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Canadian Journal of Cardiology

Cardiac Complications of Common Drugs of Abuse: Pharmacology, Toxicology, and Management

Published:November 01, 2021DOI:https://doi.org/10.1016/j.cjca.2021.10.008

      Abstract

      Cardiovascular complications from drugs of abuse are becoming more apparent because of increased usage worldwide. Substance abuse can cause acute and chronic cardiovascular complications and is increasing in prevalence especially in young adults. These substances contribute to the development of acute coronary syndrome, type 2 myocardial injury, arrhythmias, and cardiomyopathies, and have numerous other cardiovascular complications. Although no screening guidelines exist, clinical awareness of these potential complications and their prevention, clinical presentation, diagnosis, and treatment are critically important. Management of cardiovascular disease should be coupled with appropriate social and mental health interventions to provide sustained clinical benefit. The higher the number of substances used recreationally, the greater the risk of premature heart disease. Epidemiological studies showed that 1 in 5 young adults misuse several substances and often start using at younger ages with a greater risk for adverse health outcomes over the long term. The aim of this review is to highlight the basic epidemiology, cardiac complications, and disease-specific treatment options of commonly abused substances including methamphetamine, cocaine, alcohol, anabolic-androgenic steroids, cannabis, and tobacco.

      Résumé

      Les complications cardiovasculaires des drogues toxicomanogènes deviennent plus apparentes en raison de l’augmentation de la consommation dans le monde. L’abus de substances peut causer des complications cardiovasculaires aiguës et chroniques et sa prévalence augmente en particulier chez les jeunes adultes. Ces substances contribuent au développement de syndromes coronariens aigus, de lésions myocardiques de type 2, d’arythmies et de cardiomyopathies, et de nombreuses autres complications cardiovasculaires. Bien qu’il n’y ait pas de lignes directrices en matière de dépistage, la connaissance des complications possibles et de leur prévention, ainsi que du tableau clinique, du diagnostic et du traitement de celles-ci est d’une importance capitale. Pour que la prise en charge des maladies cardiovasculaires procure des bienfaits cliniques soutenus, elle doit être accompagnée d’interventions sur le plan social et en santé mentale. Plus le nombre de substances à usage récréatif est élevé, plus le risque de maladies cardiaques prématurées est important. Selon des études épidémiologiques, un jeune adulte sur cinq fait un usage abusif de plusieurs substances et commence souvent à consommer celles-ci à un plus jeune âge, ce qui accroît à long terme le risque d’effets défavorables sur la santé. Cette revue a pour objet de mettre en évidence les données épidémiologiques de base, les complications cardiaques et les choix de traitement propres aux maladies liées aux substances couramment consommées de façon abusive, soit la méthamphétamine, la cocaïne, l’alcool, les stéroïdes anabolisants androgènes, le cannabis et le tabac.
      Cardiovascular disease (CVD) is the leading cause of global mortality and substance use is a hidden determinant.
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      Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study.
      There continues to be a sharp increase in the usage of drugs of abuse and substance use disorder throughout the world and Canada (Fig. 1).
      United Nations Office on Drugs and Crime (UNODC). World Drug Report 2021
      United Nations publication, United Nations:.
      GBD 2016 Alcohol and Drug Use Collaborators
      The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease study 2016.
      Health Canada. Canadian Tobacco Alcohol and Drugs (CTADS): 2017
      Canadian Tobacco, Alcohol and Drugs (CTADS).
      Because of this, cardiac complications secondary to drugs of abuse are becoming more apparent. Epidemiological studies suggest that 1 in 5 young adults misuse several substances and that these “polysubstance users” often start using at younger ages, leading to progressive worsening of long-term health.
      GBD 2016 Alcohol and Drug Use Collaborators
      The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease study 2016.
      ,
      • Chadi N.
      • Bagley S.M.
      • Hadland S.E.
      Addressing adolescents’ and young adults’ substance use disorders.
      ,
      • Falkner B.
      • Gidding S.
      Life course implications of pediatric risk factors for cardiovascular disease.
      Specific drugs of abuse such as cocaine, methamphetamines, and alcohol have well known cardiac complications.
      • Wood S.
      • Sage J.R.
      • Shuman T.
      • Anagnostaras S.G.
      Psychostimulants and cognition: a continuum of behavioral and cognitive activation.
      • Abbruscato T.J.
      • Trippier P.C.
      DARK classics in chemical neuroscience: methamphetamine.
      • Drake L.R.
      • Scott P.J.H.
      DARK classics in chemical neuroscience: cocaine.
      However, with the increasing usage of anabolic-androgenic steroids (AAS), their cardiac complications are also becoming more relevant.
      • Perry J.C.
      • Schuetz T.M.
      • Memon M.D.
      • Faiz S.
      • Cancarevic I.
      Anabolic steroids and cardiovascular outcomes: the controversy.
      With the legalization of cannabis in many jurisdictions, cannabis usage is very common, making cardiac complications more clear in what was thought to be a relatively benign drug.
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      • Karila L.
      • Blecha L.
      • Benyamina A.
      Cannabis, cannabinoids, and health.
      ,
      • Anthony J.C.
      • Lopez-Quintero C.
      • Alshaarawy O.
      Cannabis epidemiology: a selective review.
      Electronic cigarette usage is increasing, making nicotine more popular again despite the public health interventions related to smoking cessation.
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      • Burbank A.D.
      Cardiovascular toxicity of nicotine: implications for electronic cigarette use.
      ,
      • Nayeri A.
      • Middlekauff H.
      Vaping instead of cigarette smoking: a panacea or just another form of cardiovascular risk?.
      Conventional cigarette usage is still common and tobacco is a well known risk factor for coronary artery disease (CAD); however, other cardiac complications need to be recognized.
      • Watson M.
      • Dardari Z.
      • Kianoush S.
      • et al.
      Relation between cigarette smoking and heart failure (from the Multiethnic Study of Atherosclerosis).
      ,
      • Gopal D.M.
      • Kalogeropoulos A.P.
      • Georgiopoulou V.V.
      • et al.
      Cigarette smoking exposure and heart failure risk in older adults: the Health, Aging, and Body Composition Study.
      The coexistence of mental illness with substance abuse is a major comorbidity that should be recognized and managed appropriately.
      • Correll C.U.
      • Solmi M.
      • Veronese N.
      • et al.
      Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3,211,768 patients and 113,383,368 controls.
      It is well known that there is a link between adolescent psychiatric disorders and cardiovascular risk, and the concurrent usage of substances are likely to make this risk more profound.
      • Goldstein B.I.
      • Korczak D.J.
      Links between child and adolescent psychiatric disorders and cardiovascular risk.
      The aim of this review is to highlight the basic epidemiology, cardiovascular complications, and potential disease-specific treatment options of commonly abused substances including methamphetamine, cocaine, alcohol, AAS, cannabis, and tobacco. Because of the limited literature and the nature of the effects of cardiovascular complications and drugs of abuse, most data can demonstrate associations, but not necessarily causation. This should be taken into consideration when reading this review.
      Figure thumbnail gr1
      Figure 1Prevalence of substance use globally and in Canada. Substance usage disorder globally in 1990 compared with that in 2016 (A). Global substance use disorder, in 10 thousands. Estimates from the Global Burden of Disease Study 2016. Twelve-month prevalence of drugs of abuse usage in Canada in 2013 compared with that in 2017 (B). Self-reported survey data for methamphetamine, cocaine, cannabis, tobacco, and alcohol from Health Canada. First survey of this nature was in 2013, with the most recent survey in 2017.

      Psychostimulant Drugs of Abuse and Addiction: Methamphetamine and Cocaine

      Psychostimulants, initially freely available, have evolved into one of the most commonly abused drugs.
      • Abbruscato T.J.
      • Trippier P.C.
      DARK classics in chemical neuroscience: methamphetamine.
      ,
      • Heal D.J.
      • Smith S.L.
      • Gosden J.
      • Nutt D.J.
      Amphetamine, past and present--a pharmacological and clinical perspective.
      Despite numerous clinical applications for medicinal usage, they are abused for their effects of increased wakefulness, euphoria, and appetite suppression.
      • Heal D.J.
      • Smith S.L.
      • Gosden J.
      • Nutt D.J.
      Amphetamine, past and present--a pharmacological and clinical perspective.
      ,
      • Fleckenstein A.E.
      • Volz T.J.
      • Riddle E.L.
      • Gibb J.W.
      • Hanson G.R.
      New insights into the mechanism of action of amphetamines.
      Methamphetamine, colloquially known as “crystal meth,” is a synthetic molecule closely related to over-the-counter decongestants whereas cocaine is produced biosynthetically.
      • Abbruscato T.J.
      • Trippier P.C.
      DARK classics in chemical neuroscience: methamphetamine.
      ,
      • Drake L.R.
      • Scott P.J.H.
      DARK classics in chemical neuroscience: cocaine.
      Cocaine and methamphetamine can be referred to as psychostimulant drugs of abuse and addiction (PDAA).
      • Wood S.
      • Sage J.R.
      • Shuman T.
      • Anagnostaras S.G.
      Psychostimulants and cognition: a continuum of behavioral and cognitive activation.
      The past 12-month prevalence usage as per the United Nations Office on Drugs and Crime is estimated to be 0.40% for cocaine and 0.54% for methamphetamine globally, with the North American prevalence being higher at 2.12% and 2.29% for cocaine and methamphetamine, respectively.
      United Nations Office on Drugs and Crime (UNODC). World Drug Report 2021
      United Nations publication, United Nations:.

      Pharmacology

      PDAA can be used intravenously, intranasally, or inhaled, with cocaine also used topically, and methamphetamines also used orally.
      • Fleckenstein A.E.
      • Volz T.J.
      • Riddle E.L.
      • Gibb J.W.
      • Hanson G.R.
      New insights into the mechanism of action of amphetamines.
      The onset of methamphetamine varies, but ranges from 15 minutes to 3 hours, whereas the onset of cocaine ranges from seconds to minutes.
      • Fleckenstein A.E.
      • Volz T.J.
      • Riddle E.L.
      • Gibb J.W.
      • Hanson G.R.
      New insights into the mechanism of action of amphetamines.
      The half-life of cocaine is close to 90 minutes, whereas methamphetamine has a half-life closer to 12 hours.
      • Cho A.K.
      • Melega W.P.
      Patterns of methamphetamine abuse and their consequences.
      Topically, cocaine acts as a local anesthetic by blocking sodium channels in neurons.
      • Goldstein R.A.
      • DesLauriers C.
      • Burda A.
      • Johnson-Arbor K.
      Cocaine: history, social implications, and toxicity: a review.
      In the central nervous system, cocaine inhibits multiple neurotransmitter reuptake transporters.
      • Drake L.R.
      • Scott P.J.H.
      DARK classics in chemical neuroscience: cocaine.
      The euphoric effects of increased alertness are from the mesolimbic and mesocortical areas of the brain, where cocaine impairs dopamine reuptake resulting in sustained stimulation of dopaminergic receptors.
      • Leshner A.I.
      Molecular mechanisms of cocaine addiction.
      This causes an addictive affect from the depletion of dopaminergic stores in the presynaptic neurons after chronic usage.
      • Leshner A.I.
      Molecular mechanisms of cocaine addiction.
      Methamphetamine not only blocks the reuptake transporters of catecholamines, but also stimulates the release of them making it more potent than cocaine.
      • Courtney K.E.
      • Ray L.A.
      Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature.
      High levels of dopamine from PDAA usage leads to the accumulation of reactive oxygen species and oxidative stress causing long-term neurotoxicity.
      • Berman S.
      • O’Neill J.
      • Fears S.
      • Bartzokis G.
      • London E.D.
      Abuse of amphetamines and structural abnormalities in the brain.
      Because methamphetamine is more potent and longer-acting than cocaine, it is thought that cardiac toxicity is exaggerated with methamphetamine usage.
      • Won S.
      • Hong R.A.
      • Shohet R.V.
      • Seto T.B.
      • Parikh N.I.
      Methamphetamine-associated cardiomyopathy.
      PDAA are not direct sympathomimetics, but have sympathomimetic effects through the increased levels of dopamine, norepinephrine, epinephrine, and serotonin.
      • Fleckenstein A.E.
      • Volz T.J.
      • Riddle E.L.
      • Gibb J.W.
      • Hanson G.R.
      New insights into the mechanism of action of amphetamines.

      Cardiovascular complications

      Because of the pharmacology of PDAA, acute and chronic cardiac toxicity occurs with its usage (Table 1).
      • Kim S.T.
      • Park T.
      Acute and chronic effects of cocaine on cardiovascular health.
      The acute cardiac complications of PDAA are severe hypertension, myocardial infarction (MI), stroke, aortic dissection (AD), and cardiac arrhythmias.
      • Kim S.T.
      • Park T.
      Acute and chronic effects of cocaine on cardiovascular health.
      ,
      • Paratz E.D.
      • Cunningham N.J.
      • MacIsaac A.I.
      The cardiac complications of methamphetamines.
      Chronic complications from the usage of PDAA include the development of cardiomyopathies, accelerated atherosclerosis, and some limited evidence suggests that usage might cause pulmonary hypertension.
      • Kim S.T.
      • Park T.
      Acute and chronic effects of cocaine on cardiovascular health.
      ,
      • Paratz E.D.
      • Cunningham N.J.
      • MacIsaac A.I.
      The cardiac complications of methamphetamines.
      PDAA increases the heart rate (HR) and blood pressure (BP) through blocking the reuptake of norepinephrine throughout the sympathetic nervous system.
      • Shanti C.M.
      • Lucas C.E.
      Cocaine and the critical care challenge.
      These effects lead to an increase in myocardial demand. Cocaine increases endothelin-1 (vasoconstrictor) production and longer exposure decreases nitric oxide production and endothelial nitric oxide synthase expression, contributing to chronic hypertension.
      • Pradhan L.
      • Mondal D.
      • Chandra S.
      • Ali M.
      • Agrawal K.C.
      Molecular analysis of cocaine-induced endothelial dysfunction: role of endothelin-1 and nitric oxide.
      Table 1Acute and chronic cardiovascular complications of drugs of abuse
      AcuteChronic
      PDAAHypertensive crisis
      • Kim S.T.
      • Park T.
      Acute and chronic effects of cocaine on cardiovascular health.
      • Paratz E.D.
      • Cunningham N.J.
      • MacIsaac A.I.
      The cardiac complications of methamphetamines.
      • Shanti C.M.
      • Lucas C.E.
      Cocaine and the critical care challenge.


      Myocardial infarction
      • Kim S.T.
      • Park T.
      Acute and chronic effects of cocaine on cardiovascular health.
      ,
      • Paratz E.D.
      • Cunningham N.J.
      • MacIsaac A.I.
      The cardiac complications of methamphetamines.
      ,
      • Chen J.
      • López J.A.
      Interactions of platelets with subendothelium and endothelium.


      Stroke
      • Kim S.T.
      • Park T.
      Acute and chronic effects of cocaine on cardiovascular health.
      ,
      • Paratz E.D.
      • Cunningham N.J.
      • MacIsaac A.I.
      The cardiac complications of methamphetamines.
      ,
      • Volkow N.D.
      • Mullani N.
      • Gould K.L.
      • Adler S.
      • Krajewski K.
      Cerebral blood flow in chronic cocaine users: a study with positron emission tomography.


      Aortic dissection
      • Kim S.T.
      • Park T.
      Acute and chronic effects of cocaine on cardiovascular health.
      ,
      • Paratz E.D.
      • Cunningham N.J.
      • MacIsaac A.I.
      The cardiac complications of methamphetamines.
      ,
      • Su J.
      • Li J.
      • Li W.
      • Altura B.
      • Altura B.
      Cocaine induces apoptosis in primary cultured rat aortic vascular smooth muscle cells: possible relationship to aortic dissection, atherosclerosis, and hypertension.


      Cardiac arrhythmias
      • Kim S.T.
      • Park T.
      Acute and chronic effects of cocaine on cardiovascular health.
      ,
      • Paratz E.D.
      • Cunningham N.J.
      • MacIsaac A.I.
      The cardiac complications of methamphetamines.
      ,
      • Schwartz B.G.
      • Rezkalla S.
      • Kloner R.A.
      Cardiovascular effects of cocaine.


      Infective endocarditis
      • Kim S.T.
      • Park T.
      Acute and chronic effects of cocaine on cardiovascular health.
      ,
      • Paratz E.D.
      • Cunningham N.J.
      • MacIsaac A.I.
      The cardiac complications of methamphetamines.
      ,
      • Cooper H.L.
      • Brady J.E.
      • Ciccarone D.
      • Tempalski B.
      • Gostnell K.
      • Friedman S.R.
      Nationwide increase in the number of hospitalizations for illicit injection drug use-related infective endocarditis.


      Stress cardiomyopathy
      • Kim S.T.
      • Park T.
      Acute and chronic effects of cocaine on cardiovascular health.
      ,
      • Paratz E.D.
      • Cunningham N.J.
      • MacIsaac A.I.
      The cardiac complications of methamphetamines.
      ,
      • Restrepo C.S.
      • Rojas C.A.
      • Martinez S.
      • et al.
      Cardiovascular complications of cocaine: imaging findings.
      Cardiomyopathies
      • Kim S.T.
      • Park T.
      Acute and chronic effects of cocaine on cardiovascular health.
      ,
      • Paratz E.D.
      • Cunningham N.J.
      • MacIsaac A.I.
      The cardiac complications of methamphetamines.
      ,
      • Reddy P.K.V.
      • Ng T.M.H.
      • Oh E.E.
      • Moady G.
      • Elkayam U.
      Clinical characteristics and management of methamphetamine-associated cardiomyopathy: State-of-the-Art Review.
      ,
      • Jafari Giv M.
      Exposure to amphetamines leads to development of amphetamine type stimulants associated cardiomyopathy (ATSAC).


      Accelerated atherosclerosis
      • Kim S.T.
      • Park T.
      Acute and chronic effects of cocaine on cardiovascular health.
      ,
      • Paratz E.D.
      • Cunningham N.J.
      • MacIsaac A.I.
      The cardiac complications of methamphetamines.
      ,
      • Huang M.
      • Pang X.
      • Letourneau R.
      • Boucher W.
      • Theoharides T.C.
      Acute stress induces cardiac mast cell activation and histamine release, effects that are increased in apolipoprotein E knockout mice.


      Pulmonary hypertension
      • Kim S.T.
      • Park T.
      Acute and chronic effects of cocaine on cardiovascular health.
      ,
      • Paratz E.D.
      • Cunningham N.J.
      • MacIsaac A.I.
      The cardiac complications of methamphetamines.
      AlcoholAtrial tachyarrhythmias
      • Ettinger P.O.
      • Wu C.F.
      • De La Cruz Jr., C.
      • Weisse A.B.
      • Ahmed S.S.
      • Regan T.J.
      Arrhythmias and the “Holiday Heart”: alcohol-associated cardiac rhythm disorders.


      Decreased contractility
      • Maisch B.
      Alcoholic cardiomyopathy: the result of dosage and individual predisposition.


      Myocardial inflammation
      • Waszkiewicz N.
      • Szulc A.
      • Zwierz K.
      Binge drinking-induced subtle myocardial injury.


      Hypertension
      • Puddey I.B.
      • Mori T.A.
      • Barden A.E.
      • Beilin L.J.
      Alcohol and hypertension-new insights and lingering controversies.
      Atrial fibrillation
      • Kodama S.
      • Saito K.
      • Tanaka S.
      • et al.
      Alcohol consumption and risk of atrial fibrillation: a meta-analysis.


      Coronary artery disease
      • Puddey I.B.
      • Mori T.A.
      • Barden A.E.
      • Beilin L.J.
      Alcohol and hypertension-new insights and lingering controversies.
      • Djoussé L.
      • Gaziano J.M.
      Alcohol consumption and heart failure: a systematic review.
      • Carvalho M.V.H.
      • Kroll P.C.
      • Kroll R.T.M.
      • Carvalho V.N.
      Cirrhotic cardiomyopathy: the liver affects the heart.
      • Kupari M.
      • Koskinen P.
      Alcohol, cardiac arrhythmias and sudden death.


      Cardiomyopathies
      • Djoussé L.
      • Gaziano J.M.
      Alcohol consumption and heart failure: a systematic review.
      ,
      • Carvalho M.V.H.
      • Kroll P.C.
      • Kroll R.T.M.
      • Carvalho V.N.
      Cirrhotic cardiomyopathy: the liver affects the heart.


      AASCardiac arrhythmias
      • Ghorbani Baravati H.
      • Joukar S.
      • Fathpour H.
      • Kordestani Z.
      Nandrolone plus moderate exercise increases the susceptibility to lethal arrhythmias.


      Myocardial infarction
      • Baggish A.L.
      • Weiner R.B.
      • Kanayama G.
      • et al.
      Cardiovascular toxicity of illicit anabolic-androgenic steroid use.
      Accelerated atherosclerosis
      • Perry J.C.
      • Schuetz T.M.
      • Memon M.D.
      • Faiz S.
      • Cancarevic I.
      Anabolic steroids and cardiovascular outcomes: the controversy.
      ,
      • Baggish A.L.
      • Weiner R.B.
      • Kanayama G.
      • et al.
      Cardiovascular toxicity of illicit anabolic-androgenic steroid use.
      • Payne J.R.
      • Kotwinski P.J.
      • Montgomery H.E.
      Cardiac effects of anabolic steroids.
      • Baggish A.L.
      • Weiner R.B.
      • Kanayama G.
      • et al.
      Long-term anabolic-androgenic steroid use is associated with left ventricular dysfunction.
      • Nottin S.
      • Nguyen L.D.
      • Terbah M.
      • Obert P.
      Cardiovascular effects of androgenic anabolic steroids in male bodybuilders determined by tissue Doppler imaging.
      • Hassan N.A.
      • Salem M.F.
      • Sayed M.A.
      Doping and effects of anabolic androgenic steroids on the heart: histological, ultrastructural, and echocardiographic assessment in strength athletes.


      Cardiomyopathies
      • Baggish A.L.
      • Weiner R.B.
      • Kanayama G.
      • et al.
      Cardiovascular toxicity of illicit anabolic-androgenic steroid use.
      ,
      • Baggish A.L.
      • Weiner R.B.
      • Kanayama G.
      • et al.
      Long-term anabolic-androgenic steroid use is associated with left ventricular dysfunction.
      • Nottin S.
      • Nguyen L.D.
      • Terbah M.
      • Obert P.
      Cardiovascular effects of androgenic anabolic steroids in male bodybuilders determined by tissue Doppler imaging.
      • Hassan N.A.
      • Salem M.F.
      • Sayed M.A.
      Doping and effects of anabolic androgenic steroids on the heart: histological, ultrastructural, and echocardiographic assessment in strength athletes.


      Metabolic syndrome
      • McCullough D.
      • Webb R.
      • Enright K.J.
      • et al.
      How the love of muscle can break a heart: impact of anabolic androgenic steroids on skeletal muscle hypertrophy, metabolic and cardiovascular health.


      Hypertension
      • Rasmussen J.J.
      • Schou M.
      • Madsen P.L.
      • et al.
      Increased blood pressure and aortic stiffness among abusers of anabolic androgenic steroids: potential effect of suppressed natriuretic peptides in plasma?.
      CannabisTachycardia
      • Gash A.
      • Karliner J.S.
      • Janowsky D.
      • Lake C.R.
      Effects of smoking marihuana on left ventricular performance and plasma norepinephrine.
      • Singh A.
      • Saluja S.
      • Kumar A.
      • et al.
      Cardiovascular complications of marijuana and related substances: a review.
      • Karschner E.L.
      • Darwin W.D.
      • McMahon R.P.
      • et al.
      Subjective and physiological effects after controlled Sativex and oral THC administration.


      Hypertension
      • Gash A.
      • Karliner J.S.
      • Janowsky D.
      • Lake C.R.
      Effects of smoking marihuana on left ventricular performance and plasma norepinephrine.
      • Singh A.
      • Saluja S.
      • Kumar A.
      • et al.
      Cardiovascular complications of marijuana and related substances: a review.
      • Karschner E.L.
      • Darwin W.D.
      • McMahon R.P.
      • et al.
      Subjective and physiological effects after controlled Sativex and oral THC administration.


      Myocardial infarction
      • Ladha K.S.
      • Mistry N.
      • Wijeysundera D.N.
      • et al.
      Recent cannabis use and myocardial infarction in young adults: a cross-sectional study.


      Stress cardiomyopathy
      • Kaushik M.
      • Alla V.M.
      • Madan R.
      • Arouni A.J.
      • Mohiuddin S.M.
      Recurrent stress cardiomyopathy with variable regional involvement.


      Cardiac arrhythmias
      • Singh G.K.
      Atrial fibrillation associated with marijuana use.
      • Kosior D.A.
      • Filipiak K.J.
      • Stolarz P.
      • Opolski G.
      Paroxysmal atrial fibrillation following marijuana intoxication: a two-case report of possible association.
      • Akins D.
      • Awdeh M.R.
      Marijuana and second-degree AV block.
      • Baranchuk A.
      • Johri A.M.
      • Simpson C.S.
      • Methot M.
      • Redfearn D.P.
      Ventricular fibrillation triggered by marijuana use in a patient with ischemic cardiomyopathy: a case report.


      Prolonged hypotension
      • Montecucco F.
      • Di Marzo V.
      At the heart of the matter: the endocannabinoid system in cardiovascular function and dysfunction.
      ,
      • Lake K.D.
      • Compton D.R.
      • Varga K.
      • Martin B.R.
      • Kunos G.
      Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors.
      Prothrombotic state
      • Dahdouh Z.
      • Roule V.
      • Lognoné T.
      • Sabatier R.
      • Grollier G.
      Cannabis and coronary thrombosis: what is the role of platelets?.
      ,
      • Deusch E.
      • Kress H.G.
      • Kraft B.
      • Kozek-Langenecker S.A.
      The procoagulatory effects of delta-9-tetrahydrocannabinol in human platelets.


      Coronary artery disease
      • Achar S.
      • Rostamian A.
      • Narayan S.M.
      Cardiac and metabolic effects of anabolic-androgenic steroid abuse on lipids, blood pressure, left ventricular dimensions, and rhythm.
      ,
      • Angell P.
      • Chester N.
      • Green D.
      • Somauroo J.
      • Whyte G.
      • George K.
      Anabolic steroids and cardiovascular risk.
      • Vanberg P.
      • Atar D.
      Androgenic anabolic steroid abuse and the cardiovascular system.
      • Souza F.R.
      • Dos Santos M.R.
      • Porello R.A.
      • et al.
      Diminished cholesterol efflux mediated by HDL and coronary artery disease in young male anabolic androgenic steroid users.
      • Thompson P.D.
      • Cullinane E.M.
      • Sady S.P.
      • et al.
      Contrasting effects of testosterone and stanozolol on serum lipoprotein levels.
      • Hartgens F.
      • Rietjens G.
      • Keizer H.A.
      • Kuipers H.
      • Wolffenbuttel B.H.R.
      Effects of androgenic-anabolic steroids on apolipoproteins and lipoprotein (a).


      Hypertension
      • Gash A.
      • Karliner J.S.
      • Janowsky D.
      • Lake C.R.
      Effects of smoking marihuana on left ventricular performance and plasma norepinephrine.
      • Singh A.
      • Saluja S.
      • Kumar A.
      • et al.
      Cardiovascular complications of marijuana and related substances: a review.
      • Karschner E.L.
      • Darwin W.D.
      • McMahon R.P.
      • et al.
      Subjective and physiological effects after controlled Sativex and oral THC administration.
      TobaccoMyocardial infarction
      • Linneberg A.
      • Jacobsen R.K.
      • Skaaby T.
      • et al.
      Effect of smoking on blood pressure and resting heart rate: a Mendelian randomization meta-analysis in the CARTA Consortium.
      ,
      • Narkiewicz K.
      • van de Borne P.J.
      • Hausberg M.
      • et al.
      Cigarette smoking increases sympathetic outflow in humans.
      Hypertension
      • Dikalov S.
      • Itani H.
      • Richmond B.
      • et al.
      Tobacco smoking induces cardiovascular mitochondrial oxidative stress, promotes endothelial dysfunction, and enhances hypertension.
      ,
      • Leone A.
      Does smoking act as a friend or enemy of blood pressure? Let release Pandora’s Box.


      Coronary artery disease
      • Benowitz N.L.
      • Burbank A.D.
      Cardiovascular toxicity of nicotine: implications for electronic cigarette use.
      ,
      • Grubb A.F.
      • Greene S.J.
      • Fudim M.
      • Dewald T.
      • Mentz R.J.
      Drugs of abuse and heart failure.


      Cardiomyopathies
      • Watson M.
      • Dardari Z.
      • Kianoush S.
      • et al.
      Relation between cigarette smoking and heart failure (from the Multiethnic Study of Atherosclerosis).
      ,
      • Gopal D.M.
      • Kalogeropoulos A.P.
      • Georgiopoulou V.V.
      • et al.
      Cigarette smoking exposure and heart failure risk in older adults: the Health, Aging, and Body Composition Study.
      AAS, anabolic-androgenic steroids; PDAA, psychostimulant drugs of abuse and addiction.
      Myocardial ischemia is a complication of PDAA usage with plaque rupture, increased myocardial demand, accelerated atherosclerosis, and coronary artery vasospasm all contributing.
      • Chen J.
      • López J.A.
      Interactions of platelets with subendothelium and endothelium.
      PDAA also causes vasoconstriction of the coronary arteries, in part related to the endothelin-1 and nitric oxide imbalance known as vasospastic angina (Prinzmetal angina).
      • Pradhan L.
      • Mondal D.
      • Chandra S.
      • Ali M.
      • Agrawal K.C.
      Molecular analysis of cocaine-induced endothelial dysfunction: role of endothelin-1 and nitric oxide.
      ,
      • Picard F.
      • Sayah N.
      • Spagnoli V.
      • Adjedj J.
      • Varenne O.
      Vasospastic angina: a literature review of current evidence.
      These prothrombotic effects are likely enhanced by the vasoconstrictive effects.
      • Chen J.
      • López J.A.
      Interactions of platelets with subendothelium and endothelium.
      Cocaine causes platelet activation and an increase in platelet factor-4 which also leads to a prothrombotic state, further contributing to myocardial ischemia.
      • Agrawal P.R.
      • Scarabelli T.M.
      • Saravolatz L.
      • et al.
      Current strategies in the evaluation and management of cocaine-induced chest pain.
      In combination with the hypertensive effects from the catecholamine surge, the procoagulable state and the decreased cerebral flow, strokes are also a complication of PDAA usage.
      • Volkow N.D.
      • Mullani N.
      • Gould K.L.
      • Adler S.
      • Krajewski K.
      Cerebral blood flow in chronic cocaine users: a study with positron emission tomography.
      The same principles apply for increasing the risk of AD, but an additional theory is that cocaine-induced apoptosis at the endothelial level also plays a role in arterial dissection.
      • Su J.
      • Li J.
      • Li W.
      • Altura B.
      • Altura B.
      Cocaine induces apoptosis in primary cultured rat aortic vascular smooth muscle cells: possible relationship to aortic dissection, atherosclerosis, and hypertension.
      Within cardiomyocytes, PDAA block sodium/potassium channels, and decrease the depolarization and amplitude of the action potential, with the potential to precipitate cardiac dysrhythmias acutely.
      • Schwartz B.G.
      • Rezkalla S.
      • Kloner R.A.
      Cardiovascular effects of cocaine.
      Ischemic events cause myocardial scarring, and in combination with the blockage of voltage-gated sodium channels there is also an increased likelihood of arrhythmias from chronic usage.
      • Schwartz B.G.
      • Rezkalla S.
      • Kloner R.A.
      Cardiovascular effects of cocaine.
      The most common arrythmia is sinus tachycardia from the increased sympathetic tone but PDAA can cause atrial fibrillation (AF), supraventricular tachycardias, ventricular tachycardia, and ventricular fibrillation (VF).
      • Shanti C.M.
      • Lucas C.E.
      Cocaine and the critical care challenge.
      Intravenous drug usage of PDAA is a common cause of infective endocarditis and patients can present acutely or subacutely.
      • Cooper H.L.
      • Brady J.E.
      • Ciccarone D.
      • Tempalski B.
      • Gostnell K.
      • Friedman S.R.
      Nationwide increase in the number of hospitalizations for illicit injection drug use-related infective endocarditis.
      Commonly with intravenous drug usage, the tricuspid valve is infected, and the most common pathogen is staphylococcus aureus.
      • Cooper H.L.
      • Brady J.E.
      • Ciccarone D.
      • Tempalski B.
      • Gostnell K.
      • Friedman S.R.
      Nationwide increase in the number of hospitalizations for illicit injection drug use-related infective endocarditis.
      ,
      • Long B.
      • Koyfman A.
      Infectious endocarditis: an update for emergency clinicians.
      Cocaine users have increased rates of atherosclerosis and more pronounced atherosclerosis upon presentation of acute chest pain, compared with control groups.
      • Ebersberger U.
      • Sudarski S.
      • Schoepf U.J.
      • et al.
      Atherosclerotic plaque burden in cocaine users with acute chest pain: analysis by coronary computed tomography angiography.
      Histamine release from mast cells increases the endothelial permeability leading to leukocyte migration and low-density lipoprotein migration, contributing to atherosclerosis.
      • Huang M.
      • Pang X.
      • Letourneau R.
      • Boucher W.
      • Theoharides T.C.
      Acute stress induces cardiac mast cell activation and histamine release, effects that are increased in apolipoprotein E knockout mice.
      ,
      • Gan X.
      • Zhang L.
      • Berger O.
      • et al.
      Cocaine enhances brain endothelial adhesion molecules and leukocyte migration.
      Acutely, PDAA can cause Takotsubo stress cardiomyopathy secondary to the catecholamine surge (Fig. 2).
      • Restrepo C.S.
      • Rojas C.A.
      • Martinez S.
      • et al.
      Cardiovascular complications of cocaine: imaging findings.
      However, with chronic PDAA usage, oxidative stress is a major cause of myocardial damage causing a dilated cardiomyopathy with a reduced ejection fraction.
      • Reddy P.K.V.
      • Ng T.M.H.
      • Oh E.E.
      • Moady G.
      • Elkayam U.
      Clinical characteristics and management of methamphetamine-associated cardiomyopathy: State-of-the-Art Review.
      In addition, accelerated apoptosis, increased p53 activity, cardiomyocyte necrosis, fatty acid toxicity, and defects in intracellular calcium hemostasis contribute to the development of cardiomyopathy.
      • Reddy P.K.V.
      • Ng T.M.H.
      • Oh E.E.
      • Moady G.
      • Elkayam U.
      Clinical characteristics and management of methamphetamine-associated cardiomyopathy: State-of-the-Art Review.
      ,
      • Jafari Giv M.
      Exposure to amphetamines leads to development of amphetamine type stimulants associated cardiomyopathy (ATSAC).
      PDAA can also cause a hypertrophic cardiomyopathy secondary to elevated BP with chronic usage.
      • Restrepo C.S.
      • Rojas C.A.
      • Martinez S.
      • et al.
      Cardiovascular complications of cocaine: imaging findings.
      Figure thumbnail gr2
      Figure 2Drugs of abuse and the common pathophysiological mechanisms of heart disease resulting from their usage. Considerable overlap exists between different classes of drugs of abuse in the mechanisms leading to heart disease. The heart disease resulting from drugs of abuse includes dilated and hypertrophic cardiomyopathies, coronary artery disease, and increased arrhythmia burden. AAS, anabolic-androgenic steroids; EC, excitation-contraction; PDAA, psychostimulants drugs of abuse.

      Treatment

      The treatment for PDAA-associated cardiac complications is specific to the different effects it can cause (Table 2). Because the theory of β-blockade causing unopposed α stimulation resulting in a paradoxical increase in BP and coronary artery vasoconstriction, clinicians have advocated against the use of β-blockers for the treatment of PDAA toxicity.
      • Richards J.R.
      • Garber D.
      • Laurin E.G.
      • et al.
      Treatment of cocaine cardiovascular toxicity: a systematic review.
      As per the American Heart Association guidelines, when a patient with suspected PDAA use is seen with chest pain compatible with MI and ST-segment elevation, sublingual nitroglycerin or calcium channel blocker should be administered immediately.
      • Anderson J.L.
      • Adams C.D.
      • Antman E.M.
      • et al.
      2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      If there is no response, coronary angiography should be performed to rule out type 1 MI.
      • Anderson J.L.
      • Adams C.D.
      • Antman E.M.
      • et al.
      2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      The American Heart Association guidelines recommend for PDAA-associated hypertension and sinus tachycardia, administration of combined α- and β-blocking agents be given provided they have already recently received a vasodilator.
      • Anderson J.L.
      • Adams C.D.
      • Antman E.M.
      • et al.
      2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      If an MI and AD has been excluded, other sources recommend ongoing treatment with benzodiazepines and nitrates.
      • Schwartz B.G.
      • Rezkalla S.
      • Kloner R.A.
      Cardiovascular effects of cocaine.
      For cardiac arrhythmias, in addition to routine care, consideration of sodium bicarbonate treatment for counteracting cocaine’s sodium-blocking effect and intravenous lipid emulsion therapy might be helpful in those with extreme cocaine overdose due to cocaine’s lipophilic properties.
      • Schwartz B.G.
      • Rezkalla S.
      • Kloner R.A.
      Cardiovascular effects of cocaine.
      ,
      • Arora N.P.
      • Berk W.A.
      • Aaron C.K.
      • Williams K.A.
      Usefulness of intravenous lipid emulsion for cardiac toxicity from cocaine overdose.
      Treatment for AD, heart failure, cardiomyopathies, and stroke should be treated as per guidelines with the addition of cessation of using the PDAA.
      • Schwartz B.G.
      • Rezkalla S.
      • Kloner R.A.
      Cardiovascular effects of cocaine.
      Although there is no pharmacotherapy approved for PDAA cessation, a multidisciplinary approach for the addiction likely has some utility.
      • Soares E.
      • Pereira F.C.
      Pharmacotherapeutic strategies for methamphetamine use disorder: mind the subgroups.
      Table 2Treatment options
      Drug-specific treatmentTreatment
      PDAAMI:

      Sublingual NTG or CCB
      • Anderson J.L.
      • Adams C.D.
      • Antman E.M.
      • et al.
      2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.


      Hypertension:

      Benzodiazepines and vasodilators. If persistent, consider combined α- and β-blocking agents
      • Anderson J.L.
      • Adams C.D.
      • Antman E.M.
      • et al.
      2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.


      Persistent cardiac arrhythmias:

      Consideration of sodium bicarbonate and intravenous lipid emulsion in extreme cases
      • Schwartz B.G.
      • Rezkalla S.
      • Kloner R.A.
      Cardiovascular effects of cocaine.
      ,
      • Arora N.P.
      • Berk W.A.
      • Aaron C.K.
      • Williams K.A.
      Usefulness of intravenous lipid emulsion for cardiac toxicity from cocaine overdose.
      Cessation of the offending agent; referral to a drug rehabilitation programContinue with guideline-directed therapies
      AlcoholWithdrawal:

      CIWA-Ar protocol
      • Dixit D.
      • Endicott J.
      • Burry L.
      • et al.
      Management of acute alcohol withdrawal syndrome in critically ill patients.


      Correct possible QT prolongation
      • Rodrigo C.
      • Fernando T.
      • Samarakoon L.
      • et al.
      Acute coronary events during alcohol withdrawal.
      ,
      • Rodrigo C.
      • Epa D.S.
      • Sriram G.
      • Jayasinghe S.
      Acute coronary ischemia during alcohol withdrawal: a case report.
      AASWithdrawal:

      TRT, SERM, hCG, and aromatase inhibitors
      • McCullough D.
      • Webb R.
      • Enright K.J.
      • et al.
      How the love of muscle can break a heart: impact of anabolic androgenic steroids on skeletal muscle hypertrophy, metabolic and cardiovascular health.
      • Bates G.
      • Van Hout M.C.
      • Teck J.T.W.
      • McVeigh J.
      Treatments for people who use anabolic androgenic steroids: a scoping review.
      • Rahnema C.D.
      • Lipshultz L.I.
      • Crosnoe L.E.
      • Kovac J.R.
      • Kim E.D.
      Anabolic steroid-induced hypogonadism: diagnosis and treatment.
      CannabisHyperadrenergic state:

      Consideration of β-blockade
      • Kanakis C.
      • Pouget J.M.
      • Rosen K.M.
      The effects of delta-9-tetrahydrocannabinol (cannabis) on cardiac performance with and without beta blockade.
      TobaccoCessation in an acute cardiac presentation:

      NRT
      • Narkiewicz K.
      • van de Borne P.J.
      • Hausberg M.
      • et al.
      Cigarette smoking increases sympathetic outflow in humans.


      Bupropion: might benefit long term
      • Narkiewicz K.
      • van de Borne P.J.
      • Hausberg M.
      • et al.
      Cigarette smoking increases sympathetic outflow in humans.
      ,
      • Tonstad S.
      • Farsang C.
      • Klaene G.
      • et al.
      Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre, randomised study.


      Varenicline: caution in ACS
      • Narkiewicz K.
      • van de Borne P.J.
      • Hausberg M.
      • et al.
      Cigarette smoking increases sympathetic outflow in humans.
      AAS, anabolic-androgenic steroids; ACS, acute coronary syndrome; CCB, calcium channel blocker; CIWA-Ar, Clinical Institute Withdrawal Assessment for Alcohol-Revised; hCG, human chorionic gonadotropin; MI, myocardial infarction; NRT, nicotine replacement therapy; NTG, nitroglycerin; PDAA, psychostimulant drugs of abuse and addiction; SERM, selective estrogen receptor modulators; TRT, testosterone replacement therapy.

      Ethanol

      Ethanol (alcohol) use has been established as a leading risk factor for premature death and disability with connections to numerous diseases including liver cirrhosis, cancer, and nutritional deficiencies.
      GBD 2016 Alcohol Collaborators
      Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease study 2016.
      ,
      • Peacock A.
      • Leung J.
      • Larney S.
      • et al.
      Global statistics on alcohol, tobacco and illicit drug use: 2017 status report.
      Previous research suggested that low to moderate doses of alcohol consumption is cardioprotective and reduces all-cause mortality; however, these findings have been criticized because of poor methodological design and sample size.
      GBD 2016 Alcohol Collaborators
      Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease study 2016.
      More recent evidence has suggested that alcohol provides nonsignificant health benefits and is causative of CVD.
      GBD 2016 Alcohol Collaborators
      Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease study 2016.
      ,
      • Knott C.S.
      • Coombs N.
      • Stamatakis E.
      • Biddulph J.P.
      All cause mortality and the case for age specific alcohol consumption guidelines: pooled analyses of up to 10 population based cohorts.

      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 acute or chronic alcohol consumption. Both are demarcated by dilation, thinning, and impaired contraction of 1 or both ventricles with severity associated with disease progression.
      • Maisch B.
      Alcoholic cardiomyopathy: the result of dosage and individual predisposition.
      Acute consumption promotes myocardial inflammation, which can be clinically detectable by an elevated serum troponin level.
      • Waszkiewicz N.
      • Szulc A.
      • Zwierz K.
      Binge drinking-induced subtle myocardial injury.
      Cardiovascular pathogenesis secondary to alcohol consumption, specifically alcoholic cardiomyopathy (ACM), also includes a myriad of pathophysiological mechanisms mediated by alcohol and its principal metabolites including acetaldehyde and ethyl esters.
      • El-Mas M.M.
      • Abdel-Rahman A.A.
      Role of alcohol oxidative metabolism in its cardiovascular and autonomic effects.
      Cardiomyocyte hypertrophy, apoptosis and necrosis, uncoupling of excitation-contraction, oxidative damage, mitochondrial degeneration, and myocardial fibrosis are the major determinants of the adverse cardiac remodelling.
      • Rodrigues P.
      • Santos-Ribeiro S.
      • Teodoro T.
      • et al.
      Association between alcohol intake and cardiac remodeling.
      ,
      • Ren J.
      • Wold L.E.
      Mechanisms of alcoholic heart disease.

      Cardiovascular complications

      Cardiovascular complications tend to be observed when consumption passes the unique individual alcohol threshold leading to elevated susceptibility (Table 1). An acute cardiac complication of binge drinking is AF (holiday heart syndrome).
      • Ettinger P.O.
      • Wu C.F.
      • De La Cruz Jr., C.
      • Weisse A.B.
      • Ahmed S.S.
      • Regan T.J.
      Arrhythmias and the “Holiday Heart”: alcohol-associated cardiac rhythm disorders.
      Holiday heart syndrome was first coined in 1978 when patients presented with AF to hospital after a binge drinking weekend.
      • Ettinger P.O.
      • Wu C.F.
      • De La Cruz Jr., C.
      • Weisse A.B.
      • Ahmed S.S.
      • Regan T.J.
      Arrhythmias and the “Holiday Heart”: alcohol-associated cardiac rhythm disorders.
      Current hypotheses suggest a combination of cellular and electrophysiologic damage from the toxicity of alcohol causing atrial conduction abnormalities.
      • Voskoboinik A.
      • Prabhu S.
      • Ling L.H.
      • Kalman J.M.
      • Kistler P.M.
      Alcohol and atrial fibrillation: a sobering review.
      Common chronic complications of alcohol usage are persistent atrial arrhythmias, atherosclerosis, hypertension, and ACM. A recent meta-analysis identified that the relative risk (RR) for AF increased by 10% for each drink per day consumed.
      • Kodama S.
      • Saito K.
      • Tanaka S.
      • et al.
      Alcohol consumption and risk of atrial fibrillation: a meta-analysis.
      Heavy long-term alcohol consumption is also associated with ventricular arrythmias, systematic atherosclerosis, sudden cardiac death, beriberi cardiomyopathy, and cirrhotic cardiomyopathy.
      • Puddey I.B.
      • Mori T.A.
      • Barden A.E.
      • Beilin L.J.
      Alcohol and hypertension-new insights and lingering controversies.
      • Djoussé L.
      • Gaziano J.M.
      Alcohol consumption and heart failure: a systematic review.
      • Carvalho M.V.H.
      • Kroll P.C.
      • Kroll R.T.M.
      • Carvalho V.N.
      Cirrhotic cardiomyopathy: the liver affects the heart.
      • Kupari M.
      • Koskinen P.
      Alcohol, cardiac arrhythmias and sudden death.
      Rapid withdrawal of alcohol might increase the risk of coronary events and QT prolongation.
      • Rodrigo C.
      • Fernando T.
      • Samarakoon L.
      • et al.
      Acute coronary events during alcohol withdrawal.
      ,
      • Rodrigo C.
      • Epa D.S.
      • Sriram G.
      • Jayasinghe S.
      Acute coronary ischemia during alcohol withdrawal: a case report.
      ACM is a major cardiac complication secondary to alcohol consumption and a leading cause of nonischemic cardiomyopathy, comprising approximately 21%-36% of all nonischemic cardiomyopathies (Fig. 2).
      • Shaaban A.
      • Gangwani M.K.
      • Pendela V.S.
      • Vindhyal M.R.
      Alcoholic cardiomyopathy.
      ACM is caused by long-term alcohol exposure, but it is unclear the duration and amount of consumption required; although variations in genetics, sex, metabolism, and lifestyle factors might lead to differences in the alcohol threshold required to induce ACM.
      • Guzzo-Merello G.
      • Cobo-Marcos M.
      • Gallego-Delgado M.
      • Garcia-Pavia P.
      Alcoholic cardiomyopathy.
      The 4-year mortality for ACM can range up to 50%, making it a major cause of premature death.
      • Sidorenkov O.
      • Nilssen O.
      • Nieboer E.
      • Kleshchinov N.
      • Grjibovski A.M.
      Premature cardiovascular mortality and alcohol consumption before death in Arkhangelsk, Russia: an analysis of a consecutive series of forensic autopsies.

      Treatment

      Treatment of ACM is primarily driven by alcohol abstinence or reduction of alcohol consumption although the efficacy of this strategy remains unclear (Table 2).
      • Renault A.
      • Mansourati J.
      • Genet L.
      • Blanc J.J.
      Dilated cardiomyopathies in severe cardiac failure in chronic alcoholics: clinical course after complete withdrawal [in French].
      Upon presentation to hospital, alcohol withdrawal can be serious, the mainstay of treatment is the use of the benzodiazepines and the Clinical Institute Withdrawal Assessment for Alcohol–Revised (CIWA-Ar) but consideration of QT monitoring should also be given.
      • Rodrigo C.
      • Fernando T.
      • Samarakoon L.
      • et al.
      Acute coronary events during alcohol withdrawal.
      ,
      • Rodrigo C.
      • Epa D.S.
      • Sriram G.
      • Jayasinghe S.
      Acute coronary ischemia during alcohol withdrawal: a case report.
      ,
      • Dixit D.
      • Endicott J.
      • Burry L.
      • et al.
      Management of acute alcohol withdrawal syndrome in critically ill patients.
      Pharmacotherapies currently established for alcohol abstinence or reduction of alcohol consumption are targeted at reducing the psychological craving associated with alcohol ingestion and often involve specialized teams and medical therapy tailored to the patients’ clinical and demographic characteristics. Treatment of heart failure secondary to ACM is nonspecific outside of targeted alcohol cessation/reduction.

      Anabolic-Androgenic Steroids

      AAS are synthetic derivatives of testosterone, which have been used for decades to enhance physique and athletic performance by increasing muscle mass and strength.
      • Bhasin S.
      • Storer T.W.
      • Berman N.
      • et al.
      The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men.
      Drugs that are commonly used in this class include testosterone, androstenedione, stanozolol, nandrolone, and methandrostenolone.
      • Perry J.C.
      • Schuetz T.M.
      • Memon M.D.
      • Faiz S.
      • Cancarevic I.
      Anabolic steroids and cardiovascular outcomes: the controversy.
      ,
      • Kicman A.T.
      Pharmacology of anabolic steroids.
      Lifetime prevalence rates of AAS use around the globe have been estimated at 3.3%, with a rate of 6.4% for men and 1.6% for women.
      • Sagoe D.
      • Molde H.
      • Andreassen C.S.
      • Torsheim T.
      • Pallesen S.
      The global epidemiology of anabolic-androgenic steroid use: a meta-analysis and meta-regression analysis.
      Historically, the use of AAS was primarily limited to sport but has shifted into a public health concern with increasing ease of access.
      • Sjöqvist F.
      • Garle M.
      • Rane A.
      Use of doping agents, particularly anabolic steroids, in sports and society.
      Over recent years, the idealized male body has shifted toward higher levels of masculinity and has been reflected by an increased prevalence of muscle dysmorphia and subsequent AAS use in young men.
      • Kanayama G.
      • Hudson J.I.
      • Pope J.H.G.
      Anabolic-androgenic steroid use and body image in men: a growing concern for clinicians.

      Pharmacology

      Although AAS can increase fat-free mass and muscle size and strength, there are also long-term adverse effects of these drugs on the body. These include but are not limited to the reproductive, musculoskeletal, renal, immunological, and endocrine systems.
      • Bhasin S.
      • Storer T.W.
      • Berman N.
      • et al.
      The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men.
      ,
      • Maravelias C.
      • Dona A.
      • Stefanidou M.
      • Spiliopoulou C.
      Adverse effects of anabolic steroids in athletes: a constant threat.
      The effects of AAS throughout the body are regulated at the cellular level through steroid-converting enzymes at each target tissue.
      • Kicman A.T.
      Pharmacology of anabolic steroids.
      In the CVS, AAS might bind directly to androgen receptors in the heart and major arteries resulting in growth-promoting effects on cardiac tissue, whereas high doses of AAS also reduces vasodilation which furthers these growth-promoting effects.
      • Achar S.
      • Rostamian A.
      • Narayan S.M.
      Cardiac and metabolic effects of anabolic-androgenic steroid abuse on lipids, blood pressure, left ventricular dimensions, and rhythm.

      Cardiovascular complications

      Direct cardiotoxic effects of AAS include cardiac hypertrophy resulting in ventricular dysfunction and accelerated coronary atherosclerosis (Table 1, Fig. 2).
      • Perry J.C.
      • Schuetz T.M.
      • Memon M.D.
      • Faiz S.
      • Cancarevic I.
      Anabolic steroids and cardiovascular outcomes: the controversy.
      ,
      • Baggish A.L.
      • Weiner R.B.
      • Kanayama G.
      • et al.
      Cardiovascular toxicity of illicit anabolic-androgenic steroid use.
      • Payne J.R.
      • Kotwinski P.J.
      • Montgomery H.E.
      Cardiac effects of anabolic steroids.
      • Baggish A.L.
      • Weiner R.B.
      • Kanayama G.
      • et al.
      Long-term anabolic-androgenic steroid use is associated with left ventricular dysfunction.
      • Nottin S.
      • Nguyen L.D.
      • Terbah M.
      • Obert P.
      Cardiovascular effects of androgenic anabolic steroids in male bodybuilders determined by tissue Doppler imaging.
      • Hassan N.A.
      • Salem M.F.
      • Sayed M.A.
      Doping and effects of anabolic androgenic steroids on the heart: histological, ultrastructural, and echocardiographic assessment in strength athletes.
      Long-term AAS use might result in reduced left ventricular systolic and diastolic function, which might increase the risk of heart failure in these individuals.
      • Baggish A.L.
      • Weiner R.B.
      • Kanayama G.
      • et al.
      Cardiovascular toxicity of illicit anabolic-androgenic steroid use.
      ,
      • Baggish A.L.
      • Weiner R.B.
      • Kanayama G.
      • et al.
      Long-term anabolic-androgenic steroid use is associated with left ventricular dysfunction.
      • Nottin S.
      • Nguyen L.D.
      • Terbah M.
      • Obert P.
      Cardiovascular effects of androgenic anabolic steroids in male bodybuilders determined by tissue Doppler imaging.
      • Hassan N.A.
      • Salem M.F.
      • Sayed M.A.
      Doping and effects of anabolic androgenic steroids on the heart: histological, ultrastructural, and echocardiographic assessment in strength athletes.
      AAS users tend to have more left ventricular hypertrophy, which correlated with the degree of systolic and diastolic dysfunction.
      • Baggish A.L.
      • Weiner R.B.
      • Kanayama G.
      • et al.
      Cardiovascular toxicity of illicit anabolic-androgenic steroid use.
      Strength-trained athletes (ie, power lifters who might be more likely to abuse AAS) might already have hearts with more a concentric pattern of left ventricular growth, predisposing them to increased risk from AAS use and resulting changes to myocardial growth.
      • Payne J.R.
      • Kotwinski P.J.
      • Montgomery H.E.
      Cardiac effects of anabolic steroids.
      ,
      • Pluim B.M.
      • Zwinderman A.H.
      • van der Laarse A.
      • van der Wall E.E.
      The athlete’s heart. A meta-analysis of cardiac structure and function.
      Other direct cardiac effects of AAS include increased arrythmia risk, which might predispose individuals to sudden cardiac arrest.
      • Achar S.
      • Rostamian A.
      • Narayan S.M.
      Cardiac and metabolic effects of anabolic-androgenic steroid abuse on lipids, blood pressure, left ventricular dimensions, and rhythm.
      Chronic coadministration of AAS with moderate-intensity endurance exercise resulted in VF occurrence in rats.
      • Ghorbani Baravati H.
      • Joukar S.
      • Fathpour H.
      • Kordestani Z.
      Nandrolone plus moderate exercise increases the susceptibility to lethal arrhythmias.
      Other translational work also showed that supraphysiological doses of AAS caused electrical remodelling of the left ventricle, in addition to morphological remodelling of both ventricles.
      • Medei E.
      • Marocolo M.
      • Rodrigues Dde C.
      • et al.
      Chronic treatment with anabolic steroids induces ventricular repolarization disturbances: cellular, ionic and molecular mechanism.
      Many AAS users use a variety of AAS and might combine drugs such as diuretics to achieve stacking effects, which can be lethal.
      • Liu J.D.
      • Wu Y.Q.
      Anabolic-androgenic steroids and cardiovascular risk.
      AAS users have also been reported to have higher coronary plaque volume relative to nonusers and experienced early MI whereas nonusers in the same study had no history of MI or stenting.
      • Baggish A.L.
      • Weiner R.B.
      • Kanayama G.
      • et al.
      Cardiovascular toxicity of illicit anabolic-androgenic steroid use.
      There is evidence suggesting that AAS induces alterations in lipid metabolism, such as a reduction in high-density lipoprotein and an increase in low-density lipoprotein, effects that cumulatively increase risk of CAD.
      • Achar S.
      • Rostamian A.
      • Narayan S.M.
      Cardiac and metabolic effects of anabolic-androgenic steroid abuse on lipids, blood pressure, left ventricular dimensions, and rhythm.
      ,
      • Angell P.
      • Chester N.
      • Green D.
      • Somauroo J.
      • Whyte G.
      • George K.
      Anabolic steroids and cardiovascular risk.
      • Vanberg P.
      • Atar D.
      Androgenic anabolic steroid abuse and the cardiovascular system.
      • Souza F.R.
      • Dos Santos M.R.
      • Porello R.A.
      • et al.
      Diminished cholesterol efflux mediated by HDL and coronary artery disease in young male anabolic androgenic steroid users.
      • Thompson P.D.
      • Cullinane E.M.
      • Sady S.P.
      • et al.
      Contrasting effects of testosterone and stanozolol on serum lipoprotein levels.
      • Hartgens F.
      • Rietjens G.
      • Keizer H.A.
      • Kuipers H.
      • Wolffenbuttel B.H.R.
      Effects of androgenic-anabolic steroids on apolipoproteins and lipoprotein (a).
      AAS might contribute to dyslipidemia and CAD because of impaired cholesterol efflux, which is mediated by high-density lipoprotein.
      • Souza F.R.
      • Dos Santos M.R.
      • Porello R.A.
      • et al.
      Diminished cholesterol efflux mediated by HDL and coronary artery disease in young male anabolic androgenic steroid users.
      Chronic AAS can lead to increased systolic BP and is also associated with increased aortic stiffness secondary to reduced plasma concentrations of natriuretic peptides (atrial and brain natriuretic peptides).
      • Rasmussen J.J.
      • Schou M.
      • Madsen P.L.
      • et al.
      Increased blood pressure and aortic stiffness among abusers of anabolic androgenic steroids: potential effect of suppressed natriuretic peptides in plasma?.
      Taken together, the role of AAS in dyslipidemia and hypertension points to AAS’ detrimental effect on metabolism and the role they play in contributing to metabolic syndrome in its users despite decreasing their body fat percentage.
      • McCullough D.
      • Webb R.
      • Enright K.J.
      • et al.
      How the love of muscle can break a heart: impact of anabolic androgenic steroids on skeletal muscle hypertrophy, metabolic and cardiovascular health.

      Treatment

      To reduce CVD risk, cessation of AAS is highly recommended because it has been shown to improve lipid profiles, insulin sensitivity, and BP (Table 2).
      • McCullough D.
      • Webb R.
      • Enright K.J.
      • et al.
      How the love of muscle can break a heart: impact of anabolic androgenic steroids on skeletal muscle hypertrophy, metabolic and cardiovascular health.
      Discontinuation of AAS remains challenging because of the various withdrawal effects of AAS including hypogonadism, depression, and libido reduction.
      • Liu J.D.
      • Wu Y.Q.
      Anabolic-androgenic steroids and cardiovascular risk.
      ,
      • McCullough D.
      • Webb R.
      • Enright K.J.
      • et al.
      How the love of muscle can break a heart: impact of anabolic androgenic steroids on skeletal muscle hypertrophy, metabolic and cardiovascular health.
      Despite few evidence-driven approaches for treatment of AAS withdrawal, testosterone replacement therapies, selective estrogen receptor modulators, human chorionic gonadotropin, and aromatase inhibitors have been suggested.
      • McCullough D.
      • Webb R.
      • Enright K.J.
      • et al.
      How the love of muscle can break a heart: impact of anabolic androgenic steroids on skeletal muscle hypertrophy, metabolic and cardiovascular health.
      • Bates G.
      • Van Hout M.C.
      • Teck J.T.W.
      • McVeigh J.
      Treatments for people who use anabolic androgenic steroids: a scoping review.
      • Rahnema C.D.
      • Lipshultz L.I.
      • Crosnoe L.E.
      • Kovac J.R.
      • Kim E.D.
      Anabolic steroid-induced hypogonadism: diagnosis and treatment.

      Cannabis

      Cannabis is a term used to describe preparations from the Cannabis sativa or C indica plants.
      • Atakan Z.
      Cannabis, a complex plant: different compounds and different effects on individuals.
      These psychoactive plants contain more than 400 chemical entities, including Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol.
      • Lafaye G.
      • Karila L.
      • Blecha L.
      • Benyamina A.
      Cannabis, cannabinoids, and health.
      ,
      • Atakan Z.
      Cannabis, a complex plant: different compounds and different effects on individuals.
      Cannabis is now one of the most frequently used psychoactive substances in the world, with estimations that up to 4.9% of the world’s population have tried cannabis.
      • Lafaye G.
      • Karila L.
      • Blecha L.
      • Benyamina A.
      Cannabis, cannabinoids, and health.
      ,
      • Anthony J.C.
      • Lopez-Quintero C.
      • Alshaarawy O.
      Cannabis epidemiology: a selective review.

      Pharmacology

      Cannabinoid (CB) receptors are distributed throughout the central nervous system and other peripheral tissues, including in the arteries and heart.
      • Grotenhermen F.
      Pharmacology of cannabinoids.
      The biological effects of CBs are primarily mediated through the endocannabinoid system (ECS) via G protein-coupled receptors: CB1 and CB2.
      • Pertwee R.G.
      Pharmacology of cannabinoid CB1 and CB2 receptors.
      ,
      • Montecucco F.
      • Di Marzo V.
      At the heart of the matter: the endocannabinoid system in cardiovascular function and dysfunction.
      The ECS is a modulatory system consisting of CB receptors, endogenous CBs (endocannabinoids), and enzymes that regulate levels of these compounds.
      • Lu H.C.
      • Mackie K.
      An introduction to the endogenous cannabinoid system.
      In the CVS, CB receptors are found in the myocardium, vascular endothelial and smooth muscle cells, and circulating blood cells.
      • Pacher P.
      • Steffens S.
      • Haskó G.
      • Schindler T.H.
      • Kunos G.
      Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly.
      Additionally, the CVS can be modulated by upstream effects of CBs on the peripheral nervous system. CB1 receptors mediate CB-induced cardiovascular depressive effects such as hypotension and reduced myocardial contractility.
      • Montecucco F.
      • Di Marzo V.
      At the heart of the matter: the endocannabinoid system in cardiovascular function and dysfunction.
      ,
      • Pacher P.
      • Steffens S.
      • Haskó G.
      • Schindler T.H.
      • Kunos G.
      Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly.
      ,
      • Lake K.D.
      • Compton D.R.
      • Varga K.
      • Martin B.R.
      • Kunos G.
      Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors.
      Alternatively, CB2 receptor agonists have less pronounced cardiovascular effects.
      • Steffens S.
      • Pacher P.
      Targeting cannabinoid receptor CB2 in cardiovascular disorders: promises and controversies.

      Cardiovascular complications

      The acute CVS effects of CBs are typically driven by activation of the sympathetic nervous system in addition to inhibition of the parasympathetic nervous system, which results in an elevation of HR and systolic BP (Table 1).
      • Gash A.
      • Karliner J.S.
      • Janowsky D.
      • Lake C.R.
      Effects of smoking marihuana on left ventricular performance and plasma norepinephrine.
      • Singh A.
      • Saluja S.
      • Kumar A.
      • et al.
      Cardiovascular complications of marijuana and related substances: a review.
      • Karschner E.L.
      • Darwin W.D.
      • McMahon R.P.
      • et al.
      Subjective and physiological effects after controlled Sativex and oral THC administration.
      Taken together, the autonomic dysregulation resulting from cannabis use increases cardiac workload and myocardial oxygen demand.
      • Singh A.
      • Saluja S.
      • Kumar A.
      • et al.
      Cardiovascular complications of marijuana and related substances: a review.
      Cannabis is also associated with acute coronary syndrome (ACS), which at times occurs in patients without any classic cardiovascular risk factors.
      • Safaa A.M.
      • Markham R.
      • Jayasinghe R.
      Marijuana-induced recurrent acute coronary syndrome with normal coronary angiograms.
      ,
      • Lindsay A.C.
      • Foale R.A.
      • Warren O.
      • Henry J.A.
      Cannabis as a precipitant of cardiovascular emergencies.
      A recent cross-sectional study has provided evidence that a history of MI was more common among recent cannabis users.
      • Ladha K.S.
      • Mistry N.
      • Wijeysundera D.N.
      • et al.
      Recent cannabis use and myocardial infarction in young adults: a cross-sectional study.
      MI in these patients might occur in the absence of detectable atherosclerotic CAD.
      • Rezkalla S.
      • Kloner R.A.
      Cardiovascular effects of marijuana.
      ,
      • Dahdouh Z.
      • Roule V.
      • Lognoné T.
      • Sabatier R.
      • Grollier G.
      Cannabis and coronary thrombosis: what is the role of platelets?.
      Increased myocardial oxygen demand, reduced oxygen supply, microvascular/coronary artery spasm, and the prothrombotic state arising from cannabis use contribute to increased acute coronary syndrome risk.
      • Singh A.
      • Saluja S.
      • Kumar A.
      • et al.
      Cardiovascular complications of marijuana and related substances: a review.
      ,
      • Dahdouh Z.
      • Roule V.
      • Lognoné T.
      • Sabatier R.
      • Grollier G.
      Cannabis and coronary thrombosis: what is the role of platelets?.
      • Deusch E.
      • Kress H.G.
      • Kraft B.
      • Kozek-Langenecker S.A.
      The procoagulatory effects of delta-9-tetrahydrocannabinol in human platelets.
      • Gunawardena M.D.
      • Rajapakse S.
      • Herath J.
      • Amarasena N.
      Myocardial infarction following cannabis induced coronary vasospasm.
      The hyperadrenergic state resulting from cannabis use leads to cardiac tachyarrhythmia in the short-term and Δ9-THC increases sinus node automaticity and facilitates A-V nodal conduction (Fig. 2).
      • Singh A.
      • Saluja S.
      • Kumar A.
      • et al.
      Cardiovascular complications of marijuana and related substances: a review.
      ,
      • Miller R.H.
      • Dhingra R.C.
      • Kanakis C.
      • Amat-y-Leon F.
      • Rosen K.M.
      The electrophysiological effects of delta-9-tetrahydrocannabinol (cannabis) on cardiac conduction in man.
      Other arrythmias associated with cannabis use include VF, AF, sinus bradycardia, and second-degree atrioventricular block.
      • Singh G.K.
      Atrial fibrillation associated with marijuana use.
      • Kosior D.A.
      • Filipiak K.J.
      • Stolarz P.
      • Opolski G.
      Paroxysmal atrial fibrillation following marijuana intoxication: a two-case report of possible association.
      • Akins D.
      • Awdeh M.R.
      Marijuana and second-degree AV block.
      • Baranchuk A.
      • Johri A.M.
      • Simpson C.S.
      • Methot M.
      • Redfearn D.P.
      Ventricular fibrillation triggered by marijuana use in a patient with ischemic cardiomyopathy: a case report.
      The mechanisms driving clinical arrythmias in cannabis users are not well known, but it is likely that adrenergic stimulation, myocardial ischemia, and microvascular dysfunction all contribute to AF development and perpetuation in cannabis users.
      • Korantzopoulos P.
      • Liu T.
      • Papaioannides D.
      • Li G.
      • Goudevenos J.A.
      Atrial fibrillation and marijuana smoking.
      There is also an association between stress cardiomyopathy and cannabis use,
      • Kaushik M.
      • Alla V.M.
      • Madan R.
      • Arouni A.J.
      • Mohiuddin S.M.
      Recurrent stress cardiomyopathy with variable regional involvement.
      • Nogi M.
      • Fergusson D.
      • Chiaco J.M.
      Mid-ventricular variant Takotsubo cardiomyopathy associated with cannabinoid hyperemesis syndrome: a case report.
      • Meera S.J.
      • Vallabhaneni S.
      • Shirani J.
      Cannabis-induced basal-mid-left ventricular stress cardiomyopathy: a case report.
      which is likely driven through a combination of the hyperadrenergic state and modulation of the ECS resulting in reduced myocardial contractility.
      • Kaushik M.
      • Alla V.M.
      • Madan R.
      • Arouni A.J.
      • Mohiuddin S.M.
      Recurrent stress cardiomyopathy with variable regional involvement.

      Treatment

      It is crucial for physicians and other health care professionals to be aware of the potential health complications of cannabis in the midst of its growing legalization worldwide and increasing evidence of its temporal association with cardiovascular complications.
      • Ladha K.S.
      • Mistry N.
      • Wijeysundera D.N.
      • et al.
      Recent cannabis use and myocardial infarction in young adults: a cross-sectional study.
      ,
      • Hammond D.
      • Goodman S.
      • Wadsworth E.
      • Rynard V.
      • Boudreau C.
      • Hall W.
      Evaluating the impacts of cannabis legalization: the International Cannabis Policy Study.
      Specifically, patients with preexisting cardiovascular risk factors, strong family history of heart disease, or other heart conditions should be cautioned against cannabis use.
      • Grubb A.F.
      • Greene S.J.
      • Fudim M.
      • Dewald T.
      • Mentz R.J.
      Drugs of abuse and heart failure.
      There is evidence that β-blockade might blunt the response of the CVS to Δ9-THC, but this has not been extensively studied (Table 2).
      • Kanakis C.
      • Pouget J.M.
      • Rosen K.M.
      The effects of delta-9-tetrahydrocannabinol (cannabis) on cardiac performance with and without beta blockade.
      As legalization progresses around the globe, long-term follow-up studies and clinical practices should be in place to monitor the health outcomes of cannabis users.

      Tobacco and Nicotine

      Tobacco use is a worldwide public health concern killing more than 8 million people a year.
      • WHO. WHO
      Global Report on Trends in Prevalence of Tobacco Use 2000-2025.
      Despite public health interventions, vaping nicotine liquids continues to gain increasing popularity as young users start with vaping nicotine before transitioning to smoking tobacco, and chronic tobacco smokers transition to vaping nicotine liquids.
      • Nayeri A.
      • Middlekauff H.
      Vaping instead of cigarette smoking: a panacea or just another form of cardiovascular risk?.
      ,
      • WHO. WHO
      Global Report on Trends in Prevalence of Tobacco Use 2000-2025.
      ,
      • Perez-Warnisher M.T.
      • Carballosa de Miguel M.D.P.
      • Seijo L.M.
      Tobacco use worldwide: legislative efforts to curb consumption.
      Tobacco is commonly smoked in cigarettes, and cigarette smoke is a mixture of nicotine, carbon monoxide, and oxidant chemicals, toxic to the CVS.
      • Salahuddin S.
      • Prabhakaran D.
      • Roy A.
      Pathophysiological mechanisms of tobacco-related CVD.

      Pharmacology

      Tobacco has an increased risk in causing CVD through numerous mechanisms, including a procoagulable state, endothelial damage, and reduced oxygen delivery.
      • Benowitz N.L.
      • Burbank A.D.
      Cardiovascular toxicity of nicotine: implications for electronic cigarette use.
      ,
      • Grubb A.F.
      • Greene S.J.
      • Fudim M.
      • Dewald T.
      • Mentz R.J.
      Drugs of abuse and heart failure.
      These mechanisms can exacerbate CAD but also are an independent risk factor for developing heart failure.
      • Watson M.
      • Dardari Z.
      • Kianoush S.
      • et al.
      Relation between cigarette smoking and heart failure (from the Multiethnic Study of Atherosclerosis).
      ,
      • Gopal D.M.
      • Kalogeropoulos A.P.
      • Georgiopoulou V.V.
      • et al.
      Cigarette smoking exposure and heart failure risk in older adults: the Health, Aging, and Body Composition Study.
      Tobacco-smoking has shown mitochondrial oxidative stress, contributing to endothelial dysfunction causing an association with hypertension.
      • Dikalov S.
      • Itani H.
      • Richmond B.
      • et al.
      Tobacco smoking induces cardiovascular mitochondrial oxidative stress, promotes endothelial dysfunction, and enhances hypertension.
      ,
      • Leone A.
      Does smoking act as a friend or enemy of blood pressure? Let release Pandora’s Box.
      Smoking is also associated with a reasonably increased prevalence of type 2 diabetes (RR, 1.37) in observational studies,
      • Pan A.
      • Wang Y.
      • Talaei M.
      • Hu F.B.
      • Wu T.
      Relation of active, passive, and quitting smoking with incident type 2 diabetes: a systematic review and meta-analysis.
      likely driven by associated changes in body composition and insulin sensitivity.
      • Maddatu J.
      • Anderson-Baucum E.
      • Evans-Molina C.
      Smoking and the risk of type 2 diabetes.
      Tobacco also elicits the generation of free radicals that likely cause damage to the myocardium.
      • Kelesidis T.
      • Zhang Y.
      • Tran E.
      • Sosa G.
      • Middlekauff H.R.
      Increased expression of proatherogenic proteins in immune cell subtypes in tobacco cigarette smokers but not in electronic cigarette vapers.
      Inflammatory markers are increased in association with tobacco smoking, specifically C-reactive protein, white blood cell count, and fibrinogen.
      • Bakhru A.
      • Erlinger T.P.
      Smoking cessation and cardiovascular disease risk factors: results from the Third National Health and Nutrition Examination Survey.
      Additionally smoking can contribute to the development of atrial fibrosis through toxic effects from nicotine.
      • Goette A.
      • Lendeckel U.
      • Kuchenbecker A.
      • et al.
      Cigarette smoking induces atrial fibrosis in humans via nicotine.
      Electronic cigarettes have a moderate cardiovascular risk compared with combustible tobacco products, which have the greatest risk.
      • Nayeri A.
      • Middlekauff H.
      Vaping instead of cigarette smoking: a panacea or just another form of cardiovascular risk?.
      ,
      • Kelesidis T.
      • Zhang Y.
      • Tran E.
      • Sosa G.
      • Middlekauff H.R.
      Increased expression of proatherogenic proteins in immune cell subtypes in tobacco cigarette smokers but not in electronic cigarette vapers.
      This is potentially secondary to the proatherogenic proteins found in tobacco cigarette smokers but not in electronic cigarette vapers.
      • Kelesidis T.
      • Zhang Y.
      • Tran E.
      • Sosa G.
      • Middlekauff H.R.
      Increased expression of proatherogenic proteins in immune cell subtypes in tobacco cigarette smokers but not in electronic cigarette vapers.

      Cardiovascular complications

      With the increase in cardiovascular risk factors and the direct effect on atherosclerosis, smoking is associated with an increase in CAD and dose-response relationship with the risk of ischemic stroke (Table 1).
      • Markidan J.
      • Cole J.W.
      • Cronin C.A.
      • et al.
      Smoking and risk of ischemic stroke in young men.
      ,
      • Kondo T.
      • Nakano Y.
      • Adachi S.
      • Murohara T.
      Effects of tobacco smoking on cardiovascular disease.
      Nicotine provides sympathetic stimulation increasing resting HR, BP, and cardiac output, all contributing to increased myocardial demand potentially worsening any CAD the patient might have, causing acute ischemic events (Fig. 2).
      • Linneberg A.
      • Jacobsen R.K.
      • Skaaby T.
      • et al.
      Effect of smoking on blood pressure and resting heart rate: a Mendelian randomization meta-analysis in the CARTA Consortium.
      ,
      • Narkiewicz K.
      • van de Borne P.J.
      • Hausberg M.
      • et al.
      Cigarette smoking increases sympathetic outflow in humans.
      Smokers have increased risk of chronic obstructive pulmonary disease, which is a risk factor for AF, however, smoking might contribute to an increased risk of AF through sympathetic stimulation from nicotine and atrial fibrosis (RR, 1.32).
      • Pirie K.
      • Peto R.
      • Reeves G.K.
      • Green J.
      • Beral V.
      The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK.
      ,
      • Aune D.
      • Schlesinger S.
      • Norat T.
      • Riboli E.
      Tobacco smoking and the risk of atrial fibrillation: a systematic review and meta-analysis of prospective studies.
      The mechanisms all contribute to an increased risk of heart failure despite adjusting for these risk factors.
      • Aune D.
      • Schlesinger S.
      • Norat T.
      • Riboli E.
      Tobacco smoking and the risk of heart failure: a systematic review and meta-analysis of prospective studies.
      This risk is likely attributed to damage to the myocardium at the cellular level through increased levels of inflammation in the body but studies at this time are limited.
      • Aune D.
      • Schlesinger S.
      • Norat T.
      • Riboli E.
      Tobacco smoking and the risk of heart failure: a systematic review and meta-analysis of prospective studies.

      Treatment

      Although there is no specific treatment for cardiac complications secondary to tobacco, the hallmark of treatment is smoking cessation (Table 2).
      • Aune D.
      • Schlesinger S.
      • Norat T.
      • Riboli E.
      Tobacco smoking and the risk of heart failure: a systematic review and meta-analysis of prospective studies.
      Smoking cessation intervention programs should be encouraged by all clinicians, which has been shown to reduce mortality.
      • Narkiewicz K.
      • van de Borne P.J.
      • Hausberg M.
      • et al.
      Cigarette smoking increases sympathetic outflow in humans.
      Nicotine replacement therapy is a viable option to use in patients with acute CVD presentations despite the increase in sympathetic activation, and can decrease acute withdrawal symptoms.
      • Narkiewicz K.
      • van de Borne P.J.
      • Hausberg M.
      • et al.
      Cigarette smoking increases sympathetic outflow in humans.
      Bupropion helps with outpatient smoking cessation but is not effective during an admission for an acute cardiovascular event because it requires long-term use.
      • Narkiewicz K.
      • van de Borne P.J.
      • Hausberg M.
      • et al.
      Cigarette smoking increases sympathetic outflow in humans.
      ,
      • Tonstad S.
      • Farsang C.
      • Klaene G.
      • et al.
      Bupropion SR for smoking cessation in smokers with cardiovascular disease: a multicentre, randomised study.
      Varenicline is another option that is also safe for patients with stable CVD but requires caution in patients with an acute cardiovascular event because of conflicting evidence.
      • Narkiewicz K.
      • van de Borne P.J.
      • Hausberg M.
      • et al.
      Cigarette smoking increases sympathetic outflow in humans.

      Heart Transplantation and Left Ventricular Assist Devices

      Consensus guidelines state that substance usage (including tobacco and alcohol) is an absolute contraindication to heart transplantation.
      • Mehra M.R.
      • Canter C.E.
      • Hannan M.M.
      • et al.
      The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update.
      ,
      • Chih S.
      • McDonald M.
      • Dipchand A.
      • et al.
      Canadian Cardiovascular Society/Canadian Cardiac Transplant Network position statement on heart transplantation: patient eligibility, selection, and post-transplantation care.
      There are no guidelines for duration of substance cessation before transplantation, however, the general consensus is that tobacco smoking should not be used for more than 6 months before transplantation, which seems reasonable to apply this timeline to other substances as well.
      • Mehra M.R.
      • Canter C.E.
      • Hannan M.M.
      • et al.
      The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update.
      ,
      • Chih S.
      • McDonald M.
      • Dipchand A.
      • et al.
      Canadian Cardiovascular Society/Canadian Cardiac Transplant Network position statement on heart transplantation: patient eligibility, selection, and post-transplantation care.
      Under appropriate circumstances, left ventricular assist devices have been shown to be successful in bridging for improvement of patients with severe dilated cardiomyopathy after chronic methamphetamine usage.
      • Soucy-Giguère M.C.
      • Cinq-Mars A.
      • Charbonneau É.
      • et al.
      Usefulness of left ventricular assist device in the recovery of severe amphetamine-associated dilated cardiomyopathy.
      Left ventricular assist devices are something that can be considered when recovery is expected or as a bridge to transplantation. Local guidelines should be referenced before making these important decisions.

      Conclusion

      PDAA, alcohol, AAS, cannabis, and tobacco are frequently used recreational and legal substances that contribute to CVD. These substances all contribute to the development of cardiomyopathies, heart failure, and arrhythmias through independent mechanisms and have numerous other cardiac complications. It is important for clinicians to approach cessation with their patients, and to be aware of these cardiac complications. Although no screening guidelines exist, if the clinician is aware of these complications and their symptoms, treatment can be provided earlier. With time there will be more information regarding these substances and their complications, and further research is still needed on other illicit drugs such as opioids. There is a growing need for a nationwide education campaign on the potential long-term damage being done to the CVS in patients with substance use disorders. Further studies are needed to develop screening guidelines and specific treatment guidelines for cardiovascular complications secondary to drugs of abuse.

      Funding Sources

      G.Y.O is supported by the Heart and Stroke Foundation of Canada , Alberta Innovates–Health Solutions, Canadian Institutes of Health Research , and the Canada Research Chairs program .

      Disclosures

      The authors have no conflicts of interest to disclose.

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