Cardiovascular Drugs and Therapy

, Volume 26, Issue 5, pp 401–408

Propionyl-L-Carnitine Improves Endothelial Function, Microcirculation and Pain Management in Critical Limb Ischemia

  • S. De Marchi
  • S. Zecchetto
  • A. Rigoni
  • M. Prior
  • L. Fondrieschi
  • A. Scuro
  • F. Rulfo
  • E. Arosio
Article

Abstract

Introduction

Chronic critical limb ischemia (CLI) is a severe condition of hypo-perfusion of lower limbs, which is associated with inflammation and a pro-coagulative state. It is a disease at high risk of amputation and cardiovascular death. Propionyl-L-carnitine (PLC) is efficacious in improving pain free walking distance in peripheral arterial disease with claudication; it also exerts favorable effects on the arterial wall and on endothelial function. The purpose of this study was to evaluate the effects of PLC on microcirculation, endothelial function and pain relief in patients affected by CLI not suitable for surgical intervention.

Patients and methods

We enrolled 48 patients with CLI. Patients were randomized into two groups: the first group was treated with PLC, the second was treated with saline solution. All of them underwent the following tests: laser Doppler flowmetry at the forefoot at rest and after ischemia, trans cutaneous oxygen partial pressure and carbon dioxide partial pressure at the forefoot at rest and after ischemia, endothelium dependent dilation of the brachial artery. All tests were repeated after treatments. Pain was assessed by visual analog pain scale.

Results

Endothelium dependent dilation increased after PLC (9.5 ± 3.2 vs 4.9 ± 1.4 %; p < 0.05). Post-ischemic peak flow with laser-Doppler flow increased after PLC. TcPO2 increased, while TcPCO2 decreased after PLC; CO2 production decreased after PLC. VAS showed a significant reduction in pain perception after active treatment.

Conclusions

In CLI patients, PLC can improve microcirculation (post ischemic hyperemia, TcPO2 and TcPCO2 production). PLC also enhances endothelium dependent dilation and reduces analgesic consumption and pain perception.

Key words

Critical limb ischemia Carnitine Endothelium Laser-Doppler 

References

  1. 1.
    Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Department of Surgery, University Hospital, Orebro, Sweden. J Vasc Surg. 2007;45:S5–67.PubMedCrossRefGoogle Scholar
  2. 2.
    Second european consensus document on chronic critical leg ischemia. Circulation 1991;84:1–26.Google Scholar
  3. 3.
    Dormandy JA, Heeck L, Vig S. The fate of patients with critical leg ischemia. Semin Vasc Surg. 1999;12:142–7.PubMedGoogle Scholar
  4. 4.
    Nash GB, Thomas PRS, Dormandy J. Abnormal flow properties of white cells in patients with severe ischaemia of the leg. Br Med J. 1988;296:1699–701.CrossRefGoogle Scholar
  5. 5.
    Signorelli SS, Malaponte G, Di Pino L, Digrandi D, Pennisi G, Mazzarino MC. Effects of ischemic stress on leukocyte activation process in patients with chronic peripheral occlusive arterial disease: role of LPC administration. Pharmacol Res. 2001;44:305–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Bevilacqua MP, Pober JS, Majeau GR, Cotrau RS, Gimbrone Jr MA. Interleukin 1(1–14) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelia cells. J Exp Med. 1984;160:618.PubMedCrossRefGoogle Scholar
  7. 7.
    Indiveri C, Tonazzi A, Palmieri F. Identification and purification of the carnitine carrier from rat liver mitochondria. Biochim Biophys Acta. 1990;1020:81–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Brevetti G, Diehm C, Lambert D. European multicentre study on propionyl-L-carnitine in intermittent claudication. J Am Coll Cardiol. 1999;34:1618–24.PubMedCrossRefGoogle Scholar
  9. 9.
    Sethi R, Wang X, Ferrari R, Dhalla NS. Improvement of cardiac function and beta adrenergic signal transduction by propionyl-L-carnitine in congestive heart failure due to myocardial infarction. Coron Artery Dis. 2004;15:65–71.PubMedCrossRefGoogle Scholar
  10. 10.
    Lango R, Smolenski RT, Rogowski J, Siebert J, Wuitewicz M, Slominska EM, Lysiak-Szdlowska W, Yacoub MH. Propionyl-L-carnitine improves haemodynamics and metabolic markers of cardiac perfusion during coronary surgery in diabetic patients. Cardiovasc Drug Ther. 2005;19:267–75.CrossRefGoogle Scholar
  11. 11.
    Orlandi A, Marcellini M, Pesce D, Calvani M, Spagnoli LG. PLC reduces intimal hyperplasia after injury in normocholesterolemic rabbit carotid artery by modulating proliferation and caspase 3-dependent apoptosis of vascular smooth muscle cells. Atherosclerosis. 2002;160:81–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Cipolla MJ, Nicholoff A, Rebello T, Amato A, Porter JM. PLC dilates human subcutaneous arteries through an endothelium dependent mechanism. J Vasc Surg. 1999;29:1097–103.PubMedCrossRefGoogle Scholar
  13. 13.
    Bueno R, Alvarez de Sotomayor M, Perez Guerrero C, Gomez Amores L, Vazquez CM, Herrera MD. L-carnitine and propionyl-L-carnitine improve endothelial dysfunction in spontaneously hypertensive rats: different participation of NO and COX products. Life Sci. 2005;77:2082–97.PubMedCrossRefGoogle Scholar
  14. 14.
    Vanella A, Russo A, Acquaviva R, Campisi A, Di Giacomo C, Sorrenti V, Barcellona ML. L-propionyl-carnitine as superoxide scavenger, antioxidant and DNA cleavage protector. Cell Biol Toxicol. 2000;16:99–104.PubMedCrossRefGoogle Scholar
  15. 15.
    Loffredo L, Pignatelli P, Cangemi R, Andreozzi P, Panico MA, Meloni V, Violi F. Imbalance between nitric oxide generation and oxidative stress in patients with peripheral arterial disease: effect of antioxidant treatment. J Vasc Surg. 2006;44:525–30.PubMedCrossRefGoogle Scholar
  16. 16.
    Del Guercio R. Evaluation of postischemic hyperemia on the skin using laser Doppler velocimetry: study on patients with intermittens claudication. Microvasc Res. 1986;32:289–99.PubMedCrossRefGoogle Scholar
  17. 17.
    De Marchi S, Prior M, Rigoni A, Zecchetto S, Rulfo F, Arosio E. Ascorbic acid prevents vascular dysfunction induced by oral glucose load in healthy subjects. Eur J Intern Med. 2012;23:54–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Arosio E, De Marchi S, Prior M, Zannoni M, Lechi A. Effects of nebivolol and atenolol on small arteries and microcirculatory endothelium-dependent dilation in hypertensive patients undergoing isometric stress. J Hypertens. 2002;20:1793–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Arosio E, De Marchi S, Zannoni M, Prior M, Lechi A. Effect of glutathione infusion on leg arterial circulation, cutaneous microcirculation, and pain-free walking distance in patients with peripheral obstructive arterial disease: a randomized, double-blind, placebo-controlled trial. Majo Clin Proc. 2002;77:754–9.CrossRefGoogle Scholar
  20. 20.
    Larsen JF, Cristensen CR. Forefoot transcutaneous oxygen tension at different leg positions in patients with peripheral vascular disease. Eur J Vasc Surg. 1990;8:185–8.CrossRefGoogle Scholar
  21. 21.
    Melillo E, Ferrari M, Balbarini A, Pedrinelli R. Transcutaneous oxygen and carbon dioxide levels in iloprost administration in diabetic critical limb ischemia. Vasc Endovasc Surg. 2006;40:303–11.CrossRefGoogle Scholar
  22. 22.
    Melillo E, Nuti M, Pedrinelli R, Buttitta F, Balbarini A. Is transcutaneous oxygen and carbon dioxide monitoring indispensable in short and long term therapeutic management of non reconstructable lower critical limb ischemia? Minerva Cardioangiol. 2006;54:481–98.PubMedGoogle Scholar
  23. 23.
    Gersbach PA, Argitis V, Gardaz JP, von Segesser LK, Haesler E. Late outcome of spinal cord stimulation for unreconstructable and limb-treatening lower limb ischemia. Eur J Vasc Endovasc Surg. 2007;33:717–24.PubMedCrossRefGoogle Scholar
  24. 24.
    Andreozzi GM, Rigigo F, Butto’ G, Barresi M, Leone A, Pennisi G, Martini R, Signorelli S. Transcutaneous PCO2 level as an index of tissue resistance to ischemia. Angiology. 1995;46:1097–102.PubMedCrossRefGoogle Scholar
  25. 25.
    Celemajer DS, Sorensen KE, Goock VM, Spieghelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–5.CrossRefGoogle Scholar
  26. 26.
    Sorensen KE, Celermajer DS, Spiegelhalter DJ. Non-invasive measurement of endothelium-dependent arterial responses in man: accuracy and reproducibility. Br Heart J. 1995;74:247–53.PubMedCrossRefGoogle Scholar
  27. 27.
    Takase B, Uehata A, Akima T. Endothelium-dependent flow-mediated vasodilation in coronary and brachial arteries in suspected coronary artery disease. Am J Cardiol. 1998;82:1535–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Arosio E, De Marchi S, Rigoni A, Prior M, Delva P, Lechi A. Forearm haemodynamics, arterial stiffness and microcirculatory reactivity in rheumatoid arthritis. J Hypertens. 2007;25:1273–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Ruger LJ, Irnich D, Abaji TN, Crispin A, Hoffmann U, Lang PM. Characteristics of chronic ischemic pain in patients with peripheral arterial disease. Pain. 2008;139:201–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Milio G, Novo G, Genova C, Almasio PL, Novo S, Pinto A. Pharmacological treatment of patients with chronic critical limb ischemia: L-propionyl-carnitine enhances the short-term effects of PGE-1. Cardiovasc Drugs Ther. 2009;23:301–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Calo LA, Pagnin E, Davis PA, Semplicini A, Nicolai R, Calvani M, Pessina AC. Antioxidant effect of L-carnitine and its short chain esters: relevance for the protection from oxidative stress related cardiovascular damage. Int J Cardiol. 2006;107:54–60.PubMedCrossRefGoogle Scholar
  32. 32.
    Vita JA, Hamburg NM. Does endothelial dysfunction contribute to the clinical status of patients with peripheral arterial disease? Can J Cardiol. 2010;26:45A–50.PubMedCrossRefGoogle Scholar
  33. 33.
    Stasi MS, Scioli MG, Arcuri G, Mattera GG, Lombardo K, Marcellini M, Riccioni T, De Falco S, Pisano C, Spagnoli LG, Borsini F, Orlandi A. Propionyl-L-carnitine improves postischemic blood flow recovery and arteriogenetic revascularization and reduces endothelial NADPH-oxidase 4 mediated superoxyde production. Arterioscler Thromb Vasc Biol. 2010;30:426–35.PubMedCrossRefGoogle Scholar
  34. 34.
    Allegra C, Antignani PL, Schacter I, Koverech A, Messano M, Virmani A. Propionyl-L-carnitine in Leriche-Fontaine stage II peripheral arterial obstructive disease. Ann Vasc Surg. 2008;22:552–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Packer L, Valenza M, Serbinova E, Starke-Reed P, Frost K, Kagan V. Free radical scavenging is involved in the protective effect of L-propionyl-carnitine against ischemia-reperfusion injury of the heart. Arch Biochem Biophys. 1991;288:533–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Ferrari R, Merli E, Cicchitelli G, Mele D, Fucili A, Ceconi C. Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review. Ann N Y Acad Sci. 2004;1033:79–91.PubMedCrossRefGoogle Scholar
  37. 37.
    Melillo E, Nuti M, Pedrinelli R, Buttitta F, Balbarini A. Is transcutaneous oxygen and carbon dioxide monitoring indispensable in short- and long-term therapeutic management of non-reconstructable lower critical limb ischemia? Minerva Cardioangiol. 2006;54:481–98.PubMedGoogle Scholar
  38. 38.
    McMackin CJ, Widlansky ME, Hamburg NM, Huang AL, Weller S, Holbrook M, Gocke N, Hagen TM, Keaney JF, Vita JA. Effect of combined treatment with alpha-lipoic acid and acetyl-L-carnitine on vascular function and blood pressure in patients with coronary artery disease. Clin Hypertens. 2007;9:249–55.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • S. De Marchi
    • 1
    • 3
  • S. Zecchetto
    • 1
  • A. Rigoni
    • 1
  • M. Prior
    • 1
  • L. Fondrieschi
    • 1
  • A. Scuro
    • 2
  • F. Rulfo
    • 1
  • E. Arosio
    • 1
  1. 1.Division of Vascular Rehabilitation, Department of MedicineUniversity of VeronaVeronaItaly
  2. 2.Division of General Surgery A, Unit of Vascular SurgeryUniversity of VeronaVeronaItaly
  3. 3.Unità Operativa di Riabilitazione VascolareOspedale PoliclinicoVeronaItaly

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