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.
Similar content being viewed by others
References
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.
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.
United Nations Office on Drugs and Crime. (2016). World drug report. New York: United Nations Publication.
United Nations Office on Drugs and Crime. (2014). World drug report. New York: United Nations Publication.
US Department of Justice National Drug Intelligence Center. (2011). National Drug Threat Assessment 2011, Pennsylvania.
Terplan, M., Smith, E. J., Kozloski, M. J., & Pollack, H. A. (2009). Methamphetamine use among pregnant women. Obstetrics and Gynecology, 113, 1285–1291.
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.
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.
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.
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.
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.
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.
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.
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.
Ayres, P. R. (1983). Amphetamine cardiomyopathy. Annals of Internal Medicine, 98, 110.
Jacobs, L. J. (1989). Reversible dilated cardiomyopathy induced by methamphetamine. Clinical Cardiology, 12, 725–727.
Srikanth, S., Barua, R., & Ambrose, J. (2008). Methamphetamine-associated acute left ventricular dysfunction: A variant of stress-induced cardiomyopathy. Cardiology, 109, 188–1892.
Karch, S. B. (2011). The unique histology of methamphetamine cardiomyopathy: A case report. Forensic Science International, 212, e1–e4.
Croft, C. H., Firth, B. G., Phil, D., & Hillis, L. D. (1982). Propylhexedrine-induced left ventricular dysfunction. Annals of Internal Medicine, 97, 560–561.
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.
Jacobs, W. (2006). Fatal amphetamine-associated cardiotoxicity and its medicolegal implications. American Journal of Forensic Medicine and Pathology, 27, 156–160.
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.
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.
Fulcher, J., & Wilcox, I. (2013). Basal stress cardiomyopathy induced by exogenous catecholamines in younger adults. International Journal of Cardiology, 68, e158–e160.
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.
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.
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.
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.
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.
Mohamed, H. A. (2007). Tachycardia-induced cardiomyopathy (Tachycardiomyopathy). The Libyan Journal of Medicine, 2, 26–29.
Sharkey, S. W., Lesser, J. R., & Maron, B. J. (2011). Takotsubo (Stress) cardiomyopathy. Circulation, 124, e460–e462.
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.
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.
Gupta, S., & Figueredo, V. M. (2014). Tachycardia mediated cardiomyopathy: Pathophysiology, mechanisms, clinical features and management. International Journal of Cardiology, 172, 40–46.
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.
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.
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.
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.
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.
Zuppinger, C., Timolati, F., & Suter, T. M. (2007). Pathophysiology and diagnosis of cancer drug induced cardiomyopathy. Cardiovascular Toxicology, 7, 61–66.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Kurien, V. A., & Oliver, M. F. (1971). Free fatty acids during acute myocardial infarction. Progress in Cardiovascular Diseases, 13, 361–373.
Schulze, P. C. (2009). Myocardial lipid accumulation and lipotoxicity in heart failure. Journal of Lipid Research, 50, 2137–2138.
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.
Pinter, E. J., & Patee, C. J. (1968). Fat-mobilizing action of amphetamine. Journal of Clinical Investigation, 47, 394–402.
Zucchi, R., & Daneshi, R. (2003). Cardiac toxicity of antineoplastic anthracyclines. Current Medicinal Chemistry: Anti-Cancer Agents, 3, 151–171.
Takemura, G., & Fujiwara, H. (2007). Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Progress in Cardiovascular Diseases, 49, 330–552.
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.
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.
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.
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.
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.
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.
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.
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.
Hong, R., Matsuyama, E., & Nur, K. (1991). Cardiomyopathy associated with the smoking of crystal methamphetamine. JAMA, 265, 1152–1154.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Madias, J. E. (2016). Methamphetamine-triggered Takotsubo syndrome and methamphetamine-associated cardiomyopathy: A continuum? Internal Medicine Journal, 46, 752–753.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The author declares that there is no conflict of interest.
Rights and permissions
About this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12012-016-9385-8