a b s t r a c t

Objectives: To compare methamphetamine users who develop heart failure to those who do not and determine predictors.

Methods: Patients presenting over a two-year period testing positive for methamphetamine on their toxicology screen were included. Demographics, vital signs, echocardiography and labs were compared between patients with normal versus abnormal B-type Natriuretic Peptide .

Results: 4407 were positive for methamphetamine, 714 were screened for heart failure, and 450 (63%) had abnor- mal BNP. The prevalence of abnormal BNP in methamphetamine-positive patients was 10.2% versus 6.7% for those who were negative or not tested. For methamphetamine-positive patients, there was a tendency for higher age and male gender with abnormal BNP. A higher proportion of Whites and former smokers had abnormal BNP and higher heart and respiratory rates. Echocardiography revealed disparate proportions for normal left ventric- ular ejection fraction (LVEF) and severe dysfunction (LVEF b 30%), LV Diastolic function, biventricular dimensions, and Pulmonary arterial pressures between subgroups. For methamphetamine-positive patients with abnormal BNP, creatinine was significantly higher, but not Troponin I. Logistic regression analysis revealed predictors of ab- normal BNP and LVEF b 30% in methamphetamine-positive patients, which included age, race, smoking history, elevated creatinine, and respiratory rate.

Conclusion: Methamphetamine-positive patients have a significantly higher prevalence of heart failure than the general emergency department population who are methamphetamine-negative or not tested. The metham- phetamine-positive subgroup who develop heart failure tend to be male, older, White, former smokers, and have higher creatinine, Heart and respiratory rates. This subgroup also has greater biventricular dysfunction, dimensions, and higher pulmonary arterial pressures.

(C) 2018

Introduction

Methamphetamine was first synthesized in the early 20th century and marketed as a bronchodilator [1]. It was soon thereafter misused for various conditions, such as dieting and to increase wakefulness. Legal availability of methamphetamine ended in 1970, when it was des- ignated as a controlled Schedule II drug. Methamphetamine faded from popularity until the late 1980s, when it reappeared in the western United States and Hawaii [2]. An increasing trend of methamphetamine-using patients presenting to emergency departments with chest pain, stroke, Mental status change, skin infection, and traumatic injury was noted for the next two decades [3-6]. A nexus between methamphetamine use

* Corresponding author at: Department of Emergency Medicine, PSSB 2100, U.C. Davis Medical Center, 2315 Stockton Boulevard, Sacramento, CA 95817.

E-mail address: [email protected] (J.R. Richards).

and the development of heart failure was first recognized during this pe- riod [7-19]. At present, methamphetamine use remains a significant problem that is expanding domestically and worldwide [20]. From the most recently published National Survey on Drug Use and Health (NSDUH) in 2015, approximately 897,000 people aged 12 or older were current users of methamphetamine, a substantial increase from 569,000 the prior year [21]. Visits to the emergency department have also in- creased significantly in the past decade [22]. According to the 2017 United Nations Drug Report, there are over 37 million estimated regular multinational methamphetamine users, with an annual prevalence of 0.77% [23]. Based on these statistics, it seems certain the prevalence of heart failure from methamphetamine use will increase in parallel, espe- cially in younger patients with no other significant cardiac risk factors [24]. To address this issue, and to investigate the differences between methamphetamine users who develop heart failure versus those who do not, we extensively reviewed two years of clinical data. Another aim of our study was to determine if there were any predictive factors for the development of heart failure in patients using methamphetamine.

https://doi.org/10.1016/j.ajem.2018.01.001

0735-6757/(C) 2018

Methods

From August 1, 2014 to July 31, 2016, a retrospective review of all emergency department patients for whom BNP was tested was per- formed at an urban, academic Level I trauma center with an annual cen- sus of 80,000 visits. This facility serves a population of 500,000 within its city limits and 1.6 million in the surrounding area. The hospital serves as a tertiary referral center for Northern and Central California and is also the de facto public hospital providing care for a significant number of

Table 1

Characteristics and differences of methamphetamine-positive patients with normal and elevated BNP

BNP <= 100 BNP N 100 Total P

(n = 264)		(n = 450)	(n = 714)
Demographics Age	52.1 +- 11.0	55.0 +- 9.4	53.9 +- 11.8	0.0003
Female	94 (35.6%)	123 (27.3%)	217 (30.4%)
Male	170 (64.4%)	327 (72.7%)	497 (69.6%)	0.02*
Height (inches)	68.1 +- 4.1	68.1 +- 4.0	68.1 +- 4.0	0.9

patients with substance abuse and psychiatric issues, as well as those	Weight (lbs)	190.5 +-	190.3 +- 56.2	190.4 +- 58.6	0.9
brought in by law enforcement. Patients who also underwent rapid		63.3
qualitative urine toxicologic screening for illicit drugs, which included methamphetamine, cocaine, barbiturates, benzodiazepines, and opi-	BMI (kg/m2) Race White	29.1 +- 9.7 101 (38.3%)	28.7 +- 8.8 223 (49.6%)	28.8 +- 9.1 324 (45.4%)	0.6 0.004*
oids, were selected for further analysis. Patients with co-ingestion of co-	Black	112 (42.4%)	136 (30.2%)	248 (34.7%)	0.001*
caine and ethanol were excluded, as well as those with prior diagnoses	Hispanic	24 (9.1%)	51 (11.3%)	75 (10.5%)	0.4*
of cardiomyopathy and/or coronary arterial disease. The qualitative	Asian	21 (8.0%)	26 (5.8%)	47 (6.6%)	0.3*
urine toxicology screen was performed using a UniCel DxC 800 Synchron (Beckman Coulter Inc., Brea, California) to detect amphet-	Native American/Hawaiian Smoker	6 (2.3%)	14 (3.1%)	20 (2.8%)	0.6*
amines and other drugs of abuse. For the purpose of the study, “amphet-	Current	216 (81.8%)	345 (76.7%)	561 (78.6%)	0.1*
amines” detected on this qualitative screen are assumed to be	Former	20 (7.6%)	72 (16.0%)	92 (12.8%)	0.001*
methamphetamine, as this is the most commonly-used illegal	Never	28 (10.6)	33 (7.3%)	61 (8.6%)	0.2*
substance in our region. There is no standardized protocol in place in Vital signs Heart rate (beats/min) 86.9 +- 12.8 90.5 +- 13.3 89.2 +- 5.0 0.0004
the emergency department for ordering toxicology screens, with the ex-	SBP (mmHg)	129.2 +-	125.8 +- 16.8	127.1 +- 16.5	0.01
ception of trauma patients admitted to the hospital and patients on 72-h		17.2
psychiatric holds. Otherwise the decision to obtain toxicology screens is	DBP (mmHg)	77.8 +- 12.0	78.7 +- 11.9	78.4 +- 11.9	0.3

at the discretion of the treating clinician.

MAP (mmHg)	94.6 +- 13.8	94.4 +- 12.5	94.5 +- 12.9	0.8
RR (breaths/min)	18.1 +- 2.3	19.4 +- 2.5	18.9 +- 2.5	b
0.0001

The electronic medical record of each patient was accessed, and data

diastolic blood pressure, mean arterial pressure, respiratory rate, and temperature. Echocardiography results associated with each patient were compared, and laboratory studies were also recorded, including B-type natriuretic peptide , Troponin I, and creatinine. Echocar- diographic levels of dysfunction were based on American College of Cardiology (ACC) guidelines [25]. From our hospital laboratory refer- ence ranges, abnormal BNP, Troponin I, and creatinine were defined as N 100 pg/mL, 0.04 ng/mL, and 1.27 mg/dL, respectively. Data were entered into Excel (version 14, Microsoft, Redmond, Washington) and analyzed with Stata (version 12, StataCorp, College Station, Texas). Statistical analysis was performed using ?², unpaired Student’s t-test, and multiple logistic regression. Results are reported as mean +- stan- dard deviation (SD) and 95% confidence intervals (CI) unless otherwise stated. Statistical significance is assumed at a level P <= 0.05. This study was approved by the institutional review board at our institution.

were recorded on a standardized form by the study authors. Variables	Temperature (?F)	98.1 +- 0.6	97.9 +- 0.7	98.0 +- 0.7	0.002
included demographics such as age, gender, race, tobacco smoking	Laboratory
history, height, weight, and body mass index (BMI). Vital signs for each patient visit were recorded and included heart rate, systolic and	BNP (pg/mL) Troponin I (ng/mL)	39.2 +- 24.1 0.53 +- 3.8	1256.5 +- 1209.1 0.66 +- 3.9	806.4 +- 1125.5 0.61 +- 3.9	0.0001 0.6

Results

For the two-year study period, there were a total of 113,015 patients age greater than or equal to 18 years evaluated in the emergency de- partment, and 4407 patients were positive for methamphetamine on their toxicology screen. Of these methamphetamine-positive patients, 714 were screened for heart failure with BNP testing (Table 1). The prevalence of abnormal BNP (N 100 pg/mL) in the methamphetamine- tested patient group was 10.2% (450/4407) versus 6.7% (7263/ 108,608) in the combined methamphetamine-negative and non-tested groups (?² = 109.3, df= 1, P b 0.0001). With regard to methamphet- amine-positive patient demographics, there were significant differences in age and gender, with a tendency for higher age and male gender for patients with abnormal BNP. Height, weight, and BMI did not differ be- tween methamphetamine-positive patients with normal and abnormal BNP, but a significantly higher proportion of white patients and lower proportion of black patients had abnormal BNP. A higher proportion of methamphetamine-positive patients who were former tobacco

Creatinine (mg/dL) 1.2 +- 0.7 1.7 +- 1.6 1.5 +- 1.3 0.0001

BNP = B-type natriuretic peptide; BMI = body mass index; SBP = systolic blood pressure; DBP = diastolic blood pressure; MAP = mean arterial pressure; RR = respiratory rate.

* = ?² test; otherwise Student’s t-test; Values are expressed as mean +- standard deviation.

smokers had abnormal BNP compared to ongoing smokers and those who never smoked.

Vital signs were also compared between the two BNP subgroups, which revealed significantly higher heart and respiratory rate in meth- amphetamine-positive patients with abnormal BNP, but lower systolic blood pressure and temperature (Table 1). A total of 575 methamphet- amine-positive patients underwent echocardiography, and the mea- sured results were analyzed between subgroups (Table 2). There were significantly different proportions for normal (50-70%) left ventricular ejection fraction (LVEF) and severely dysfunctional (LVEF b 30%) find- ings on echocardiography for methamphetamine-positive patients with normal versus abnormal BNP, but not for mild to moderate (LVEF 30-49%) and hyperdynamic (LVEF N 70%) findings. Other significant differences included worsened LV diastolic function, increased LV and right ventricular (RV) dimensions, and elevated pulmonary arterial pressures in the abnormal BNP subgroup. Laboratory values were compared, and creatinine was found to be significantly higher for those methamphetamine-positive patients with abnormal BNP, but not Troponin I.

To determine if predictors of abnormal BNP and severe cardiac dys- function (LVEF b 30%) existed for methamphetamine-positive patients, multiple logistic regression analyses of demographics, vital signs, and laboratory values were performed (Table 3). For abnormal BNP, the re- gression model was statistically significant, with ?² = 168.3, df = 8, P b 0.0001 and area under the receiver operating characteristic (ROC) curve

0.79 (95% CI: 0.76 to 0.82). This model predicted 28.7% (Nagelkerke R²) cases of abnormal BNP and correctly classified 74.5%. Black patients were 2.12 times less likely and former tobacco smokers were 1.96 times more likely to have abnormal BNP. For each year increase in age,

Table 2

Comparison of echocardiography testing for methamphetamine-positive patients with normal and abnormal BNP

		BNP <= 100	BNP N 100	Total	Normal	P
	Echocardiography	(n = 147)	(n = 428)	(n = 575)	range
	LV systolic function
	LVEF (%)	56.9 +- 12.2	34.2 +- 17.9	40.0 +- 19.4		b 0.0001
	Normal	111 (75.5%)	116 (27.1%)	227 (39.5%)	(50-70%)	b 0.0001*
	Dysfunction:
	Severe	5 (3.4%)	215 (50.2%)	220 (38.3%)	(b 30%)	b 0.0001*
	Mild to Moderate	26 (17.7%)	91 (21.3)	117 (20.3%)	(30-49%)	0.4*
	Hyperdynamic	5 (3.4%)	6 (1.4%)	11 (1.9%)	(N 70%)	0.2*
	LV diastolic function
	MV E/e’	8.9 +- 3.8	13.1 +- 7.2	12.0 +- 1.8	b 8	b 0.0001
	2D measurements
	IVSd (cm)	1.2 +- 0.3	1.2 +- 0.3	1.2 +- 0.3	0.7-1.1	0.7
	LVPW (cm)	1.1 +- 0.2	1.2 +- 0.2	1.2 +- 0.2	0.7-1.1	0.01
	LVIDs (cm)	3.2 +- 0.9	4.4 +- 1.4	4.1 +- 1.4	2.0-4.0	b 0.0001
	LVIDd (cm)	4.6 +- 0.8	5.5 +- 1.1	5.3 +- 1.1	3.4-5.7	b 0.0001
	Aortic root (cm)	3.1 +- 0.3	3.3 +- 0.4	3.3 +- 0.4	2.0-4.0	0.4
	RVD (cm)	3.2 +- 0.8	3.8 +- 0.9	3.7 +- 0.9	1.9-3.5	b 0.0001
	AVA (cm2)	2.6 +- 0.7	2.6 +- 0.7	2.6 +- 0.7	3.0-4.0	0.8
	MVA PHT (cm2)	4.0 +- 1.2	4.5 +- 1.6	4.4 +- 1.5	4.0-5.0	b 0.0001
	sPAP (mmHg)	32.7 +- 10.3	41.7 +- 14.8	39.9 +- 14.4	b 35	b 0.0001
	TAPSE (cm)	2.1 +- 0.5	1.8 +- 0.6	1.9 +- 0.6	N 1.6	b 0.0001

BNP = B-type natriuretic peptide; LVEF = left ventricular ejection fraction; LV = left ventricle; MV = mitral valve; IVSd = interventricular septum thickness at end diastole; LVPW = left ventricular posterior wall; LVIDs = left ventricular internal dimension at end systole; LVIDd = left ventricular internal dimension at end diastole; RVD = right venticular diameter; AVA = aortic valve area; MVA PHT = mitral valve area pressure half-time; sPAP = systolic pulmonary artery pressure; TAPSE = tricuspid annular plane systolic excursion.

*= ?² test; otherwise Student’s t-test; Values are expressed as mean +- standard deviation.

the odds of having abnormal BNP increased 1.04. For vital signs, each unit increase in respiratory rate (breaths/min) increased the odds of having abnormal BNP by 1.37, and for mean arterial pressure each unit increase in mmHg increased the odds by 1.08. A lower temperature was associated with a higher likelihood of abnormal BNP, and each unit rise in creatinine increased the odds of abnormal BNP by 1.86. For severe cardiac dysfunction, the regression model was also significant, with ?²

= 11.35, df = 1, P = 0.0008 and area under the ROC curve 0.85 (95%

CI: 0.80 to 0.90). This model predicted 25.9% of cases with LVEF b 30% and correctly classified 97.3%. The only variable found to be predictive of LVEF b 30% was respiratory rate, with each unit increase in breaths/ min having increased odds of 2.8. (Table 3).

Discussion

Our study demonstrated a high prevalence (10.2%) of heart failure in methamphetamine-positive patients with younger age and limited or no risk factors who were screened by BNP compared to methamphet- amine-negative patients and those not tested (6.7%) presenting to the emergency department. The worldwide prevalence of heart failure among adults is approximately 1-2%, and N 10% among persons older

than 70 years of age [26]. In the United States, the overall prevalence is 2.5% [27]. Heart failure is a major source of morbidity, mortality, and Economic burden to society. The cost of heart failure in the United States was $30.7 billion in 2012, and it is projected to increase 127% to $69.7 billion by 2030 [27]. It is safe to assume the incidence of methamphet- amine-associated heart failure will rise in parallel. Unless there are major changes in focused law enforcement, penalties for production and possession, international border control, availability, pricing, and rehabilitation options for treatment of addiction, the methamphet- amine problem is predicted to worsen [28].

The pathogenesis of methamphetamine-associated cardiomyopathy is multifactorial and includes catecholamine excess, direct cardiotoxic effects, coronary Arterial vasoconstriction, and ischemia. Methamphet- amine is an amphipathic molecule which can cross the blood-brain barrier and placenta and increases concentrations of catecholamines through multiple mechanisms. Methamphetamine blockade of plasmalemmal and vesicular transporters results in elevated levels of catecholamines in the cytoplasm and synapse, respectively [29]. Meth- amphetamine causes reverse transport of cytoplasmic monoamines across the cell membrane of presynaptic neurons into the synaptic space, disrupts vesicular storage of catecholamines, and inhibits the

Table 3

Multiple logistic regression analyses for predicting abnormal BNP and severe cardiac dysfunction (LVEF b30%) in methamphetamine-positive patients

			Standard
	Variable	B	Error	Wald		Odds Ratio		95% CI	P
	BNP N 100 Age	0.04	0.01	18.99		1.04		1.02 to 1.06	b0.0001
	Black	-0.75	0.19	15.86		0.47		0.32 to 0.68	0.0001
	Former smoker	0.67	0.29	5.37		1.96		1.11 to 3.45	0.0205
	SBP (mmHg)	-0.07	0.01	29.19		0.93		0.91 to 0.96	b0.0001
	MAP (mmHg)	0.08	0.02	21.75		1.08		1.05 to 1.12	b0.0001
	RR (breaths/min)	0.32	0.05	45.18		1.37		1.25 to 1.50	b0.0001
	Temperature (?F)	-0.44	0.15	8.79		0.65		0.49 to 0.86	0.003
	Creatinine (mg/dL)	0.62	0.12	27.18		1.86		1.47 to 2.35	b0.0001
	Constant	35.97	14.31	6.32					0.012
	LVEF b 30%
	RR (breaths/min)	1.03	0.35	8.47		2.8		1.39 to 5.61	0.0036
	Constant	-14.73	6.04	5.95					0.0147

BNP = B-type natriuretic peptide; LVEF = left ventricular ejection fraction; CI = confidence interval; SBP = systolic blood pressure; MAP = mean arterial pressure; RR = respiratory rate.

degradative enzymes monoamine oxidase A and B [30]. Acute and chronic elevation of catecholamines from stress or stimulants is one pathophysiological explanation for development of cardiomyopathy [31-33]. Even at modest dosages, methamphetamine causes unpredict- able and prolonged elevations in heart rate and blood pressure, which in turn, increases myocardial oxygen demand. Methamphetamine- induced coronary micro- and macro-vascular constriction further exac- erbates this condition by reducing myocardial oxygen supply [24]. These catecholamine-driven factors may explain the significant heart and respiratory rate differences found in our study, which were higher in the abnormal BNP subgroup compared to normal (Table 1).

It is well-established that chronic methamphetamine use is associ- ated with the development of heart failure through myriad histopatho- logical mechanisms [24,32]. These include cardiac myocytolysis, eosinophilic degeneration, intracellular vacuolization, altered calcium homeostasis, and contraction band necrosis and fibrosis [24,32,34,35]. Oxidative stress and free radical production from the metabolism of methamphetamine represent other prevailing theories. Mitochondrial superoxide production and increased protein tyrosine residue nitration leading to the induction of Fas- and mitochondria-dependent apoptosis has also been detailed [36-38]. Methamphetamine is also implicated in the promotion of p53 activity in cells with resultant apoptosis [39]. His- toPathologic changes resulting from these deleterious processes were observed on autopsy in 68% of methamphetamine-related deaths in a recent case-control study [40]. These histopathological changes may be partially or wholly reversible with cessation of methamphetamine use [41-44].

There were unique demographic differences between subgroups in our study. Methamphetamine-positive patients were predominantly male, and those screened with BNP for heart failure were on average over a decade older (53.9 +- 11.8) than those not screened (40.1 +- 13.0 years). Increasing age was determined to be a significant predictor for the development of heart failure in this subgroup. This trend to- wards older age may reflect changing national demographics as a result of declining fertility and rising longevity, referred to as the “Silver Tsu- nami” [45-47]. The racial distribution observed in our study reflected a predominance of White methamphetamine-positive patients, but it does not correlate with the most recent census taken for our county, in which 45% of the population identifies as White, 27% as Hispanic, 14.6% as Black, and 18% as Asian [48]. The methamphetamine-positive subgroup who developed heart failure, as evidenced by an abnormal BNP, was an even higher White proportion than those with normal BNP. As such, abnormal BNP may be a marker for chronic use. Because of its low expense and wide availability in our region, methamphet- amine is commonly used as an unanticipated substitute for other stimulants, such as cocaine and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). These different stimulants do not share a common user group with regard to demographic and geographic preferences [49]. For example, cocaine use is concentrated to inner cities, whereas methamphetamine use is more common in suburban or rural areas [50].

Tobacco smoking is a significant risk factor for the development of

cardiovascular disease, and 78.6% of subjects in our study were current smokers. There was a significant difference between the proportion of methamphetamine-positive former smokers who had abnormal BNP compared to those with normal BNP, and this also was determined to be a predictor of abnormal BNP in our multiple logistic regression model. This phenomenon has been detailed in the past as the “Smoker’s Paradox,” in which there appears to be potential advantages of smoking on the cardiovascular system [51]. The “Smoker’s Paradox” has been demonstrated in several clinical and preclinical studies, and theories include beneficial effects on smoking-induced cardiac gap junction remodeling, changes in vascular reactivity due to a global ischemic con- ditioning, and demographics: smokers are consistently younger on hos- pital admission, with fewer comorbidities and better overall prognosis compared to older, non- or former smokers [52,53].

Echocardiography findings, especially LV systolic and diastolic func- tion, were remarkably different between the normal and abnormal BNP methamphetamine-positive subgroups as detailed in Table 2. When fur- ther categorized using ACC guidelines, only 27.1% of echocardiograms in the abnormal BNP subgroup fell within the normal range of LVEF (50- 70%) compared to the normal BNP subgroup (75.5%). Over half of the abnormal BNP subgroup had echocardiograms demonstrating severe dysfunction compared to only 3.4% in the normal BNP subgroup. Differ- ences between LV diastolic dysfunction were confirmed by significantly elevated mitral valve (MV) E/e’ ratios, which have been shown to in- crease with severity of heart failure, correlate well with BNP levels, and decline when heart failure improves [54]. dilated cardiomyopathy, with increased LV and RV dimensions, was the most common pattern observed in the abnormal BNP subgroup. Elevated pulmonary arterial pressures and decreased RVEF as measured by the Tricuspid annular plane systolic excursion , or distance of systolic excursion of the RV annular plane towards the apex, were also observed in the abnormal BNP group.

Our study represents the largest to date specifically detailing pa- tients with methamphetamine-associated cardiomyopathy, and the first comparing methamphetamine-positive patients with normal ver- sus abnormal BNP. Our findings correlate well with the small number of past studies investigating the association of heart failure with meth- amphetamine use. In 2003, Witejunga and associates in Hawaii re- ported the first large case series of 21 patients, 16 of whom were found to have enlarged LV dimensions, 12 with Enlarged RV dimensions, and a mean LVEF of 25% [55]. This study group published two additional studies in 2007 (n = 107) and 2009 (n = 28) with similar findings [56, 57]. The authors reported a higher prevalence of elevations in creatinine in methamphetamine users with heart failure, similar to our univariate and logistic regression findings [56]. There were five studies from our state, California, with similar demographic findings regarding age, gen- der, and significantly reduced LV systolic dysfunction [58-61]. One of these studies from our institution (n = 56) suggested an association be- tween CYP2D6 genotype and development of heart failure which did not reach statistical significance [58]. Sliman et al. demonstrated in- creasing prevalence of methamphetamine-associated heart failure from 2009 to 2014 in their study from San Diego (n = 141), and they re- ported improvement in cardiac function after cessation of methamphet- amine use [59]. In an abstract presentation from 2015, Kiel and colleagues from Fresno presented similar findings (n = 121) to our study with regard to demographics and LV dysfunction [60]. Neeki and co-workers from San Bernardino reported similar age, race, and gender findings (n = 223) to our study, as well as predictors of the de- velopment of heart failure, which were methamphetamine use, male gender, and smoking history [61]. Current versus former smoking his- tory was not analyzed in their study. Most recently, Zamanian et al. demonstrated methamphetamine users with pulmonary hypertension (n = 90) had significantly higher right atrial pressure, lower stroke vol- ume index, and over twice the risk of death than non-users [62]. Our findings also suggested an association with pulmonary hypertension and methamphetamine use, as higher pulmonary arterial pressure and lower TAPSE was observed in the abnormal BNP subgroup.

Methamphetamine use resulting in cardiomyopathy has also been

reported in several international studies. Voskoboinik et al. identified 20 Australian methamphetamine users presenting with heart failure, with male predominance and average age of 35 +- 9 years [42]. The ma- jority had Severe systolic dysfunction, with mean LVEF 20%. Similar re- sults were reported by Kueh and colleagues from New Zealand, although the majority of their 25 subjects were indigenous Maori pa- tients, suggesting that ethnicity may genetically predispose patients to more severe cardiomyopathy and worse prognosis [63]. In a recent study from Iran, 230 methamphetamine users were noted to be pre- dominantly young (average age 34 years) and male (85%) [64]. Sixty underwent echocardiography, and 83% had normal examinations. The authors specifically mention both LV and RV dysfunction in those

patients with abnormal echocardiograms. These results are in contra- distinction with our findings, in which only 40% of methamphetamine users had a normal echocardiogram.

Limitations.

There are several limitations associated with this study. First, it is a retrospective review performed over a span of two years. As such, it rep- resents a “snapshot” in time of the prevalence of methamphetamine-as- sociated heart failure in our emergency department patient population, and the proportions recorded for the study could possibly have changed over the course of months to years. A several year longitudinal study would have been the best method to study this trend. Another potential limitation was the potential identification of heart failure by BNP screen- ing with a low threshold (N 100 pg/mL). This BNP level was within a sim- ilar range to other studies using BNP as a screening tool for heart failure in outpatient settings [65]. Our goal was to identify heart failure patients with objective concomitant methamphetamine use, and this was not possible using discharge Diagnostic codes as identifiers. Some heart fail- ure patients may have been missed if BNP was not tested. There is no standardized protocol in place at our emergency department for ordering toxicology screens and BNP. The decision to obtain these laboratory tests is at the discretion of the treating clinician, which may have led to sam- pling bias. The area served by our emergency department is noted to have higher than average levels of methamphetamine consumption and production, and toxicology screens may not be ordered if patients give a history of methamphetamine use. As such, our results may actually have underestimated the prevalence of methamphetamine-associated heart failure in our patient population. As it is a single center study, re- sults may not be applicable to other regional or international medical centers. No quantitative confirmation of methamphetamine-positive screens was performed, and it is possible false-positive or false-negative screens may have been recorded. It is also possible that an Amphetamine derivative other than methamphetamine, such as MDMA, may have been involved. The half-life of methamphetamine is up to 12 h, and toxicology screens may remain positive for up to 72 h. As such, definitive association between methamphetamine as the sole reason for each patient’s present- ing complaint was not possible, as the amount of time elapsed between last methamphetamine dose and presentation could not be established.

Conclusion

Methamphetamine-positive patients have a significantly higher prev- alence of heart failure than methamphetamine-negative patients or those not tested, and those who develop heart failure tend to be male, older, White, former smokers, and have higher creatinine, heart and re- spiratory rates. This subgroup also has greater biventricular dysfunction, dimensions, and higher pulmonary arterial pressures. The association of heart failure from methamphetamine use can be rationally explained from pathophysiological and toxicologic mechanisms. However, further longitudinal studies, with large sample sizes and longer follow-up pe- riods, are required to explore the nexus between methamphetamine use and the development of heart failure to meet Hill’s criteria for causa- tion. As methamphetamine use continues to rise worldwide, the inci- dence of related heart failure is also expected to rise in parallel in patients who would otherwise not fit the age and risk factors typically as- sociated with this pathologic condition. Emergency physicians represent a vanguard, in that these patients frequently present to the emergency department. As heart failure is already a tremendous burden to society, early detection in methamphetamine users will result in greater opportu- nities for treatment, multidisciplinary referral, intervention, and rehabil- itation. This is especially apropos given the evidence methamphetamine- associated cardiomyopathy may be reversible after cessation.

Disclosure

The authors report no conflicts of interest.

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