Methamphetamine and cardiovascular pathology - Wiley Online Library

REVIEW

doi:10.1111/j.1360-0443.2007.01874.x

Methamphetamine and cardiovascular pathology: a review of the evidence Sharlene Kaye1, Rebecca McKetin1, Johan Duflou1,2 & Shane Darke1 National Drug and Alcohol Research Centre, University of New South Wales,Australia1 and Department of Forensic Medicine, Central and South-western Sydney Area Health Service, School of Medicine, University of Sydney, Australia2

ABSTRACT Aims To examine the literature pertaining to the cardiovascular effects of methamphetamine and discuss the implications for methamphetamine users. Methods Relevant literature was identified through comprehensive MEDLINE and EMBASE searches. Findings and conclusions There is sufficient clinical and experimental evidence to suggest that methamphetamine can have adverse and potentially fatal effects on the cardiovascular system. The existing literature suggests that: (1) methamphetamine users are at elevated risk of cardiac pathology; (2) risk is not likely to be limited to the duration of their methamphetamine use, because of the chronic pathology associated with methamphetamine use; (3) the risk of cardiac pathology is greatest among chronic methamphetamine users; (4) pre-existing cardiac pathology, due to methamphetamine use or other factors, increases the risk of an acute cardiac event; and (5) methamphetamine use is likely to exacerbate the risk of cardiac pathology from other causes, and may therefore lead to premature mortality. Keywords

Cardiotoxicity, cardiovascular, methamphetamine, pathology.

Correspondence to: Sharlene Kaye, National Drug and Alcohol Research Centre, University of New South Wales, NSW, 2052, Australia. E-mail: [email protected] Submitted 25 September 2006; initial review completed 16 January 2007; final version accepted 21 March 2007

INTRODUCTION Methamphetamine, and its chemical analogue amphetamine, are synthetic stimulants that act by increasing catecholamine concentrations in the central and peripheral nervous systems. Methamphetamine has more potent central nervous system effects and less potent peripheral effects than amphetamine, which is its primary metabolite. There are two isomeric forms of methamphetamine, d-methamphetamine and l-methamphetamine. The d-isomer is more potent and is the form manufactured for illicit use. While adverse effects on physical health are often reported by methamphetamine users [1–3], much of the research has focused on the mental health effects [4–6] and neurotoxicity [7–9] of methamphetamine. The current review aims to review the evidence for methamphetamine-related cardiac pathology and discuss implications for methamphetamine users. Searches of MEDLINE, EMBASE and other relevant material were conducted. The main search terms were methamphetamine, amphetamine and keywords related to

cardiovascular pathology (e.g. cardiovascular; cardiac; heart; myocardial infarction; cardiomyopathy). Other relevant literature, such as book chapters and electronic articles, were also included.

CARDIOVASCULAR PATHOLOGY ASSOCIATED WITH METHAMPHETAMINE USE Acute cardiovascular pathology Emergency department data have shown consistently chest pain, cardiac arrhythmias (e.g. tachycardia), palpitations and hypertension to be among the most common presenting physical symptoms upon admission for acute meth/amphetamine intoxication [10–14]. Tachycardia and hypertension have been demonstrated reliably in animal models [15–21] and induced experimentally in humans [22]. While hypertension is an acute effect of methamphetamine intoxication, chronic methamphetamine use can lead to chronic hypertension [23]. The less frequently observed, but more serious, acute

© 2007 The Authors. Journal compilation © 2007 Society for the Study of Addiction

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Table 1 Reported cases of myocardial infarction associated with meth/amphetamine use. Author

Age/sex

Drug

Route of administration

Coronary angiogram results

Orzel [37] Carson et al. [28] Packe et al. [38] Furst et al. [31] Veenstra et al. [41] Hong et al. [32] Ragland et al. [39] Huang et al. [33] Appleby et al. [25] Bashour [26] Le Gac et al. [35] Farnsworth et al. [30] Guharoy et al. [11] Waksman et al. [42]

58/M 33/M 27/M 41/M 40/M 31/F 37/F 42/M 31/M 29/F 32/M 35/M 26/M 31/M

Oral Intravenous Intravenous Intranasal Oral Smoking Intravenous Intranasal Oral Oral Intravenous Intranasal Smoking Intravenous

– Normal Normal Coronary thrombosis Normal Normal [post-mortem examination] Normal – – Coronary thrombosis Normal Coronary stenosis – –

Costa et al. [29] Ochoa Gómez et al. [36] Sztajnkrycer et al. [40] Hung et al. [34] Brennan et al. [27]

34/M 21/M 13/F 27/M 31/F

Dextroamphetamine sulphatea Amphetamine Amphetamine Crystal methamphetamine Amphetamine Crystal methamphetamine Amphetamine Amphetamine Amphetamine Amphetamine Amphetamine Methamphetamine Crystal methamphetamine Amphetamine; methamphetamine Amphetamineb Amphetamine Amphetaminec Amphetamine Amphetamine

Oral Intranasal Oral Intravenous –

Watts & McCollester [43]

23/M

Methamphetamine

Smoking

Normal Normal – Coronary stenosis Coronary thrombosis, aneurysm, stenosis and rupture Normal

a Long-term dextroamphetamine treatment for narcolepsy; bshort-term (1 week) amphetamine treatment for weight loss; crecreational overdose of Adderall: a combination pharmaceutical preparation containing dextroamphetamine.

cardiovascular consequences of methamphetamine use include acute coronary syndrome, acute myocardial infarction, aortic dissection and sudden cardiac death. Acute coronary syndrome Acute coronary syndrome (ACS) refers to the clinical manifestations of acute myocardial ischaemia (i.e. unstable angina and acute myocardial infarction: AMI). ACS was diagnosed in 25% of US emergency department patients presenting with chest pain following methamphetamine use [14]. More recently, eight cases of ACS among crystal methamphetamine smokers were documented [24]. Acute myocardial infarction Previous literature documenting methamphetaminerelated AMI has been based overwhelmingly on individual case reports. To date, there have been 20 published reports of AMI associated with meth/amphetamine use [11,25–43] (Table 1). Reports of methamphetaminerelated AMI have also come from studies of ACS among emergency department patients [14,24] and autopsy findings [44,45]. Acute aortic dissection Acute aortic dissection is a known complication of methamphetamine use [46]. Autopsy reviews have reported

several cases of aortic dissection associated with acute methamphetamine intoxication [44,47,48]. Swalwell & Davis [48] found methamphetamine use to be the most common risk factor, after hypertension, for fatal acute aortic dissection. Sudden cardiac death The association between methamphetamine use and sudden cardiac death is well-recognized [46,49–53]. Cardiac arrhythmias, that typically cause sudden cardiac death, have been documented widely as indicators of methamphetamine toxicity [49,50,54–57]. Although cardiac arrhythmias and arrhythmic sudden death are often associated with high methamphetamine doses [50,56], lower doses may also cause sudden death due to the development of hypersensitivity [16]. CHRONIC CARDIOVASCULAR PATHOLOGY Coronary artery disease Methamphetamine users appear to be at risk of premature and accelerated coronary artery disease (CAD), with underlying cardiovascular disease found in significant proportions of methamphetamine-related deaths [44,46,58,59]. Karch et al. [44] found moderate CAD in 10% of methamphetamine using decedents, and severe


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Sharlene Kaye et al.

Table 2 Reported cases of cardiomyopathy associated with meth/amphetamine use. Author

Age/sex

Drug

Route of administration

Onset

Smith et al. [63] Call et al. [65] O’Neill et al. [66] Ayres [60] Jacobs [62] Hong et al. [32] Crean & Pohl [61]

45/F 22/F 24/M 38/M 48/F 34/F 30/F

Dextroamphetamine Amphetamine Amphetamine Dextroamphetamine Methamphetamine Crystal methamphetamine Amphetamine

Oral Intravenous Intravenous Oral Oral Smoking Oral

Chronic Acute Acute Chronic Chronic Chronic Chronic

CAD in 6%. Overall, minimal to severe CAD was found in 19% of methamphetamine users compared to 5% of agematched controls, and occurred at a significantly younger age than among the general population [44,46]. Methamphetamine users whose deaths were a direct result of methamphetamine toxicity were older, had heavier hearts and a higher prevalence of CAD than decedents in whom the presence of methamphetamine was deemed incidental. The greater heart weights of methamphetamine users with CAD, an abnormal finding irrespective of age, suggest that the higher prevalence of coronary artery pathology was not merely a function of age [44]. As such cardiac pathology takes time to develop, however, there may be a long ‘incubation’ period prior to methamphetamine-related death. CAD has also been demonstrated in a high proportion of patients presenting with ACS. Wijetunga et al. [24] found that five of the six patients tested had evidence of obstructive CAD, while Turnipseed et al. [14] found that all three patients given angiograms had CAD, with a further two patients having a prior CAD diagnosis. Cardiomyopathy While there is a substantial amount of clinical and experimental evidence to suggest that the use of methamphetamine, particularly long-term use, can induce cardiomyopathy, the association is less well documented than with cocaine [46]. Cardiomyopathy is typically a chronic disease of gradual onset and has usually been associated with chronic meth/amphetamine use [32,60– 64]. Acute onset cardiomyopathy following the administration of amphetamine has also been described [65,66]. As with AMI, much of the evidence for methamphetamine-induced cardiomyopathy in humans is in the form of single case reports [32,60–63,65,66] (Table 2). The only case series of methamphetaminerelated cardiomyopathy in the literature identified and described the characteristics of 21 crystal methamphetamine users with a diagnosis of cardiomyopathy [64]. The long-term prognosis for methamphetaminerelated cardiomyopathy is unclear. While cardiomyopa-

thy is generally regarded as chronic, there are cases in which medical treatment and the discontinuation of methamphetamine use led to a recovery of cardiovascular functioning [61,62,65]. Autopsy findings have demonstrated the presence of cardiomyopathy in cases of methamphetamine-related death [45]. Dilated cardiomyopathy is the form of cardiomyopathy associated most commonly with methamphetamine use [32,61,62,64,67]. Isolated cases of hypertrophic cardiomyopathy have also been reported among deceased users [58,68]. There is little evidence, however, to suggest that the use of methamphetamine causes hypertrophic cardiomyopathy, which is inherited in the majority of cases, although it may exacerbate the condition when already present. Experimental studies have also suggested a link between methamphetamine use and cardiomyopathy, finding that chronic methamphetamine administration to rats induces cardiac lesions similar to those seen in human cases [20,69,70].

MECHANISMS UNDERLYING THE CARDIOTOXIC EFFECTS OF METHAMPHETAMINE General mechanisms It is the action of methamphetamine on catecholamines in the peripheral nervous system (i.e. noradrenaline and dopamine), which modulates heart rate and blood pressure, that is thought to be the primary mechanism underlying its cardiotoxic effects [24,46,56,67,71,72]. High catecholamine levels are known to be cardiotoxic, causing vasoconstriction, vasospasm, tachycardia and hypertension [46,67]. While tachycardia and hypertension are associated with increased oxygen demand, vasoconstriction and vasospasm decrease cardiac oxygen supply. The co-occurrence of these conditions affects the balance of cardiac oxygen supply and demand such that the overall effect is a reduction in the availability of oxygen to the heart [29,30,39,40,72–75]. Excessive catecholamine levels can thus cause necrosis of the heart muscle. Other features of catecholamine toxicity include


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fibrosis and an increase in the size of heart muscle cells (hypertrophy) [46,67]. Much of the animal model research suggests that catecholamine toxicity is a probable mediator for methamphetamine-induced cardiotoxicity, with several studies demonstrating that methamphetamine induces deleterious changes in the cardiac muscle similar to those induced by catecholamines [20,69,70,76–79]. Indicators of catecholamine toxicity, such as necrosis, fibrosis, hypertrophy and enlargement of the heart, have also been observed in deceased methamphetamine users [23,44,46,53,63,77,80–83]. Methamphetamine also has cardiotoxic effects, such as cellular damage and hypertrophy, that are independent of catecholamine-mediated effects [77,84–87]. The mechanisms underlying these ‘direct’ or noncatecholamine mediated effects have yet to be elucidated [20].

MECHANISMS RELATED TO ACUTE CARDIOVASCULAR PATHOLOGY Acute myocardial infarction The precise mechanism underlying AMI following methamphetamine use is unclear; however, possible causes include coronary artery vasospasm [29,30,32,34,35,75,88] the rupture of atherosclerotic plaques [29–31,39] and the aggregation of blood platelets [29,31,39,42,56,72], all of which can result in coronary thrombus formation [26,29]. The combination of a catecholamine-induced increase in myocardial oxygen demand [29,30,39,75] and reduced oxygen supply caused by coronary artery stenosis and/or vasospasm in itself increases the risk of AMI [30,40]. Spontaneous coronary artery rupture as a complication arising from coronary artery aneurysm has also been reported as a cause of methamphetamine-induced AMI [27]. Given the heterogeneity of cardiac risk factors and coronary pathology findings among cases, it appears unlikely that a single mechanism can account for methamphetamine-induced AMI. An interaction of the above mechanisms is more probable [14,26,40]. Moreover, the role of underlying cardiac pathology, in association with the chronic use of methamphetamine or with other risk factors, cannot be discounted.

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tears in the inner layer that initiate aortic dissection. Once such a tear has formed, hypertension acts to propagate the dissection and precipitate its rupture [47,48]. While methamphetamine-induced hypertension can cause weakening of the aortic wall, methamphetamine may also have a direct degenerative effect on the aorta [48]. Sudden cardiac death The primary mechanism underlying sudden cardiac death is cardiac arrhythmia. Pre-existing cardiac pathology, such as myocardial hypertrophy and fibrosis, may predispose methamphetamine users to sudden cardiac death [52,53,77]. When such pathology is already present, increased levels of catecholamines induced by methamphetamine can trigger the cardiac arrhythmias that cause sudden death [46,89].

MECHANISMS RELATED TO CHRONIC CARDIOVASCULAR PATHOLOGY Coronary artery disease The mechanisms underlying the development of CAD in methamphetamine users are still unclear; however, hypertension, platelet aggregability and coronary shear forces caused by increased catecholamines have been suggested [14]. As noted above, chronic hypertension may result from chronic methamphetamine use. Cardiomyopathy The mechanisms underlying methamphetamineinduced cardiomyopathy are still unclear [61]. Explanations include catecholamine-mediated effects, such as myocardial necrosis and recurrent coronary artery vasospasm [26,49,56,62,64,66]. While animal research suggests that methamphetamine has direct cardiotoxic effects [77,84–87], the contribution of such effects to the development of cardiomyopathy in humans has not been ascertained because of the difficulty controlling for catecholamine levels.

FACTORS AFFECTING METHAMPHETAMINE-RELATED CARDIOTOXICITY

Aortic dissection

Methamphetamine dosage

While the precise role of methamphetamine in aortic dissection remains undetermined [46], methamphetamineinduced hypertension is a plausible underlying mechanism [47,48]. There is a high incidence of hypertension among aortic dissection cases in general [48]. Hypertension and weakening of the aortic wall lead to

The severity of the cardiovascular effects of methamphetamine is often thought to be dose-related. Blood pressure, for example, has been reported to increase in a dose-related manner [19,56]. The development of tolerance with chronic use of methamphetamine, however, complicates the dose–effect relationship [10,71]. There is


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some evidence that tolerance to the tachycardic effects of methamphetamine may develop with repeated administration [12,16,22,49,67]. The findings of animal research regarding the development of such tolerance, however, have been mixed [16]. Methamphetamine-induced cardiac arrhythmias and sudden arrhythmic death have been associated with large methamphetamine doses [16,56]. Even small doses, however, have been known to cause death [16,46]. Autopsy reports have shown that methamphetaminerelated death can be associated with low or high levels of blood methamphetamine, with toxicological findings typically yielding a broad concentration range [16,45,46,58,90]. In circumstances where methamphetamine-related cardiac disease is present and there is a history of chronic methamphetamine abuse, post-mortem toxicology may reveal low blood methamphetamine concentrations [46]. Sensitization or ‘reverse-tolerance’ to the cardiovascular effects of methamphetamine has been suggested as a contributory factor in cases where low methamphetamine doses lead to cardiac arrhythmias and sudden cardiac death [16]. Sensitization to the tachycardic and hypertensive effects of methamphetamine has been postulated to occur with intermittent administration. Experimental animal studies have found greater increases in heart rate and blood pressure when doses of methamphetamine were interspersed with intervals of several days than when there were short intervals between dosing [16,20,21]. Such findings suggest that a similar phenomenon may occur in humans after periods of abstinence following long-term or binge use of methamphetamine and that this may account for some cases in which low methamphetamine doses resulted in death [16]. The necessary and sufficient dose to produce serious cardiovascular complications or death (the ‘toxic’ dose) is unclear, as the response to a specific dose varies due to individual differences in responsiveness and variations in degree of tolerance. Thus, estimating the level of methamphetamine toxicity should be based on the clinical presentation, rather than on the reported dose [10,12,49,57,71,91]. Route of administration Methamphetamine is available in a variety of forms. Prescription meth/amphetamine is typically in tablet form (e.g. dexamphetamine and Ritalin®). Illicit methamphetamine is usually sold in powder or in crystalline form (ice). Powder can be used orally, intranasally and intravenously, and while ice is often smoked it can also be used orally and intravenously. The literature indicates that cardiovascular complications associated with methamphetamine use can occur

with all of the major routes of administration. The risk of complications are likely to be higher, however, with administration routes that deliver a higher dose of the drug and are associated with frequent use (e.g. injecting and smoking) [2,92,93]. To date, no studies have investigated the relative risk of cardiovascular complications associated with different forms of methamphetamine administration. Interactions with other drugs Research suggests that when methamphetamine is combined with alcohol, cocaine or opioids, toxicity and stress on the cardiovascular system is increased [49,94]. Accordingly, methamphetamine is often detected in combination with other drugs at autopsy [44,58,90]. Using methamphetamine with cocaine places the user at considerable risk of adverse cardiovascular effects. Cocaine is a powerful vasoconstrictor and there appears to be a synergistic vasoconstrictive effect when the two drugs are combined [72]. Animal research has shown that the cardiotoxic effects (e.g. decreased contractile function and cardiac muscle cell damage) are greater when methamphetamine is combined with cocaine than when either drug is administered alone [87]. The majority of regular methamphetamine users also smoke tobacco, which is a known risk factor for heart disease. The possibility, therefore, that tobacco contributes to and exacerbates some of the cardiac pathology found among methamphetamine users cannot be discounted. IMPLICATIONS The research to date indicates that the most common cardiovascular effects of methamphetamine use are an acute increase in heart rate and blood pressure. In the majority of cases, these symptoms may abate without further consequence. Nevertheless, in the context of chronic use and pre-existing cardiovascular pathology, these changes in cardiovascular functioning can trigger serious, and potentially fatal, events. Low-level use of methamphetamine—for example, sporadic, low-dosage use—does not appear to be associated with major acute complications such as AMI, or chronic cardiovascular disease, in an otherwise healthy user. Methamphetamine may, however, exacerbate preexisting underlying cardiac pathology, such as coronary atherosclerosis or cardiomyopathy [58]. Methamphetamine use may have serious implications, for example, in young users with genetically inherited hypertrophic cardiomyopathy, which is often not detected until after death. Long-term methamphetamine users appear to be most at risk of cardiovascular damage, such as prema-


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ture, accelerated CAD and enlargement of the heart [44,46]. There may be an ‘incubation’ period of several years prior to methamphetamine-related death, as increased heart size and CAD take time to develop [63].

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SUMMARY There is sufficient clinical and experimental evidence to suggest that methamphetamine can have adverse and potentially fatal effects on the cardiovascular system. When fatalities have occurred among methamphetamine users, the main types of acute pathology implicated are AMI, sudden cardiac death and aortic dissection. In addition to acute forms of cardiac pathology, methamphetamine use has also been associated with chronic cardiac pathology which may increase the risk of an acute cardiac event. In summary, the existing literature suggests that: 1 Methamphetamine users are at elevated risk of cardiac pathology. 2 Risk is not likely to be limited to the duration of methamphetamine use, because of the chronic pathology associated with methamphetamine use. 3 The risk of cardiac pathology is likely to be greatest among chronic methamphetamine users, as they will be compounding the long-term and acute cardiotoxic risks. 4 Pre-existing cardiac pathology, due to methamphetamine use or other factors, increases the risk of an acute cardiac event. 5 Methamphetamine use is likely to exacerbate the risk of cardiac pathology from other causes, and may therefore lead to premature mortality. The risk of cardiac events is unable to be determined purely on the basis of dose and level of use. Other factors interact to play an important role in the reaction to any use occasion. For this reason, information about the potential for methamphetamine to induce cardiovascular complications should be targeted to all users of the drug, not just dependent and chronic users.

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Acknowledgements This research was funded by the Australian Government Department of Health and Ageing. The authors would like to thank Annie Bleeker, James Shearer and Tomoko Sugiura for their assistance with the translation of nonEnglish articles.

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