Metabolic and contractile dysfunction in HFpEF

About This Grant

Heart failure with preserved ejection fraction (HFpEF) is a systemic disorder affecting 3-4 million patients in the USA, predominantly older women. HFpEF leads to a significant loss of muscle strength and power (contractile dysfunction), contributing to disability, increased risk of falls, and death. Our proposal focuses on contractile dysfunction, which has been linked to mitochondrial impairments. However, the exact connection between metabolic abnormalities and loss of strength and power remains unclear. We have developed rat model that, in male and female animals, mirrors the cardiometabolic features and peripheral myopathy of HFpEF in patients. This model revealed a potential link between mitochondrial and contractile dysfunction in HFpEF involving accumulation of a TCA cycle metabolite that causes post-translational modification of sarcomere and EC-coupling proteins. Aging and HFpEF decrease TCA cycle and mitochondrial ETC enzymes that promote the accumulation of TCA cycle metabolites. Our data show that patients and rats with with HFpEF have increased post-translational modification by TCA cycle metabolites. Limb muscles from rats with HFpEF also have decreased abundance of the key enzyme responsible for reversing the post-translational modification. Ex vivo acute exposure of healthy muscles and single fibers to TCA cycle metabolite that accumulates in HFpEF increased post-translational modification of sarcomere and Ca2+ handling proteins and replicated the loss of force and power seen in HFpEF. Our central hypothesis is that PTM modifications of Ca2+ handling and sarcomeric proteins induced by TCA cycle metabolite impair Ca2+ release and contractile machinery structure- function, causing loss of force and peak power in postmenopausal HFpEF. The first aim is to investigate the mechanisms and establish the role of contractile dysfunction caused by TCA cycle metabolite in healthy muscle and rats with HFpEF. The second aim is to define the biophysical and biochemical mechanisms of contractile dysfunction in older women with HFpEF. We will focus on patients with advanced HFpEF and diagnosis including invasive hemodynamics (gold standard). Our studies in both aims will use comprehensive and complementary state-of-the-art techniques including intact muscle and single fiber contractile properties and [Ca2+], x-ray diffraction, ATPase activity in single fibers, high-frequency (4 kHz) oscillations to examine sarcomere level mechanics, electron microscopy, proteomics, mitochondrial phenotyping, and histology. The studies proposes are critical to provide insights on structural and biochemical modifications that impair function, establish optimal targets to combat loss of force or power using small-molecule modulators of Ca2+ release or sarcomeric proteins, and reveal novel mechanisms of postmenopausal HFpEF myopathy.