The Failing Heart — An Engine Out of Fuel

Abstract

H eart failure is an enormous medical and societal burden. 1,2 It is a common disease: more than 2% of the U.S. population, or almost 5 million people, are affected, and 30 to 40% of patients die from heart failure within 1 year after receiving the diagnosis. 3 Heart failure can be disabling, and it can severely reduce a patient's quality of life. It consumes approximately 2% of the National Health Service budget in the United Kingdom, and in the United States, the total annual cost of treatment for heart failure is approximately $28 billion. Moreover, the financial burden of heart failure will increase in coming decades because of the aging population and the improved treatments of its causes. Over the past 20 years, there has been considerable progress in the treatment of chronic heart failure with angiotensin-converting-enzyme (ACE) inhibitors, 4,5 aldosterone antagonists, 6 beta-receptor blockers, 7,8 and resynchronization therapy. 9,10 Even with the very best of modern therapy, however, heart failure is still associated with an annual mortality rate of 10%. 10 The search for better treatments is one of the major challenges in cardiology. Chronic heart failure is multifactorial. There are many reasons why a human heart can fail, 11 but the available evidence suggests that the failing heart is an engine out of fuel-that is, altered energetics play an important role in the mechanisms of heart failure. For this reason, the modulation of cardiac metabolism has promise as a new approach to the treatment of heart failure. This review describes cardiac energy metabolism, appraises the methods used for its assessment, evaluates the role of impaired energy metabolism in heart failure, and gives options for metabolic therapy. The Energy-S ta rvat ion H y p o the sis The concept that the failing heart is an energy-starved engine that has run out of fuel is decades old. It was proposed in 1939 by Herrmann and Decherd, 12 who, in their article entitled "The Chemical Nature of Heart Failure," described a significantly reduced creatine content in failing myocardium. Over the next 20 years, the energy-depletion hypothesis was pursued by various groups, 13-15 and today, energy metabolism in the heart-myocardial energetics-is a topic of considerable interest. 16-24 A major reason for the attention to this topic is that any energy-sparing treatment for heart failure such as beta-receptor blockers, 7,8 ACE inhibitors, 4,5 or angiotensin II blockers 25,26 improves the prognosis. The failing heart has been compared to a weak and tired horse, and if this horse is nourished properly, it can recover and work in the long term, albeit at a reduced level. 27 C a r di ac Energy Me ta bol ism Deprivation of cardiac energy has a major role in heart failure. 18 The heart consumes more energy than any other organ. It cycles about 6 kg of ATP every day

A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I

“…26 Such a mechanism could serve to sustain contractile function in an energy-deprived state such as in the failing heart. 56 Top-down MS/MS analysis of TnI isolated from healthy rat, mouse, and pig hearts have revealed that cTnI is basally phosphorylated solely at the Ser22 and Ser23, the PKA sites, [31][32][33] consistent with the topdown MS/MS results of cTnI treated with inactive AMPK [Fig. 4(B)].…”

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

“…Cardiac and peripheral organ metabolic impairment have been long recognized as an intrinsic component of HF pathophysiology 47, 48. Although metabolic derangements have been well described in HFrEF patients and animal models, limited data exist characterizing metabolic impairments in HFpEF 8, 9, 13.…”

Polymer Functionalization of Isolated Mitochondria for Cellular Transplantation and Metabolic Phenotype Alteration

“…As an example, high‐energy requiring cancer cells exhibit a phenotypic transition from oxidative phosphorylation (OXPHOS) to aerobic glycolysis (i.e., the Warburg effect),1 a phenomenon that in turn facilitates the growth and spread of these cells 2. On the other hand, reduced phosphocreatine‐to‐adenosine triphosphate (ATP) ratios observed in failing hearts highlight the energy‐depleted nature of the organ 3. Moreover, mitochondrial dysfunction is a hallmark of neurological conditions such as Parkinson's4 and Alzheimer's5 disease.…”