Cardiovascular diseases (CVD) are the leading cause of global mortality worldwide and substance use is a hidden determinant . There continues to be a sharp increase in the use of drugs of abuse and substance use disorders worldwide.
Because of this, cardiac complications secondary to illicit drug abuse are increasingly evident. Epidemiological studies suggest that 1 in 5 young adults misuse multiple substances, and that these “polysubstance users” often begin using at younger ages, leading to progressively worsening long-term health.
Specific drugs of abuse such as cocaine, methamphetamine, and alcohol are associated with well-known cardiac complications. However, cardiac complications associated with the increasing use of anabolic androgenic steroids are also becoming more important .
In many regions, after legalization, cannabis consumption has increased greatly, which has led to cardiac complications becoming more evident and more knowledge, no longer considering cannabis to be a relatively benign drug.
E-cigarette use is increasing, making nicotine use more popular again, despite public health interventions related to smoking cessation. Conventional cigarette use is still common and tobacco is a well-known risk factor for coronary artery disease. However, other cardiac complications must be recognized.
The coexistence of mental illness with substance abuse is an important comorbidity that must be recognized and managed appropriately.
The existence of a link between adolescent psychiatric disorders, cardiovascular risk and concomitant substance use is well known, which probably further increases this risk.
Due to the limited evidence and nature of cardiovascular complications of drugs of abuse, most data can demonstrate associations but not necessarily causality.
| Psychostimulant drugs of abuse and addiction |
> Methamphetamine and cocaine
Psychostimulants , initially freely available, have evolved to be one of the most abused drugs . Despite numerous clinical applications for medicinal use, they are abused for their effects: increased wakefulness, euphoria, and anorexia. Methamphetamine , colloquially known as “crystal methamphetamine,” is a synthetic molecule closely related to over-the-counter decongestants , while cocaine is produced by biosynthesis. Cocaine and methamphetamine can be called psychostimulant drugs of abuse and addiction (DPAA).
- Pharmacology
Psychostimulant drugs of abuse and addiction (DPAA) can be used intravenously, intranasally, or inhaled. Cocaine can also be used topically, while methamphetamine is also used orally. The onset of action for methamphetamine varies between 15 minutes and 3 hours, and for cocaine, from seconds to minutes. The half-life of cocaine is almost 90 minutes, while the half-life of methamphetamine is about 12 hours. Topically, cocaine acts as a local anesthetic by blocking neuronal sodium channels.
In the central nervous system, cocaine inhibits multiple neurotransmitter transporters. The euphoric effects of increased alertness come from the mesolimbic and mesocortical areas, where cocaine impairs dopamine reuptake resulting in sustained stimulation of dopamine receptors.
After chronic use, this causes a cumulative effect by depleting dopaminergic stores in presynaptic neurons. Methamphetamine not only blocks the reuptake of catecholamine transporters but also stimulates their release, making it more potent than cocaine.
Elevated levels of dopamine from the use of psychostimulant drugs of abuse and addiction (DPAA) leads to the accumulation of reactive oxygen species and oxidative stress causing long-term neurotoxicity. Because methamphetamine is more potent and longer-acting than cocaine, toxicity is thought to be greater with methamphetamine use. DPAA do not have a direct sympathomimetic action but have sympathomimetic effects by increasing the levels of dopamine, norepinephrine, epinephrine and serotonin.
- Cardiovascular complications
Due to the pharmacology of psychostimulant drugs of abuse and addiction, their consumption is associated with acute and chronic cardiac toxicity.
Acute cardiac complications of AAPD are severe hypertension, myocardial infarction (MI), cerebrovascular accident (CVA), aortic dissection, and cardiac arrhythmias. Chronic complications from DPAA use include the development of cardiomyopathy and accelerated atherosclerosis. There is some limited evidence that such use could cause pulmonary hypertension. DPAA lases increase heart rate and blood pressure due to blocking norepinephrine reuptake throughout the sympathetic nervous system. These effects lead to an increase in myocardial demand.
Cocaine increases endothelin-1 (vasoconstrictor) while longer exposure decreases nitric oxide production and endothelial nitric oxide expression, contributing to chronic hypertension. Myocardial ischemia is a complication of DPAA use with plaque rupture, increased myocardial demand, acceleration of atherosclerosis, and vasospasm of the coronary arteries all contributing.
DPAA also cause vasoconstriction of the coronary arteries , partly related to endothelin-1 and nitric oxide, an imbalance known as vasospastic angina (Prinzmetal’s angina pectoris). These prothrombotic effects are probably increased due to vasoconstrictive effects. Cocaine causes platelet activation and increase in platelet factor 4 which also leads to a prothrombotic state, which further contributes to myocardial ischemia.
| Acute and chronic cardiovascular complications of drugs of abuse | ||
| Acute | Chronicles | |
| DPAA | Hypertensive crisis Myocardial infarction Cerebrovascular accident Aortic dissection Cardiac arrhythmias Infective endocarditis Stress cardiomyopathy | Cardiomyopathies Accelerated atherosclerosis Pulmonary hypertension |
| Alcohol | Myocardial inflammation Hypertension Atrial tachyarrhythmias Decreased contractility Myocardial inflammation Hypertension | Atrial fibrillation Coronary artery disease Cardiomyopathies |
| EAA | Cardiac arrhythmias Myocardial infarction | Accelerated atherosclerosis Cardiomyopathies Metabolic syndrome Hypertension |
| Cannabis | Tachycardia Hypertension Myocardial infarction Stress cardiomyopathy Cardiac arrhythmias Prolonged hypotension | Prothrombotic state Coronary artery disease Hypertension |
| Tobacco | Myocardial infarction | Hypertension Coronary artery disease Cardiomyopathies |
| DPAA: psychoactive drugs of abuse and addiction. EEA: anabolic androgenic steroids | ||
The use of psychostimulant drugs of abuse and addiction (DPAA) is also complicated by stroke due to the combination of hypertensive effects derived from increased catecholamines with the increased propensity for coagulation and decreased cerebral flow. The same principles explain the increased risk of arterial disease, but another theory proposes that cocaine-induced endothelial apoptosis also plays a role in cocaine-induced arterial dissection.
Within cardiomyocytes, DPAA block sodium/potassium channels and decrease depolarization and action potential amplitude, potentially precipitating acute cardiac arrhythmias. Ischemic events cause myocardial scarring and, in combination with blockade of voltage-gated sodium channels, there is also an increased likelihood of arrhythmias from chronic use. The most common arrhythmia is sinus tachycardia due to increased sympathetic activity, but APADs can cause atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, and ventricular fibrillation.
The use of intravenous psychostimulant drugs of abuse and addiction (DPAA) is a common cause of acute or subacute infective endocarditis.
Commonly, with intravenous use, the tricuspid valve is infected with Staphylococcus aureus being the most common pathogen. Cocaine users have higher rates of atherosclerosis and more pronounced atherosclerosis at the presentation of acute precordialgia, compared to control groups. Histamine release from mast cells increases endothelial permeability leading to migration of leukocytes and low-density lipoproteins, contributing to atherosclerosis.
Acutely, DPAA can cause Takotsubo stress cardiomyopathy , secondary to increased catecholamines. However, with chronic use of DPAA, oxidative stress is a major cause of myocardial damage leading to dilated cardiomyopathy with reduced ejection fraction.
Furthermore, accelerated apoptosis, increased p53 activity, cardiomyocyte necrosis, fatty acid toxicity, and defects in intracellular calcium hemostasis contribute to the development of cardiomyopathy. With chronic use, DPAAs can also cause hypertrophic cardiomyopathy secondary to high blood pressure.
- Treatment
The treatment of cardiac complications associated with DPAA is specific for the different effects they can cause. Because of the theory that the stimulation caused by β-blockers causes paradoxical increases in blood pressure and vasoconstriction of the coronary arteries, physicians have opposed their use for the treatment of DPAA toxicity.
|
> Ethanol
Ethanol (alcohol) consumption has been established as a risk factor for premature death and major disability, with links to numerous diseases, including liver cirrhosis, cancer, and nutritional deficiencies. Previous research suggested that consumption of low to moderate doses of alcohol is cardioprotective and reduces overall mortality. However, these findings have been criticized due to methodological deficiencies, design and sample size. The most recent evidence has suggested that alcohol provides non-significant health benefits and causes CVD.
- Pharmacology
Alcohol induces several acute and long-term effects mediated by the alcohol molecule itself and its active metabolites. The pathogenesis of alcohol in the context of the cardiovascular system (CVS) varies, depending on whether alcohol consumption is acute or chronic. Both are marked by dilation, thinning, and impaired contraction of one or both ventricles, with severity associated with disease progression. Acute consumption promotes myocardial inflammation, which may be clinically detectable by an elevated serum troponin level.
Cardiovascular pathogenesis secondary to alcohol consumption, specifically alcoholic cardiomyopathy (ACM), also includes a myriad of pathophysiological mechanisms mediated by alcohol and its major metabolites, including acetaldehyde and ethyl esters. The main determinants of adverse effects are: cardiomyocyte hypertrophy, apoptosis and necrosis, excitation-contraction uncoupling, oxidative damage, mitochondrial degeneration and myocardial fibrosis.
- Cardiovascular complications
Cardiovascular complications tend to be observed when consumption exceeds the unique individual alcohol threshold, leading to elevated susceptibility. An acute cardiac complication resulting from excessive alcohol consumption is atrial fibrillation (vacation heart syndrome). This syndrome was first mentioned in 1978 when patients came to the hospital with atrial fibrillation after excessive alcohol consumption over the weekend. Current hypotheses suggest a combination of cellular and electrophysiological damage caused by alcohol toxicity causing atrial conduction abnormalities.
Common chronic complications of alcohol consumption are persistent atrial arrhythmias, atherosclerosis, hypertension, and alcoholic cardiomyopathy. A recent meta-analysis showed that the relative risk of atrial fibrillation increased by 10% for each drink consumed per day. Long-term heavy alcohol consumption is also associated with ventricular arrhythmias, atherosclerosis, sudden cardiac death, beriberi cardiomyopathy, and cirrhotic cardiomyopathy. Rapid alcohol withdrawal may increase the risk of coronary events and QT prolongation.
Alcoholic cardiomyopathy is a major cardiac complication secondary to alcohol consumption and a leading cause of nonischemic cardiomyopathy, comprising approximately 21%-36% of all nonischemic cardiomyopathies). It is caused by prolonged exposure to alcohol, but the duration and amount of consumption required is unclear; although variations in genetics, sex, metabolism and lifestyle may result in differences in the alcohol threshold required to induce cardiomyopathy. Four-year mortality from this cause can reach up to 50%, making it an important cause of premature death.
- Treatment
Treatment of alcoholic cardiomyopathy (ACM) is primarily based on alcohol abstinence or reduction of alcohol consumption, although the effectiveness of this strategy remains unclear. When the patient presents to the hospital, alcohol withdrawal can be serious. The basis of treatment is the use of benzodiazepines and evaluation using the Clinical Institute Withdrawal Assessment for AlcoholeRevised (CIWA-Ar) but the QT interval should also be monitored.
Currently, established pharmacotherapy for alcohol withdrawal or reduction of alcohol consumption aims to reduce the psychological craving associated with alcohol ingestion, which often involves the intervention of specialized teams and medical therapy adapted to the clinical and demographic characteristics of the patients. patients.
Treatment of heart failure secondary to ACM is not specific outside of achieving cessation or reduction of alcohol consumption.
> Anabolic androgenic steroids
Anabolic androgenic steroids ( AAS) are synthetic derivatives of testosterone that have been used for decades to improve physical and athletic performance, increasing muscle mass and strength. Drugs commonly used in this class include testosterone, androstenedione, stanozolol, nandrolone, and methandrostenolone. Its lifetime prevalence rates worldwide have been estimated at 3.3%, with a rate of 6.4% for men and 1.6% for women.
Historically, AAS use was primarily limited to athletes, but it has become a public health concern, with increasing ease of access. In recent years, the idealized male body has shifted toward higher levels of masculinity and has been reflected in an increase in the prevalence of muscle dysmorphia and subsequently its use by young men.
- Pharmacology
Although anabolic androgenic steroids (AAS) can increase lean mass, muscle size and strength, they also cause long-term adverse effects on the body, including the reproductive, musculoskeletal, renal, immune, and endocrine systems, among others. . The effects of EAAs throughout the body are regulated at the cellular level by converting steroid enzymes in each target tissue. In CVS, EAAs could bind directly to androgen receptors in the heart and major arteries, promoting cardiac tissue growth, while high doses of EAAs also reduce vasodilation, promoting growth.
- Cardiovascular complications
The direct cardiotoxic effects of AAS include cardiac hypertrophy resulting in ventricular dysfunction and acceleration of coronary atherosclerosis.
Long-term use of AAS could result in reduced left ventricular systolic and diastolic function, which could increase the risk of heart failure in these individuals. AAS users tend to have more left ventricular hypertrophy, which correlates with the degree of systolic and diastolic dysfunction. Strength-training athletes (e.g., weightlifters, who are most likely to abuse AAS) may already have a more concentric-shaped left ventricular growth pattern, predisposing them to greater risk. and myocardial growth due to the use of AAS.
Other direct cardiac effects of AAS include increased risk of arrhythmia, which could predispose people to cardiac arrest. In rats, chronic coadministration of EAA with moderate-intensity resistance exercise caused the development of ventricular fibrillation.
Other works also showed that supraphysiological doses of EAA caused electrical remodeling of the left ventricle, in addition to morphological remodeling of both ventricles. Many AAS users use a variety of AAS and may combine medications such as diuretics to mitigate the effects, which can be lethal. They were also shown to have increased coronary plaque volume relative to non-users and suffered an early MI, whereas non-users in the same study had no history of MI or stenting.
There is evidence to suggest that EAAs induce alterations in lipid metabolism, such as a reduction in high-density lipoproteins and an increase in low-density lipoproteins. These effects cumulatively increased the risk of coronary artery disease.
EAAs may contribute to dyslipidemia and coronary heart disease due to impaired cholesterol efflux, which is mediated by high-density lipoproteins. Chronic AAS use may cause an increase in systolic blood pressure and is also associated with increased aortic stiffness secondary to lower plasma concentrations of natriuretic peptides (atrial and brain natriuretic peptides). Taken together, the role of AAS in dyslipidemia and hypertension points to their detrimental effect on metabolism and their relationship with metabolic syndrome in those who use them, despite decreasing the percentage of body fat.
- Treatment
To reduce the risk of CVD, the recommendation to discontinue its use is emphasized because it has been shown to improve lipid profiles, insulin sensitivity, and blood pressure. Discontinuation of AAS remains a challenge due to the different effects that appear in relation to its interruption such as hypogonadism, depression and reduced libido. Although there are few evidence-based approaches for the treatment of AAS withdrawal, testosterone replacement therapies, selective estrogen receptor modulators, human chorionic gonadotropin, and aromatase inhibitors have been suggested. .
> Cannabis
Cannabis is a term used to describe preparations from the plants of Cannabis sativa or C. indica . These psychoactive plants contain more than 400 chemical entities, including ∆9-tetrahydrocannabinol (∆9-THC) and cannabidiol. Cannabis is currently one of the most consumed psychoactive substances in the world. It is estimated that up to 4.9% of the world’s population has tried cannabis.
- Pharmacology
Cannabinoid receptors are distributed throughout the central nervous system and other peripheral tissues, including the arteries and heart. Its biological effects are mainly mediated by the endocannabinoid system, through receptors coupled to G proteins: CB1 and CB2. The endocannabinoid system is a modulatory system made up of cannabinoid receptors, endogenous CB (endocannabinoids) and enzymes that regulate the levels of these compounds. In CVS, cannabis receptors are found in the myocardium, vascular endothelium, and circulating blood and smooth muscle cells.
Furthermore, SCV can be modulated by the ascending effects of cannabis on the peripheral nervous system. Cannabis CB1 receptors mediate cannabis-induced cardiovascular depressive effects such as hypotension and reduced myocardial contractility. Alternatively, CB2 receptor agonists have less pronounced cardiovascular effects.
- Cardiovascular complications
The acute effects of cannabis on CVS are typically driven by activation of the sympathetic nervous system in addition to inhibition of the parasympathetic nervous system, resulting in elevation of heart rate and systolic blood pressure .
Taken together, the autonomic dysregulation resulting from cannabis use increases cardiac workload and myocardial oxygen demand.
Cannabis is also associated with acute coronary heart disease, which sometimes occurs in patients without any classic cardiovascular risk factors. A recent cross-sectional study has provided evidence that a history of MI was more common among recent cannabis users. In these patients, MI may occur in the absence of detectable atherosclerotic CVD symptoms. The increased myocardial oxygen demand, reduced oxygen supply, microvascular/coronary artery spasm, and prothrombotic state arising from cannabis use contribute to the increased risk of acute coronary syndrome.
The hyperadrenergic state resulting from cannabis use leads to short-term cardiac tachyarrhythmias while ∆9-THC increases sinus node automaticity and facilitates AV node conduction. Other arrhythmias associated with cannabis use include ventricular fibrillation, atrial fibrillation, sinus bradycardia, and second-degree AV block. The mechanisms driving clinical arrhythmias in cannabis users are not well understood but are likely to involve adrenergic stimulation, myocardial ischemia, and microvascular dysfunction, which contribute to the development and perpetuation of atrial fibrillation.
There is also an association between stress cardiomyopathy and cannabis use, which is probably favored by the combination of the hyperadrenergic state and the modulation of the endocannabinoid system by reducing myocardial contractility.
- Treatment
It is very important for doctors and other health professionals to consider the possible health complications of cannabis, taking into account its increasing legalization worldwide and the increasing abundance of evidence of its temporal association with cardiovascular complications. Specifically, it is important to warn patients with pre-existing cardiovascular risk factors, a strong family history of heart disease, or other cardiac conditions against cannabis use.
There is evidence that β-blockers could mitigate the SCV response to ∆9-THC, but this has not been widely studied. Given the advances in legalization around the world, follow-up studies must be done to implement long-term clinical practices and monitor the health outcomes of cannabis users.
> Tobacco and nicotine
Tobacco use is a global public health problem. Despite public health interventions, vaping of nicotine-containing liquids continues to gain increasing popularity and young people continue to vape nicotine-containing liquids and then transition to tobacco smoking while chronic tobacco smokers transition to nicotine vaping. Tobacco is commonly smoked in cigarettes. Cigarette smoke is a mixture of nicotine, carbon monoxide, and oxidizing chemicals toxic to MCS.
- Pharmacology
Tobacco is at increased risk of causing CVD through numerous mechanisms, including a state of increased coagulability, endothelial damage, and reduced oxygen delivery.
These mechanisms can exacerbate coronary artery disease but are also an independent risk factor for developing heart failure. Smoking causes mitochondrial oxidative stress that contributes to endothelial dysfunction causing an association with hypertension.
In observational studies it has been found that smoking is also associated with a higher prevalence of type 2 diabetes , probably due to the associated changes in body composition and insulin sensitivity.
Tobacco also causes the generation of free radicals that are likely to cause myocardial damage. Inflammatory markers increase in association with smoking, specifically C-reactive protein, white blood cell count, and fibrinogen. Furthermore, smoking may contribute to the development of atrial fibrosis due to the toxic effects of nicotine.
E-cigarettes have a moderate cardiovascular risk compared to combustible tobacco products, which have the highest risk, potentially secondary to proatherogenic proteins found in tobacco cigarette smokers but not in e-vapers.
- Cardiovascular complications
Due to increased cardiovascular risk factors and direct effect on atherosclerosis, smoking is associated with increased coronary artery disease and a dose-response risk of ischemic stroke.
The stimulant effect of nicotine increases heart rate, blood pressure, and resting cardiac output, all of which contribute to increased myocardial demand, potentially worsening any coronary artery disease the patient may have, causing acute ischemic events. .
Smokers are at increased risk of chronic obstructive pulmonary disease, which is a risk factor for atrial fibrillation. However, smoking could contribute to an increased risk of atrial fibrillation and atrial fibrosis through sympathetic stimulation from nicotine.
All mechanisms contribute to an increased risk of heart failure despite adjusting for these risk factors. This risk likely comes from myocardial damage at the cellular level caused by increased levels of inflammation in the body, but so far, studies are limited.
- Treatment
Although there is no specific treatment for cardiac complications secondary to smoking, the hallmark of treatment is smoking cessation. All physicians should intervene by promoting smoking cessation programs, as they have been shown to reduce mortality.
Nicotine replacement therapy is a viable option to use in patients with an acute presentation despite increased sympathetic activation, and may decrease acute withdrawal symptoms. It helps with smoking cessation in outpatients, but is not effective during an admission for an acute cardiovascular event because it requires long-term use. Another option is varenicline, which is also safe for patients with stable CVD but requires caution in patients with an acute cardiovascular event because the evidence is conflicting.
| Heart and left ventricle transplant |
- Assistive devices
Consensus guidelines state that substance use (including tobacco and alcohol) is an absolute contraindication to heart transplantation.
There are no guidelines for the duration of substance cessation before transplant, but abstinence from tobacco for more than 6 months before transplant is generally recommended. It seems reasonable to apply this schedule to other substances.
Under appropriate circumstances, ventricular assist devices have been shown to improve patients with severe dilated cardiomyopathy secondary to chronic methamphetamine use. Use of these left ventricular assist devices may be considered while awaiting recovery or as a bridge to transplant. Before putting these important decisions into practice, local guides should be consulted.
| Conclusion |
Psychoactive drugs of abuse and addiction, alcohol, anabolic androgenic steroids, cannabis, and tobacco are frequently used as recreational and legal substances that contribute to cardiovascular disease.
All of these substances contribute to the development of cardiomyopathies, heart failure and arrhythmias, through independent mechanisms, and have many other mechanisms of cardiac complications.
It is important for physicians to address the topic of smoking cessation with their patients and be aware of the associated cardiac complications. Although there are no screening guidelines, if the doctor takes these complications and their symptoms into account, treatment can be provided early. Over time there will be more information about these substances and their complications, and more research is still needed on other illicit drugs such as opioids.
There is a growing need for a nationwide educational campaign regarding potential long-term damage to the cardiovascular system in patients with substance use disorders.
More studies are needed to develop specific screening guidelines and treatment guidelines for cardiovascular complications secondary to drugs of abuse.
