Normal Muscle Myopathy of PAD Mild PAD Myopathy Severe PAD - - PowerPoint PPT Presentation

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It’s Not Just Blood Flow: Muscle Changes with Claudication and the 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 It’s Not Just Blood Flow: Muscle Changes with Claudication and the Implications for Rehabilitation

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Normal Muscle

Polygonal cells Similar shape and size Peripherally located nuclei Thin perimysium

Myopathy of PAD

Mild PAD Myopathy Severe PAD myopathy

Myofiber atrophy and degeneration Fibrosis Fatty infiltration

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Principal pathophysiologic features of the 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 Skeletal muscle mitochondriopathy in PAD

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

Weiss , Casale et al, J Transl Med 2013 Pipinos et al, Free Radic Biol Med. 2006

ADDUCTED CARBONYL GROUPS

PAD SPECIMEN CONTROL SPECIMEN

Skeletal muscle oxidative damage in PAD

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

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Skeletal muscle oxidative damage in 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

Pathophysiology of PAD Mitochondrial dysfunction and the associated

• xidative damage are central pathophysiologic

features in the myopathy of PAD Pathophysiology of PAD Mitochondrial dysfunction and the associated

• xidative damage are central pathophysiologic

features in the myopathy of PAD How do they respond to revascularization

• perations?

Mitochondrial Respiration Pre vs. Post Revascularization

20 40 60 80 100 120 20 40 60 80 100 120 Mitochondrial Respiration (nanoatom O2·min−1·unit CS activity−1) Post Revascularization Mitochondrial Respiration (nanoatom O2·min−1·unit CS activity−1) Pre Revascularization Pre: 55.7 ± 2.0 Post: 68.8 ± 2.5 Difference: ↑ 23.5% p < 0.001

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Oxidative Damage Pre vs. Post Revascularization

500 750 1,000 1,250 1,500 1,750 2,000 2,250 2,500 500 750 1,000 1,250 1,500 1,750 2,000 2,250 2,500 Carbonyl Signal (gsu) Post Revascularization Carbonyl Signal (gsu) Pre Revascularization Pre: 1,588 ± 53 Post: 1,357 ± 58 Difference: ↓ 14.5% p<0.001

Maximum Claudication Distance Pre vs. Post Revascularization

Revascularization for PAD patients

Revascularization operations improve the mitochondrial dysfunction and

• xidative damage of PAD limbs, in association with improvements of limb

function and quality of life.

Revascularization for PAD patients

Revascularization operations improve the mitochondrial dysfunction and

• xidative damage of PAD limbs, in association with improvements of limb

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?

4/3/2014 5 Revascularization for PAD patients

Revascularization operations improve the mitochondrial dysfunction and

• xidative damage of PAD limbs, in association with improvements of limb

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?

Are there other therapies that can target the mitochondrial dysfunction and the elevated oxidant state of PAD limbs and in result produce improvements in the function of PAD patients?

Therapies for PAD patients

Therapies that can target the mitochondrial dysfunction and the elevated oxidant state of PAD limbs may include:

• Exercise therapy
• Pharmacotherapy
• Stem cell therapy

Stimulate mitochondrial bioenergetics

Improve the function of the respiratory chain with coenzyme Q10, idebenone, mito-Q and synthetic electron scavenging drugs (lipoic acid,plastoquinol)

Camara et al. Antioxid Redox Signal 2010 McCarty et al., Medical Hypotheses (2008) Skulachev et al. Biochim Biophys Acta, Biofactors 2009

Enhance the function of complexes with melatonin (Complexes Ι and ΙΙΙ) and Gingko biloba products (complexes ΙΙ and ΙV)

Dobesh,Pharmacotherapy 2009 Fosslien, Ann Clin Lab Sci 2001 Reiter, Ann N Y Acad Sci 2001

Optimize energy metabolism in defective mitochondria

Enhance b-Oxidation and Improve Acetyl-CoA metabolism L-Carnitine and propionyl-L-Carnitine

Hiatt WR, Ann NY Acad Sci 2004 Hiatt WR, Am J Med 2001

Shift metabolic pathways from fatty acid to glucose oxidation via activation of Pyruvate Dehydrogenase Dichloroacetate, Ranolazine (Ranexa), Trimetazidine (Vastarel), Naftidrofuryl (Stimlor)

Dobesh PP,Pharmacotherapy 2009 Greenhaff P, Br J Clin Pharmacol 2003 Morin D, Expert Opin Ther Targets 2002

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Reduce ROS production and remove excess ROS

Coenzyme Q10, its synthetic analog Idebenone, Succinate, Nicotinamide and acetylcysteine

Chinnery PF, The Cochrane Collaboration 2009 Schon EA, J Clin Invest 2003 Gold DR, Semin Neurol 2001

Mimetics of the two basic antioxidant enzymes, MnSOD (Metalloporphyrins, Nitroxides) and GPX (Ebselen)

Masella R, J.Nutr.Biochem 2005 Muscoli C, Br J Pharmacol 2003

Ιncrease of the production of glutathione, by increasing gamma- glutamylcysteine synthase (Melatonin)

McCarty MF, Medical Hypotheses 2010

Combined actions

DRUG ACTIONS

• stimulate mitochondrial biogenesis
• anti-Inflammatory actions, modulation of NF-kB,TNFa, ICAM-1, VCAM-1 etc.
• direct scavenging of ROS
• induction of antioxidant enzymes (superoxide dismutases, catalase)
• inhibition of oxidases (NADPH and Xanthine oxidase)
• metal chelation

FLAVONOIDS Resveratrol, Quecertin, Myricetin, Delphinidin Activators of Sirtuin-1 (Silent Information Regulator-1) and PGC-1a (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) TRITERPENOIDS CDDO-ME (methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate methyl ester) Activators of NRF-2 (Nuclear respiratory factor 2) REXINOIDS Synthetic rexinoid LG100268 Activators of retinoid X receptors (RXR) and 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

Normal Muscle Severe PAD muscle

Future Directions

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 Collaborators 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 Grants: NIA, NHLBI, Aastrom Biosciences Other support: VA Nebraska-Western Iowa Health Care System Support