Methamphetamines are highly addictive drugs that stimulate release of catecholamines, resulting in a variety of stimulant effects including increased focus and energy, anorexia, and euphoria.¹ Recreational use of methamphetamines is rising globally and is associated with significant morbidity and mortality due to cardiovascular disease, in particular dilated cardiomyopathy and PAH.

Methamphetamine-Associated Cardiomyopathy

Methamphetamine-associated cardiomyopathy is thought to be due to heightened sympathetic activation resulting in hypertension, tachycardia, and vasoconstriction/vasospasm leading to increased myocardial wall stress or ischemia.² Methamphetamines can also induce direct myocardial cell toxicity.² These combined factors lead to myocardial contractile dysfunction, chronic inflammation, and ultimately loss of myocytes due to replacement fibrosis resulting in dilated cardiomyopathy.² Typical echocardiographic features include a dilated cardiomyopathy with severely reduced left ventricular (LV) systolic function and enlarged atrial and biventricular chambers.² Patients with methamphetamine-associated cardiomyopathy are more prone to development of intracardiac thrombi, which is found in up to 33% of patients.³ Methamphetamine users have more severe dilated cardiomyopathy, biventricular enlargement, and a severely reduced LV systolic function compared to non-users with dilated cardiomyopathy.³ The diagnostic evaluation includes a history of methamphetamine use or positive urine toxicology screen, but other etiologies of heart failure need to be excluded. A contrast-enhanced echocardiogram or cardiac magnetic resonance imaging should be considered to screen for intracardiac thrombi due to the high prevalence in this patient population.²

An important feature of methamphetamine-associated cardiomyopathy is the potential for significant recovery of cardiac function with cessation of methamphetamine use.³ A registry study from Germany in 2017 found that discontinuation of methamphetamine use was associated with improvement in heart failure symptoms and cardiac function, but continued use led to persistently reduced systolic function, hospitalizations for heart failure, and increased risk of death.³

Treatment of methamphetamine-associated cardiomyopathy is with guideline-directed medical therapy for reduced ejection fraction. Consideration of a primary prevention implantable cardioverter-defibrillator should follow the guidelines for heart failure with reduced ejection fraction. A recent study found that only 14% of patients with methamphetamine-associated cardiomyopathy with reduced ejection fraction received an implantable cardioverter-defibrillator for primary prevention of sudden cardiac death.⁴ Because studies have provided objective evidence that cardiac function can improve after drug cessation, LV function should be re-assessed after abstinence.^2-4 Clinical focus should also be on patient rehabilitation for complete cessation of methamphetamine use.

Methamphetamine-Associated PAH

The definition of pulmonary arterial hypertension was updated in 2019; it is defined as an elevated pulmonary vascular resistance ≥3 Wood units with mean pulmonary artery pressure >20 mmHg and pulmonary artery wedge pressure ≤15 mmHg.⁵

PAH is classified based on similar pathophysiologic mechanisms and clinical presentations. In the current WHO classification, PAH is defined in Group I as idiopathic, heritable, or associated with a multitude of conditions including connective tissue diseases, human immunodeficiency virus infection, and portal hypertension. Due to phenotypic similarities with idiopathic PAH, drug-and-toxin-induced PAH is included in WHO Group I.⁵ The drug-and-toxin-induced PAH category is further subdivided into definite association and possible association. Drugs with a definite association with PAH are defined by data based on outbreaks, case control studies, or large multi-center trials, whereas those with a possible association are suggested by multiple case series with drugs of similar mechanism of action.⁵

Drug-induced PAH first came to light in the 1960s with an outbreak of PAH associated with an amphetamine-derived drug that was marketed for weight loss.⁶ There was a second outbreak in the 1990s, again associated with anorexic amphetamine derivatives (fenfluramine and phentermine).⁶ These drugs have since been removed from the market. Methamphetamines share a similar chemical structure to these agents and are now listed as definite associations with PAH.⁵ A study using positron emission tomography scans with use of radiolabeled methamphetamine demonstrated that lungs have the highest accumulation and most rapid uptake of methamphetamine compared to other organs.⁷ This could explain the pulmonary toxicity and vascular damage seen with methamphetamine use.⁷ An interesting feature of methamphetamine-associated PAH is that only a subset of users develop PAH, suggesting a possible genetic component.⁸ Recent studies have used genetic sequencing to identify a gene (carboxylesterase 1) that may play a role in the development of methamphetamine-associated PAH in genetically susceptible individuals.^4,11

Several cohort studies have looked at methamphetamine use and risk of PAH. In 2006, Chin et al. found that patients with idiopathic PAH were 10 times more likely to have a history of stimulant use than patients with PAH and known risk factors.⁹ In a prospective cohort study by Zamanian et al. in 2018, patients with methamphetamine-associated PAH had more severe pulmonary vascular disease, more dilated and dysfunctional right ventricles, and worse prognosis compared to idiopathic PAH.¹⁰ The researchers found that 85% of their patients with drug-and-toxin-induced PAH carried a diagnosis of methamphetamine use, and this inferred a much worse survival, with a median 5-year survival of 35%.⁹

A 2018 retrospective analysis in JACC: Heart Failure by Zhao characterized patients with methamphetamine-associated PAH and cardiomyopathy compared to methamphetamine users with structurally normal hearts.⁴ They found that patients with methamphetamine-associated cardiomyopathy and PAH had significantly higher morbidity and mortality compared to those methamphetamine users with structurally normal hearts.⁴ Predisposing factors for development of cardiomyopathy included history of alcohol abuse, male sex, and presence of hypertension, whereas female sex was associated with PAH.⁴ Management includes complete cessation of methamphetamine use and treatment regimens similar to other patients with WHO Group I PAH.

Methamphetamines are the second most commonly abused drugs worldwide, and it is imperative that medical providers be aware of the strong connection between methamphetamine use and development of PAH and dilated cardiomyopathy. Clinicians need to take a thorough drug history from patients and screen patients with toxicology tests to identify current or prior methamphetamine use. Because there is a chance to recover cardiac function and improve symptoms with early detection and cessation of methamphetamine use, the first step is identifying and stopping the offending agent.

References

1. Heal DJ, Smith SL, Gosden J, Nutt DJ. Amphetamine, past and present--a pharmacological and clinical perspective. J Psychopharmacol 2013;27:479-96.
2. Reddy PK, Ng TM, Oh EE, Moady G, Elkayam U. Clinical Characteristics and Management of Methamphetamine-Associated Cardiomyopathy: State-of-the-Art Review. J Am Heart Assoc 2020;9:e016704.
3. Schürer S, Klingel K, Sandri M, et al. Clinical Characteristics, Histopathological Features, and Clinical Outcome of Methamphetamine-Associated Cardiomyopathy. JACC Heart Fail 2017;5:435-45.
4. Zhao SX, Kwong C, Swaminathan A, Gohil A, Crawford MH. Clinical Characteristics and Outcome of Methamphetamine-Associated Pulmonary Arterial Hypertension and Dilated Cardiomyopathy. JACC Heart Fail 2018;6:209-18.
5. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension Eur Respir J 2019;53:1801913.
6. Montani D, Seferian A, Savale L, Simonneau G, Humbert M. Drug-induced pulmonary arterial hypertension: a recent outbreak. Eur Respir Rev 2013;22:244-50.
7. Volkow ND, Fowler JS, Wang GJ, et al. Distribution and pharmacokinetics of methamphetamine in the human body: clinical implications. PloS One 2010;5:e15269.
8. Ramirez RL 3rd, De Jesus Perez V, Zamanian RT. Methamphetamine and the risk of pulmonary arterial hypertension. Curr Opin Pulm Med 2018;24:416-24.
9. Chin KM, Channick RN, Rubin LJ. Is methamphetamine use associated with idiopathic pulmonary arterial hypertension? Chest 2006;130:1657-63.
10. Zamanian RT, Hedlin H, Greuenwald P, et al. Features and Outcomes of Methamphetamine-associated Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 2018;197:788-800.
11. De Jesus Perez V. Drug-Induced Pulmonary Hypertension: The First 50 Years. Adv Pulm Hypertens 2017;15:133-7.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Implantable Devices, SCD/Ventricular Arrhythmias, Pulmonary Hypertension, Hypertension

Keywords: Hypertension, Pulmonary, Methamphetamine, Cardiomyopathies, Amphetamine, Cardiomyopathy, Dilated, Retrospective Studies, Phentermine, Pulmonary Wedge Pressure, Defibrillators, Implantable, Fenfluramine, Cardiovascular Diseases, Catecholamines, Vasoconstriction, Anorexia, Euphoria, Alcoholism

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