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A Moderate Carnitine Deficiency Exacerbates Isoproterenol-Induced Myocardial Injury in Rats

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Abstract

Purpose

The myocardium is largely dependent upon oxidation of fatty acids for the production of ATP. Cardiac contractile abnormalities and failure have been reported after acute emotional stress and there is evidence that catecholamines are responsible for acute stress-induced heart injury. We hypothesized that carnitine deficiency increases the risk of stress-induced heart injury.

Methods

Carnitine deficiency was induced in Wistar rats by adding 20 mmol/L of sodium pivalate to drinking water (P). Controls (C) received equimolar sodium bicarbonate and a third group (P + Cn) received pivalate along with 40 mmol/L carnitine. After 15 days, 6 rats/group were used to evaluate function of isolated hearts under infusion of 0.1 μM isoproterenol and 20 rats/group were submitted to a single subcutaneous administration of 50 mg/kg isoproterenol.

Results

Isoproterenol infusion in C markedly increased the heart rate, left ventricular (LV) systolic pressure and coronary flow rate. In P rats, isoproterenol increased the heart rate and LV systolic pressure but these increases were not paralleled by a rise in the coronary flow rate and LV diastolic pressure progressively increased. Subcutaneous isoproterenol induced 15 % mortality rate in C and 50 % in P (p < 0.05). Hearts of surviving P rats examined 15 days later appeared clearly dilated, presented a marked impairment of LV function and a greater increase in tumor necrosis factor α (TNFα) levels. All these detrimental effects were negligible in P + Cn rats.

Conclusions

Our study suggests that carnitine deficiency exposes the heart to a greater risk of injury when sympathetic nerve activity is greatly stimulated, for example during emotional, mental or physical stress.

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References

  1. Rebouche CJ. Carnitine function and requirements during life cycle. Faseb j. 1992;6:3379–86.

    CAS  PubMed  Google Scholar 

  2. Pons R, De Vivo DC. Primary and secondary carnitine deficiency syndromes. J Child Neurol. 1995;10:S8–S24.

    Article  PubMed  Google Scholar 

  3. Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet. 2006;142:77–85.

    Article  Google Scholar 

  4. Magoulas PL, El-Hattab AW. Systemic primary carnitine deficiency: an overview of clinical manifestations, diagnosis, and management. Orphanet J Rare Dis. 2012;7:68.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Evans AM, Fornasini G. Pharmacokinetics of L-carnitine. Clin Pharmacokinet. 2003;42:941–67.

    Article  CAS  PubMed  Google Scholar 

  6. Brass EP. Pivalate-generating prodrugs and carnitine homeostasis in man. Pharmacol Rev. 2002;54:589–98.

    Article  CAS  PubMed  Google Scholar 

  7. Jia YY, Lu CT, Feng J, et al. Impact on L-carnitine homeostasis of short-term treatment with the pivalate prodrug tenofovir dipivoxil. Basic Clin Pharmacol Toxicol. 2013;113:431–5.

    Article  CAS  PubMed  Google Scholar 

  8. Boemer F, Schoos R, de Halleux V, Kalenga M, Debray FG. Surprising causes of C5-carnitine false positive results in newborn screening. Mol Genet Metab. 2014;111:52–4.

    Article  CAS  PubMed  Google Scholar 

  9. Ricciolini R, Scalibastri M, Carminati P, Arduini A. The effect of pivalate treatment of pregnant rats on body mass and insulin levels in the adult offspring. Life Sci. 2001;69:1733–8.

    Article  CAS  PubMed  Google Scholar 

  10. Broderick TL. Hypocarnitinaemia induced by sodium pivalate in the rat is associated with left ventricular dysfunction and impaired energy metabolism. Drugs R&D. 2006;7:153–61.

    Article  CAS  Google Scholar 

  11. Rasmussen J, Nielsen OW, Lund AM, Køber L, Djurhuus H. Primary carnitine deficiency and pivalic acid exposure causing encephalopathy and fatal cardiac events. J Inherit Metab Dis. 2013;36:35–41.

    Article  CAS  PubMed  Google Scholar 

  12. Cebelin M, Hirsch CS. Human stress cardiomyopathy. Hum Pathol. 1980;11:123–32.

    Article  CAS  PubMed  Google Scholar 

  13. Wittstein IS, Thiemann DR, Lima JAC, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352:539–48.

    Article  CAS  PubMed  Google Scholar 

  14. Martin AS. The brain–heart connection. Circulation. 2007;116:77–84.

    Article  Google Scholar 

  15. Templin C, Ghadri JR, Diekmann J, et al. Clinical features and outcomes of takotsubo (stress) cardiomyopathy. N Engl J Med. 2015;373:929–38.

    Article  CAS  PubMed  Google Scholar 

  16. Analóczy Z Role of catecholamines in stress-induced heart disease. In: Beamish RE, Panagia V, Dhalla NS, editors. Pathogenesis of stress-induced heart disease. Boston: Martinus Nijhoff; 1985. p. 213–27.

    Chapter  Google Scholar 

  17. Downing SE, Chen V. Myocardial injury following endogenous catecholamine release in rabbits. J Mol Cell Cardiol. 1985;17:377–87.

    Article  CAS  PubMed  Google Scholar 

  18. Rona G Involvement of catecholamines in the development of myocardial cell damage. In: Beamish RE, Panagia V, Dhalla NS, editors. Pathogenesis of stress-induced heart disease. Boston: Martinus Nijhoff; 1985. p. 228–36.

    Chapter  Google Scholar 

  19. Arakawa H, Kodama H, Matsuoka N, Yamaguchi I. Stress increases plasma enzyme activities in rats: differential effects of adrenergic and cholinergic blockades. J Pharmacol Exp Ther. 1997;280:1296–303.

    CAS  PubMed  Google Scholar 

  20. Willis BC, Salazar-Cantú A, Silva-Platas C, et al. Impaired oxidative metabolism and calcium mishandling underlie cardiac dysfunction in a rat model of post-acute isoproterenol-induced cardiomyopathy. Am J Physiol Heart Circ Physiol. 2015;308:H467–77.

    Article  CAS  PubMed  Google Scholar 

  21. Costoli T, Bartolomucci A, Graiani G, Stilli D, Laviola G, Sgoifo A. Effects of chronic psycho-social stress on cardiac autonomic responsiveness and myocardial structure in mice. Am J Physiol Heart Circ Physiol. 2004;286:H2133–40.

    Article  CAS  PubMed  Google Scholar 

  22. Bianchi PB, Davis AT. Sodium pivalate treatment reduces tissue carnitines and enhances ketosis in rats. J Nutr. 1991;121:2029–36.

    CAS  PubMed  Google Scholar 

  23. Bergmeyer HU. Methoden der enzymatischen analyse. Verlag Chemie: Weinheim; 1974.

    Google Scholar 

  24. Pace JA, Wannemacher RW, Neufeld HA Improved radiochemical assay for carnitine and its derivatives in plasma and tissue extracts. Clin Chem. 1978;24:32–5.

    CAS  PubMed  Google Scholar 

  25. Ramesh CV, Malarvannan P, Jayakumar R, Jayasundar S, Puvanakrishnan R. Effect of a novel tetrapeptide derivative in a rat model of isoproterenol induced myocardial necrosis. Mol Cell Biochem. 1998;187:173–82.

    Article  CAS  PubMed  Google Scholar 

  26. Rasmussen J, Thomsen JA, Olesen JH, Lund TM, Mohr M, Clementsen J, Nielsen OW, Lund AM. Carnitine levels in skeletal muscle, blood, and urine in patients with primary carnitine deficiency during intermission of L-carnitine supplementation. JIMD Rep. 2015;20:103–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90:207–58.

    Article  CAS  PubMed  Google Scholar 

  28. Dennis SC, Gevers W, Opie LH. Protons in ischemia: where do they come from; where do they go to? J Mol Cell Cardiol. 1991;23:1077–86.

    Article  CAS  PubMed  Google Scholar 

  29. Liu Q, Docherty JC, Rendell JC, Clanachan AS, Lopaschuk GD. High levels of fatty acids delay the recovery of intracellular pH and cardiac efficiency in post-ischemic hearts by inhibiting glucose oxidation. J Am Coll Cardiol. 2002;39:718–25.

    Article  CAS  PubMed  Google Scholar 

  30. Hool LC. What cardiologists should know about calcium ion channels and their regulation by reactive oxygen species. Heart Lung Circ. 2007;16:361–72.

    Article  CAS  PubMed  Google Scholar 

  31. Garcia-Dorado D, Ruiz-Meana M, Inserte J, Rodriguez-Sinovas A, Piper HM. Calcium-mediated cell death during myocardial reperfusion. Cardiovasc Res. 2012;94:168–80.

    Article  CAS  PubMed  Google Scholar 

  32. Betgem RP, de Waard GA, Nijveldt R, Beek AM, Escaned J, van Royen N. Intramyocardial haemorrhage after acute myocardial infarction. Nat Rev Cardiol. 2015;12:156–67.

    Article  PubMed  Google Scholar 

  33. Burnstock G, Ralevic V. Purinergic signaling and blood vessels in health and disease. Pharmacol Rev. 2013;66:102–92.

    Article  PubMed  Google Scholar 

  34. Broderick TM, Christos SC, Wolf BA, et al. Fatty acid oxidation and cardiac function in the sodium pivalate model of secondary carnitine deficiency. Metabolism. 1995;44:499–505.

    Article  CAS  PubMed  Google Scholar 

  35. Sushamakumari S, Jayadeep A, Kumar JS, Menon VP. Effect of carnitine on malondialdehyde, taurine and glutathione levels in heart of rats subjected to myocardial stress by isoproterenol. Indian J Exp Biol. 1989;27:134–7.

    CAS  PubMed  Google Scholar 

  36. Mathew S, Menon PV, Kurup PA. Effect of administration of carnitine on the severity of myocardial infarction induced by isoproterenol in rats. Aust J Exp Biol Med Sci. 1986;64:79–87.

    Article  CAS  PubMed  Google Scholar 

  37. Morris GS, Zhou Q, Wolf BA, et al. Sodium pivalate reduces cardiac carnitine content and increases glucose oxidation without affecting cardiac functional capacity. Life Sci. 1995;57:2237–44.

    Article  CAS  PubMed  Google Scholar 

  38. Takahashi R, Asai T, Murakami H, et al. Pressure overload-induced cardiomyopathy in heterozygous carrier mice of carnitine transporter gene mutation. Hypertension. 2007;50:497–502.

    Article  CAS  PubMed  Google Scholar 

  39. Kuwajima M, Lu K, Sei M, et al. Characteristics of cardiac hypertrophy in the juvenile visceral steatosis mouse with systemic carnitine deficiency. J Mol Cell Cardiol. 1998;30:773–81.

    Article  CAS  PubMed  Google Scholar 

  40. Lahjouji K, Elimrani I, Wu J, Mitchell GA, Qureshi IA. A heterozygote phenotype is present in the jvs +/− mutant mouse livers. Mol Genet Metab. 2002;76:76–80.

    Article  CAS  PubMed  Google Scholar 

  41. Koizumi A, Nozaki J, Ohura T, et al. Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. Hum Mol Genet. 1999;8:2247–54.

    Article  CAS  PubMed  Google Scholar 

  42. Amat di San Filippo C, MR T, Mestroni L, LD B, Longo N. Cardiomyopathy and carnitine deficiency. Mol Genet Metab. 2008;94:162–6.

    Article  CAS  PubMed  Google Scholar 

  43. Scaglia F, Wang Y, Singh RH, et al. Defective urinary carnitine transport in heterozygotes for primary carnitine deficiency. Genet Med. 1998;1:34–9.

    Article  CAS  PubMed  Google Scholar 

  44. Di Liberato L, Arduini A, Rossi C, Di Castelnuovo A, et al. L-Carnitine status in end-stage renal disease patients on automated peritoneal dialysis. J Nephrol. 2014;27:699–706.

    Article  PubMed  Google Scholar 

  45. Converse Jr RL, Jacobsen TN, Toto RD, et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med. 1992;327:1912–8.

    Article  PubMed  Google Scholar 

  46. Abrahamsson K, Mellander M, Eriksson BO, et al. Transient reduction of human left ventricular mass in carnitine depletion induced by antibiotics containing pivalic acid. Br Heart J. 1995;74:656–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Burke AP, Virmani R. Pathophysiology of acute myocardial infarction. Med Clin North Am. 2007;91:553–72.

    Article  PubMed  Google Scholar 

  48. Willerson JT, Ridker PM Inflammation as a cardiovascular risk factor. Circulation. 2004;109:II2–II10.

    Article  PubMed  Google Scholar 

  49. Gasparyan AY Cardiovascular risk and inflammation: pathophysiological mechanisms, drug design, and targets. Curr Pharm Des. 2012;18:1447–9.

    Article  CAS  PubMed  Google Scholar 

  50. Lee BJ, Lin JS, Lin YC, Lin PT. Antiinflammatory effects of L-carnitine supplementation (1000 mg/d) in coronary artery disease patients. Nutrition. 2015;31:475–9.

    Article  CAS  PubMed  Google Scholar 

  51. Vescovo G, Ravara B, Gobbo V, et al. L-carnitine: a potential treatment for blocking apoptosis and preventing skeletal muscle myopathy in heart failure. Am J Physiol Cell Physiol. 2002;283:C802–10.

    Article  CAS  PubMed  Google Scholar 

  52. Jiang F, Zhang Z, Zhang Y, Wu J, Yu L, Liu S. L-carnitine ameliorates the liver inflammatory response by regulating carnitine palmitoyltransferase I-dependent PPARγ signaling. Mol Med Rep 2015

  53. Hua X, Su Z, Deng R, Lin J, Li DQ, Pflugfelder SC. Effects of L-carnitine, erythritol and betaine on pro-inflammatory markers in primary human corneal epithelial cells exposed to hyperosmotic stress. Curr Eye Res. 2015;40:657–67.

    Article  CAS  PubMed  Google Scholar 

  54. Ussher JR, Wang W, Gandhi M, Keung W, et al. Stimulation of glucose oxidation protects against acute myocardial infarction and reperfusion injury. Cardiovasc Res. 2012;94:359–69.

    Article  CAS  PubMed  Google Scholar 

  55. Heusch G, Libby P, Gersh B, et al. Cardiovascular remodelling in coronary artery disease and heart failure. Lancet. 2014;383:1933–43.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Arduini A, Bonomini M, Savica V, Amato A, Zammit V. Carnitine in metabolic disease: potential for pharmacological intervention. Pharmacol Ther. 2008;120:149–56.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was in part supported by funds from: Programma Operativo Nazionale [01_00937] - MIUR “Modelli sperimentali biotecnologici integrati per lo sviluppo e la selezione di molecole di interesse per la salute dell’uomo”. The authors are gratefull Daniela Heuberger for the excellent technical assistance.

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Authors and Affiliations

  1. Research and Development, Sigma Tau Pharmaceuticals, Via Pontina Km 30.400, 00071, Pomezia, Italy

    Pietro Lo Giudice

  2. Institute of Nephrology, Department of Medicine, G. d’Annunzio University, Via dei Vestini, 66013, Chieti, Italy

    Mario Bonomini

  3. Department of Research & Development, CoreQuest Sagl, Tecnopolo, Stabile Suglio, Via Cantonale 18, 6928, Manno, Switzerland

    Arduino Arduini

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  1. Pietro Lo Giudice
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Correspondence to Arduino Arduini.

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There are no known conflicts of interest associated with this publication for Prof. Mario Bonomini. Dr. Pietro Lo Giudice and Dr. Arduino Arduini confirm that they are employees of Sigma Tau Pharmaceuticals and CoreQuest Sagl, respectively.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Giudice, P.L., Bonomini, M. & Arduini, A. A Moderate Carnitine Deficiency Exacerbates Isoproterenol-Induced Myocardial Injury in Rats. Cardiovasc Drugs Ther 30, 119–127 (2016). https://doi.org/10.1007/s10557-016-6647-4

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