Comparison of Clinical Characteristics and Outcomes of Patients With Reversible Versus Persistent Methamphetamine-Associated Cardiomyopathy

ARTICLE IN PRESS Comparison of Clinical Characteristics and Outcomes of Patients With Reversible Versus Persistent Methamphetamine-Associated Cardiomyopathy Susan X. Zhao, MDa,*, Sakara Seng, DOb, Andres Deluna, MDa, Elizabeth C. Yu, MD, PhDa, and Michael H. Crawford, MDc Anecdotal cases of reversible methamphetamine-associated cardiomyopathy (rMAC) have been reported, but not well understood. This study sought to determine the clinical characteristics, outcomes and predictors of reversibility among patients with rMAC as compared with patients with persistent MAC (pMAC). We retrospectively studied adult MAC patients with left ventricular ejection fraction (LVEF) ≤40% at a single center between 2004 and 2018. rMAC was defined as increase in LVEF by ≥20 points or to ≥50%. Those with persistent LVEF ≤40% constituted the pMAC group. 357 MAC cases were identified: 250 patients had pMAC and 107 had rMAC. After a median follow-up of 45 months (interquartile range 27 to 70), LVEF increased by 28.3 § 6.9% in rMAC (p <0.001), whereas it was unchanged in pMAC (D: 0.5 § 8.7%, p = 0.350). Heart failure hospitalizations and New York Heart Association Class III/IV heart failure were both significantly reduced for rMAC than the pMAC group. All-cause mortality was 21.6% overall, 28% in pMAC and 6.5% in the rMAC group (p <0.001). Kaplan-Meier survival curves demonstrated significantly higher cumulative survival for rMAC (Log Rank p <0.001). Multivariable logistic regression identified MA cessation (odds ratio/OR: 4.23, 95% confidence interval/CI: 2.47 to 7.38, p <0.001) and baseline right ventricular end systolic area (OR: 0.92, 95% CI: 0.87 to 0.97, p = 0.001) as strongly predictive of MAC reversal. In conclusion, MAC reversal is not uncommon and is associated with significant clinical improvement including reduced mortality. It can be facilitated by MA cessation when the cardiac chambers, especially the right ventricle, are not severely dilated. © 2019 Elsevier Inc. All rights reserved. (Am J Cardiol 2019;00:1−8)

Methamphetamine (MA) is a highly addictive stimulant drug that produces powerful feelings of euphoria and energy when it is abused. MA has been associated with various cardiac pathologies through its sympathomimetic properties, causing coronary vasoconstriction, tachycardia, hypertension, and/or direct cardiac toxicity.1 Methamphetamine-associated cardiomyopathy (MAC) is one of the better recognized cardiac manifestations of MA abuse.2−9 Our group has previously reported a series of patients with MAC from a major public hospital in Northern California.8 During that study, it was discovered that a notable number of patients with MAC completely or nearly completely recovered their cardiac function. Multiple case reports and smaller series have also documented this reversibility phenomenon. 4,10−13 This study was undertaken to compare the clinical profile and long term outcome of the reversible MAC (rMAC) versus a Division of Cardiology, Santa Clara Valley Medical Center, San Jose, CA; bDepartment of Medicine, Santa Clara Valley Medical Center, San Jose, CA; and cDivision of Cardiology, University of California, San Francisco, San Francisco, CA. Manuscript received August 8, 2019; revised manuscript received and accepted September 17, 2019. Source of funding: This work was unfunded. Financial disclosures: The authors have reported that they have no relationships relevant to the contents of this paper to disclose. See page 7 for disclosure information. *Corresponding author: Tel: (408) 885-4389; fax: (408) 885-4387. E-mail addresses: [email protected]; [email protected] (S.X. Zhao).

0002-9149/© 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjcard.2019.09.030

those with persistent methamphetamine-associated cardiomyopathy (pMAC). Methods We retrospectively studied consecutive adult patients with documented MA abuse, using the International Classification of Diseases- 9th and 10th Revision-Clinical Modification: ICD 9 code 304.4x and ICD-10 code F15 (any diagnosis related to amphetamines) and/or positive urine toxicology at Santa Clara Valley Medical Center, San Jose, California, between January 2004 and August, 2018. MAC was defined as left ventricular ejection fraction (LVEF) ≤40% on index transthoracic echocardiogram (TTE) with documented MA abuse. Patients with known causes of cardiomyopathy, including coronary artery disease (with history of percutaneous coronary intervention or coronary artery bypass graft surgery or significant regional perfusion defect on nuclear perfusion imaging), primary valvular heart disease, hyperthyroidism, idiopathic, viral, alcohol, chemotherapy or hypertension-related cardiomyopathy were excluded. rMAC was defined as increase in LVEF (from index TTE to follow-up TTE that were at least 3 months apart) by ≥20 points or to ≥50%. Those with persistently low LVEF (≤40%) constituted the pMAC group. Clinical and demographic data collected included age, sex, race, body mass index, body surface area, urine toxicology, homelessness, use of tobacco products, alcohol www.ajconline.org

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abuse, and other drug abuse as well as other common medical co-morbidities. Medical therapy for heart failure and placement of automatic implantable cardioverter-defibrillator (AICD) or cardiac resynchronization therapy-defibrillator (CRT-D) devices were recorded. Echocardiographic parameters assessed included the following: LVEF (%), left ventricular end diastolic volume index (LVEDVI, ml/m2), left ventricular end systolic volume index (LVESVI, ml/ m2), left atrial volume index (LAVI, ml/m2), right atrial volume index (RAVI, ml/m2), right ventricular end-diastolic area (RVEDA, cm2), right ventricular end-systolic area (RVESA, cm2), right ventricular fractional area change (FAC, %), and estimated right ventricular systolic pressure (RVSP, mm Hg) according to published standards.14,15 Presence of at least moderate degree of atrioventricular valve regurgitation (mitral or tricuspid)16 were reported as well. Follow-up duration, compliance with heart failure therapy (defined as attending at least 2 clinic visits after diagnosis as well as no documentation of non-compliance),

cessation of MA use (defined as chart documentation and/ or negative subsequent urine toxicology), New York Heart Association (NYHA) heart failure class at last clinical encounter, number of heart failure hospitalizations (not including index hospitalization) and total hospitalization days were reported. Death was ascertained by chart documentation as well as cross-referencing the Social Security Death Index. All continuous variables, presented as mean §SD or medians with interquartile range (IQR) as appropriate, were compared by using student t test (or paired t test) or nonparametric Mann-Whitney test. Categorical variables were expressed as percentages and were compared with the use of chi-square test, Fisher exact test or McNemar test, as appropriate. Multivariable logistic regression analysis with backward elimination was performed to determine covariates of MAC reversibility by starting with baseline univariable predictors with a p value of <0.10. Time-to-event curves were analyzed according to the Kaplan-Meier method, and group comparisons were made

Figure 1. Study flowchart. Abbreviations: LVEF = left ventricular ejection fraction; MAC = methamphetamine-associated cardiomyopathy; MA-PAH = methamphetamine-associated pulmonary arterial hypertension.

ARTICLE IN PRESS Cardiomyopathy/Reversible Methamphetamine-Associated Cardiomyopathy

by applying the log-rank test. For all tests, significance was accepted as a p value <0.05. All statistical analyses were performed using SPSS version 22 software (IBM, Armonk, New York) and R version 3.3.3 software (R project, Vienna, Austria). The Institutional Review Board of the Santa Clara Valley Medical Center approved the study protocol. Results Total of 3,068 adult patients with LVEF ≤40% were identified during the study period. After patients with cardiomyopathy of other causes were excluded, 544 patients were found to have cardiomyopathy with no other cause other than a history of MA abuse (MAC). After excluding those with only one echocardiogram and other disqualifying conditions, 357 patients remained in the cohort: 250 patients in the pMAC group, and 107 patients in the rMAC group (Figure 1). Of note, 168 out of the 250 patients in the pMAC group were previously described.8 Table 1 outlines the demographic and clinical profile of these 2 groups of patients. There were more females present

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in the rMAC group than in the pMAC group (22% vs 14%, p = 0.049), whereas the racial/ethnic makeup of the 2 groups were statistically similar with the majority of patients being either White or Hispanic. There were notably more cases of left ventricular thrombus in the pMAC group than the rMAC group (15% vs 5%, p = 0.007). Other co-morbidities such as hypertension, diabetes mellitus, atrial fibrillation/ atrial flutter, chronic kidney disease showed no significant between group differences. ECG at time of diagnosis showed that the mean QRS duration in pMAC was 103.4 § 22.2 msec versus 100.6 § 18.1msec in the rMAC group (p = 0.22). There were 47 cases of bundle branch blocks (34 left bundle branch block/LBBB and 13 right bundle branch block/RBBB) in pMAC versus 10 cases (8 LBBB and 2 RBBB) in rMAC (p = 0.03). During the median follow-up of 45 months (IQR 27 to 70), significantly more patients were compliant with HF medical therapy/clinic visits in the rMAC group (70%) than patients in the pMAC group (30%, p <0.001). Similarly, cessation of MA use was also substantially higher in the rMAC group (60%) than in the pMAC group (26%,

Table 1 Demographic and clinical characteristics of persistent (pMAC) versus reversible methamphetamine-associated cardiomyopathy (rMAC) Variables

All (n = 357)

pMAC (n = 250)

rMAC (n = 107)

Age (years) Female Body mass index (kg/m2) Race, % White Hispanic Asian/Pacific island Black Other or unknown Concurrent substance abuse, % Alcohol Cocaine Other illicit drug use Tobacco Co-morbidities Homelessness Hypertension Diabetes mellitus Atrial fibrillation/flutter Prior transient ischemic attack/stroke Left ventricular thrombus Chronic kidney disease (≥ stage 3) Outcomes Follow-up duration (months) Compliance with HF therapy Cessation from MA use NYHA heart failure class III/IV at last clinical encounter # of heart failure hospitalizations after diagnosis # of days hospitalized All-cause mortality Therapy Loop diuretics ACE inhibitor/Angiotensin receptor blocker Beta blocker Mineralocorticoid receptor antagonist Automatic implantable cardioverter-defibrillator/ cardiac resynchronization therapy

47.2 § 10.0 59 (17%) 31.4 § 7.8

47.0 § 9.8 35 (14%) 31.2 § 7.9

47.4 § 10.50 24 (22%) 31.9 § 7.7

140 (39%) 131 (37%) 34 (10%) 50 (14%) 2 (0.6%)

97 (39%) 90 (36%) 23 (9%) 38 (15%) 2 (0.8%)

43 (40%) 41 (38%) 11 (10%) 12 (11%) 0 (0%)

191 (54%) 73 (20%) 62 (17%) 275 (77%)

137 (55%) 52 (21%) 36 (14%) 201 (80%)

54 (50%) 21 (20%) 26 (24%) 74 (69%)

0.430 0.801 0.035 0.017

100 (28%) 272 (76%) 101 (28%) 87 (24%) 58 (16%) 42 (12%) 107 (30%)

77 (31%) 191 (76%) 73 (29%) 65 (26%) 42 (17%) 37 (15%) 80 (32%)

23 (21%) 81 (76%) 28 (26%) 22 (21%) 16 (15%) 5 (5%) 27 (25%)

0.073 0.838 0.560 0.264 0.654 0.007 0.201

45 (27-70) 150 (42%) 130 (36%) 175 (49%) 2 (0-5) 8 (0-23.3) 77 (21.6%)

42.5 (27.3-69) 75 (30%) 66 (26%) 164 (66%) 3 (1-6) 14 (4-34) 70 (28%)

50 (26.5-70.5) 75 (70%) 64 (60%) 11 (10%) 0 (0-1) 0 (0-5.5) 7 (6.5%)

316 (89%) 314 (88%) 332 (93%) 83 (23%) 53 (15%)

227 (91%) 214 (86%) 230 (92%) 61 (24%) 44 (18%)

Values are n (%), mean § SD or median (IQR).

89 (83%) 100 (93%) 102 (95%) 22 (21%) 9 (8%)

p Value 0.758 0.049 0.425 0.746

0.658 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.062 0.037 0.259 0.431 0.025

ARTICLE IN PRESS <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.146 0.006 0.009 0.636 0.018 <0.001 <0.001 <0.001 0.685 0.699 0.873 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 28.3 § 6.9 35.0 § 31.8 41.6 § 24.1 15.3 § 15.5 9.1 § 15.5 4.7 § 7.0 4.8 § 6.0 9.0 § 12.0 31 23 15.0 § 17.2 56.2 § 6.2 57.8 § 20.1 25.8 § 11.1 27.1 § 10.3 20.2 § 10.5 17.6 § 5.7 9.7 § 3.9 45.5 § 8.4 0 (0%) 2 (1.9%) 31.3 § 11.2 27.9 § 6.6 92.8 § 29.7 67.3 § 24.4 42.3 § 16.0 29.3 § 15.5 22.2 § 7.4 14.5 § 6.5 36.5 § 10.7 31 (29.0%) 25 (23.4%) 46.4 § 14.1 0.350 0.010 0.011 0.322 <0.001 0.001 0.002 0.761 0.603 0.382 0.487 Values are mean § SD or n (%).

26.2 § 7.5 110.3 § 42.3 81.7 § 37.2 44.0 § 17.2 39.8 § 23.2 27.4 § 10.3 19.9 § 9.2 29.4 § 11.22 85 (34.0%) 73 (29.2%) 46.2 § 11.9 LV ejection fraction (%) LV end diastolic volume index (mL/m2) LV end systolic volume index (mL/m2) Left atrial volume index (mL/m2) Right atrial volume index (mL/m2) RV end diastolic area (cm2) RV end systolic area (cm2) RV fractional area change (%) Functional mitral regurgitation Functional tricuspid regurgitation Right ventricular systolic pressure (mm Hg)

26.7 § 7.2 104.0 § 37.4 76.4 § 31.9 43.0 § 15.2 33.9 § 16.6 25.4 § 7.7 18.2 § 7.4 29.7 § 10.5 80 (32.0%) 65 (26.0%) 45.4 § 12.9

0.5 § 8.7 6.2 § 38.1 5.3 § 32.9 1.1 § 17.1 5.9 § 22.5 2.1 § 9.5 1.7 § 8.4 0.3 § 12.9 5 8 0.9 § 15.1

D p (between dx and f/u) D TTE @ f/u TTE @ dx

pMAC (n = 250) Variables

Table 2 Echocardiographic/Doppler indices of the pMAC and rMAC groups

p <0.001). The pMAC group was more likely to be hospitalized for heart failure (p <0.001), with longer hospital stays (p <0.001) and more likely to be in NYHA class III or IV heart failure (p <0.001) at time of follow-up (Table 1). Median time to reversal for the rMAC group (from index TTE at diagnosis to first TTE showing normalized LVEF) was 16 months (IQR 8 to 30). All-cause mortality was 21.6% for the whole cohort, 28% for the pMAC group and 6.5% for the rMAC group (p <0.001). Kaplan-Meier curves are presented in Figure 2, demonstrating significant separation (Log rank p <0.001) between the pMAC and rMAC groups in terms of cumulative survival. Baseline echocardiographic parameters showed similar baseline LVEF (26.7 § 7.2 in the pMAC group and 27.9 § 6.6 in the rMAC group, p = 0.146), but LV chamber size (as represented by LVEDVI and LVESVI) and RV chamber size (as represented by RVEDA and RVESA) were substantially bigger in the pMAC group than the rMAC group (Table 2), (“Comparison between pMAC and rMAC” “TTE @ dx”). At time of follow-up TTE, LVEF had increased to 56.2 § 6.2 in the rMAC group, whereas it stayed statistically unchanged at 26.2 § 7.5 in the pMAC group. Improvement in LVEF was accompanied by significant reduction in LVEDVI, LVESVI, LAVI, RAVI, RVEDA, RVESA as well as RVSP in the rMAC group as compared with the pMAC group (Table 2, “Comparison between pMAC and rMAC”, “D”. Also as shown in Figure 3). In univariable analysis of the whole cohort (Table 3), of all the clinically meaningful variables evaluated, homelessness, tobacco use, cocaine use, other illicit drug use, cessation of MA, compliance with HF therapy, baseline LVEDVI, LVESVI, RVEDA, RVESA, and RAVI were shown to be associated with reversal of MAC (p <0.10). Of the correlated variables, only those with clinical plausibility or stronger odds ratios/p values were entered into a multivariable logistic regression model (Model #1). The outputs of Model #1 demonstrated that 2 variables were retained: cessation of MA use (odds ratio/OR= 4.23, 95% confidence interval/CI: 2.47 to 7.38, p <0.001) and baseline RVESA

TTE @ dx

Figure 2. Comparison of cumulative survival between the pMAC and rMAC groups.

TTE @ f/u

rMAC (n = 107)

p (between dx and f/u)

TTE @dx

TTE @ f/u

D

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Comparison between pMAC and rMAC, p value

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ARTICLE IN PRESS Cardiomyopathy/Reversible Methamphetamine-Associated Cardiomyopathy

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Figure 3. Comparison of changes between diagnosis and follow-up TTEs in the pMAC and rMAC groups. (A) LVEDVI (left ventricular end diastolic volume index); (B) LVESVI (left ventricular end systolic volume index); (C) LVEF (left ventricular ejection fraction); (D) RVEDA (right ventricular end diastolic area); (E) RVESA (right ventricular end systolic area); (F) FAC (RV fractional area change); (G) LAVI (left atrial volume index); (H) RAVI (right atrial volume index); (I) RVSP (right ventricular systolic pressure). Error bar= § 1 standard deviation.

(OR 0.92, 95% CI (0.87 to 0.97), p = 0.001). Model #2 included 5 variables (Male sex, Tobacco use, cessation of MA use, LVEDVI and RVESA). Model #3 included the 2 clinical variables from our study hypothesis that the rMAC group patients may be younger in general and more likely to be female than the pMAC group, in addition to cessation and baseline RVESA. Models #1-3 have consistently identified the 2 variables strongly associated with improvement in LVEF in rMAC patients: Cessation of MA use and a smaller right ventricular size (as represented by RVESA) at time of diagnosis (Table 3). A receiver operator curve was constructed to assess baseline RVESA as a test in identifying pMAC (Figure 4). The test performance was modest with an area under the curve of 0.66, p <0.001. Using the commonly adopted upper reference value for RVESA of 14cm2,15 which was coincidental with the mean baseline rMAC RVESA (14.5 § 6.5 cm2), a cutoff value for RVESA of 14 cm2 yielded a sensitivity of 67% (true positives for pMAC) and 1-specificity of 46% (false positives). A higher cutoff value for RVESA of 18 cm2 (based on mean baseline pMAC RVESA

of 18.2 § 7.4 cm2) yielded a sensitivity of 47% (true positives) and 1-specificity of 23% (false positives). Discussion Methamphetamine is one of the most commonly abused illicit substances worldwide and can lead to a wide range of cardiovascular pathologies including hypertension, aortic dissection, acute coronary syndromes, pulmonary arterial hypertension, and methamphetamine-associated cardiomyopathy. Our group previously described a cohort of methamphetamine-associated cardiomyopathy based on data from a large safety net hospital in Northern California.8 During that study, 68 patients were excluded as a result of resolution of their severe MAC. This finding, together with case reports of similar instances, prompted the current study to look into the unique features of those with reversed MAC versus those with persistent MAC. In this single center retrospective study of 357 MAC patients, we present the largest cohort of patients with reversed MAC, validating previous anecdotal observations. It

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Table 3 Univariable and multivariable logistic regression analyses of factors associated with rMAC Variables

Age Male Body surface area Body mass index Homelessness Alcohol abuse Cocaine abuse Other illicit drug abuse Tobacco Hypertension Diabetes mellitus ≥stage 3 chronic kidney disease Compliance Cessation Left ventricular ejection fraction LV end diastolic volume index LV end systolic volume index Left atrial volume index RV end diastolic area RV end systolic area RV fractional area change Right atrial volume index Presence of significant MR or TR Right ventricular systolic pressure

Univariable analysis

Multivariable model #1

Multivariable model #2

Multivariable model #3

Adjusted OR (95% CI)

p Value

Adjusted OR (95% CI)

0.82 (0.42-1.64)

0.57

Unadjusted OR (95% CI)

p Value

Adjusted OR (95% CI)

p Value

1.00 (0.98-1.03) 0.56 (0.32-1.01) 0.97 (0.45-2.06) 1.01 (0.98-1.04) 0.62 (0.36-1.04) 0.83 (0.53-1.31) 1.35 (1.02-1.80) 1.91 (1.08-3.35) 0.54 (0.32-0.90) 0.94 (0.56-1.63) 0.86 (0.51-1.42) 0.72 (0.43-1.18) 5.77 (3.52-9.65) 4.53 (2.79-7.42) 1.02 (0.99-1.06) 0.99 (0.98-1.00) 0.99 (0.98-1.00) 1.00 (0.98-1.01) 0.94 (0.91-0.97) 0.92 (0.88-0.95) 1.06 (1.04-1.09) 0.98 (0.97-1.00) 0.84 (0.52-1.33) 1.00 (0.98-1.02)

0.750 0.051 0.942 0.429 0.074 0.430 0.038 0.025 0.018 0.838 0.560 0.202 <0.001 <0.001 0.146 0.007 0.010 0.635 <0.001 <0.001 <0.001 0.019 0.455 0.873

1.01 (0.98-1.04) 0.83 (0.41-1.69)

0.389 0.593

0.73 (0.38-1.38)

0.336

1.07 (0.54-2.09) 2.27 (0.60-9.09) 0.64 (0.35-1.18)

0.835 0.234 0.149

0.70 (0.39-1.27)

0.233

4.23 (2.47-7.38)

<0.001

4.08 (2.45-6.89)

<0.001

0.99 (0.98-1.00)

0.128

0.99 (0.99-1.00)

0.116

0.92 (0.87-0.97)

0.001

0.93 (0.89-0.97)

<0.001

1.01 (0.99-1.03)

0.588

p Value

1.01 (0.99-1.04) 0.80 (0.41-1.58)

0.382 0.507

4.34 (2.60-7.36)

<0.001

0.92 (0.88-0.96)

<0.001

OR = odds ratio; CI = confidence interval.

is worth noting that rMAC is not a rare, isolated phenomenon. Of the 357 eligible patients included (those with LVEF ≤40% in the setting of documented MA abuse, without an alternative diagnosis for their cardiomyopathy and with at least 2 echocardiograms 3 months apart), 107 patients, which

Figure 4. ROC curve for baseline RVESA in identifying pMAC patients. Area under the curve: 0.66. p <0.001.

represented 30% of the whole cohort, reversed their severe methamphetamine-associated cardiomyopathy. It is no surprise that cessation of MA abuse emerged as 1 of the only 2 factors associated with reversal of MAC with a remarkable OR of 4.23 (95% CI: 2.47 to 7.38, p <0.001, Model #1, Table 3). Cessation of MA abuse and to a lesser extent, compliance with goal directed heart failure medical therapy have also been previously shown to be a critical determinant of recovery by case reports and small case series.4,10,11 Cessation and abstinence, though powerful, may be a necessary yet insufficient condition for reversing MAC. An important co-determinant that was shown in our multivariable regression models to be a strong predictor of MAC reversal was smaller RV size (as represented by RVESA). Despite similarly reduced LVEF at time of diagnosis, the pMAC and rMAC groups were distinctively different echocardiographically. The rMAC group was substantially less remodeled than the pMAC group in that the left ventricle, the right atrium, and the right ventricle were all significantly smaller in the rMAC group at time of diagnosis, yet only baseline RVESA, not LV or LA size as shown by a small case series,12 emerged as a strong predictor associated with reversal of MAC. The right ventricle is part of a cardiopulmonary unit with connections to the pulmonary circulation, venous return, atria, and left ventricle. It is being recognized for its crucial role in determining functional status and predicting mortality not only in heart failure, but also in pulmonary hypertension, congenital heart disease, and cardiothoracic surgery.17−19 Does RV dilatation signify a crucial and ominous milepost beyond

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which recovery is less unlikely? Further studies are needed to establish the timing of RV remodeling along the natural history of left heart failure (with reduced or preserved ejection fraction) and its impact on reversibility in various cardiomyopathic processes. The median time from diagnosis to recovery was 16 months (IQR 8 to 30). This information is instrumental when counseling MAC patients that a delayed response may be expected and persistent abstinence and compliance with therapy are necessary if meaningful improvement is desired. This finding also suggests that for patients with MAC, the usual period of ≥3 months of guideline-directed medical therapy20 may not be long enough before recommendation of primary prevention devices such as AICD or CRT-D. In the rMAC group, there were 9 AICD/CRT-D device implants (9 of 107 or 8%), which may have been obviated with what we now know as the determinants of MAC reversibility. A longer waiting period, coupled with targeted counseling for medication compliance and cessation/abstinence from MA abuse, may be a prudent approach in this unique group of patients with dilated cardiomyopathy. Our data have also shown that normalization of LVEF in the rMAC group was accompanied by sweeping improvement in LV, LA, RV, RA chamber sizes, severity of functional atrioventricular valve regurgitation as well as the degree of RVSP elevation. These echocardiographic changes further translated into favorable clinical outcomes in that the rMAC group enjoyed fewer subsequent HF admissions, fewer overall hospitalization days, fewer NYHA III/IV heart failure, and overall significantly improved survival. The 6.5% all-cause mortality in the rMAC group was approaching the 4.5% seen in the historical control patients with MA abuse and structurally normal heart.8 Lastly, our study adds MAC to the list of conditions (tachycardia, Takotubo, hyperthyroidism, peripartum) that may lead to heart failure with improved ejection fraction (HEiEF).21 Our study was the only one that identified RV size, not LV dimensions as found by others,22−24 as a stronger predictor of reversal/improvement. In conclusion, our study has found that MAC reversal is neither rare nor random. Cessation of MA abuse and normal baseline right heart size are 2 strong predictors of reversibility. The rMAC group’s improvement of LVEF and other echocardiographic parameters leads to near normalization of the attendant morbidities and mortalities. As the methamphetamine epidemic25 continues to exact heavy tolls on diverse communities and strains healthcare delivery systems in the United States, our findings provide clinicians and public health agencies with a powerful mandate to outreach, educate and care for patients with MAC. Intense efforts ought to be targeting the at-risk population to reduce the impact of this preventable, now proven reversible disease. Limitations of our study include the inherent weaknesses associated with retrospective design. Potential confounding was minimized by using logistic regression modeling but not fully eliminated. Additionally, information about the duration and route of methamphetamine abuse, which may play a role in determining the reversibility of MAC, was incomplete in our cohort. Lastly, only echocardiographic/ Doppler indices available in our clinical protocol were included in this study. 3-dimensional volumetric assessment,

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tricuspid annular plane systolic excursion (TAPSE) or strain analysis were not part of routine protocol and not available for analysis. Disclosures The authors have no conflicts of interest to disclose. 1. Kaye S, McKetin R, Duflou J, Darke S. Methamphetamine and cardiovascular pathology: a review of the evidence. Addiction 2007;102: 1204–1211. 2. Yeo K-K, Wijetunga M, Ito H, Efird JT, Tay K, Seto TB, Alimineti K, Kimata C, Schatz IJ. The association of methamphetamine use and cardiomyopathy in young patients. Am J Med 2007;120:165–171. 3. Wijetunga M, Seto T, Lindsay J, Schatz I. Crystal methamphetamineassociated cardiomyopathy: tip of the iceberg? J Toxicol Clin Toxicol 2003;41:981–986. 4. Sch€urer S, Klingel K, Sandri M, Majunke N, Besler C, Kandolf R, Lurz P, Luck M, Hertel P, Schuler G, Linke A, Mangner N. Clinical characteristics, histopathological features, and clinical outcome of methamphetamine-associated cardiomyopathy. JACC Heart Fail 2017;5:435–445. 5. Ito H, Yeo K-K, Wijetunga M, Seto TB, Tay K, Schatz IJ. A comparison of echocardiographic findings in young adults with cardiomyopathy: with and without a history of methamphetamine abuse. Clin Cardiol 2009;32:E18–E22. 6. Won S, Hong RA, Shohet RV, Seto TB, Parikh NI. Methamphetamine-associated cardiomyopathy. Clin Cardiol 2013;36:737–742. 7. Jafari Giv M. Exposure to amphetamines leads to development of Amphetamine Type Stimulants Associated Cardiomyopathy (ATSAC). Cardiovasc Toxicol 2017;17:13–24. 8. Zhao SX, Kwong C, Swaminathan A, Gohil A, Crawford MH. Clinical characteristics and outcome of methamphetamine-associated pulmonary arterial hypertension and dilated cardiomyopathy. JACC Heart Fail 2018;6:209–218. 9. Nishimura M, Ma J, Fox S, Toomu A, Mojaver S, Juang DK, Maisel AS, Thomas IC. Characteristics and outcomes of methamphetamine abuse among veterans with heart failure. Am J Cardiol 2019;124:907– 911. 10. Jacobs LJ. Reversible dilated cardiomyopathy induced by methamphetamine. Clin Cardiol 1989;12:725–727. 11. Sliman S, Waalen J, Shaw D. Methamphetamine-associated congestive heart failure: increasing prevalence and relationship of clinical outcomes to continued use or abstinence. Cardiovasc Toxicol 2016; 16:381–389. 12. Voskoboinik A, Ihle JF, Bloom JE, Kaye DM. Methamphetamineassociated cardiomyopathy: patterns and predictors of recovery. Intern Med J 2016;46:723–727. 13. Lopez JE, Yeo K, Caputo G, Buonocore M, Schaefer S. Recovery of methamphetamine associated cardiomyopathy predicted by late gadolinium enhanced cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2009;11:46. 14. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt J-U. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28. 1-39.e14. 15. Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, Solomon SD, Louie EK, Schiller NB. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685–713. 16. Zoghbi W. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and doppler echocardiography. J Am Soc Echocardiogr 2003;16:777–802. 17. Amsallem M, Mercier O, Kobayashi Y, Moneghetti K, Haddad F. Forgotten no more: a focused update on the right ventricle in cardiovascular disease. JACC Heart Fail 2018;6:891–903.

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