct, a mechanism that is sensitive to diuretic agents that have this nephron segment as their site of action, in whole or in part (spironolactone, amiloride and hydrochlorothiazide). Our review suggests various potential clinical strategies by which TZD-induced fluid retention might be effectively monitored and addressed.
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PMID:Thiazolidinediones and their fluid-related adverse effects: facts, fiction and putative management strategies. 1772 67

Three forms of PPARs are expressed in the heart. In animal models, PPARgamma agonist treatment improves lipotoxic cardiomyopathy; however, PPARgamma agonist treatment of humans is associated with peripheral edema and increased heart failure. To directly assess effects of increased PPARgamma on heart function, we created transgenic mice expressing PPARgamma1 in the heart via the cardiac alpha-myosin heavy chain (alpha-MHC) promoter. PPARgamma1-transgenic mice had increased cardiac expression of fatty acid oxidation genes and increased lipoprotein triglyceride (TG) uptake. Unlike in cardiac PPARalpha-transgenic mice, heart glucose transporter 4 (GLUT4) mRNA expression and glucose uptake were not decreased. PPARgamma1-transgenic mice developed a dilated cardiomyopathy associated with increased lipid and glycogen stores, distorted architecture of the mitochondrial inner matrix, and disrupted cristae. Thus, while PPARgamma agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function.
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PMID:Cardiomyocyte expression of PPARgamma leads to cardiac dysfunction in mice. 1782 55

Thiazolidinediones (TZDs) are relatively new agents for the treatment of type 2 diabetes. They act as agonists at the PPAR-gamma nuclear receptor and their therapeutic effects include decreased insulin resistance and hyperglycaemia, an improved plasma lipid, inflammation and pro-coagulant profile, and amelioration of hypertension, microalbuminuria and hepatic steatosis. The most common side effects of TZDs include weight gain and oedema, with occasional reports of congestive heart failure (CHF). This review discusses the benefit-risk profile of TZDs in treating patients with type 2 diabetes, with particular reference to the heart. To provide context, we explore briefly the epidemiology and pathophysiology of heart failure in patients with type 2 diabetes, touch on the association of heart disease and cardiovascular mortality with antihyperglycaemic treatment modalities other than TZDs, and then focus on the effects of TZDs on the heart, cardiovascular risk factors and outcomes. We describe the cluster of host factors, which seems to predispose patients with type 2 diabetes to TZD-induced or TZD-exacerbated oedema and CHF and then provide an overview of the putative mechanisms of these TZD-related side effects. We also propose that certain diuretics (amiloride and spironolactone), by targeting the distal nephron that expresses PPARgamma in collecting duct cells, might be of benefit in ameliorating the fluid retention and oedema associated with TZDs.
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PMID:Thiazolidinedione insulin sensitizers and the heart: a tale of two organs? 1833 90

The same drugs are used to treat hemorrhagic rectocolitis (HRC) and Crohn's disease (CD), although the aims are very different. Aminosalicylates are highly beneficial in HRC but virtually ineffective in CD, a disease in which immunosuppressants are more useful. Aminosalicylates exert their antiinflammatory effect directly on the lesions. Various oral and rectal preparations have been developed in order to deliver the active molecule to the intestinal target segment. These drugs are now known to act by stimulating the nuclear receptor PPAR-gamma, and this knowledge should help with the development of new agents. Chronic aminosalicylate treatment appears to diminish the risk of malignant transformation. Systemic steroids are still the mainstay of treatment for exacerbations of HRC and CD, yielding remissions in 60 to 90% of cases. In contrast, systemic steroids should not be used for maintenance therapy. Budesonide is a preparation that selectively releases steroids in the ileocolonic region, thereby reducing systemic adverse effects. Immunosuppressants such as azathioprine and 6-mercaptopurine, and also methotrexate in some cases, are used for maintenance therapy of steroid-dependent and highly recurrent forms. These drugs stabilize the disease in about half the patients who receive them. Treatment typically lasts several years and necessitates regular monitoring, especially of hematological status. Cyclosporine is used intravenously in severe HRC. Infliximab (RemicadeR), a chimeric monoclonal antibody targeting TNF is effective in acute forms and as maintenance therapy for CD. It was also recently shown to be effective in HRC. Infliximab is indicated in steroid-resistant forms and contraindicated in patients with latent systemic infections (tuberculosis, hepatitis B) and heart failure. Artificial nutrition is now only used in children with acute forms, in order to avoid the need for steroids. Probiotics might have a place in maintenance treatment of HRC. Surgical treatment of HRC consists of colectomy or, more radically, ileoprotectomy followed by ileoanal anastomosis with resection: however, the likely benefits and potential complications (especially nocturnal diarrhea) must be carefully weighed up. Surgical treatment of CD consists of resecting the worst-affected segments. As available medical and surgical treatments can only control these diseases, without curing them, patient management must be planned on a long-term basis. Control of exacerbations is judged on the basis of clinical parameters and biological markers of inflammation, rather than on lesion healing. The choice of maintenance therapy depends on the nature of the disease (HRC or CD) and its progressive nature. Surgery is reserved for patients with complicated and drug-resistant forms.
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PMID:[Treatment of chronic inflammatory bowel diseases]. 1840 68

Activation of PPAR-gamma through the administration of glitazones has shown promise in preserving function following cardiac injury, although recent evidence has suggested their use may be contraindicated in the case of severe heart failure. This study tested the hypothesis that PPAR-gamma expression increases in a time dependent manner in response to chronic volume overload (VO) induced heart failure. Additionally, we attempted to determine what effect 4 week administration of Urotensin II (UTII) may have on PPAR-gamma expression. VO induced heart failure was produced in Sprague-Dawley rats (n=32) by aorta-caval fistula. Animals were sacrificed at 1, 4, and 14 weeks following shunt creation. In a separate set of experiments, animals were administered 300 pmol/kg/h of UTII for 4 weeks, subjected to 4 weeks of volume overload, or given UTII+VO. Densitometric analysis of left ventricular (LV) protein demonstrated PPAR-gamma expression was significantly ((*)p<0.05) upregulated at 4 and 14 weeks (31.5% and 37%, respectively) post-fistula formation compared to control values. PPAR-gamma activation was decreased in the 4 and 14 week (39.16% and 42.4%, respectively), but not in the 1-week animals, and these changes did not correlate with NF-kappaB activity. Animals given UTII either with or without VO demonstrated increased expression of PPAR-gamma as did animals subjected to 4 week VO alone. Animals given UTII either with or without VO had decreased activity vs. control. These data suggest PPAR-gamma may play a role in the progression of heart failure, however, the exact nature has yet to be determined.
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PMID:PPAR-gamma expression in animals subjected to volume overload and chronic Urotensin II administration. 1842 37

Although the concept of energy starvation in the failing heart was proposed decades ago, still very little is known about the origin of energetic failure. Recent advances in molecular biology have started to elucidate the transcriptional events governing mitochondrial biogenesis. In particular, a great step was taken with the discovery that peroxisome proliferator-activated receptor gamma co-activator (PGC-1alpha) is the master regulator of mitochondrial biogenesis. The molecular mechanisms underlying the downregulation of PGC-1alpha and the consequent decrease in mitochondrial function in heart failure are, however, still poorly understood. Indeed, the main pathways involved in mitochondrial biogenesis are thought to be up- rather than down-regulated in pathological hypertrophy and heart failure. The current review summarizes recent advances in this field and is restricted to the heart when cardiac data are available.
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PMID:Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. 1843 Jul 51

Cardiovascular morbidity and mortality in patients with type 2 diabetes are a major problem in clinical practice. Thiazolidinediones (TZDs) are agonists of the peroxisome proliferator-activated receptor gamma which improve glycaemic control by reducing insulin resistance. TZDs also seem to have beneficial effects on various cardiovascular risk factors and consequently may have the potential to reduce the risk of cardiovascular disease (CVD). Although the first large-scale clinical trial evaluating the effect of a TZD on secondary prevention of major adverse cardiovascular outcomes supported this hypothesis, a recently published meta-analysis raised substantial uncertainty about the cardiovascular safety of rosiglitazone. This article summarises the evidence from completed and ongoing outcome trials with TZDs, as well as the recent meta-analytic data on their cardiovascular safety, aiming to provide an up-to-date and balanced view of a very important field. Data from clinical trials consistently indicate that treatment with glitazones significantly increase the risk of heart failure. Despite the fact that rosiglitazone and pioglitazone have much more similarities than differences with regards to their effects on cardiovascular risk factors, pioglitazone seems to have more favourable effects on major cardiovascular outcomes. This issue also highlights the potential hazards involved in using surrogate end-points for drug approval.
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PMID:The controversial effects of thiazolidinediones on cardiovascular morbidity and mortality. 1868 30

The PPAR gene pathway consists of interrelated genes that encode transcription factors, enzymes, and downstream targets which coordinately act to regulate cellular processes central to glucose and lipid metabolism. The pathway includes the PPAR genes themselves, other class II nuclear hormone receptor transcription factors within the PPAR family, PPAR co-activators, PPAR co-repressors, and downstream metabolic gene targets. This review focuses on the transcription factors that comprise the PPAR transcriptional activator complex--the PPARs (PPARalpha, PPARbeta, or PPARgamma), PPAR heterodimeric partners, such as RXRalpha, and PPAR co-activators, such as PPARgamma coactivator 1alpha (PGC-1alpha) and the estrogen-related receptors (ERRalpha, ERRbeta, and ERRgamma). These transcription factors have been implicated in the development of myocardial hypertrophy and dilated cardiomyopathy as well as response to myocardial ischemia/infarction and, by association, ischemic cardiomyopathy. Human expression studies and animal data are presented as the background for a discussion of the emerging field of pharmacogenetics as it applies to these genes and the consequent implications for the individualization of therapy for patients with heart failure.
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PMID:PPAR transcriptional activator complex polymorphisms and the promise of individualized therapy for heart failure. 1899 7

Heart failure is a cause of significant morbidity and mortality in developed nations, and results from a complex interplay between genetic and environmental factors. To discover gene regulatory networks underlying heart failure, we analyzed DNA microarray data based on left ventricular free-wall myocardium from 59 failing (32 ischemic cardiomyopathy, 27 idiopathic dilated cardiomyopathy) and 33 non-failing explanted human hearts from the Cardiogenomics Consortium. In particular, we sought to investigate cardiac gene expression changes at the level of individual genes, as well as biological pathways which contain groups of functionally related genes. Utilizing a combination of computational techniques, including Comparative Marker Selection and Gene Set Enrichment Analysis, we identified a subset of downstream gene targets of the master mitochondrial transcriptional regulator, peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), whose expression is collectively decreased in failing human hearts. We also observed decreased expression of the key PGC-1alpha regulatory partner, estrogen-related receptor alpha (ERRalpha), as well as ERRalpha target genes which may participate in the downregulation of mitochondrial metabolic capacity. Gene expression of the antiapoptotic Raf-1/extracellular signal-regulated kinase (ERK) pathway was decreased in failing hearts. Alterations in PGC-1alpha and ERRalpha target gene sets were significantly correlated with an important clinical parameter of disease severity - left ventricular ejection fraction, and were predictive of failing vs. non-failing phenotypes. Overall, our results implicate PGC-1alpha and ERRalpha in the pathophysiology of human heart failure, and define dynamic target gene sets sharing known interrelated regulatory mechanisms capable of contributing to the mitochondrial dysfunction characteristic of this disease process.
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PMID:PGC-1alpha and ERRalpha target gene downregulation is a signature of the failing human heart. 1906 96

We have previously shown that metoprolol decreases carnitine palmitoyltransferase-1 (CPT-1) activity, a mechanism which may partly explain its beneficial effects in heart failure. It is possible that this effect occurs as a result of repression of cardiac CPT-1B expression. CPT-1B is induced by the transcription factors peroxisome proliferator activated receptor-alpha (PPAR-alpha) and PPAR-gamma-coactivator 1alpha (PGC1alpha) and repressed by upstream stimulatory factor-2 (USF-2). We therefore hypothesized that metoprolol represses CPT-1B by increasing USF-2-mediated repression of PGC1alpha. Male Wistar Rats were divided into 4 groups: control, control treated with metoprolol for 5 weeks, diabetic and diabetic treated with metoprolol for 5 weeks. After termination, the expression of CPT-1 isoforms, PPAR-alpha, PGC1alpha USF-1 and USF-2, as well as downstream targets were measured. Binding of PPAR-alpha, PGC1alpha and USF-2 to PGC1alpha was measured using coimmunoprecipitation. The occupation of PPAR-alpha and MEF-2A consensus sites in the CPT-1B promoter was measured using chromatin immunoprecipitation assays. Chronic metoprolol treatment decreased the expression of CPT-1B in diabetic hearts. The expression of USF-2 was increased by metoprolol in both control and diabetic hearts, but the association of USF-2 with PGC1alpha was increased by metoprolol only in diabetic hearts. Metoprolol prevented the increase in PGC1alpha occupation of the CPT-1B promoter region observed in the diabetic heart without affecting PPAR-alpha occupation. Metoprolol decreases CPT-1B expression by decreasing PGC1alpha-mediated coactivation of PPAR-alpha and MEF-2A. This is associated with increased PGC1alpha/ USF-2 binding, suggesting that USF-2 mediates the metoprolol-induced repression of PGC1alpha.
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PMID:Metoprolol represses PGC1alpha-mediated carnitine palmitoyltransferase-1B expression in the diabetic heart. 1923 64


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