Skip to main content

Advertisement

Log in

Exposure to Amphetamines Leads to Development of Amphetamine Type Stimulants Associated Cardiomyopathy (ATSAC)

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

With rapidly rising prevalence of exposure to Amphetamine Type Stimulants (ATS), novel insights into cardiotoxic effects of this substance are being presented in the literature and remarkably ATS Associated Cardiomyopathy (ATSAC) is emerging as a novel cardiovascular condition with its distinctive pathogenesis, risk factors, clinical features and prognosis. A comprehensive systematic review was performed to explore and analyze the current evidence on the association between ATS exposure and development of cardiomyopathy, biological mechanisms involved in pathogenesis of ATSAC, risk factors, clinical features and course of patients with ATSAC. Several animal studies, case reports, case series and case-control studies support the association between ATS exposure and ATSAC. Oxidative stress, accelerated apoptosis, increased p53 activity, cardiomyocyte necrosis, perfusion defects, fatty acid toxicity, altered gene expression, abnormal cardiac protein synthesis and function in addition to defects in intracellular calcium hemostasis present themselves as likely mechanisms of cardiotoxicity in ATSAC. Majority of patients with ATSAC were found to be male, young and presented late with severe dilated cardiomyopathy. Female ATS users predominantly develop Takotsubo type of ATSAC and in particular its atypical basal variant. Overall, cessation of ATS exposure seems to be associated with some degree of reversibility and recovery in ATSAC sufferers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Alles, G. A., & Prinzmetal, M. (1933). The comparative physiological actions of dl-β-phenylisopropylamine. I. Pressor effect and toxicity. Journal of Pharmacology and Experimental Therapeutics, 47, 339–354.

    CAS  Google Scholar 

  2. Rasmussen, N. (2006). Making the first anti-depressant: Amphetamine in American medicine, 1929–1950. Journal of the History of Medicine and Allied Sciences, 61, 288–323.

    Article  PubMed  Google Scholar 

  3. United Nations Office on Drugs and Crime. (2016). World drug report. New York: United Nations Publication.

    Google Scholar 

  4. United Nations Office on Drugs and Crime. (2014). World drug report. New York: United Nations Publication.

    Google Scholar 

  5. US Department of Justice National Drug Intelligence Center. (2011). National Drug Threat Assessment 2011, Pennsylvania.

  6. Terplan, M., Smith, E. J., Kozloski, M. J., & Pollack, H. A. (2009). Methamphetamine use among pregnant women. Obstetrics and Gynecology, 113, 1285–1291.

    Article  PubMed  Google Scholar 

  7. Sliman, S., Waalen, J., & Shaw, D. (2015). Methamphetamine-associated congestive heart failure: Increasing prevalence and relationship of clinical outcomes to continued use or abstinence. Cardiovascular Toxicology. doi:10.1007/s12012-015-9350-y.

    Google Scholar 

  8. Kiel, R. G., Ambrose, J., Khatri, B., Bhullar, M., Nalbandyan, M., & Ronaghi, R. (2015). The prevalence and presentation of methamphetamine associated cardiomyopathy: A single Center Experience. JACC, 65, 10_S.

    Article  Google Scholar 

  9. Yi, S. H., Yang, T. T., Liu, L., Wang, H., & Liu, Q. (2008). Myocardial lesions after long-term administration of methamphetamine in rats. Chinese Medical Sciences Journal, 23, 239–243.

    Article  PubMed  Google Scholar 

  10. Lord, K. C., Shenouda, S. K., McIlwain, E., Charalampidis, D., Lucchesi, P. A., & Varner, K. J. (2010). Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction. Cardiovascular Research, 78, 111–118.

    Article  Google Scholar 

  11. Vaupel, D. B., Schindler, C. W., & Chefer, S. (2016). Delayed emergence of methamphetamine’s enhanced cardiovascular effects in nonhuman primates during protracted methamphetamine abstinence. Drug and Alcohol Dependence, 159, 181–189.

    Article  CAS  PubMed  Google Scholar 

  12. Smith, H. J., Roche, A. H. G., Jagusch, M. F., & Herdson, P. B. (1976). Cardiomyopathy associated with amphetamine administration. American Heart Journal, 91, 792–797.

    Article  CAS  PubMed  Google Scholar 

  13. Call, T. D., Hartneck, J., Dickinson, W. A., Hartman, C. W., & Bartel, A. G. (1982). Acute cardiomyopathy secondary to intravenous amphetamine use. Annals of Internal Medicine, 97, 559–560.

    Article  CAS  PubMed  Google Scholar 

  14. O’Neill, M. E., Arnolda, L. F., Coles, D. M., & Nokolic, G. (1983). Acute amphetamine cardiomyopathy in a drug addict. Clinical Cardiology, 6, 189–191.

    Article  PubMed  Google Scholar 

  15. Ayres, P. R. (1983). Amphetamine cardiomyopathy. Annals of Internal Medicine, 98, 110.

    Article  CAS  PubMed  Google Scholar 

  16. Jacobs, L. J. (1989). Reversible dilated cardiomyopathy induced by methamphetamine. Clinical Cardiology, 12, 725–727.

    Article  CAS  PubMed  Google Scholar 

  17. Srikanth, S., Barua, R., & Ambrose, J. (2008). Methamphetamine-associated acute left ventricular dysfunction: A variant of stress-induced cardiomyopathy. Cardiology, 109, 188–1892.

    Article  PubMed  Google Scholar 

  18. Karch, S. B. (2011). The unique histology of methamphetamine cardiomyopathy: A case report. Forensic Science International, 212, e1–e4.

    Article  CAS  PubMed  Google Scholar 

  19. Croft, C. H., Firth, B. G., Phil, D., & Hillis, L. D. (1982). Propylhexedrine-induced left ventricular dysfunction. Annals of Internal Medicine, 97, 560–561.

    Article  CAS  PubMed  Google Scholar 

  20. Wijetunga, M., Seto, T., Lindsay, J., & Schatz, I. (2003). Crystal methamphetamine-associated cardiomyopathy: Tip of the iceberg? Journal of Toxicology—Clinical Toxicology, 41, 981–986.

    Article  CAS  PubMed  Google Scholar 

  21. Jacobs, W. (2006). Fatal amphetamine-associated cardiotoxicity and its medicolegal implications. American Journal of Forensic Medicine and Pathology, 27, 156–160.

    Article  PubMed  Google Scholar 

  22. Sadeghi, R., Agin, K., Taherkhani, M., Najm-Afshar, L., & Nelson, L. S. (2012). Report of methamphetamine use and cardiomyopathy in three patients. DARU, 20, 20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hawley, L. A., Auten, J. D., Matteucci, M. J., Decker, L., Hurst, N., Beer, W., et al. (2013). Cardiac complications of adult methamphetamine exposures. Journal of Emergency Medicine, 45, 821–827.

    Article  PubMed  Google Scholar 

  24. Fulcher, J., & Wilcox, I. (2013). Basal stress cardiomyopathy induced by exogenous catecholamines in younger adults. International Journal of Cardiology, 68, e158–e160.

    Article  Google Scholar 

  25. Voskoboinik, A., Ihle, J. F., Bloom, J. E., & Kaye, D. M. (2016). Methamphetamine-associated cardiomyopathy: Patterns and predictors of recovery. Internal Medicine Journal, 46, 723–727.

    Article  CAS  PubMed  Google Scholar 

  26. Kueh, S. A., Gabriel, R. S., Lund, M., Sutton, T., Bradley, J., Kerr, A. J., et al. (2016). Clinical characteristics and outcomes of patients with amphetamine-associated cardiomyopathy in South Auckland, New Zealand. Journal of Heart, Lung and Circulation. doi:10.1016/j.hlc.2016.03.008.

    Google Scholar 

  27. Yeo, K. K., Wijetunga, M., Ito, H., Efird, J. T., Tay, K., Seto, T. B., et al. (2007). The association of methamphetamine use and cardiomyopathy in young patients. American Journal of Medicine, 120, 165–171.

    Article  CAS  PubMed  Google Scholar 

  28. Ito, H., Yeo, K. K., Wijetunga, M., Seto, T. B., Tay, K., & Schatz, I. J. (2009). A comparison of echocardiographic findings in young adults with cardiomyopathy: With and without a history of methamphetamine abuse. Clinical Cardiology, 32, E18–E22.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Sutter, M. E., Gaedigk, A., Albertson, T. E., Southard, J., Owen, K. P., Mills, L. D., et al. (2013). Polymorphisms in CYP2D6 may predict methamphetamine related heart failure. Clinical Toxicology (Philadelphia), 51, 540–544.

    Article  CAS  Google Scholar 

  30. Mohamed, H. A. (2007). Tachycardia-induced cardiomyopathy (Tachycardiomyopathy). The Libyan Journal of Medicine, 2, 26–29.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Sharkey, S. W., Lesser, J. R., & Maron, B. J. (2011). Takotsubo (Stress) cardiomyopathy. Circulation, 124, e460–e462.

    Article  PubMed  Google Scholar 

  32. Mobine, H. R., Baker, A. B., Wang, L., Wakimoto, H., Jacobsen, K. C., Seidman, C. E., et al. (2009). Pheochromocytoma-induced cardiomyopathy is modulated by the synergistic effects of cell-secreted factors. Circulation: Heart Failure, 2, 121–128.

    PubMed Central  Google Scholar 

  33. Redfords, B., Shao, Y., Ali, A., & Omerovic, E. (2014). Current hypotheses regarding the pathophysiology behind the takotsubo syndrome. International Journal of Cardiology, 177, 771–779.

    Article  Google Scholar 

  34. Gupta, S., & Figueredo, V. M. (2014). Tachycardia mediated cardiomyopathy: Pathophysiology, mechanisms, clinical features and management. International Journal of Cardiology, 172, 40–46.

    Article  PubMed  Google Scholar 

  35. Jiang, J. P., & Downing, S. E. (1990). Catecholamine cardiomyopathy: Review and analysis of pathogenetic mechanisms. The Yale Journal of Biology and Medicine, 63, 581–591.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Brown, J. M., & Yamamoto, B. K. (2003). Effects of amphetamines on mitochondrial function: Role of free radicals and oxidative stress. Pharmacology & Therapeutics, 99, 45–53.

    Article  CAS  Google Scholar 

  37. Badon, L. A., Hicks, A., Lord, K., Ogden, B. A., Meleg-Smith, S., & Varner, K. J. (2002). Changes in cardiovascular responsiveness and cardiotoxicity elicited during binge administration of Ecstasy. Journal of Pharmacology and Experimental Therapeutics, 302, 898–907.

    Article  CAS  PubMed  Google Scholar 

  38. Bolton, J. L., Trush, M. A., Penning, T. M., Dryhurst, G., & Monks, T. J. (2000). Role of quinones in toxicology. Chemical Research in Toxicology, 13, 135–160.

    Article  CAS  PubMed  Google Scholar 

  39. Shenouda, S. K., Varner, K. J., Carvalho, F., & Lucchesi, P. A. (2009). Metabolites of MDMA induce oxidative stress and contractile dysfunction in adult rat left ventricular myocytes. Cardiovascular Toxicology, 9, 30–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zuppinger, C., Timolati, F., & Suter, T. M. (2007). Pathophysiology and diagnosis of cancer drug induced cardiomyopathy. Cardiovascular Toxicology, 7, 61–66.

    Article  CAS  PubMed  Google Scholar 

  41. Gao, W. D., Liu, Y., & Marban, E. (1996). Selective effects of oxygen free radicals on excitation-contraction coupling in ventricular muscle. Implications for the mechanism of stunned myocardium. Circulation, 94, 2597–2604.

    Article  CAS  PubMed  Google Scholar 

  42. He, X., Liu, Y., Sharma, V., Dirksen, R. T., Waugh, R., Sheu, S. S., et al. (2003). ASK1 associates with troponin T and induces troponin T phosphorylation and contractile dysfunction in cardiomyocytes. American Journal of Pathology, 163, 243–251.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Itoh, S., Ding, B., Bains, C. P., Wang, N., Takeishi, Y., Jalili, T., et al. (2005). Role of p90 ribosomal S6 kinase (p90RSK) in reactive oxygen species and protein kinase C beta (PKC-beta)-mediated cardiac troponin I phosphorylation. Journal of Biological Chemistry, 280, 24135–24142.

    Article  CAS  PubMed  Google Scholar 

  44. Cadet, J. L., Jayanthi, S., & Ding, X. (2005). Methamphetamine-induced neuronal apoptosis involves the activation of multiple death pathways. Review. Neurotoxicity research, 8, 199–206.

    Article  CAS  PubMed  Google Scholar 

  45. Iwasa, M., Maeno, Y., Inoue, H., Koyama, H., & Matoba, R. (1996). Induction of apoptotic cell death in rat thymus and spleen after a bolus injection of methamphetamine. International Journal of Legal Medicine, 109, 23–28.

    Article  CAS  PubMed  Google Scholar 

  46. Chen, P. I., Perez-Martinez, S., Cao, A., Rhodes, C. J., Wang, L., & Rabinovitch, M. (2013). Amphetamine induces pulmonary arterial endothelial cell dysfunction by increasing vulnerability to apoptosis and production of pro-inflammatory cytokines. In American Thoracic Society International Conference Abstracts A52. Mechanisms of Pulmonary Vascular Disease A1747.

  47. Montiel-Duarte, C., Varela-Rey, M., Osés-Prieto, J. A., López-Zabalza, M. J., Beitia, G., Cenarruzabeitia, E., et al. (2002). 3,4-Methylenedioxymethamphetamine (“Ecstasy”) induces apoptosis of cultured rat liver cells. Biochimica et Biophysica Acta, 1588, 26–32.

    Article  CAS  PubMed  Google Scholar 

  48. Hu, A., Jiao, X., Gao, E., Koch, W. J., Sharifi-Azad, S., Grunwald, Z., et al. (2006). Chronic beta-adrenergic receptor stimulation induces cardiac apoptosis and aggravates myocardial ischemia/reperfusion injury by provoking inducible nitric-oxide synthase-mediated nitrative stress. Journal of Pharmacology and Experimental Therapeutics, 318, 469–475.

    Article  CAS  PubMed  Google Scholar 

  49. Pasumarthi, K. B. S., Daud, A. I., Field, L. J. (2000). Regulation of cardiomyocyte proliferation and apoptosis. Madame Curie Bioscience Database [Internet] Landes Bioscience. http://www.ncbi.nlm.nih.gov/books/NBK6014/. Accessed August 6, 2016.

  50. Imam, S. Z., Itzhak, Y., Cadet, J. L., Islam, F., Slikker, W. J., & Ali, S. F. (2001). Methamphetamine-induced alteration in striatal p53 and bcl-2 expressions in mice. Molecular Brain Research, 91, 174–178.

    Article  CAS  PubMed  Google Scholar 

  51. Chen, J. P. (2007). Methamphetamine-associated acute myocardial infarction and cardiogenic shock with normal coronary arteries: Refractory global coronary microvascular spasm. The Journal of Invasive Cardiology, 19, E89–E92.

    Article  PubMed  Google Scholar 

  52. Hung, M. J., Kuo, L. T., & Cherng, W. J. (2003). Amphetamine-related acute myocardial infarction due to coronary artery spasm. International Journal of Clinical Practice, 57, 62–64.

    CAS  PubMed  Google Scholar 

  53. Kurien, V. A., & Oliver, M. F. (1971). Free fatty acids during acute myocardial infarction. Progress in Cardiovascular Diseases, 13, 361–373.

    Article  CAS  PubMed  Google Scholar 

  54. Schulze, P. C. (2009). Myocardial lipid accumulation and lipotoxicity in heart failure. Journal of Lipid Research, 50, 2137–2138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Marfella, R., Di Filippo, C., Portoghese, M., Barbieri, M., Ferraraccio, F., Siniscalchi, M., et al. (2009). Myocardial lipid accumulation in patients with pressure-overloaded heart and metabolic syndrome. Journal of Lipid Research, 50, 2314–2323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Pinter, E. J., & Patee, C. J. (1968). Fat-mobilizing action of amphetamine. Journal of Clinical Investigation, 47, 394–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zucchi, R., & Daneshi, R. (2003). Cardiac toxicity of antineoplastic anthracyclines. Current Medicinal Chemistry: Anti-Cancer Agents, 3, 151–171.

    CAS  PubMed  Google Scholar 

  58. Takemura, G., & Fujiwara, H. (2007). Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Progress in Cardiovascular Diseases, 49, 330–552.

    Article  CAS  PubMed  Google Scholar 

  59. Yeh, E. T., Tong, A. T., Lenihan, D. J., Yusuf, S. W., Swafford, J., Champion, C., et al. (2004). Cardiovascular complications of cancer therapy: Diagnosis, pathogenesis, and management. Circulation, 109, 3122–3131.

    Article  PubMed  Google Scholar 

  60. Turdi, S., Schamber, R. M., Roe, N. D., Chew, H. G., Culver, B., & Ren, J. (2009). Acute methamphetamine exposure inhibits cardiac contractile function. Toxicology Letters, 189, 152–158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shyu, K. G., Wang, B. W., Yang, Y. H., Tsai, S. C., Lin, S., & Lee, C. C. (2004). Amphetamine activates connexin43 gene expression in cultured neonatal rat cardiomyocytes through JNK and AP-1 pathway. Cardiovascular Research, 63, 98–108.

    Article  CAS  PubMed  Google Scholar 

  62. Tiangco, D. A., Lattanzio, F. A., Osgood, C. J., Beebe, S. J., Kerry, J. A., & Hargrave, B. Y. (2005). 3,4-Methylenedioxymethamphetamine activates nuclear factor-κB, increases intracellular calcium, and modulates gene transcription in rat heart cells. Cardiovascular Toxicology, 5, 301–310.

    Article  CAS  PubMed  Google Scholar 

  63. Cerratani, D., Riezzo, I., Fiaschi, A. I., Centini, F., Giorgi, G., D’Errico, S., et al. (2008). Cardiac oxidative stress determination and myocardial morphology after a single ecstasy (MDMA) administration in a rat model. International Journal of Legal Medicine, 122, 461–469.

    Article  Google Scholar 

  64. Tiangco, D. A., Halcomb, S., Lattanzio, F. A., & Hargrave, B. Y. (2010). 3,4-Methylenedioxymethamphetamine alters left ventricular function and activates nuclear factor-kappaB (NF-κB) in a time and dose dependent manner. International Journal of Molecular Sciences, 11, 4843–4863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Mau, M. K., Seto, T. B., Kaholokula, J. K., Howards, B., & Ratner, R. E. (2014). Association of modifiable risk factors and left ventricular ejection fraction among hospitalized native Hawaiians and Pacific Islanders with heart failure. Hawai’i Journal of Medicine & Public Health, 73(Suppl 3), 14–20.

    Google Scholar 

  66. Pinto, Y. M., Elliott, P. M., Arbustini, E., Adler, Y., Anastasakis, A., Böhm, M., et al. (2016). Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: A position statement of the ESC working group on myocardial and pericardial diseases. European Heart Journal, 37, 1850–1858.

    Article  PubMed  Google Scholar 

  67. Hong, R., Matsuyama, E., & Nur, K. (1991). Cardiomyopathy associated with the smoking of crystal methamphetamine. JAMA, 265, 1152–1154.

    Article  CAS  PubMed  Google Scholar 

  68. Crean, A. M., & Pohl, J. E. F. (2004). ‘Ally McBeal heart?’—Drug induced cardiomyopathy in a young woman. British Journal of Clinical Pharmacology, 58, 558–559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Mizia-Stec, K., Gasior, Z., Wojnicz, R., Haberka, M., Mielczarek, M., Wierzbicki, A., et al. (2008). Severe dilated cardiomyopathy as a consequence of Ecstasy intake. Cardiovascular Pathology, 17, 250–253.

    Article  PubMed  Google Scholar 

  70. Innasimuthu, A. L., Sankarnarayanan, R., Rao, G. K., & Hornung, R. S. (2009). An unusual cause of breathlessness in a young man. Canadian Journal of Cardiology, 25, 369–371.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Stokes, M. B., Fernando, H., & Taylor, A. J. (2016). Cardiogenic shock secondary to methamphetamine induced cardiomyopathy requiring veno-arterial extra-corporeal membrane oxygenation. International Journal of Cardiology, 207, 134–135.

    Article  PubMed  Google Scholar 

  72. Bruno, V. D., Duggan, S., Capoun, R., & Ascione, R. (2014). Methamphetamine-induced cardiomyopathy causing severe mitral valve regurgitation. Archives of Medical Science, 10, 630–631.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Ramaraj, R., & Movahed, M. R. (2010). Reverse or inverted takotsubo cardiomyopathy (reverse left ventricular apical ballooning syndrome) presents at a younger age compared with the mid or apical variant and is always associated with triggering stress. Congestive Heart Failure, 16, 284–286.

    Article  PubMed  Google Scholar 

  74. Nishida, N., Ikeda, N., Kudo, K., & Esaki, R. (2003). Sudden unexpected death of a methamphetamine abuser with cardiopulmonary abnormalities: A case report. Medicine, Science and the Law, 43, 267–271.

    Article  Google Scholar 

  75. Aleksova, A., Sabbadini, G., Merlo, M., Pinamonti, B., Barbati, G., Zecchin, M., et al. (2009). Natural history of dilated cardiomyopathy: From asymptomatic left ventricular dysfunction to heart failure—A subgroup analysis from the Trieste Cardiomyopathy Registry. Journal of Cardiovascular Medicine (Hagerstown), 10, 699–705.

    Article  Google Scholar 

  76. Lopez, J. E., Yeo, K., Caputo, G., Buonocore, M., & Schaefer, S. (2009). Recovery of methamphetamine associated cardiomyopathy predicted by late gadolinium enhanced cardiovascular magnetic resonance. Journal of Cardiovascular Magnetic Resonance, 11, 46.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Islam, M. N., Kuroki, H., Hongcheng, B., Ogura, Y., Kawaguchi, N., Onishi, S., et al. (1995). Cardiac lesions and their reversibility after long term administration of methamphetamine. Forensic Science International, 75, 29–43.

    Article  CAS  PubMed  Google Scholar 

  78. Madias, J. E. (2016). Methamphetamine-triggered Takotsubo syndrome and methamphetamine-associated cardiomyopathy: A continuum? Internal Medicine Journal, 46, 752–753.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mahsa Jafari Giv.

Ethics declarations

Conflict of interest

The author declares that there is no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jafari Giv, M. Exposure to Amphetamines Leads to Development of Amphetamine Type Stimulants Associated Cardiomyopathy (ATSAC). Cardiovasc Toxicol 17, 13–24 (2017). https://doi.org/10.1007/s12012-016-9385-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-016-9385-8

Keywords

Navigation