On the hypothesis that the failing heart is energy starved: Lessons learned from the metabolism of ATP and creatine

Adenosine triphosphate (ATP) and phosphocreatine fall in the failing heart. New insights into the control of ATP synthesis, supply, and utilization, and how this changes in the failing heart, have emerged. In this article, we address four questions: What are the mechanisms explaining loss of ATP and creatine from the failing heart? What are the consequences of these changes? Can metabolism be manipulated to restore a normal ATP supply? Does increasing energy supply have physiologic consequences (ie, does it lead to improved contractile [systolic and/or diastolic] performance)? In part I we focus on ATP, in part 2 on creatine, and in part 3 on the relationship between creatine and purine metabolism and purine nucleotide signaling.