Multimodality assessment of heart failure with preserved ejection fraction skeletal muscle reveals differences in the machinery of energy fuel metabolism
Payman Zamani, Elizabeth A Proto, Neil Wilson, Hossein Fazelinia, Hua Ding, Lynn A Spruce, Antonio Davila Jr, Thomas C Hanff, Jeremy A Mazurek, Stuart B Prenner, Benoit Desjardins, Kenneth B Margulies, Daniel P Kelly, Zoltan Arany, Paschalis-Thomas Doulias, John W Elrod, Mitchell E Allen, Shana E McCormack, Gayatri Maria Schur, Kevin D'Aquilla, Dushyant Kumar, Deepa Thakuri, Karthik Prabhakaran, Michael C Langham, David C Poole, Steven H Seeholzer, Ravinder Reddy, Harry Ischiropoulos, Julio A Chirinos, Payman Zamani, Elizabeth A Proto, Neil Wilson, Hossein Fazelinia, Hua Ding, Lynn A Spruce, Antonio Davila Jr, Thomas C Hanff, Jeremy A Mazurek, Stuart B Prenner, Benoit Desjardins, Kenneth B Margulies, Daniel P Kelly, Zoltan Arany, Paschalis-Thomas Doulias, John W Elrod, Mitchell E Allen, Shana E McCormack, Gayatri Maria Schur, Kevin D'Aquilla, Dushyant Kumar, Deepa Thakuri, Karthik Prabhakaran, Michael C Langham, David C Poole, Steven H Seeholzer, Ravinder Reddy, Harry Ischiropoulos, Julio A Chirinos
Abstract
Aims: Skeletal muscle (SkM) abnormalities may impact exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF). We sought to quantify differences in SkM oxidative phosphorylation capacity (OxPhos), fibre composition, and the SkM proteome between HFpEF, hypertensive (HTN), and healthy participants.
Methods and results: Fifty-nine subjects (20 healthy, 19 HTN, and 20 HFpEF) performed a maximal-effort cardiopulmonary exercise test to define peak oxygen consumption (VO2, peak ), ventilatory threshold (VT), and VO2 efficiency (ratio of total work performed to O2 consumed). SkM OxPhos was assessed using Creatine Chemical-Exchange Saturation Transfer (CrCEST, n = 51), which quantifies unphosphorylated Cr, before and after plantar flexion exercise. The half-time of Cr recovery (t1/2, Cr ) was taken as a metric of in vivo SkM OxPhos. In a subset of subjects (healthy = 13, HTN = 9, and HFpEF = 12), percutaneous biopsy of the vastus lateralis was performed for myofibre typing, mitochondrial morphology, and proteomic and phosphoproteomic analysis. HFpEF subjects demonstrated lower VO2,peak , VT, and VO2 efficiency than either control group (all P < 0.05). The t1/2, Cr was significantly longer in HFpEF (P = 0.005), indicative of impaired SkM OxPhos, and correlated with cycle ergometry exercise parameters. HFpEF SkM contained fewer Type I myofibres (P = 0.003). Proteomic analyses demonstrated (a) reduced levels of proteins related to OxPhos that correlated with exercise capacity and (b) reduced ERK signalling in HFpEF.
Conclusions: Heart failure with preserved ejection fraction patients demonstrate impaired functional capacity and SkM OxPhos. Reductions in the proportions of Type I myofibres, proteins required for OxPhos, and altered phosphorylation signalling in the SkM may contribute to exercise intolerance in HFpEF.
Keywords: Exercise; HFpEF; Skeletal muscle.
Conflict of interest statement
Dr. Zamani has consulted for Vyaire (modest). Dr. Mazurek has received advisory board honoraria from Actelion Pharmaceuticals (modest) and United Therapeutics (modest). Dr. Margulies receives research funding from Sanofi‐Aventis (significant), Merck (significant), and GlaxoSmithKline (significant). Dr. Kelly received advisory board honoraria from Pfizer (significant) and Amgen (modest). Dr. Ischiropoulos is the Gisela and Dennis Alter endowed chair. Dr. Chirinos has received consulting honoraria from Sanifit (significant), Microsoft (modest), Fukuda‐Denshi (modest), Bristol‐Myers Squibb (modest), OPKO Healthcare (modest), Ironwood Pharmaceuticals (modest), Pfizer (modest), Akros Pharma (modest), Merck (modest), Edwards Lifesciences (modest), and Bayer (significant). Dr. Chirinos has received research grants from Microsoft, Fukuda‐Denshi and Bristol‐Myers Squibb (all significant). He is named as inventor in an UPenn patent for the use of inorganic nitrates/nitrites for the treatment of HFpEF and a patent application for the use of novel neoepitope biomarkers of tissue fibrosis in heart failure.
© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
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