Effect of Methamphetamine Abuse on Cardiac Markers Troponin,

Creatine Kinase and LDH at Khartoum State

Abdalla Eltoum Ali , Hoyam Abdalla Mohammed Ahmed Abdalla

Abstract

Background: Cardiovascular complications are the second most common cause of death in
methamphetamine use following accidental overdose. Methamphetamine use is growing
worldwide regardless of wealth, location, and culture.

Aim: To study the Effect of methamphetamine Abuse on cardiac markers (Troponin, CK MB

and HDL) in Khartoum state, Sudan.

Material and Method: This was Case-control study, conducts in Khartoum state includes 80
participants and divided into groups as 40 of them as case and 40 of healthy individual as
control. Data will be tabulated and analyzed using the Statistical Package for Social Sciences
(SPSS).

Results: Majority of them presented among age group 20-25years old and 26-31 years as
(32.5%) and (27.5%) respectively, with fewer participants being more than 37 years old (7.5%)
The mean and std of CK mb was 37.3 ± 5.5 among case group and 11.9 ± 3.5 among control
group with P.value was 0.000 which considered significant increased among case than
control ,The mean and std of Troponin were 0.49 ± 0.14 among case group and 0.06 ± 0.04
among control group with P.value was 0.000 which considered significant increased among
case than control and The mean and std of LDH was 155.4 ± 12.9 among case group and 132.5
± 3.6 among control group with P.value was 0.001 which considered significant increased
among case than control .Majority of them used Methamphetamine by smoking as (47.5%)
followed by oral used as 20% and injection as 20% and 12.5% used combination . Most of
them used concentration 50 mg of oral used for one /day as 12.5% followed by 7.5%used
two/day, the concentration of injection was 20-40 ml used and Abuser used 1ml per day in 20%
of participants, majority of them used smoking in used as 32.5% used for one/day and 15%
used for two/day, the combination of used either used oral and injection as 5% or oral and
smoking as 7.5%.

1
Conclusion: There was positive correlation between Troponin and duration of
Methamphetamine used (P.value 0.362, r =0.148), CK-mb and duration of Methamphetamine
used (P.value 0.0498, r =0.110) and LDH and duration of Methamphetamine used (P.value

0.055, r =0.306) respectively .

1.1. 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
designated 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. A nexus between methamphetamine uses and the development of heart
(3)
failure was first recognized during this period. At present, methamphetamine use remains a
significant problem that is expanding domestically and worldwide. 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. Visits to the emergency department have also increased significantly in
(4)
the past decade. According to the 2017 United Nations Drug Report, there are over 37
million estimated regular multinational methamphetamine users, with an annual prevalence of
(5)
0.77%. Based on these statistics, it seems certain the prevalence of heart failure from
methamphetamine use will increase in parallel, especially in younger patients with no other
(6)
significant cardiac risk factors. Acute myocardial infarction with associated increased
creatine kinase (CK) and MB fractions has been described in the literature; myocardial injury
(7)
with elevated troponin I (TnI) secondary to amphetamine abuse has not been described.
(8)
Several cardiovascular complications have been associated to amphetamines. The most
common short-term effects are tachycardia and hypertension. In addition, vascular spasm,
myocardial infarction, cardiac dysrhythmias, cardiomyopathy, myocarditis, and necrotizing
vasculitis. Although hypertension is common in methamphetamine abuse, severe hypotension
related to paradoxical central sympathetic depression and ventricular impairment can occur. (9)

2
Sudan is in need for a serious shift in overall thinking about how drug addicts should be
treated. Drug addiction might cause of many social distresses which can result in offensive act.
it can cause psychological problems including, psychosis, depression, and violence, and also
can lead to serious physical ailments, including heart attack, stroke, organ failure and death (10)
Methamphetamine MA is a stimulant drug whose mechanism of action lies in increasing
activation of the central nervous system through the release of multiple neurotransmitters,
including dopamine (DA), noradrenaline, adrenaline, and serotonin. The mechanism of action
that has been most implicated in the rewarding effects of MA is in the release of DA in the
striatum. This increase in extracellular DA is associated with the rush or “high” experienced
following acute MA use. Acutely, MA use leads to a range of physiological and subjective
effects such as increased heart rate, increased energy, decreased appetite, feelings of euphoria,
decreased fatigue, elevated blood pressure and other 3 physiological arousal symptoms. With
increased dosage, users may also experience effects such as paranoia, hallucination, confusion,
and panic attacks. (2)

The half-life of MA is approximately 10 hours and remains similar across types of

administration. Peak subjective effects and cardiovascular changes occur within approximately
5-15 minutes of using the drug, while subjective effects typically last approximately four
hours. In comparison, MA maintains in the system longer and diminishes slower than another
well-known stimulant, cocaine, which declines rapidly following use and has a half-life of
approximately one hour. (11) The extended duration of the subjective and physiological effects
of MA increases its appeal as an alternative to shorter half-life stimulants such as cocaine, thus
adding to the abuse liability of MA.(12)

MA comes in various forms, such as pill, powder, and crystalline, and can be administered in a
number of ways. The most popular routes of administration include oral ingestion (e.g.,
swallowing, drinking, eating MA), snorting/sniffing, injecting, and smoking the substance;
however other more uncommon routes of administration include inserting the substance
(12)
rectally or vaginally. MA administration through smoking and injecting allow for the
quickest “high” due to the immediate absorption into the bloodstream and up to the brain,
possibly contributing to greater addictive potential. (13)

Epidemiological studies demonstrate that amphetamine-type stimulants are the most widely
used illicit drug in the world after cannabis, with ≤51 million global users between the ages of
15 and 64 years. Methamphetamine use is a growing worldwide phenomenon, with the
consumption of the drug occurring independently of wealth, geographic location, and culture.
(16)

3
Methamphetamine (N-methyl-alpha-methylphenethylamine) is a cationic molecule and chiral
compound based around a phenylethylamine core, obviously distinguishable from its
amphetamine analogs by an additional methyl group (Figure 1). This moiety makes
methamphetamine highly lipophilic, thereby allowing it to increasingly penetrate the blood-
brain barrier. (17) Methamphetamine functions in neuronal tissue by promoting catecholamine
(eg, dopamine and norepinephrine) signaling through multiple mechanisms. Methamphetamine
binds vesicular monoamine transporter-2 and accumulates in vesicles where it alters the pH
resulting in catecholamine release into the cytosol (Figure 1) (18). Although this results in acute
increases in dopamine and norepinephrine signaling driving the methamphetamine-associated
euphoria, chronic methamphetamine use induces neurotoxicity in dopaminergic axon
terminals, associated with reduced dopamine production and reduced expression of the DAT.
Additionally, methamphetamine induces neuronal cell death associated with endoplasmic
reticulum stress, mitochondrial dysfunction, and enhanced reactive oxygen species (ROS)
production. (19)

While exposure of methamphetamine results in deleterious consequences to the neurological

system, it also elicits a range of other adverse effects. Several clinical and postmortem studies
clearly associate the use of methamphetamine with cardiovascular disease, and cardiovascular
disease represents the second leading cause of death among methamphetamine abusers
following only accidental overdose. (20) Methamphetamine can have adverse and potentially
fatal effects on arteries and blood vessels, including elevated blood pressure, acute vasospasm,
and atherosclerotic cardiovascular disease. In addition, methamphetamine induces structural
and electrical remodeling of cardiac tissue leading to arrhythmias and heart failure. However,
the mechanisms surrounding these and other pathological responses of the cardiovascular
system in methamphetamine abusers remain largely unknown. (21) Methamphetamine may
induce cardiovascular complications through catecholamine toxicity. (21)

Methamphetamine administration in human subjects results in an acute, rapid increase in both

heart rate and blood pressure. (24)

Methamphetamine usage reduces traditional risk factors associated with atherosclerosis, such
as elevated serum cholesterol and obesity, consistent with its known function as an appetite
suppressor. (37)

4
Methamphetamine use is associated with cardiac structural and cellular changes that are
typically linked to cardiac arrhythmias. Endomyocardial biopsies from the ventricles from
patients with methamphetamine-associated cardiomyopathy showed increased markers of
inflammation and fibrosis. Ventricular fibrosis in patients with methamphetamine-associated
cardiomyopathy has been corroborated by cardiac magnetic resonance imaging by other
investigators. (46) The extent of fibrosis directly correlated with duration of methamphetamine
use and predicted recovery with discontinuation of the drug. In addition to structural
remodeling described above, methamphetamine is also associated with cardiac electrical
remodeling. Animal studies show decreased expression and activity of multiple potassium
channels and voltage-gated calcium channels, which recovered significantly by week 8 of
(47)
withdrawing methamphetamine. In isolated ventricular myocytes, methamphetamine
inhibited transient outward potassium current, inward rectifier potassium current, and L-type
calcium current in a dose-dependent manner. In contrast, Sugimoto et al found that
methamphetamine treatment increases rat neonatal ventricular myocyte beating rates and
calcium spark frequency in an L-type calcium channel– dependent manner. However, both
studies highlight the ability of methamphetamine to directly affect cardiac myocyte function
independent of catecholaminergic changes associated with the in vivo model.(48)

Methamphetamine-related cardiomyopathy is associated with severe systolic dysfunction, left

ventricular chamber dilation. Clinical and autopsy reports obtained from long-term
methamphetamine users showed indicators of cardiomyopathy, such as necrosis, fibrosis,
(49)
hypertrophy, and enlargement of the heart. The degree of fibrosis predicts the functional
recovery following cessation of methamphetamine use, whereas cardiac function did not
(50)
improve in any of the patients who continued methamphetamine use. Methamphetamine-
associated cardiotoxic effects have been reported following acute administration, chronic
administration, and binge administration (ie, frequent doses followed by a period of
abstinence), suggesting both a rapid and sustained influence on myocardial function. (51)

3. Materials and Methods

3.1 Study design:

5
This was observational analytical case-control study.

3.1 Study area and duration:

The study conducts in Hayat Center for Addiction Cure at Khartoum state and AbdelAal
ElIdrissi hospital for Mental and Mental illnesses at Khartoum North, during 2022-2023.

3.3 Study population:

Only those individuals had known of Methamphetamine abuse were included in the study as
case group. Data collected including the demographic characteristics and laboratory and
clinical findings of the patients. blood samples were taken from each patient.

3.4 Sample size and sampling technique:

3.4.1 Inclusion Criteria:

Patients with had used of Methamphetamine were included.

3.4.2 Exclusion criteria:

Patients with a history of underlying cardiovascular disease or a family history of cardiac

disease and those with diabetes mellitus, proven hypertension or hyperlipidemia were excluded
from the study. In addition, chronic drug users without any evidence of recent abuse were not
included.

3.5. Sample size:

80 patients were enrolled in this study, 40 as case had used Methamphetamine as case group
and 40 healthy control subjects.

3. 6.data collection and data tools

Venous blood collected using sterile disposable plastic syringe after cleaning the venipuncture
area with (70%) ethanol, the blood added to the anticoagulant and gently mix. Patients were
evaluated and examined the cardiac biomarker tests, including levels of troponin I by Ichroma
Tm
, creatinine kinase (CK)-MB by spectrophotometric and LDH.

6
3.7 data analysis and Data presentation:

Data were tabulated and analyzed using the Statistical Package for Social Sciences (SPSS). Chi
squire test was used and significance differences (P value) were adjusted with confidence
interval (CI) 95% (P < 0.05 significant, P > 0.05 not significant). Data was analyzed by using
the SPSS computer program version 22. Data presented in form of tables and figures.

3.8 Laboratory processing

3.8.1. Estimation of troponin by Ichroma TM

3.8.1. Principle

The test uses a sandwich immunodetection method; the detector antibody in buffer binds to
antigen in sample, forming antigen- antibody complexes, and migrates onto nitrocellulose
matrix to be captured by the other immobilized-antibody on test strip. The more antigen in
sample forms the more antigen-antibody complex and leads to stronger intensity of
fluorescence signal on detector antibody, which is processed by instrument for ichroma™ tests
to show Tn-I concentration in sample.

3.8.2. Procedure:

transferred 75 µL to an empty sample mixing tube using a transfer pipette and 75 µwere added
detection buffer to it. Close the lid of the sample mixing tube and mixed the sample thoroughly
by shaking it about 10 times. The sample mixture was used immediately, Pipette out 75 µL of a
sample mixture and load it into the sample well on the cartridge. Leave the sample-loaded
cartridge at room temperature for 12 minutes. the sample-loaded cartridge was Scanned
immediately when the incubation time is over. If not, it will cause inexact test result. scan the
sample-loaded cartridge, insert it into the cartridge holder of the instrument for ichroma™
tests. Ensure proper orientation of the cartridge before pushing it all the way inside the
cartridge holder. An arrow has been marked on the cartridge especially for this purpose. Press
‘Select’ button on the instrument for ichroma™ tests to start the scanning process. Instrument
for ichroma™ tests will start scanning the sample loaded cartridge immediately. Read the test
result on the display screen of the instrument for ichroma™ tests.

7
3.8.2. Creatinine kinase (CK)

3.8.2.1. Principle of the method

Creatine kinase (CK) catalyzes the phosphorylation of ADP, in the presence of creatine
phosphate, to form ATP and creatine. The catalytic concentration is determined from the rate
of NADPH formation, measured at 340 nm, by means of the hexokinase (HK) and glucose-
6phosphate dehydrogenase (G6P-DH) coupled reactions.

3.8.2.2. Procedure

Adjusted the instrument to zero with distilled water or air, Working Reagent 1000 (µL) and
from Sample 40 (µL) were Pipetted into a cuvette, mixed gently by inversion, insert cuvette
into the cell holder and stopwatch was started, incubate for 5 minutes and record initial
absorbance reading, Repeated the absorbance readings exactly after 1, 2 and 3 minutes and
calculate the average change in absorbance per minute by used Wavelength 340 nm.

3.8.3. Lactate Dehydrogenase (LDH)

3.8.3.1. Principle of the method

Lactate dehydrogenase (LD or LDH) catalyzes the reduction of pyruvate by NADH, to form
lactate and NAD+. The catalytic concentration is determined from the rate of decrease of
NADH, measured at 340 nm. 3.8.3.2. Procedure bring the Working Reagent and the
instrument to reaction temperature. Pipette into a cuvette: Working Reagent 1.0 mL Sample 20
mix and insert the cuvette into the photometer. Start the stopwatch. After 30 seconds, record
initial absorbance and at 1-minute intervals thereafter for 3 minutes. Calculate the difference
between consecutive absorbances, and the average absorbance difference per minute.

3.9 Data Collection Tools and presentation:

A questionnaire was designed to fulfill the objectives of the study. The questionnaire was filled
with the patients. The first step is the taken of informed consent after describing the purpose of

8
the study and privacy as well as the confidentiality. The second step clarifying the
questionnaire items and filling the questions from with the patients with interviewer
administered consent.

Data were collected by staff nurse directly from patients and from lab records.

3.10. Ethical consideration:

Ethical approval was obtained from ethical committee of Alzaiem Alazhari University, and
Informed consent was taken from all the participants prior to their inclusion in the study.

4. Results

This was Case-control study, conducts in Khartoum state includes 80 participants and divided

into groups as 40 of them as case group and 40 of healthy individual as control. Data will be

tabulated and analyzed using the Statistical Package for Social Sciences (SPSS). Majority of

them presented among age group 20-25years old and 26-31 years as (32.5%) and (27.5%)

respectively, with fewer participants being more than 37 years old (7.5%) as showed in Table

(1)., The mean and std of CK mb was 37.3 ± 5.5 among case group and 11.9 ± 3.5 among

control group with P.value was 0.000 which considered significant increased among case than

control ,The mean and std of Troponin were 0.49 ± 0.14 among case group and 0.06 ± 0.04

among control group with P.value was 0.000 which considered significant increased among

case than control and The mean and std of LDH was 155.4 ± 12.9 among case group and 132.5

± 3.6 among control group with P.value was 0.001 which considered significant increased

among case than control as showed in Table (2), Majority of them used Methamphetamine by

smoking as

9
(47.5%) followed by oral used as 20% and injection as 20% and 12.5% used combination as in

Table (3) Most of them used concentration 50 mg of oral used for one /day as 12.5% followed

by 7.5%used two/day, the injection used 1ml per day in 20% of participants , majority of them

used smoking in used as 32.5% used for one/day and 15% used for two/day , the combination

of used either used oral and injection as 5% or oral and smoking as 7.5% as showed in Table

(4). There was positive correlation between Troponin and duration of Methamphetamine used

(P.value 0.362, r =0.148) , CK-mb and duration of Methamphetamine used (P.value 0.0498 , r

=0.110) and LDH and duration of Methamphetamine used (P.value 0.055 , r =0.306)
respectively

Table (1): Distribution of age group among study population (N=80)

Age group Case Control

less than 20 8 (20%) 3 (7.5%)
20-25 13 (32.5%) 15 (37.5%)
26-31 11(27.5%) 13(32.5%)
32-37 5(12.5%) 9(22.5%)
more than 37 3(7.5%) 0(0.0)
Total 40 (100.0%) 40(100.0%)

10
 Figure (1): Distribution of age group among study population (N=80)

Table (2): comparison between mean and STD Tests among case and control of study
population (N=80)

Tests Case Mean Control P. value

± std Mean ± std

CK mb 37.3 ± 5.5 11.9 ± 3.5 0.000

Troponin 0.49 ± 0.14 0.06 ± 0.04 0.000

LDH 155.4 ± 12.9 132.5 ± 3.6 0.001

Age 26.5 ± 6.5 26.8 ± 5.0 0.758

11
Table (3): Distribution of Method of used Methamphetamine among case study
population (N=40)

Frequency Percentage
Smoking 19 47.5%

Oral 8 20.0%

Injection 8 20.0%

Combination 5 12.5%

Total 40 100

Majority of them used Methamphetamine by smoking as (47.5%) followed by oral used as 20%
and injection as 20% and 12.5% used combination.

Percentage Frequency

12.50%
Combination
5

20.00%
Injection
8

20.00%
Oral
8

47.50%
Smoking
19

Figure (2): Distribution of Method of used Methamphetamine among case study

population (N=40)

12
Table (4): Distribution of time of used the Methamphetamine among case study
population (N=40)

Frequency and percentage

Oral (50mg)

One per day 5 (12.5%)

Two per day 3 (7.5%)

Injection (1ml)

1-2 per day 8 (20.0%)

Smoking

One day 13 (32.5%)

Two/day 6 (15.0%)

Combination

Oral and injection 2 (5.0%)

Oral and smoking 3 (7.5%)

Total 40 (100%)

Most of them used concentration 50 mg of oral used for one /day as 12.5% followed by
7.5%used two/day, the injection used 1ml per day in 20% of participants, majority of them
used smoking in used as 32.5% used for one/day and 15% used for two/day, the combination
of used either used oral and injection as 5% or oral and smoking as 7.5% .

Table (5): Distribution of HIV result among case study population (N=40)

13
 Frequency Percentage
Positive 24 60.0%

Negative 16 40.0%

Total 40 100

40%

60% Positive
Negative

14
Figure (3) Scatter plot of correlation between Troponin and duration of Methamphetamine
used (P.value 0.362, r =0.148)

15
Figure (4) Scatter plot of correlation between CK-mb and duration of Methamphetamine used
(P.value 0.498 , r =0.110)

16
Figure (5) Scatter plot of correlation between LDH and duration of Methamphetamine used
(P.value 0.055 , r =0.306)

17
5.1 Discussion

Methamphetamine (MA) and related substances have become the second most frequently used
(56).
drugs in the world. In 2013, there were approximately 33,900,000 users world-wide
Methamphetamine is a highly potent synthetic amine stimulant that is structurally similar to
(56)
amphetamine . Methamphetamines produce significant effects on physical, behavioral,
cognitive, and psychiatric well-being. Methamphetamine use has become an epidemic in this
country and worldwide.

This was case -control study conducted at Khartoum state among 40 of patients used
Methamphetamine as case group and 40 of healthy individuals as control group. According to
the findings of the current study, methamphetamine abuse occurred mostly among individuals
aged 20-25years old and 26-31 years as (32.5%) and (27.5%) respectively, with fewer
participants being more than 37 years old (7.5%). Other studies have shown that drug abuse is
(57,58)
more prevalent among young people. another agreement with previous research that
(59,60).
indicated the mean age of drug abusers is low the mean of age was 26.5 years among case
and this similar to study of drug abuse cases in Taiwan reported a mean age of 26.7 years
(61)
among those who abused drugs. our finding disagreement with a study of
methamphetamine-related fatalities in Australia, Kaye et al. found that the mean age of patients
was 32.7 years and that 77% were male (62). In the current study, all of the subjects were male.

In the current study, approximately half of the patients exclusively used methamphetamine
drugs via inhalation, followed by oral used and intravenous injection while other drugs in
(60)
combination this similar to Bazmi et al., found majority were used drug by smoking and
Kaye et al. (62) found that 89% of their subjects had used drugs other from methamphetamine.

In the current study the mean and std of CK mb was 37.3 ± 5.5 among case group and 11.9 ±
3.5 among control group with P.value was 0.000 which considered significant increased among
case than control, The mean and std of Troponin were 0.49 ± 0.14 among case group and 0.06
± 0.04 among control group with P.value was 0.000 which considered significant increased
(60)
among case than control this finding agreement with Bazmi et al., found the Mean CK-MB
level in U/mL

35.9 ± 4.3 Mean troponin I level in ng/mL 0.60 ± 0.2

18
Also our finding agreement with study found Troponin I and CK-MB levels were very high
among methamphetamine drugs users in the present study, indicating cardiac damage; these
findings were consistent with those of various previously published research (63,64,65,66,67)

Moreover, Wijetunga et al. found that 84% of crystal methamphetamine users had
cardiomyopathy and global ventricular disorders.(68) In another study, Maeno et al. found that
methamphetamine use directly led to cellular hypertrophy and could potentially result in
disorders of cardiac function among adult rats.(69) Varner et al. demonstrated that
methamphetamine administration could significantly change cardiovascular responses and lead
to severe cardiac pathology; moreover, they also showed that methamphetamine elicited
biphasic heart rate responses consisting of initial bradycardia followed by tachycardia .(70)
According to a review of methamphetamine-induced cardiac complications by Paratz et al.,
dilated, hypertrophic and stress cardiomyopathies are the most common methamphetamine-
associated cardiomyopathies.(71) Additionally, intranasal administration of d-amphetamine
reportedly lead to a more rapid response compared with oral administration.(71)

In current study the mean and std of LDH was 155.4 ± 12.9 among case group and 132.5 ± 3.6
among control group with P.value was 0.001 which considered significant increased among
case than control that similar to study done by Zhang et al., 2018 which Found increased in
LDH in case than control (72).

In the present study most of individual in case had HIV positive as 24 /40 (60%) this agreement
(73,74).
with study found high prevalence of HIV infection in METH using population METH is
one of the most widely abused illicit drugs among HIV-infected individuals. METH use and
HIV infection frequently coexist due to the association of METH use with engagement of high-
risk behaviors (74)

19
 5.2 Conclusion

➢ Troponin I levels were high among methamphetamine drugs users than control
group.
➢ CK-MB levels were high among methamphetamine drugs users than control group
➢ LDH were high among methamphetamine drugs users than control group.

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