Methamphetamine is the third most commonly abused drug in the world after cannabis and opioids with 34 million global users in 2016.1 Terms for amphetamine include speed, meth, crystal, crystal meth, glass, shards, ice and tic. In New Zealand, it is commonly known as ‘P’. In the recent New Zealand Health Survey report 1.1% of adult New Zealanders admitted to methamphetamine use in the past year.2 Cardiac toxicity from methamphetamine use is an increasingly recognised entity in the modern era. Patients may present with cardiomyopathy, hypertension, arrhythmias, sudden cardiac death, acute coronary syndrome, vascular dissection and stroke or pulmonary hypertension.3–5 Possible pathophysiological mechanisms for methamphetamine-associated cardiomyopathy (MAC) include direct myocardial toxicity, vasospasm, hypertension, mitochondrial injury and free-radical formation.3–5

Our group has previously published the largest MAC cohort to date in Australasia, and one of the largest internationally, evaluating the clinical characteristics and outcomes of these patients.6 Patients with MAC were often young men of New Zealand Māori descent and from socioeconomically deprived areas. They presented acutely unwell with heart failure and significant left ventricular (LV) impairment. The LV remained significantly dilated and remodelled despite a small improvement in LV ejection fraction (EF) on serial follow-up imaging. The long-term prognosis was poor with a high mortality rate. Readmission with decompensated heart failure was common, and frequently due to non-compliance with treatment. However, evidence to guide management of this group of patients and understanding its outcomes, and how it differs from other cardiomyopathies, remain limited. This study aims to describe the clinical features, course and outcome of MAC, and compared with a contemporary, age-matched cohort of patients with non-ischaemic cardiomyopathy (NCM).

Methods

Patient population

Patients admitted to Middlemore Hospital (Auckland, New Zealand) with symptoms and signs of heart failure according to Framingham criteria and with echocardiographic evidence of dilated cardiomyopathy with reduced ejection fraction were retrospectively identified between January 2005 and January 2019. Patients were included if they had a documented history of either current or past methamphetamine use and methamphetamine was thought be an important contributing factor to their cardiomyopathy after initial investigations. The index admission was the first presentation with heart failure to our institution. Demographic, past history, laboratory, echocardiographic and angiographic data of the study population were obtained as previously described.6 The New Zealand Deprivation (NZDep) Index was used as a measure of socioeconomic deprivation.7

NCM cohort

The Heart Failure registry, as part of the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) registry, prospectively collects patients admitted with heart failure to Middlemore Hospital.8 Patients with a diagnosis of cardiomyopathy (history of heart failure symptoms and signs, and LVEF<50%) not related to ischaemic heart disease, methamphetamine, alcohol or other recreational drugs with first presentation of heart failure between January 2005 and January 2019 were randomly selected. This group was matched to the MAC group in terms of numbers, age range of 20–65 years old and year of diagnosis.

Outcomes

The primary outcome was mortality in MAC patients during the follow-up period until 31 January 2019. In-hospital complications defined as cardiogenic shock and/or use of inotropes, endotracheal intubation and ventilation, acute renal failure requiring renal replacement therapy and death were recorded. Other follow-up outcomes collected include myocardial infarction, stroke and resuscitated cardiac arrest. Readmissions due to heart failure or any cardiovascular causes were recorded. The latest transthoracic echocardiogram results were also collected and reduction in severity by one or more category (normal, mild, moderate or severe) from the initial echocardiogram for LV and right ventricular (RV) dimension and LVEF were recorded. Cardiology clinic attendance is also collected.

Statistical analysis

Quantitative and categorical variables were presented as median (lower quartile-upper quartile) and frequency (percentage) respectively unless specified. Mann-Whitney U Test and Fisher’s exact test were used for their corresponding univariable analysis for cross-sectional variables. Kaplan-Meier curves were used to present survival data, and log-rank test used for longitudinal outcome comparisons to calculate hazards ratios. All collected variables were tested in univariable analysis with the outcomes of interest (mortality and heart failure readmissions in MAC patients during follow-up), and those with P<0.20 identified. These significant parameters were then entered into a Cox proportional hazards regression multivariable model to identify independent predictors. P-value <0.05 was considered statistically significant, and all tests were two-tailed. The study was approved by the Northern Regional Ethics Committee (research 1750) as a clinical audit.

Results

Sixty-two consecutive patients with MAC were included in the study. The clinical characteristics of MAC patients are presented in Table 1. In comparison to the NCM group, MAC patients were younger (median age 41 versus 48 years, P=0.001), had a higher proportion of men (87% versus 69%, P=0.028) and New Zealand Māori descent (63% versus 32%, P<0.001). The unemployment rate (60% versus 18%, P<0.001) and documented use of other recreational drugs (26% versus 2%, P<0.001) were also higher in MAC patients.

MAC patients had higher median peak N terminal pro brain natriuretic peptide (NT-proBNP) levels (616 versus 295pmol/L, P=0.002), lower LVEF (20% versus 25%, P=0.004) and higher left ventricular end systolic diameter (LVESD) than NCM patients (5.9 versus 5.3cm, P=0.005) during index admission (Table 2).

None of the MAC patients or the NCM patients died during the index admission (Table 3). Cardiogenic shock and/or inotrope use was higher in MAC patients (16% versus 3%), while there were no differences in mechanical ventilation, renal replacement therapy or length of index admission (P=0.244, 0.619 and 0.977).

The mean follow-up time for the study was 3.0±2.9 years. There were 15 deaths after hospital discharge for the MAC patients, all from end-stage congestive heart failure, and four had resuscitated cardiac arrest, compared to seven and one respectively for the NCM group. During follow-up, 30 MAC patients had at least one readmission to hospital with decompensated heart failure (Table 4). Figure 1 illustrates the survival curves of a) mortality and b) heart failure readmissions during follow-up. MAC patients had a higher mortality rate (hazards ratio 2.7, 95% confidence interval 1.1–6.2, P=0.029) and a trend towards higher heart failure re-admission rate (hazards ratio 1.6, 95% confidence interval 1.0–2.8, P=0.075). One-, three- and five-year survival were 93%, 73% and 55% for MAC patients and 96%, 88% and 88% for NCM cohort. MAC patients also had less improvement in LVEF by at least one category during follow-up (20% versus 63%, P=0.001). MAC patients also had a higher rate of non-attendance to clinic appointments (27% versus 7%, P=0.002).

In multivariable analysis, LVEDD per centimetre was independently associated with higher mortality during follow-up (HR 5.1, 95% CI 1.4–18), while improvement in RV systolic function by at least one category was associated with lower mortality during follow-up (HR 0.36, 95% CI 0.14–0.92). Improvement in LVEF by at least one category was associated with fewer heart failure readmissions during follow-up (HR 0.24, 95% CI 0.07–0.87) (Table 5).

Table 1: Clinical characteristics at presentation.

MAC, methamphetamine-associated cardiomyopathy; NCM, non-ischaemic cardiomyopathy.

Table 2: Investigation results at presentation.

MAC, methamphetamine-associated cardiomyopathy; NCM, non-ischaemic cardiomyopathy.

Table 3: In-hospital complications.

MAC, methamphetamine-associated cardiomyopathy; NCM, non-ischaemic cardiomyopathy.

Table 4: Outcomes during follow-up.

MAC, methamphetamine-associated cardiomyopathy; NCM, non-ischaemic cardiomyopathy.

Table 5: Multivariable analysis for MAC patients.

MAC, methamphetamine-associated cardiomyopathy; NCM, non-ischaemic cardiomyopathy.

Figure 1: Kaplan-Meier curves for long-term outcomes a) death and b) heart failure readmissions.

Discussion

To our knowledge, this study was the largest series of patients with MAC published to date in Australasia and one of the largest in the world describing the natural history of MAC. Ito and colleagues previously described a case-controlled study comparing echocardiographic findings of cardiomyopathy with and without a history of methamphetamine abuse, demonstrating high prevalence of methamphetamine abuse among young patients with cardiomyopathy or heart failure. Methamphetamine abusers also had larger cardiac dimensions and more severe left ventricular dysfunction, compared with the methamphetamine non-abuser.9 Our study, on the other hand, is a case-controlled study showing that MAC is a serious consequence of chronic methamphetamine use, and has a worse prognosis than patients with other non-ischaemic cardiomyopathies.

The true prevalence and incidence of MAC is unknown. Increasing incidence of MAC has been reported in one study from the US.10 The most recently available national household survey found 1.1% of New Zealanders (aged 16–64 years) reported using methamphetamines in the previous year in 2015/16 similar to the levels found in previous years.2 Male predominance in patients with MAC has been found in previously published reports.9,11,12 More than half of our cohort was of indigenous Māori men. Young Māori males were identified in a recent New Zealand Health Survey as the greatest users of methamphetamine.2 According to a recent report released by the Illicit Drug Monitoring System (IDMS), the proportion of frequent methamphetamine users who are Māori increased from 22% in 2006 to 38% in 2016 in New Zealand.13

Middlemore Hospital is one of the largest tertiary hospitals in New Zealand, providing services to more than 500,000 people in the Counties Manukau district. The ethnicity mix of the Counties Manukau population varies by age, with younger groups having higher proportions of Māori, Pacific and Asian peoples than the population aged 65 years and over, where two-thirds of the population are New Zealand European/Other groups. Among residents of Counties Manukau, 36% were in the most socioeconomically deprived quintile defined by residential address (NZDep2013 Deciles 9 and 10). The percentage living in NZDep2013 Deciles 9 and 10 was much higher for Māori (58%) and Pacific peoples (76%) than for European (17%), Asian (22%) and the Middle Eastern, Latin American and African (29%) groups.14 The ethnic disparity seen in our cohort is a reflection of the socioeconomic disparity seen within our community. Low socioeconomic status measures may be a proxy for variables such as psychosocial stress, poor access to healthcare and reduced adherence to therapy, which could contribute to the higher incidence of MAC in Māori.

Unemployment and use of other recreational drugs are more common in the MAC cohort compared to the NCM cohort. The proportion of frequent methamphetamine users who were unemployed increased from 64% in 2006 to 71% in 2016.13,14 In addition, the frequent methamphetamine users had used a mean of eight drug types in the past six months in 2016 (median 8, range 1–18). The drug types most commonly used in the previous six months were methamphetamine (98%), tobacco (89%), cannabis (81%), alcohol (77%), crystal methamphetamine (Ice) (76%), ecstasy (31%), amphetamine (30%), gamma-hydroxybutyric acid (27%) and synthetic cannabinoids (26%). Concurrent use of alcohol and cannabis use may contribute to the development of cardiomyopathy in our cohort due to additive and synergistic cardiac toxicity.15,16

Of particular concern is that MAC patients had a lower LVEF and a higher in-hospital complication rates compared to controls with non-methamphetamine-associated cardiomyopathy, indicating that they were critically ill at presentation. This finding was similar to previous studies which reported that patients abusing methamphetamines consistently have worsened severity of disease compared to controls with non-methamphetamine-associated cardiomyopathy.3,9 The mechanisms underlying cardiomyopathy in methamphetamine use are most likely multifactorial. Catecholamine excess, coronary vasospasm and ischaemia, increases in reactive oxygen species have been proposed as the aetiologies for cardiac injury.3 Methamphetamine, like cocaine, has sympathomimetic properties. A high catecholamine state induced by methamphetamine is thought to cause vasoconstriction of the coronary arteries, tachycardia, hypertension and/or direct myocardial toxicity. The mechanisms of excess catecholamine include inhibition of the presynaptic catecholamine reuptake, promotion of the norepinephrines release at adrenergic nerve endings, and prevention of the circulating norepinephrines metabolism.17,18 Indeed, the sympathomimetic and toxic effects on the heart induced by methamphetamines are likely worse than cocaine because it increases catecholamine release rather than just inhibiting its re-uptake.

Among methamphetamine abusers who develop a nonischaemic cardiomyopathy, a variety of patterns of methamphetamine-induced cardiomyopathy have been described in the literature19 Majority of our patients with MAC had dilated cardiomyopathies with global ventricular systolic impairment, suggesting direct myocardial toxicity of the methamphetamines rather than ischaemia.

Compared to the NCM cohort, MAC patients had a higher NT-pro BNP level at presentation. This finding was similar to those of Richards et al, who reported a higher prevalence of abnormal brain natriuretic peptide (BNP) in methamphetamine-positive patients with heart failure.20 BNP is a natriuretic hormone initially identified in the brain but released primarily from the heart, particularly the ventricles. The release of BNP is increased in heart failure, as ventricular cells are recruited to secrete BNP in response to the high ventricular filling pressures. The relationship between admission plasma BNP levels and the risk of in-hospital mortality for patients with acute decompensated HF was assessed in the ADHERE registry, demonstrating that an elevated admission BNP level is a significant predictor of in-hospital mortality in acute decompensated HF with either reduced or preserved systolic function, independent of other clinical and laboratory variables.21

Of the 62 MAC patients discharged alive in our cohort, 24% died during follow-up. Although none of the MAC patients died during the index admission, we found that MAC patients were associated with a post-discharge mortality HR of 2.7 compared with that of an age-matched NCM cohort. In addition, MAC patients also had a trend towards higher rate of heart failure readmissions during follow-up. LV dimension at baseline, in particular LVEDD, and improvement in LV and RV systolic function by at least one category predicted post-discharge mortality or heart failure readmission. These findings were similar to other studies reporting LV dilation is an independent predictor of overall and sudden death in heart failure patients. These may be important surrogate markers to set as targets in managing MAC patients.22,23

We observed lower rates of LV systolic function recovery in MAC patients during the follow-up period compared to the NCM cohort. There are two possible explanations for this. Firstly, it is likely that MAC patients had chronic amphetamine use, and by the time they came to medical attention they had advanced cardiomyopathy from myocardial fibrosis and the pathological process is therefore irreversible. Secondly, adherence to medical therapy and abstinence from methamphetamines are important contributing factors. The rate of non-attendance to our cardiology clinics during the study period for all ethnicities and diagnoses was 9.4% and 17.7% for all Māori patients. The lower attendance to cardiology outpatient clinics and higher hospital readmissions with decompensated heart failure in MAC patients may reflect the non-adherence to medical therapy in this group of patients.

Clinical implications

Methamphetamine and related substances are now among the most abused drugs worldwide. There is a growing body of evidence that methamphetamine abuse is associated with cardiomyopathy, although the mechanism for cardiac dysfunction is still unclear. Population education and health policies to increase awareness of the adverse health and particularly cardiovascular effects of methamphetamine must play a central role in prevention. High-risk groups including young and middle-aged males, Māori ethnicity, unemployed and recreational drug use need to be targeted. Abstinence from methamphetamine is an absolutely critical starting point to preventing deterioration and improving cardiac function and needs to be reinforced whether MAC is present or absent.3,10,24

MAC may be confounded by polysubstance abuse, particularly alcohol use. Mendelson et al showed that the concurrent administration of alcohol with methamphetamine increased the rate-pressure product as compared with methamphetamine use alone.25 This increase in workload may have a synergistic deleterious effect on the process of cardiomyopathy. Therefore, abstinence of alcohol and other recreational drugs should also be recommended in MAC patients.

To our knowledge, there was no data to support the use of particular medical regimen in patients with MAC. The main pharmacological therapies remain those recommended by guidelines for heart failure with reduced ejection fraction.26,27 Many uncertainties remain in management of MAC patients, including the appropriate therapeutic interventions not only for MAC itself, but also for methamphetamine abuse in general. There appears to be an unclear window during which reversibility of cardiac dysfunction can occur with cessation of methamphetamine. Important areas for future research include finding the incidence and prevalence of cardiac pathology in methamphetamine abusers and risk factors for and prognosis of MAC. Future studies will need to adjust for concomitant drug use, including alcohol.

Long-term follow-up of MAC patients can pose a significant challenge, as some are reluctant to engage in healthcare. There are many barriers for frequent methamphetamine users to seek help, including social pressures to continue using methamphetamine, fear of involvement of authorities, concern about career impact and costs.13 It is important that cardiologists are alert to identifying patients with MAC and counselling and treating them appropriately, given the high morbidity and high mortality in this group of patients. Regular echocardiographic surveillance is important to assess the response of management strategies implemented. Early and ongoing involvement of cultural support groups including Māori and Pacific healthcare teams can significantly help these patients to achieve treatment goals.

Study limitations

There were several limitations in our study. We were unable to quantify the amount of methamphetamine use and the duration from clinical documents as the history relied solely on patients’ willingness to disclose this information. Similarly, we were unable to establish if patients had continued to use methamphetamines following discharge from index admission. Due to our single-centre design, our results may not be generalisable to other settings and populations. The study population is only of small size, and our analysis includes a small number of outcomes, which limits the conclusion that can be drawn. Only 12 MAC patients had their coronary anatomy studied during the index admission as ischaemia contributing to their cardiomyopathy was suspected. Concomitant CAD in MAC patients may contribute to the development of the cardiomyopathy and poor prognosis. There were also no data on compliance to medical therapy, symptoms and quality of life, all of which are important as some patients may have improved clinically despite minimal improvement in LV function.

Conclusion

Methamphetamine use is a growing major health and societal problem. The adverse effects of methamphetamine on the heart are not well recognised or understood. In this study, we demonstrate the differences in demographics, presentation and outcomes in patients with MAC, when compared to a cohort of age matched patients with cardiomyopathy with a non-ischaemic aetiology.

Patients presenting to hospital with MAC are of young age, male sex, predominantly of Māori ethnicity and are of high socioeconomic deprivation. When compared with patients presenting with other cardiomyopathies, they are more critically ill at presentation, with more dilated LV size and with worse left ventricular function. They have lower attendance to outpatient appointments and low rates of improvement in LV dilation and function on serial imaging. Patients with MAC have very high rates of post-discharge mortality and heart failure readmissions.

MAC is a serious consequence of chronic methamphetamine use, and has a worse prognosis than patients with other non-ischaemic cardiomyopathies. Understanding the reasons for the ethnic and demographic differences, as well as addressing the modifiable risk factors such as methamphetamine abstinence, adherence to medications and appointment attendance are critical to preventing and improving outcomes in this condition.

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