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Nashville, TN
Drs. Willers and Newman are affiliated with the Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine.
Correspondence to: Elisabeth D. Willers, MD, VUMC T1218 Medical Center North, Nashville, TN 37232-2650; e-mail: elisabeth.willers{at}vanderbilt.edu
The current classification divides pulmonary arterial hypertension (PAH) into disease without an identifiable cause (idiopathic PAH [IPAH]) and that with a known cause, such as porto-pulmonary hypertension (PH), HIV-related PH, collagen vascular diseases, congenital systemic-to-pulmonary shunts, persistent PH of the newborn, and drug-related PH.1 Drugs considered to have a definite link to PAH are aminorex, fenfluramine, and dexfenfluramine.1 Stimulant use has been associated with vascular damage ranging from intracerebral hemorrhage2 to retinal vasculitis.3 Amphetamines are classified as "very likely" risk factors for PAH, while methamphetamine and cocaine are classified as "possible" risk factors.1 Given the continued use of stimulants as over-the-counter diet aids,4 the high prevalence of illicit drug use,4 and the increasing prevalence of attention deficit hyperactivity disorder, which is treated with methylphenidate,5 there is a need to firmly establish which drugs within this heterogeneous group of stimulants are true risks for PAH.
In this issue of CHEST (see page 1657), Chin and colleagues6 describe the prevalence of amphetamine, methamphetamine, and cocaine use in IPAH patients, and compare this group with secondary PAH patients and those with chronic thromboembolic disease. About half of the stimulant users had extensive exposures lasting > 6 months to years. Data were obtained by retrospective chart review. After adjustment for confounders, the age-adjusted odds ratios for a history of prior stimulant use was 10.14 in IPAH patients compared to PAH patients with known risk factors, and 7.63 compared to patients with chronic thromboemobolic disease. Although this was a retrospective review, with inherent problems such as recall bias and incomplete medical records, the study found an undeniably strong association between amphetamine use and the development of PAH.
The pathogenic link between stimulant use and pulmonary vascular disease is not yet known, but many theories exist. Proposed mechanisms include toxic endothelial injury, hypoxic insult, direct spasm, vasculitis, and dysregulation of the mediators of vascular tone.7 One plausible link could be via serotonin (5-hydroxytryptophan [5-HT]).89 5-HT is a potent pulmonary vasoconstrictor via the 5-HT receptor and a pulmonary artery smooth muscle cell mitogen via the serotonin reuptake transporter (SERT).1011 Appetite suppressants such as fenfluramine act as a substrate for the SERT12 and inhibit 5-HT clearance by inhibiting monoamine oxidase, causing an accumulation of 5-HT.13 Several amphetamine analogs have been found to elevate 5-HT plasma levels both in vitro and in vivo.14 Methylenedioxymethamphetamine (MDMA; also called ecstasy) is associated with elevated plasma levels of 5-HT,14 and neuroimaging studies in MDMA users have shown reductions in SERT densities, which is a marker of 5-HT neurotoxicity.15 Considering the complex function of 5-HT in the CNS16 and the evidence for the role of serotonin in mediating pulmonary vascular tone, one can imagine a possible link between a brain disorder and pulmonary vascular disease via this neurotransmitter. It is also possible that functional genetic polymorphisms in the 5-HT receptors or SERT may play a role in disease protection or susceptibility in amphetamine users.
The marked association of PAH with amphetamine use in this preliminary study should be a strong stimulus for further investigation. This study should be replicated in other PH centers with access to large numbers of patients, which could control for local variables and chance association. In addition, the identification of which stimulants in particular are the biggest offenders and which route of delivery (ie, oral, inhaled, or IV) is most pathogenic should be addressed. The discovery of any protective role of selective serotonin reuptake inhibitors in amphetamine users would be of great interest.
This study raises the issue of how little we know about environmental and biological risks associated with PAH. Unfortunately, in rare diseases such as IPAH, many of these questions cannot be adequately addressed because of small sample sizes. To overcome this problem, a large epidemiologic study must be done. This project should involve multicenter collaboration and should necessitate the compilation of a comprehensive database. Although this would be a large undertaking, it would allow investigators to more definitively identify risk factors for disease such as amphetamine use, obesity, thyroid disease, selective serotonin reuptake inhibitor use, oral contraceptive pill use, pregnancy, tobacco use, and other possible culprits. Obtaining thorough patient histories and keeping comprehensive medical records would be especially vital. Once these risk factors are more clearly identified, we can begin to focus on disease prevention rather than palliative care for patients with this deadly disease.
Footnotes
The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
References
This article has been cited by other articles:
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  R. B. Rothman and M. H. Baumann Methamphetamine and Idiopathic Pulmonary Arterial Hypertension: Role of the Serotonin Transporter Chest, October 1, 2007; 132(4): 1412 - 1413. [Full Text] [PDF]
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