Asymptomatic Cocaine Abuse　― Myocardial Tissue Characterization Using Cardiac Biomarkers and Cardiovascular Magnetic Resonance Imaging ―

Ulf K. Radunski; Ulrike Fuger; Sebastian Bohnen; Gunnar K. Lund; Christian Stehning; Tanja Zeller; Enver Tahir; Maxim Avanesov; Gerhard Adam; Stefan Blankenberg; Jens Reimer; Kai Muellerleile

doi:10.1253/circj.CJ-16-0941

Abstract

Background: Use of cocaine is widespread and associated with several cardiovascular diseases. Recent CMR studies indicate frequent myocardial scar/fibrosis in asymptomatic cocaine abusers (CA).

Methods and Results: This study used a combination of advanced CMR tissue characterization techniques, including late gadolinium enhancement (LGE) for focal, and extracellular volume (ECV) imaging for diffuse myocardial injury/fibrosis, with circulating biomarkers for a comprehensive characterization of myocardial injury. We included 20 cardiac asymptomatic CA and a control group of 20 healthy volunteers. The comprehensive assessment included physical examination, resting ECG, exercise ECG, cardiac biomarkers, transthoracic echocardiogram and CMR. We did not find significant differences between CA and controls either in functional CMR parameters such as LVEDVi, LVESVi, LVEF, LV mass index, or in global myocardial ECV. Neither CA nor controls had evidence of myocardial edema on T2-weighted CMR, but 8 CA (40%), and none of the controls had focal myocardial scar (P<0.01). Interestingly, CA with focal myocardial scar on LGE had significantly higher high-sensitivity troponin I (hs-TNI) compared with CA without focal scar (median, 1.7 ng/L; IQR, 1.3–2.5 ng/L vs. 0.6 ng/L; 0.4–1.3 ng/L; P<0.01).

Conclusions: Focal myocardial injury in terms of subtle LGE in 40% of asymptomatic CA was associated with higher hs-TNI. Comprehensive assessment including advanced ECV imaging indicates a focal rather than diffuse pattern of myocardial involvement in asymptomatic CA.

In 2014, the global prevalence of cocaine use was 0.4% and considerably higher in the European Union and North America, with an estimated prevalence of 1% and 1.7% in the population aged between 15 and 64, respectively (www.unodc.org/). Cocaine usage is associated with both acute and chronic cardiovascular diseases such as ischemia and infarction,¹ ventricular hypertrophy,² systolic dysfunction,³ arrhythmias,⁴ endocarditis⁵ and aortic dissection.⁶ Cocaine has cardio-toxic effects on the sympathetic nervous system, cardiomyocytes, vasculature, endothelium and platelet system.⁷ In combination, these effects simultaneously increase blood oxygen demand while decreasing myocardial oxygen supply.⁸ Therefore, regular cocaine use is associated with an increased likelihood of myocardial infarction in younger adults.⁹ Currently available data on cardiovascular diseases in cocaine abusers (CA) are very limited and primarily based on retrospective autopsy studies.¹⁰^–¹² Therefore, the prevalence of cardiovascular diseases in asymptomatic CA is of particular interest. Recently, 2 studies evaluated asymptomatic CA on cardiac magnetic resonance imaging (CMR) and found frequent focal myocardial scarring as a correlate of silent myocardial damage in 73% and 30%, respectively.¹³^,¹⁴

CMR is currently the reference technique for the assessment of cardiac volumes and function but also for non-invasive myocardial tissue characterization.¹⁵ The unique strength of CMR is the late gadolinium enhancement (LGE) technique, which serves as the non-invasive reference standard for the assessment of focal myocardial scar/fibrosis.¹⁶^,¹⁷ Moreover, its presence is associated with an adverse outcome both in ischemic and non-ischemic heart disease.¹⁸^,¹⁹ LGE, however, is of limited value for the detection of diffuse myocardial injury, which is predominantly associated with an expansion of the myocardial extracellular space.²⁰ Therefore, advanced techniques for the quantification of the extracellular space, such as the T1 mapping technique, now permit direct quantification of tissue T1 relaxation times.²⁰^,²¹ This technique allows estimation of the myocardial extracellular volume (ECV) by assessing the distribution volume of extracellular contrast media, which was recently introduced as a novel CMR-derived biomarker of diffuse myocardial disease.²⁰^,²² ECV measurement dichotomizes myocardium into its cellular and extracellular components, and changes in ECV correlate well with the collagen volume fraction in biopsies,²³^,²⁴ enabling ECV to be used as a surrogate for diffuse myocardial fibrosis in the absence of myocardial inflammation.²⁰ Furthermore, ECV expansion appears to be associated with an adverse prognosis in several cardiac diseases.²⁵^,²⁶

Given that myocardial injury in asymptomatic CA was found to be predominantly of non-ischemic etiology,¹³^,¹⁴ the aim of this study was to use advanced CMR but also circulation biomarkers for a better characterization of myocardial injury in these patients.

Methods

Patients and Healthy Volunteers

The study population included 20 cardiac asymptomatic CA and a control group of 20 healthy volunteers. Asymptomatic CA were attending in- or outpatient psychiatric rehabilitation at the Department of Psychiatry and Psychotherapy of University Medical Center Hamburg-Eppendorf due to substance use-related problems. All of them fulfilled the criteria for cocaine addiction or abuse according to the International Classification of Diseases, version 10 (ICD-10; http://www.who.int/). As a healthy reference, we recruited 20 volunteers with no history of cocaine abuse, no cardiovascular disease or cardiovascular risk factors, no cardiovascular medication, with normal cardiac biomarkers and electrocardiograms (ECG). The local ethics committee approved the study and all subjects gave written informed consent.

Psychiatric Evaluation

The consumption pattern of psychotropic substances in CA was assessed using the European addiction severity index (http://www.emcdda.europa.eu/).

Cardiovascular Status

All CA were assessed on physical examination, resting ECG, exercise ECG, laboratory test and transthoracic echocardiogram (TTE) on the day of CMR. Physical examination included documentation of weight, height, blood pressure and heart rate. Exercise ECG was performed as bicycle ergometry using a protocol involving a workload increase of 25 W every 2 min and starting at 50 W.²⁷ TTE was performed according to current guidelines on the day of CMR.²⁸ In particular, left ventricular (LV) diastolic dysfunction was diagnosed and graded according to current recommendations, including the assessment of mitral inflow with peak early filling (E-wave) and late diastolic filling (A-wave) velocities, deceleration time (DT) of early filling velocity, E/A ratio, tissue Doppler annular early (E’) and late diastolic velocities (A’), mitral inflow E velocity to tissue Doppler E’ (E/E’) ratio, and pulmonary venous flow including peak systolic (S) velocity, peak anterograde diastolic (D) velocity and the S/D ratio.²⁹ Mild diastolic dysfunction was defined as mitral E/A ratio <0.8, DT >200 ms, predominant systolic flow seen in pulmonary venous flow (S>D), annular E’ <8 cm/s and E/E’ ratio <8 (septal and lateral). Moderate diastolic dysfunction was defined as mitral E/A ratio 0.8–1, E/E’ ratio 9–12 and E’ <8 cm/s. Severe diastolic dysfunction was defined as E/A ratio ≥2, DT >200 ms and an average E/E’ ratio >13 (or septal E/E’ ≥15 and lateral E/E’ >12).²⁹ The laboratory tests included blood count, serum creatinine, creatine kinase, highly sensitivity troponin I (hs-TNI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). NT-proBNP was measured on the ELECSYS 2010 using an electrochemiluminescence immunoassay (ECLIA, Roche Diagnostics). The analytical range is 5–35,000 ng/L. Serum troponin I was determined using a highly sensitive troponin I immunoassay (ARCHITECT i2000SR; Abbott Diagnostics, USA). The limit of detection for the assay was 1.9 ng/L (range, 0–50,000 ng/L). The assay had a 10% coefficient of variation at a concentration of 5.2 ng/L.

CMR Protocol

CMR was performed on a 1.5-T scanner (Achieva, Philips Medical Systems, Best, The Netherlands) using ECG-triggered and either breath-held or respiratory navigator-gated sequences. A retrospectively gated cine-CMR short-axis stack was acquired to obtain LV volumes and function using a steady-state free precession (SSFP) sequence with the following typical imaging parameters: voxel size, 1.36×1.36×6 mm³; echo time (ET), 1.67 ms; time to repetition (TR), 3.34 ms; flip angle, 60°; parallel acquisition technique, SENSE. Edema-sensitive T2-weighted (T2w) CMR was performed on end-diastolic LV short-axes using a fat-suppressed (short inversion time inversion recovery), black-blood triple inversion recovery turbo spin-echo sequence with the following typical imaging parameters: voxel size, 1.36×1.36×10 mm³; TE, 90 ms; 25 echoes; TR, 1,600 ms. A bolus of 0.075 mmol/kg gadobenate dimeglumine was injected. Phase-sensitive inversion recovery LGE imaging was performed on end-diastolic short-axes at least 10 min after contrast administration (typical imaging parameters: voxel size, 0.94×0.94×8 mm³; TE, 2.53 ms; TR, 5.21 ms; flip angle, 15°). T1 mapping was performed on 3 representative short axes slices (basis, center, apex) using a 3(3)5 variant of the modified Look-Locker inversion recovery (MOLLI) sequence before and 15 min after contrast media administration. Typical imaging parameters were as follows: voxel size, 1.19×1.19×10 mm³; 8 single-shot balanced SSFP readout using a 3(3)5 scheme; TE, 1.59 ms; TR, 3.17 ms; flip angle, 35°; SENSE factor, 2; linear phase encoding; 10 start-up cycles to approach steady-state prior to imaging; effective inversion times 188–3,382 ms.

CMR Data Analysis

CMR data analysis was performed by 2 observers with >5 and >10 years of experience in CMR, in agreement with current guidelines.³⁰ LV end-diastolic volume index (LVEDVi), LV end-systolic volume index (LVESVi), LV mass index, stroke volume index (SVi) and LV ejection fraction (LVEF) were calculated using commercial software (ViewForum workstation R5.1, Philips Medical Systems, Best, the Netherlands). Global myocardial inflammation/edema was assessed on T2w imaging by calculating the relative T2 signal intensity (SI) ratio as SI of myocardium divided by SI skeletal muscle.³¹ The presence of focal edema and the presence and pattern of LGE lesions was qualitatively assessed by a consensus reading of the 2 observers and in agreement with current guidelines.³⁰ An ischemic pattern of LGE was defined as subendocardial or transmural LGE, whereas a non-ischemic pattern of LGE was defined as intramyocardial and/or subepicardial LGE.

T1 and ECV Quantification

T1 maps were generated of LV myocardium and blood pool from the 8 acquired images per slice using a dedicated plug-in written for OsiriX^TM (Pixmeo, Bernex, Switzerland) as described before.³²^,³³ Endo- and epicardial contours were manually drawn and propagated through the image stack. Contours were manually corrected and carefully aligned with the contours in each respective component image. Native and post-contrast T1 were measured in myocardium and blood pool. Global myocardial ECV was measured on ECV maps, which were generated using the established equation ECV=[1–hematocrit]×[∆R1]myocardium/[∆R1]blood pool.²²

R1 was defined as 1/T1 and ∆ was defined as the difference between native and post-contrast R1. Hematocrit was measured from a venous blood sample taken on the same day as the CMR. The recommended phantom studies for validation of T1 and the method were recently published.²⁰^,³³ CMR findings in an asymptomatic CA are shown in Figure.

Figure.

Cardiac magnetic resonance imaging in a 27-year-old cardiac asymptomatic cocaine abuser. (A) Short axis steady-state free precession (SSFP) indicated normal left ventricular (LV) volume, mass and function. (B) No focal edema was observed on corresponding T2-weighted short tau inversion recovery (STIR). (C) Late gadolinium enhancement (LGE) shows subtle areas of subepicardial and intramyocardial scar in the inferolateral LV wall (red arrow). (D) Extracellular volume (ECV) imaging confirmed these lesions (red areas), with focal expansion of the ECV.

Statistical Analysis

Statistical analysis was performed using GraphPad Prism version 5.00 for Windows (GraphPad Software, San Diego, CA, USA). All variables were tested for normal distribution with the D’Agostino and Pearson omnibus normality test. Continuous data were compared using Student’s t-test for normally distributed data, otherwise non-parametric Mann-Whitney test was used. Categorical data were compared using Fisher’s exact test. Statistical significance was set at P<0.05. Continuous data are presented as median (IQR). Categorical data are presented as numbers and percentage.

Results

CA Behavior and Characteristics

Table 1 lists the clinical characteristics and cardiovascular risk factors of CA. Six CA (30%) had increased blood pressure on physical examination; 6 (30%) had abnormalities on resting ECG in terms of a positive Sokolow-Lyon index (n=2; 10%) or unspecific repolarization disorders (n=4; 20%). One CA had a pathologic exercise ECG. TTE indicated mild diastolic dysfunction in 2 (10%). Median septal wall thickness was 9 mm (IQR, 7–10 mm) in CA.

Table 1. Cocaine Abuse: Patient Characteristics

	n (%) or median (IQR)
Age (years)	35 (28–44)
Male	16 (80)
BMI	26 (22–28)
SBP (mmHg)	125 (115–145)
DBP (mmHg)	80 (71–85)
RR >140/90 mmHg	6 (30)
Cardiovascular risk factors
Known arterial hypertension	0
History of smoking or active smoking	17 (85)
Dyslipidemia	0
Family history of CAD	0
Diabetes mellitus	0
ECG
Pathologic resting ECG	6 (30)
Positive Sokolow-Lyon index	2 (10)
Repolarization disorders	4 (20)
Exercise ECG
Pathologic exercise ECG	1 (5)
Max. load (W)	175 (125–181)
Max. HF (beats/min)	140 (134–157)
Max. SBP (mmHg)	200 (181–222)
Max. DBP (mmHg)	93 (89–101)
Echocardiography
Diastolic dysfunction	2 (10)
E/A	1.6 (1.3–1.8)
E/E’	5.9 (5.1–7.0)
Intraventricular septum thickness (mm)	9 (7–10)

BMI, body mass index; CAD, coronary artery disease; ECG, electrocardiogram; DBP, diastolic blood pressure; HF, heart failure; RR, respiratory rate; SBP, systolic blood pressure.

Data on drug behavior of CA are given in Table 2. Median duration of constant cocaine use was 7.5 years (IQR, 2.8–9.5 years). The majority of CA (n=15; 75%) used cocaine during the last 30 days. All patients concomitantly used other drugs: 17 CA (75%) were active smokers, 14 (70%) fulfilled dependency criteria for alcohol use (F10.2) with respect to International Classification of Diseases (ICD, version 10). Two CA (10%) stated concomitant use of opiates, 15 (75%) of cannabis, 4 (20%) of benzodiazepines, 10 (50%) of amphetamines and other stimulants; and 10 (50%), concomitant use of hallucinogens.

Table 2. Drug Use Behavior

	n (%) or median (IQR)
Cocaine
Age at first use (years)	21.5 (19.5–28.3)
Years of continuous use	7.5 (2.8–9.5)
Use during last 30 days	15 (75)
Smoking
History of smoking	17 (85)
Active smokers	17 (85)
Age at first use (years)	14.0 (13.0–15.0)
Years of continuous use	18.0 (13.0–26.0)
Alcohol
History of abuse	17 (85)
Fulfillment of dependence criteria (F10.2)	14 (70)
Age at first use (years)	14.0 (13.0–15.0)
Years of continuous use	21 (15.3–25.8)
Use during last 30 days	12 (60)
Opiates
History of use	2 (10)
Age at first use (years)	21 (19.5–22.5)
Years of continuous use	2 (1.5–2.5)
Use during last 30 days	0
Cannabis
History of use	15 (75)
Age at first use (years)	16.0 (15.0–16.5)
Years of continuous use	11.0 (8.0–14.5)
Use during last 30 days	2 (40)
Benzodiazepines
History of use	4 (20)
Age at first use (years)	25.5 (22.5–28.0)
Years of continuous use	4.5 (3.5–5.8)
Use during last 30 days	2 (10)
Amphetamines and other stimulants
History of use	10 (50)
Age at first use (years)	16.5 (16.0–20.3)
Years of continuous use	9.0 (7.3–11.0)
Use during last 30 days	5 (25)
Hallucinogens
History of use	10 (50)
Age at first use (years)	18.5 (16.3–22.3)
Years of continuous use	3.5 (2.0–5.0)
Use during last 30 days	0

CA vs. Controls

The CA and controls did not differ significantly regarding age (35 years; IQR, 28–44 years vs. 31 years; IQR, 25–41 years; P=0.68), gender (16 vs. 18 male; P=0.66), body mass index (26 kg/m²; IQR, 22–28 kg/m² vs. 24 kg/m²; IQR, 22–26 kg/m²; P=0.40), known arterial hypertension (0 vs. 0), dyslipidemia (0 vs. 0), family history of CAD (0 vs. 2, 10%; P=0.49) or diabetes mellitus (0 vs. 0). Furthermore, no significant differences were observed between CA and controls in serum creatinine kinase, glomerular filtration rate, hs-TNI or NT-proBNP (Table 3). CMR parameters of CA and controls are listed in Table 4. No significant differences were found between the groups in LVEDVi (median, 85 mL/m²; IQR, 74–94 mL/m² vs. 87 mL/m²; IQR, 81–92 mL/m²; P=0.34), LVESVi (33 mL/m²; IQR, 24–38 mL/m² vs. 33 mL/m²; IQR, 25–40 mL/m²; P=0.69), LVEF (64%; IQR, 58–68% vs. 62%; IQR, 58–67%; P=0.90) or LV mass index (68 g/m²; IQR, 59–74 g/m² vs. 63 g/m²; IQR, 54–71 g/m²; P=0.41). Neither CA nor controls had evidence of global or focal edema (Table 4). There were no significant differences between CA and controls in global myocardial native T1 (1,055 ms; IQR, 1,008–1,073 ms vs. 1,036 ms; IQR, 1,006–1,054 ms; P=0.37), global myocardial post-contrast T1 (612 ms; IQR, 589–653 ms vs. 587 ms; IQR, 579–623 ms; P=0.10) or global myocardial ECV (25%; IQR, 24–26% vs. 25%; IQR, 23–26%; P=0.61; Table 4).

Table 3. Laboratory Data

	CA (n=20)	Controls (n=20)	P value
Serum creatinine (mg/dL)	0.9 (0.7–1.0)	0.9 (0.8–1.0)	0.35
GFR (mL/min/1.73 m²)	111 (69–142)	114 (93–128)	0.68
Serum CK (U/L)	103 (83–150)	143 (101–226)	0.09
Troponin I (pg/mL)	1.3 (0.5–1.9)	1.1 (0.4–1.6)	0.59
NT-proBNP (pg/mL)	36.2 (22.2–62.0)	31.0 (17.2–52.2)	0.47

Data given as median (IQR). CA, cocaine abusers; CK, creatine kinase; GFR, glomerular filtration rate; NT-proBNP, N-terminal pro-B-type natriuretic peptide.

Table 4. CMR Parameters

	CA (n=20)	Controls (n=20)	P value
LVEDVi (mL/m²)	85 (74–94)	87 (81–92)	0.34
LVESVi (mL/m²)	33 (24–38)	33 (25–40)	0.69
SVi (mL/m²)	51 (41–62)	52 (49–59)	0.34
HR (beats/min)	62 (54–69)	65 (60–72)	0.19
LVEF (%)	64 (58–68)	62 (58–67)	0.90
LV mass index (g/m²)	68 (59–74)	63 (54–71)	0.41
Presence of focal edema	0	0	–
T2 ratio	2.09 (1.82–2.25)	2.2 (1.87–2.43)	0.16
Presence of LGE	8 (40)	0	<0.01
Non-ischemic LGE pattern	8 (40)	0	<0.01
Midmyocardial LGE	6 (30)	0	<0.01
Subepicardial LGE	1 (5)	0	0.40
LGE at RV insertion point	1 (5)	0	0.40
Native T1 (ms)	1,055 (1,008–1,073)	1,036 (1,006–1,054)	0.37
Post-contrast T1	612 (589–653)	587 (579–623)	0.10
Extracellular volume (%)	25 (24–26)	25 (23–26)	0.61

Data given as n (%) or median (IQR). CA, cocaine abusers; CMR, cardiac magnetic resonance imaging; HR, heart rate; LGE, late gadolinium enhancement; LV, left ventricular; LVEDVi, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; LVESVi, left ventricular end-systolic volume index; RV, right ventricular; SVi, stroke volume index.

Eight CA (40%) but none of the controls had non-ischemic LGE (P<0.01). The amount of LGE was low, with 1 CA presenting with 5 LGE-positive myocardial segments, whereas the remaining 7 CA presented with only 1 LGE-positive segment. LGE pattern was mid-myocardial in 6 CA, sub-epicardial in 1 and located at the inferior right ventricular (RV) insertion point in another 1. None of the CA had an ischemic LGE pattern. Figure shows an example of a CA with non-ischemic, mid-myocardial LGE. Moreover, CA and controls significantly differed with respect to history of smoking or active smoking (17, 85% vs. 1, 5%; P≤0.0001).

CA and Presence of Focal Scar

The only significantly different parameter between CA with and without focal myocardial scar on LGE was median hs-TNI, which was higher in patients with LGE compared with patients without LGE (median, 1.7 pg/mL; IQR, 1.3–2.5 pg/mL vs. 0.6 pg/mL; IQR, 0.4–1.3 pg/mL; P<0.01; Table 5). In addition, there was a non-significant increase in median LV mass indices in CA with scar on LGE (73 g/m²; IQR, 61–81 g/m² vs. 64 g/m²; IQR, 48–71 g/m²; P=0.10). There were no significant differences, however, in other parameters between the groups. Importantly, CA with and without focal scar did not differ with respect to history of smoking or active smoking (7/8, 88% vs. 10/12, 83%; P=1.0).

Table 5. Cocaine Abuser Characteristics vs. Presence of LGE

	LGE (+) (n=8)	LGE (−) (n=12)	P value
Age (years)	39 (32–44)	31 (26–44)	0.24
Male sex	7 (88)	9 (75)	0.62
BMI	28 (25–30)	24 (21–27)	0.10
Serum creatinine (mg/dL)	1.0 (0.8–1.2)	0.9 (0.6–1.0)	0.20
GFR (mL/min/1.73 m²)	142 (66–161)	74 (67–123)	0.17
Serum CK (U/L)	125 (90–293)	94 (80–132)	0.12
Troponin I (pg/mL)	1.7 (1.3–2.5)	0.6 (0.4–1.3)	0.01
NT-proBNP (pg/mL)	40.7 (20.2–58.0)	31.2 (22.2–76.9)	0.96
Pathologic resting ECG	3 (38)	3 (25)	0.64
Years of continuous cocaine use	3.0 (2.25–6.75)	8.5 (2.25–14.75)	0.23
History of smoking or active smoking	7 (88)	10 (83)	1.00
Diastolic dysfunction	1 (12.5)	1 (8)	1.00
LVEDVi (mL/m²)	84 (71–100)	87 (75–93)	1.00
LVESVi (mL/m²)	35 (24–38)	31 (26–38)	0.88
SVi (mL/m²)	56 (47–65)	50 (39–60)	0.30
HR (beats/min)	60 (54–71)	62 (55–67)	0.79
LVEF (%)	66 (61–68)	62 (57–68)	0.59
LV mass index (g/m²)	73 (61–81)	64 (48–71)	0.10
Focal edema	0	0	–
T2 ratio	2.1 (1.7–2.3)	2.1 (1.8–2.2)	0.77
Native T1 (ms)	1,010 (988–1,059)	1,056 (1,019–1,078)	0.13
Post-contrast T1	605 (540–645)	606 (585–648)	0.54
Extracellular volume (%)	27 (22–38)	25 (24–26)	0.59

Data given as n (%) or median (IQR). Abbreviations as in Tables 1,3,4.

Discussion

In this study, we performed a comprehensive cardiovascular assessment in 20 asymptomatic, long-term CA involving resting ECG, exercise ECG, circulating biomarkers, echocardiography and advanced CMR techniques such as ECV imaging to detect diffuse myocardial injury. We found that asymptomatic CA had normal LV volumes, mass and function as well as normal circulating biomarkers compared with healthy volunteers. LGE CMR, however, visualized focal myocardial scar with a non-ischemic pattern in 8 CA (40%), which was associated with significantly higher hs-TNI compared with CA without focal myocardial scar. Interestingly, we did not observe diffuse myocardial injury such as myocardial fibrosis on ECV imaging in CA.

CA Cardiovascular Status

Using cardiac biomarkers, resting ECG, exercise ECG and TTE, 55% (n=11) of CA showed abnormal results in terms of slightly increased blood pressure (30%; n=6), positive Sokolow-Lyon index (10%; n=2), unspecific repolarization disorders (20%; n=4), pathologic exercise ECG (5%; n=1) and/or diastolic dysfunction (10%; n=2). In particular, cardiac biomarkers hs-TNI and NT-proBNP were not significantly different in CA compared with the control group. These results are partially in line with Aquaro et al, who found ECG abnormalities in 63% and normal hs-TNI and NT-proBNP in their cohort of CA.¹⁴

LV Function, Volume and Mass in CA

There were no significant differences in LV function, volume and mass between the CA and the healthy control group (Table 4). These results are in line with Aquaro et al, who found normal LVEDVi, LVESVi, LV mass index and LVEF in their cohort of 30 subjects.¹⁴ In contrast, Maceira et al observed a significant increase of LVESVi (30±8 mL/m² vs. 26±5 mL/m²; P≤0.01) and LV mass index (76±15 g/m² vs. 69±4 g/m²; P≤0.01) as well as a significant decrease in LVEF (59±5% vs. 68±4%; P≤0.01) compared with their healthy control group.¹³ Nevertheless, all obtained LVEDVi, LVESVi, LV mass index and LVEF in CA in the present and the 2 recent studies were within the normal range according to recently established reference values for CMR.³⁴ Furthermore, we observed mild diastolic dysfunction only in 2 CA, which was not associated with increased LV mass or hypertension. Taken together, the present data demonstrate that LV volume, mass and function remain unaffected in the majority of asymptomatic CA. This is unexpected, given that cocaine stimulates the sympathetic nervous system with subsequent increases in blood pressure, and that autopsy studies concordantly have reported LV hypertrophy in CA in up to 57% of cocaine-related deaths.¹¹^,¹²^,³⁵^,³⁶ Thus, there is obviously a discrepancy between autopsy data derived from cocaine-related deaths and prospective CMR data derived from asymptomatic CA.

Focal and Diffuse Myocardial Injury in CA

We did not find focal edema in any of the present patients. Furthermore, neither the T2 ratio nor native myocardial T1 as indicators of diffuse myocardial edema were elevated compared with healthy controls (Table 4). While these data are in line with Maceira et al,¹³ Aquaro et al found edema in 47% (n=14) of their patients. Given that 43% (n=13) of the Aquaro et al patients had positive urine assay for cocaine metabolites at the time of CMR, the authors suggested a correlation between recent cocaine use and the presence of focal edema.¹⁴ Considering, however, that 75% of the present CA stated recent cocaine use within the last 30 days (Table 2), the present data do not support the presence of unrecognized myocardial inflammation due to recent cocaine use.

Regarding focal myocardial scar/fibrosis, LGE was noted in 40% (n=8) of the present CA. All of these CA had a non-ischemic pattern of LGE. The predominant pattern was mid-myocardial and restricted to only 1 segment in all but 1 CA. These findings are in line with Maceira et al, who found LGE in 30% (n=29) of their patients. While only 1 CA in their cohort presented with an ischemic pattern of LGE in terms of sub-endocardial LGE, all other CA had a non-ischemic pattern in terms of mid-myocardial LGE or LGE located at the inferior RV insertion point.¹³ In contrast, Aquaro et al noted LGE in 73% (n=22) of their patients. While 68% (n=15) of these patients had a non-ischemic LGE pattern, a significant number of patients (32%; n=7) presented with an ischemic pattern.¹⁴ It is important to note in this context, that non-ischemic LGE can be observed in several cardiomyopathies, but the exact mechanism underlying this pattern is not fully understood.³⁷ One important cause of intramyocardial or (sub)epicardial LGE is the presence of active or healed myocarditis.³⁸ Autopsy studies or endomyocardial biopsy studies indicated myocarditis in 20–29% of CA who died in the context of cocaine abuse,¹²^,³⁹^,⁴⁰ but autopsy findings in symptomatic CA are not automatically transferable to the present cohort of asymptomatic CA. Comparison of LGE-positive and -negative CA in the present cohort indicated a small, but significant increase of hs-TNI in LGE-positive CA, although hs-TNI was still within the normal range (Table 5).⁴¹ Irrespective of the cause of this myocardial injury, this relatively increased hs-TNI could represent a precursor of future cardiovascular events. In the case of myocarditis as an underlying mechanism, one would expect concomitant edema on T2w CMR. T2w CMR, however, appears to be not sufficiently sensitive to detect clinically silent acute myocardial inflammation, as demonstrated by a recent study on biopsy-proven myocarditis.⁴² In summary, the exclusive proof of non-ischemic LGE combined with increased hs-TNI in the present CA cohort might indicate myocardial inflammation as an underlying cause of myocardial injury, but the exact mechanism remains unclear and we cannot exclude alternative mechanisms such as vasospasm and/or thrombosis of arterioles.¹³^,⁴³ Most important, presence of LGE is associated with an adverse prognosis in patients with ischemic and several non-ischemic cardiomyopathies such as myocarditis.¹⁹^,⁴⁴^,⁴⁵ The questions of whether the presence of LGE is also associated with adverse outcome in CA and whether CMR enables the detection of more CA at risk compared with more easily available diagnostic modalities such as ECG, will need to be addressed in future studies involving long-term follow-up.

Interestingly, we did not observe diffuse myocardial involvement despite the use of advanced CMR tissue characterization techniques. In particular, global myocardial ECV, as a surrogate for interstitial myocardial disease such as myocardial fibrosis,²⁰ was not increased in the present CA. Thus, a focal, rather than diffuse, pattern of myocardial involvement was observed in the present cohort of asymptomatic CA. Nevertheless, we cannot exclude early, diffuse myocardial tissue alterations under the detectable limits, similar to other recent findings in patients with arterial hypertension.⁴⁶

Study Limitations

Major limitations of the study were the relatively small subject group and the lack of histologic data for myocardial tissue characterization in CA, given that endomyocardial biopsy in asymptomatic individuals was not acceptable to us. Nevertheless, the use of advanced CMR techniques for tissue characterization clearly indicated the presence of focal, not diffuse, myocardial injury in asymptomatic CA.

Conclusions

Focal myocardial injury in terms of subtle LGE was noted in 40% of asymptomatic CA, which was associated with higher hs-TNI. The prognostic implications of this finding await further assessment in larger, longitudinal studies. Furthermore, the present comprehensive assessment, including advanced ECV imaging, indicates a focal rather than diffuse pattern of myocardial involvement in asymptomatic CA.

Disclosures

C.S. is an employee of Philips Research, Germany. The other authors declare no conflict of interest.

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