4/3/2014 It’s Not Just Blood Flow: Muscle Changes with Claudication and It’s Not Just Blood Flow: Muscle Changes with Claudication and the the Implications for Rehabilitation Implications for Rehabilitation DISCLOSURES Grants: NIA, NHLBI, Aastrom Biosciences Other support: VA Nebraska-Western Iowa Health Care System Unlabeled/unapproved uses disclosure: Coenzyme Q10, idebenone, mito-Q, lipoic acid, plastoquinol, melatonin, Gingko biloba, L-Carnitine, propionyl-L-Carnitine, Dichloroacetate, Ranolazine, Trimetazidine, Naftidrofuryl, Succinate, Nicotinamide, Acetylcysteine, Metalloporphyrins, Nitroxides, Ebselen, Resveratrol, Quecertin, Myricetin, Delphinidin, CDDO-ME, LG100268 2 Normal Muscle Myopathy of PAD Mild PAD Myopathy Severe PAD myopathy Polygonal cells Myofiber atrophy and degeneration Similar shape and size Fibrosis Peripherally located nuclei Fatty infiltration Thin perimysium 1
4/3/2014 Principal pathophysiologic features of the Skeletal muscle mitochondriopathy in PAD myopathy of PAD Evaluation of the ultrastructure and the biochemistry of PAD muscle reveals that the primary pathophysiologic features of this myopathy are: 1) Mitochondrial Dysfunction 2) Oxidative Damage Hiatt WR, JCI 1989 Bhatt et al, Circulation 1999 Brass et al, AJP Heart 2001 Pipinos et al, J Vasc Surg 2000 Pipinos et al, J Vasc Surg 2003 Pipinos, et al. Free Radic Biol Med. 2006 Skeletal muscle oxidative damage in PAD Skeletal muscle oxidative damage in PAD ADDUCTED CARBONYL GROUPS CONTROL SPECIMEN PAD SPECIMEN Gastrocnemius specimens of PAD patients (N=34) exhibit increased oxidative damage and reduced, myofiber cross-sectional area compared to control patients (N=21) Weiss , Casale et al, J Transl Med 2013 Pipinos et al, Free Radic Biol Med. 2006 Weiss , Casale et al, J Transl Med 2013 2
4/3/2014 Skeletal muscle oxidative damage in PAD Pathophysiology of PAD Mitochondrial dysfunction and the associated oxidative damage are central pathophysiologic features in the myopathy of PAD PAD stage correlates with myofiber oxidative damage determined as the content of carbonyl groups in gastrocnemius biopsies. Controls N=21, Claudication N= 13, Rest Pain N=9 and Tissue loss N=12 Weiss , Casale et al, J Transl Med 2013 Mitochondrial Respiration Pathophysiology of PAD Pre vs . Post Revascularization Pre: 55.7 ± 2.0 Post: 68.8 ± 2.5 Difference: ↑ 23.5% p < 0.001 120 Mitochondrial dysfunction and the associated Mitochondrial Respiration (nanoatom 100 O2·min −1·unit CS activity −1 ) oxidative damage are central pathophysiologic Post Revascularization 80 features in the myopathy of PAD 60 40 How do they respond to revascularization 20 operations? 0 0 20 40 60 80 100 120 Mitochondrial Respiration (nanoatom O 2 ·min −1·unit CS activity −1 ) Pre Revascularization 3
4/3/2014 Maximum Claudication Distance Oxidative Damage Pre vs . Post Revascularization Pre vs . Post Revascularization Pre: 1,588 ± 53 Post: 1,357 ± 58 Difference: ↓ 14.5% p<0.001 2,500 Carbonyl Signal (gsu) Post Revascularization 2,250 2,000 1,750 1,500 1,250 1,000 750 500 500 750 1,000 1,250 1,500 1,750 2,000 2,250 2,500 Carbonyl Signal (gsu) Pre Revascularization Revascularization for PAD patients Revascularization for PAD patients Revascularization operations improve the mitochondrial dysfunction and Revascularization operations improve the mitochondrial dysfunction and oxidative damage of PAD limbs, in association with improvements of limb oxidative damage of PAD limbs, in association with improvements of limb function and quality of life. function and quality of life. Is this a simple association between - mitochondrial function and oxidative stress in the leg muscles and - functional improvements of PAD patients? 4
4/3/2014 Revascularization for PAD patients Therapies for PAD patients Revascularization operations improve the mitochondrial dysfunction and Therapies that can target the mitochondrial oxidative damage of PAD limbs, in association with improvements of limb dysfunction and the elevated oxidant state of PAD function and quality of life. limbs may include: Is this a simple association between - mitochondrial function and oxidative stress in the leg muscles and - functional improvements of PAD patients? -Exercise therapy Are there other therapies that can target the mitochondrial dysfunction -Pharmacotherapy and the elevated oxidant state of PAD limbs and in result produce improvements in the function of PAD patients? -Stem cell therapy Stimulate mitochondrial bioenergetics Optimize energy metabolism in defective mitochondria Enhance b-Oxidation and Improve Acetyl-CoA metabolism Improve the function of the respiratory chain with L-Carnitine and propionyl-L-Carnitine coenzyme Q10, idebenone, mito-Q and Hiatt WR, Ann NY Acad Sci 2004 synthetic electron scavenging drugs (lipoic acid,plastoquinol) Hiatt WR, Am J Med 2001 Camara et al. Antioxid Redox Signal 2010 McCarty et al., Medical Hypotheses (2008) Shift metabolic pathways from fatty acid to glucose oxidation Skulachev et al. Biochim Biophys Acta, Biofactors 2009 via activation of Pyruvate Dehydrogenase Dichloroacetate, Enhance the function of complexes with melatonin (Complexes Ι Ranolazine (Ranexa), and ΙΙΙ ) and Gingko biloba products (complexes ΙΙ and Ι V) Trimetazidine (Vastarel), Dobesh,Pharmacotherapy 2009 Naftidrofuryl (Stimlor) Fosslien, Ann Clin Lab Sci 2001 Reiter, Ann N Y Acad Sci 2001 Dobesh PP,Pharmacotherapy 2009 Greenhaff P, Br J Clin Pharmacol 2003 Morin D, Expert Opin Ther Targets 2002 5
4/3/2014 Combined actions Reduce ROS production and remove excess ROS Coenzyme Q10, its synthetic analog Idebenone, Succinate, Nicotinamide and acetylcysteine DRUG ACTIONS - stimulate mitochondrial biogenesis Chinnery PF, The Cochrane Collaboration 2009 - anti-Inflammatory actions, modulation of NF-kB,TNFa, ICAM-1, VCAM-1 etc. Schon EA, J Clin Invest 2003 - direct scavenging of ROS Gold DR, Semin Neurol 2001 - induction of antioxidant enzymes (superoxide dismutases, catalase) - inhibition of oxidases (NADPH and Xanthine oxidase) - metal chelation Mimetics of the two basic antioxidant enzymes, FLAVONOIDS MnSOD (Metalloporphyrins, Nitroxides) and GPX (Ebselen) Resveratrol, Quecertin, Myricetin, Delphinidin Activators of Sirtuin-1 (Silent Information Regulator-1) and PGC-1a (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) Masella R, J.Nutr.Biochem 2005 Muscoli C, Br J Pharmacol 2003 TRITERPENOIDS CDDO-ME (methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate methyl ester) Activators of NRF-2 (Nuclear respiratory factor 2) Ι ncrease of the production of glutathione, by increasing gamma- glutamylcysteine synthase (Melatonin) REXINOIDS Synthetic rexinoid LG100268 Activators of retinoid X receptors (RXR) and McCarty MF, Medical Hypotheses 2010 PPAR- γ (Peroxisome proliferator activated receptor gamma) Davis JM, Am J Physiol Regu 2009 Akhlaghi M, J Mol Cel Cardiol 2009 Tran AT, J Neuroinfl 2008 Tanaka T, Cancer Res 2009 Collaborators Future Directions George Casale PhD, Nick Stergiou PhD, Mark Williams PhD, Jason Johanning MD, Michael Boska PhD, Gleb Haynatzki, PhD, Rodney McComb MD, Jeyam Subbiah PhD, George Rozanski PhD, David Mercer MD, Iraklis Pipinos MD Team Members Jennifer Bradley BS, Lauren Carpenter MD, Kim Cluff PhD, Holly DeSpiegelaere RN, Duy Ha BS, Jeffrey Kaipust MS, Paul Knoll BS, Julian KS Kim PhD, Panos Koutakis MS, Melissa Messinger MS, Dimitrios Miserlis MD, Sara Myers PhD, Cindy Niemack-Brown RN, Eva Papoutsi BS, Greg Prorok MS, Valerie Shostrom MS, Stanley Swanson BS, Jonathan Thompson MD, Dustin Weiss MD, Shane Wurdeman MS, Jennifer Yentes MS, Zhen Zhu MD Normal Muscle Severe PAD muscle Support Grants: NIA, NHLBI, Aastrom Biosciences Other support: VA Nebraska-Western Iowa Health Care System 6
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