Pyruvate dehydrogenase as a therapeutic target for obesity cardiomyopathy

ABSTRACT

Introduction: Obesity cardiomyopathy is a major public health problem with few specific therapeutic options. Abnormal cardiac substrate metabolism with reduced pyruvate dehydrogenase (PDH) activity is associated with energetic and functional cardiac impairment and may be a therapeutic target.

Areas covered: This review summarizes the changes to cardiac substrate and high energy phosphorus metabolism that occur in obesity and describes the links between abnormal metabolism and impairment of cardiac function. The available evidence for the currently available pharmacological options for selective metabolic therapy in obesity cardiomyopathy is reviewed.

Expert opinion: Pharmacological restoration of PDH activity is in general associated with favourable effects upon cardiac substrate metabolism and function in both animal models and small scale human studies, supporting a potential role as a therapeutic target.

KEYWORDS:

• Obesity
• heart failure
• metabolism
• imaging

Article highlights

• A prolonged duration of obesity is associated with a twofold increased risk of developing heart failure.

• Obesity is associated with profound changes in cardiac metabolism, with excessive fatty acid uptake and oxidation and reduced carbohydrate metabolism via pyruvate dehydrogenase (PDH).

• Reduced PDH flux may lead to cardiac functional impairment by reducing oxygen efficiency, causing mitochondrial dysfunction and/or altering cardiac lipid deposition.

• Experiments involving pharmacological strategies directly or indirectly increasing PDH flux have in general shown beneficial effects on cardiac metabolism and function in obesity.

• Fatty acid oxidation inhibitors and incretin therapies currently have the strongest preclinical evidence base and may be the best candidates for human studies.

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Financial & competing interests disclosure

The authors were supported by the British Heart Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.