MRS in the failing heart: From mice to humans

Research output: Contribution to journalArticlepeer-review

Abstract

Heart failure (HF) affects over 5 million Americans and takes a significant toll of morbidity, mortality, and health-care costs worldwide. The hypothesis that abnormalities in myocardial energy production are present and underlie human HF is logical and compelling. Adenosine triphosphate (ATP) is the biochemical energy that fuels muscular contraction, and creatine kinase (CK) reaction is the primary energy reserve. Phosphorus (31P) magnetic resonance spectroscopy (MRS) is uniquely capable of measuring the principle substrates in the CK reaction in the living heart noninvasively. Experimental studies in animal models show that reductions in myocardial CK energy reserve significantly limit contractile reserve in normal hearts. Moreover, substrate reductions of [ATP], phosphocreatine (PCR), and PCR/ATP ratios observed by 31P MRS in failing hearts coincide with impaired systolic and diastolic function. The consistency of these findings across multiple species and etiologies argues strongly that metabolic abnormalities in CK energy reserve are a critical component of HF, possibly contributing to its pathophysiology. The recent extension of 31P MRS to noninvasive measurements of ATP flux through CK shows flux reductions in mild-to-moderate human HF that exceed those in the underlying substrates, and reduced CK flux is an independent predictor of subsequent clinical HF events including hospitalizations and death. Mouse models in which expression of CK is knocked out, augmented, or switched on and off are available. In two different murine models of cardiomyopathy, these methods showed that CK overexpression improves contractile function and survival. These findings suggest that impaired cardiac energetics play a central role in HF, that 31P MRS measurements could complement existing risk assessment metrics for HF patients, that strategies to augment CK ATP metabolism in the failing human heart should be pursued and that 31P MRS offers a powerful and unique tool to evaluate both the underlying causes of HF and new treatment strategies.

Original languageEnglish (US)
Pages (from-to)1271-1282
Number of pages12
JournaleMagRes
Volume5
Issue number2
DOIs
StatePublished - Jan 1 2016

Keywords

  • Creatine kinase
  • Dilated cardiomyopathy
  • Energymetabolism
  • Heart
  • Heart failure
  • Hypertrophic cardiomyopathy heart failure
  • Magnetic resonance spectroscopy (MRS)
  • Myocardial energy
  • Phosphorus (31P)

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Biomedical Engineering
  • Radiology Nuclear Medicine and imaging
  • Spectroscopy

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