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Mitochondrial Dysfunction in Heart Failure With Preserved Ejection Fraction - PubMed

  • ️Tue Jan 01 2019

Review

Mitochondrial Dysfunction in Heart Failure With Preserved Ejection Fraction

Anupam A Kumar et al. Circulation. 2019.

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome with an increasingly recognized heterogeneity in pathophysiology. Exercise intolerance is the hallmark of HFpEF and appears to be caused by both cardiac and peripheral abnormalities in the arterial tree and skeletal muscle. Mitochondrial abnormalities can significantly contribute to impaired oxygen utilization and the resulting exercise intolerance in HFpEF. We review key aspects of the complex biology of this organelle, the clinical relevance of mitochondrial function, the methods that are currently available to assess mitochondrial function in humans, and the evidence supporting a role for mitochondrial dysfunction in the pathophysiology of HFpEF. We also discuss the role of mitochondrial function as a therapeutic target, some key considerations for the design of early-phase clinical trials using agents that specifically target mitochondrial function to improve symptoms in patients with HFpEF, and ongoing trials with mitochondrial agents in HFpEF.

Keywords: MRI; exercise intolerance; heart failure with preserved ejection fraction; mitochondrial function.

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Figures

Figure 1.
Figure 1.. Utilizing multiple aspects of mitochondrial biology for the assessment of functional changes
Figure 2.
Figure 2.. Utilizing phosphorous MRS and CrCEST for the quantification of oxidative capacity in lower limbs during exercise.

Panel A shows a representative image from a phosphorous MR spectroscopy study of the lower limb. The phosphorous spectra are analyzed for each voxel before and after exercise, allowing quantification of phosphocreatine recovery as a marker of oxidative capacity. Panel B shows an example image from a CrCEST study with pre-exercise baseline and post-exercise muscle-group specific increase in free creatine signal and subsequent decay during recovery. Panel C provides a comparison of signal recovery to baseline during the post-exercise period in both phosphorous MRS and CrCEST. Reproduced from Kogan, et al.

Figure 3.
Figure 3.. Use of Near Infrared Spectroscopy for the assessment of skeletal muscle oxygen consumption.

Panel A shows measurements of oxygenated hemoglobin during intermittent occlusions post-exercise (to calculate individual slopes, indicated by arrows). This signal is calibrated according to an ischemic occlusion (panel B). A subsequent exponential fit of the slopes (panel C) allows for the measurement of oxygen consumption (MVO2).

Figure 4.
Figure 4.. Activity of mitochondria-targeted therapies

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