Effects of chronic methamphetamine exposure on heart function in uninfected and retrovirus-infected mice

Life Sciences 71 (2002) 953 – 965 www.elsevier.com/locate/lifescie

Effects of chronic methamphetamine exposure on heart function in uninfected and retrovirus-infected mice Qianli Yu a, Sergio Montes b, Douglas F. Larson b, Ronald R. Watson a,* a

College of Public Health, School of Medicine, Health Promotion Science Division, University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724, USA b Sarver Heart Center and Department of Surgery, University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724, USA Received 15 November 2001; accepted 25 February 2002

Abstract Methamphetamine (MA) increases catecholamine levels, which have detrimental effects on heart function through vasoconstriction, myocardial hypertrophy, and fibrosis. Murine retrovirus infection induces dilated cardiomyopathy (DCM). The present study investigated the cardiovascular effects of chronic MA treatment on uninfected and retrovirus-infected mice. C57BL/6 mice were studied after 12 weeks treatment. The four study groups were (group I) uninfected, MA placebo; (group II) infected, MA placebo; (group III) uninfected, MA treatment; and (group IV) infected and MA treatment. MA injections were given i.p. once a day for 5 days/week with a increasing dose from 15 mg/kg to 40 mg/kg. Left ventricular mechanics were measured in situ a using Millar conductance catheter system for pressure – volume loop analysis. Cardiac pathology was determined with histological analysis. In the uninfected mice, the load independent contractile parameters, pre-load recruitable stroke work (PRSW) and dP/dtmax vs. Ved, significantly decreased by 32% and 35% in MA treated mice when compared to the saline injected mice. In retrovirus-infected mice, although there were no significant difference in Ees, PRSW, and dP/dtmax vs. Ved due to MA treatment, they were increased 45%, 15% and 42% respectively when compared to saline treated mice. No further lowered heart function during murine AIDS may be due to the counteraction of the retroviral DCM and the MA induced myocardial fibrosis and hypertrophy (thickening of the ventricular walls). This is supported by increases in the End-diastolic volume (Ved, 38%) and End-systolic volume (Ves, 84%) in the retrovirus-infected saline injected mice, the decreases of 33% and 17% in the uninfected MAtreated mice, but no significant changes in the retrovirus-infected MA treated mice when compared to uninfected saline injected mice. These data suggest that MA induced myocardial cellular changes compensate for retrovirus induced DCM. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Methamphetamine (MA); Heart function; Murine AIDS; LP-BM5 Murine leukemia

*

Corresponding author. Tel.: +1-520-626-2850; fax: +1-520-626-6001. E-mail address: [email protected] (R.R. Watson). 0024-3205/02/$ - see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 0 0 2 4 - 3 2 0 5 ( 0 2 ) 0 1 7 6 9 - 1

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Introduction Methamphetamine (MA) is a derivative of amphetamine with strong effects on the central nervous system; it is highly addictive both physically and psychologically [1]. The cardiovascular manifestations of MA abuse are tachycardia, atrioventricular arrhythmias, myocardial ischemia and hypertension [2–4]. At autopsy after sudden death, some MA users have cardiac lesions or dilated cardiomyopathy, interstitial edema, cardiac hypertrophy, disarrangement of myofibers, rupture of myocardium and fibrosis [5–8]. Acute and overdose of MA use can cause sudden congestive heart failure leading to sudden death [9] while chronic administration of MA may cause cardiomyopathy in humans [4,10]. MA stimulates the CNS indirectly by promoting the release while inhibiting the breakdown catecholamines including norepinephrine (NE), detrimentally affecting the heart [11]. Chronic infusion of subhypertensive doses of NE in dogs causes myocardial hypertrophy [12]. Long term NE treatment in rats induced a 37% increase in interstitial fibrosis of left ventricle [13]. And also MA use increases intracellular Ca2+ concentration causing hypertrophy, atrophy, and damage to the microtubular and actin structures [10]. In cultured adult rat cardiomyocytes, MA directly induces an increase in cell size and reorganization of myofibrils, suggesting that chronic MA exposure facilitate the development of adult rat cardiomyocyte hypertrophy [6,10]. However, little is known about the heart function changes during chronic MA administration, especially in animals with existing cardiac infections. Intravenous drug use greatly increases the risk of HIV infection due to viral contamination of needles [1,14], leading to AIDS with cardiac dysfunction as a serious complication [15]. In the United States, ethanol and cocaine consumption increase the HIV-infection risk and alter cardiac contractile function, becoming a leading cause of cardiomyopathy in human [16–18]. Murine AIDS model studies also revealed that ethanol and cocaine use have accentuated negative effects on the immune system and heart function [8,19,20]. MA consumption was reported as associated with the disease progression of HIV infection and the cardiac disease in humans [1,21]. However, heart function changes due to chronic MA administration during murine AIDS are unclear. In the present study, we used a murine AIDS model to characterize the effects of chronic administration of MA on heart function in vivo, using an in situ conductance catheter system (CCS) to define cardiac effects of MA on heart hemodynamics in normal and retrovirally damaged mice.

Materials and Methods Animals Animal studies were performed with approval of the University of Arizona animal review committee. Guidelines for the Care and Use of Laboratory Animals and Principles of Laboratory animal Care were followed in this study. Thirty-two four-week-old C57BL/6 female mice were purchased from Charles River Laboratories (Wilmington, DE) and were certified virus-free. The mice were housed in the animal facility of the Arizona Health Science Center with four per cage under diurnal lighting conditions with freely accessible food. The housing facility was maintained at 22 jC and 60 to 80% relative humidity with a 12-hour light/dark cycle. Mice were fed with a NIH-31 modified mouse sterilizable diet (mouse diet

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#7001, Teklad, Madison, WI) and water ad libitum. After two weeks of adaptation, thirty-two mice were intraperitoneally infected by LP-BM5 murine leukemia retrovirus. Both uninfected and retrovirusinfected mice were randomly assigned to following four groups: uninfected saline treated (control), uninfected MA (From NIDA, Bethesda, MD) treated, infected saline treated and infected MA treated. 0.9% saline treatment was intraperitoneally given in 0.1 ml/kg 5 days/week for three months. MA (prepared immediately before injection) treatment was intraperitoneally administrated by 5 days/week for three months. We started the MA dose at 15 mg/kg according to MA neurotoxicity [22], and each week thereafter, the dose was increased according to our observation by 5 mg/kg until the dose was 40 mg/kg [8]. Then the dose was kept constant at 40 mg/kg. Eight mice from each group were used for heart function assay and those mice were exempted from injection 24 hr before assessment. LP-BM5 Murine Leukemia Retrovirus Infection The LP-BM5 retrovirus at 0.1 ml/mouse was injected intraperitoneally. The virus titer had an ecotropic (XC) of 4.5 log10 PFU /ml. It induces disease with a time course comparable to that previously published [23]. Infection of adult female C57BL/6 mice with LP-BM5 MuLV leads to the rapid induction of clinical symptoms with virtually no latent phase. In situ measurements of heart function with the Conductance Catheter System (CCS) Heart function of mice was measured in vivo with CCS as described by Yang [24]. Briefly, after the induction of anesthesia with urethane (1,000 mg/kg i.p.) followed by a-choloralose (50 mg/kg, i.p.). The mice were ventilated through a tracheotomy with a pressure-controlled respirator (RSP 1002, Kent, CT) at a rate of 120 breaths/min and FIO2 of 1.0. The mice were placed on a thermally controlled surgical plateform and maintained at 37.5 jC. A total loading volume of 300 Al of hetastarch (6% hetastarch in 0.9% saline, Abbott Laboratories, N. Chicago, IL), which provides volume loading to make up for vasodilation due to general anesthesia and any possible blood loss, was injected through the external jugular catheter prior to insertion of the Millar Catheter [24]. A transverse substernal incision was made to expose the cardiac apex and inferior vena cava. The Millar Catheter was inserted into the left ventricle through a stab wound made with a 25 gauge needle and positioned along the cardiac longitudinal axis with the distal electrode in the aortic root and the proximal electrode in the cardiac apex. With the ventilator turned off for 3 seconds, pressure–volume relationships were acquired by reducing the ventricular preload with an acute compression of the inferior vena cava. The Millar CCS Controller (Millar MCS-100) was set with a frequency select at 20 kHz, the low pass cutoff frequency at 50 kHz, the full-scale current selected at 30 AA, and the Pressure Transducer (TCB600) at 1 V/100 mmHg. The signals were acquired at a rate of 1000 Hz with BioBench custom software. The volume of the left ventricle was calibrated according to the method described by Yang et al [24]. Data Analysis The data was analyzed with Microsoft Excel according to the calculations described by Glower [25] and Kass [26]. The regression analysis between parameters was also performed with Excel. The software Pvan (Conductance Technologies, Inc. San Antonio, TX, and Millar Inc., Houston, TX) and SonoSOFT (Sonometrics Corporation, London, Ontario, Canada) were used to analyze the pressure–volume loop

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data. From the baseline loops, all of the hemodynamic parameters were calculated, and from the IVC compression loops, the parameters describing heart contractility [Ees (end systolic elastance), PRSW (preload recruitable stroke work), dP/dtmax vs.Ved] were calculated. Statistical Analysis All data was reported as mean F SEM. MINTAB Student paired t test was used to compare the differences between the parameters in the four groups. P < 0.05 was used as criteria for statistical significance.

Table 1 Effects of methamphetamine on uninfected and retrovirus-infected mice Parameter

BW HR Ved Ves Pmax SV EF CO CI SW SWI PVA SVI Ea Ees Ea/Ees H h PRSW dP/dtmax vs. Ved dP/dtmax dP/dtmin

Unit

g bpm AL AL mmHg AL % AL/min AL/min/g mmHg*AL mmHg*AL/g mmHg*AL AL/g mmHg/s mmHg/AL ms mmHg/AL mmHg AL mmHg/s mmHg/s

Uninfected injected with

Retrovirus infected injected with

Saline

MA

Saline

MA

Mean F SE

Mean F SE

Mean F SE

Mean F SE

24.4 F 0.6 545 F 15.3 20.2 F 2.8 10.3 F 1.8 92.2 F 7.2 10.7 F 1.5 53.2 F 4.3 5863 F 919 257 F 39.2 750 F 119 30.9 F 4.9 1534 F 256 0.46 F 0.06 10.7 F 1.6 24.4 F 6.7 0.47 F 0.07 6.9 F 0.4 0.03 F 0.02 105 F 6.6 899 F 173 7920 F 876 7194 F 675

a

22.3 F 0.2 485 F 18a 13.6 F 1.7a 8.5 F 1.9 71.5 F 3.7a 5.8 F 0.4a 46.2 F 6.0 2828 F 232a 126 F 9.7a 311 F 31.2a 13.9 F 1.3a 727 F 90a 0.26 F 0.02a 11.9 F 0.6 29.0 F 5.0 0.49 F 0.09 8.8 F 0.6a 0.18 F 0.05a 71 F 6.2a 586 F 94a 4654 F 465a 4782 F 501a

26.0 F 0.1 487 F 18b 27.8 F 3.9b 19.0 F 3.7b 69.3 F 2.3b 11.0 F 0.8 42.5 F 4.6 5309 F 328 204 F 8.4 615 F 57.6 23.4 F 1.6 1748 F 252 0.44 F 0.02 6.3 F 0.6 8.2 F 1.3b 0.90 F 0.18b 7.6 F 0.6 0.10 F 0.02b 72 F 10.2b 323 F 62b 5148 F 459b 4987 F 348b

25.7 F 0.9 507 F 18 19.8 F 2.1c 9.9 F 1.5c 74.9 F 9.6 11.0 F 0.9 55.5 F 4.0c 5519 F 390 217 F 18.5 646 F 103 25.8 F 4.4 1190 F 191 0.43 F 0.04 6.5 F 0.8 11.9 F 4.5 0.82 F 0.17 7.6 F 0.5 0.06 F 0.02 83 F 18.2 459 F 109 5659 F 503 5305 F 622

Hemodynamic parameters: BW, body weight; HR, heart rate; h, slope of end-diastolic pressure – volume relationship; CO, cardiac output; CI cardiac output index; SW, stroke work; SWI, stroke work index; SV, stroke volume; SVI, stroke volume index; dP/dtmax, maximum derivative of change in systolic pressure over time; dP/dtmin, maximum derivative of change in diastolic pressure over time; Ea, elastance of artery; Ees, end-systolic volume elastance; EF, ejection fraction; PVA, pressure – volume area; Ved, end-diastolic volume; Ves, end-systolic volume; H , time constant of iosvolumic relaxation; PRSW, preload recruitable stroke work; Ees/Ea, End-systolic elastance-to-arterial elastance ratio. a Indicates uninfected mice MA injected were significantly different from uninfected mice saline injected. b Indicates retrovirus-infected mice saline injected were significantly different from uninfected mice saline injected. c Indicates retrovirus-infected mice saline injected significantly different from retrovirus-infected mice MA injected.

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Results Comparison of Hemodynamics Between Uninfected and Retrovirus-infected Mice Table 1 compares the hemodynamic function parameters of uninfected and retrovirus-infected mice. Retrovirus infection significantly decreased End-systolic volume elastance (Ees, p < 0.05) (Fig. 1), and preload recruitable stroke work (PRSW, p < 0.01) (Fig. 2), by 66 and 31% respectively. Infection also lowered heart rate (HR, p < 0.05), maximum pressure (Pmax, p < 0.01) and maximum derivative of change in systolic pressure over time (dP/dtmax, p < 0.01), and dP/dtmax vs. Ved (p < 0.01). Diastolic function parameters maximum derivative of change on diastolic pressure over time (dP/dtmin), which shows the rate of diastolic relaxation was significantly (p < 0.01) decreased in retrovirus-infected mice. However retrovirus infection increased End-systolic volume (Ves, p < 0.05) and End-diastolic volume (Ved, p < 0.01) significantly by 84 and 38% respectively, along with slope of end-diastolic pressure–volume relationship (h, p < 0.05). The afterload Ea was not affected by retrovirus infection whereas the coupling ratio of arterial elastance to ventricular elastance (Ea/Ees) increased two-fold in retrovirus-infected mice compared with normal mice (p < 0.05). Hemodynamic Dysfunction Due to MA Administration in Uninfected Mice In uninfected mice, MA treatment significantly decreased HR (p < 0.05), Ved (p < 0.05), Pmax (p < 0.05), stroke volume index (SVI, p < 0.01) (Fig. 3), cardiac output index (CI, p < 0.05) Fig. 4,

Fig. 1. Changes of the end-systolic volume elastance (Ees) in four groups (uninfected, MA placebo; uninfected, MA treatment; infected, MA placebo; infected, MA treatment).

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Fig. 2. Changes of the preload recruitable stroke work (PRSW) in four groups (uninfected, MA placebo; uninfected, MA treatment; infected, MA placebo; infected, MA treatment). a indicates uninfected mice MA injected were significantly different from uninfected mice saline injected. b indicates retrovirus-infected mice saline injected were significantly different from uninfected mice saline injected.

stroke work index (SWI, p < 0.01) (Fig. 5), dP/dtmax (p < 0.01), dP/dtmin (p < 0.01), PRSW (p < 0.001), dP/dtmax vs. Ved (p < 0.05) (Table 1); however the time constant of isovolumic relaxation (H , p < 0.01) and h (p < 0.01) were significantly increased. Preload dependent parameters CI and SWI decreased by

Fig. 3. Changes of the stroke volume index (SVI) in four groups (uninfected, MA placebo; uninfected, MA treatment; infected, MA placebo; infected, MA treatment).

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Fig. 4. Changes of the cardiac output index (CI) in four groups (uninfected, MA placebo; uninfected, MA treatment; infected, MA placebo; infected, MA treatment).

51 and 55% respectively (Figs. 3 and 5), and preload independent parameters PRSW and dP/dtmax vs. Ved decreased by 32 and 35% respectively. Also Ved and Ves were decreased by 33 and 17% respectively.

Fig. 5. Changes of the stroke work index (SWI) in four groups (uninfected, MA placebo; uninfected, MA treatment; infected, MA placebo; infected, MA treatment).

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Hemodynamics Dysfunction Due to MA Administration in Retrovirus-infected Mice In retrovirus-infected mice, MA treatment significantly decreased Ved (29%, p < 0.05), Ves (48%, p < 0.05) and significantly increased (31%, p < 0.05) ejection fraction (EF) (Table 1). MA treatment did not significantly lower the load independent parameters PRSW, Ees, dP/dtmax vs. Ved; they increased them by 15, 45 and 42% respectively when compared to saline injected mice.

Discussion In the present study, chronic MA exposure effects on the cardiac system were evaluated both in uninfected and retrovirus-infected mice as well as the cardiac effect due to retrovirus infection. Retrovirus infection greatly decreased heart function from the data of hemodynamic parameters. Left ventricle (LV) contractility was significantly lower in retrovirus-infected mice than in normal mice. Ees, PRSW and dP/dtmax vs. Ved are pre-load and after-load independent parameters, quantifying the LV systolic mechanics. In addition, PRSW is based on the modified Frank–Starling law; not influenced by noise or ventricular geometry and statistically robust parameter for LV contractility due to its linear feature [25]. In our study, PRSW in retrovirus infected mice of 72 F 10.2 mmHg was significantly (p < 0.01) lower than the controls 105 F 6.6 mmHg (Fig. 2). The correlation of stroke work and enddiastolic volume is PRSW, the comparison of PRSW slope is shown in Fig. 6: Saline injected, uninfected mice (y = 104.27*x 1487.83, r2 = 0.98); MA injected, retrovirus-infected mice (y = 59.63*x 2 1083.48, r = 0.95). The decreased slope indicates that the heart function was decreased due to the MA treatment. Also, Ees and dP/dtmax vs. Ved were significantly (p < 0.01) decreased while Ves and Ved significantly (p < 0.05) increased when compared to uninfected mice. Ees was computed from the slope of the ESPVR, in retrovirus-infected mice, Ees markedly decreased and, very obviously in Fig. 7A and C, the pressure–volume relationship loops are greatly rightward shifted as compared to uninfected mice. Again this indicates the decreased heart function due MA administration. The lowered LV contractility and rightward shift of pressure–volume loops due to retrovirus infection are consistent with the human autopsy reports of HIV infected individuals of dilated cardiomyopathy (DCM) [27]. Whether rightward shift of pressure–volume loops in this study is due to DCM is not clear. It has been reported that MA administration promotes the catecholamines including norepinephrine release [11], norepinephrine can directly stimulate the cardiac adrenoceptors, enhance the expression of collagen in cardiac leading to increased fibrosis, the remodeling of rat heart results in hypertrophy [12], thus decreased the heart function. Also, direct viral activity or altered cytokine secretion may account for the decreased LV contractility due to retrovirus infection. Some animal model studies have reported that retrovirus infections through altered immune function, especially immune mediators, including cytokines and proteins, may cause the abnormal myocardium, and one of the cardiac complications of AIDS is DCM, which leads to diastole and systole dysfunction [28–30]. More evidently, in vitro studies of adult rat cardiomyocytes showed that chronic MA administration causes cellular hypertrophy [6,13], suggesting that MA has a direct effect on myocytes. Autopsies of MA abusers also found the hypertrophied cardiomyocytes and increased thickness of LV walls [27,31,32]. Wikman-Coffelt et al. reported that hypertrophied ventricle would make the pressure– volume loops leftward shift with lowered SV and pressure, as hypertrophy continues to progress, the LV contractile function decreases along with Ved decreasing [33]. Our data demonstrated that in uninfected

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Fig. 6. Comparison of The Preload Recruitable Stroke Work (PRSW) Relationship Between Uninfected and Retrovirus-infected Mice with Saline or MA Injected. Stroke work was platted against end-diastolic volume (Ved), which was acquired from a series of pressure – volume loops during inferior vena cava occlusion. Regression line is the PRSW relationship, and slope of this line is PRSW. The four representative linear PRSW relationships are shown. A: uninfected mice with saline injected, y = 104.27*x 1380.15, r2 = 0.98. B: uninfected mice with MA injected, y = 69.13*x 277.65, r2 = 0.99. C: retrovirus infected mice with saline injected mice, y = 59.63*x 1083.48, r2 = 0.95. D: retrovirus infected mice with MA injected, y = 89.80*x 969.89, r2 = 0.97.

mice, MA administration causes HR, CI, SWI, SVI, dP/dtmax and dP/dtmin significantly decreased (Table 1). From the data of PRSW and dP/dtmax vs. Ved, we can tell that MA decreases LV contractility, the mean PRSW was 105 F 6.6 mmHg in saline injected and 71 F 6.2 mmHg in MA injected mice (Fig. 2). The linear PRSW also showed the different regression in Fig. 6: Saline injected mice (y = 104.27*x 1380.15, r2 = 0.98); drug injected mice (y = 69.13*x 277.65, r2 = 0.99), however, the Ees of these two groups does not exist significantly difference while the pressure–volume loops are obviously leftward shifted (Fig. 7A and B), H was significantly (p < 0.05) increased by 28% while Ved was significantly decreased in MA injection mice, the increased H demonstrated that prolonged time in ventricular relaxation and the decreased Ved is consistent with LV chamber hypertrophy as well as decrease in chamber volume. These data are consistent with the conclusion that MA causes cardiomyocyte cellular hypertrophy, which leads to LV wall thickening, as the muscle mass increases along with the stress of LV wall, there is a significant increase in diastolic stiffness, and the contractile function is clearly decreased. In retrovirus-infected mice, Compare the hemodynamics of MA administration with saline injected, the data showed that chronic MA consumption significantly (p < 0.05) increased EF (23%) while significantly (p < 0.01) decreased Ves (92%). No significant differences existed between saline and MA treatment in PRSW, Ees and dP/dtmax vs. Ved. PRSW of two groups were by mean of 72 F 10.2 mmHg

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Fig. 7. End-systolic Pressure – volume Relationship (ESPVR) of Uninfected and Retrovirus-infected Mice with Saline or MA Injected. Response to ramping of the preload by occlusion of inferior vena cava produced the corresponding pressure – volume loops changes. End-systolic pressure (Pes) was plotted against end-systolic volume (Ves) to derive the ESPVR (dotted line). The slope of the regression line (ESPVR) is ventricular end-systolic elastance (Ees) (black line). The representative end-systolic pressure – volume relationships of the four groups are shown. A: uninfected mice with saline injected. B: uninfected mice with MA injected. C: retrovirus infected mice with saline injected mice. D: retrovirus infected mice with MA injected.

and 83 F 18.2 mmHg respectively (Fig. 2). The PRSW linear was shown in Fig. 6: saline injected mice (y = 59.63*x 1083.48, r2 = 0.95), MA injected mice (y = 89.80*x 969.89, r2 = 0.97), the enhance slope of infected and MA administrated mice suggests that MA treatment did not accentuate the negative effects of retrovirus on LV contractility since MA administration can cause dysfunction. The pressure– volume relationship loops are backup to normal (Fig. 7A and D) and so is Ved. Whether this result

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indicates MA treatment can benefit for retrovirus-induced DCM or not needs further study. And from our histopathology study, there were no significant cardiac lesions due to MA treatment (data not shown). An explanation is that chronic MA exposure induces myocytes hypertrophy, and thickens the wall of LV, it counteracts the effects of retrovirus induced dilated cardiomyopathy. Alternatively, cytokines were known to be related to heart disease and might also contribute to the toxic effects of MA, such as interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) [34,35], while they are also altered by retrovirus. Although an in vitro study of exposure of murine cells to MA enhanced NK cell function [36] and rats given a single injection of 3,4-methylenedioxymethamphetamine (MADA) developed a decreased lymphocyte responsiveness to Con A stimulation [37], those data are far from extensive to show the immunosuppression property of MA. Thus the interaction of retrovirus and MA through cytokines may moderate the cardiovascular effects of MA and need further study. However, MA is capable of directly causing neuron, splenic cells and myocardial damage via apoptosis [38,39]. MA facilitates the formation of reactive oxygen species which can form a toxic metabolite ONOO- with reactive oxygen, which in turn can cause cell damage and infarction [40]. Besides, studies showed that in brain, MA promotes the p53 mRNA expression, which is related to necrosis [41,42]. Taken together, those factors indicate that MA can cause neural damage, cardiocyte damage and cardiac dysfunction, however the result of no further heart dysfunction of MA administration to retrovirus induced DCM is worthy of further study.

Conclusion The present study of chronic MA treatment showed significantly lowered the heart function in uninfected, saline injected mice while no significant cardiac effects in retrovirus-infected mice. MA consumption does not exacerbate the heart function during murine AIDS. This may be due to the compensation of MA induced LV wall thickening and retrovirus induced dilated cardiomyopathy. Further studies are needed to establish possible factors involved in this cardiopathology, including autoantibodies of myocytes, infection of heart tissue by virus, cytokine activity and p53 expression in heart tissue. Acknowledgements We appreciate Mike Walston for his help with treatment of the mice. This research was supported by an NIDA supplement to NIH grant HL 63667. References [1] Wermuth L. Methamphetamine use: hazards and social influences. Journal of Drug Education 2000;30(4):423 – 33. [2] Mackenzie RG, Heischober B. Methamphetamine. Pediatrics in review 1997;18(9):305 – 9. [3] Anglin MD, Burke C, Perrochet B, Stamper E, Dawud-Noursi S. History of the methamphetamine problem. Journal of psychoactive drugs 2000;32(2):137 – 41. [4] Derlet RW, Horowitz BZ. Cardiotoxic drugs. Emergency medicine clinics of North America 1995;13(4):771 – 91. [5] Islam, M.N., Kuroki, H., Hongcheng, B., Ogura, Y., Kawaguchi, N., Onishi, S., Wakasugi, C. Forensic science international 1995;28;75(1):29 – 43.

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