title: Use of clinically available PPAR agonists for heart failure; do the risks outweigh the potential benefits?
abstract: PPAR agonists represent a heterogeneous group of compounds that have been used in the treatment of cardiovascular and metabolic diseases for over thirty years. While the primary indications for PPAR agonist therapy focus on hyperlipidemia and diabetes, there is a growing body of pre-clinical data that suggests they may be beneficial in the treatment of heart failure; a disease marked by abnormal myocardial metabolism, fibrosis and insulin insensitivity. PPAR agonist treatment in numerous animal models of systolic heart failure have demonstrated improvement in cardiac function with decreased fibrosis, improved contractility and endothelial function. However, considerable controversy exists on the cardiac safety profile of PPAR agonists, particularly concern for inducing lipotoxicty and precipitating or worsening heart failure. In addition during pre-clinical testing, many compounds have been associated with increased death and adverse cardiovascular outcomes casting a pall over their future use for treating disorders of myocardial function. This article will review cardiac pathways involved in PPAR activation and their potential regulation of maladaptive pathways involved in heart failure and highlight molecular mechanisms that may contribute to adverse events and raise safety concerns. Specific attention will be focused on PPAR alpha and gamma, subtypes for which commercially available PPAR agonists are currently available.
authors: Division of Cardiology, Department of Medicine, Northwestern University, Northwestern Memorial Hospital, Chicago, IL 60611, USA. s-sarma@md.northwestern.edu
authors: Satyam
authors: S
authors: Sarma
mesh_terms: D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D009206:Myocardium / Q000378:metabolism; D018384:Oxidative Stress; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists* / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047495:PPAR gamma; D047492:Peroxisome Proliferator-Activated Receptors; D005947:Glucose