Pathways Case Records: Methamphetamine-Induced Pulmonary Arterial Hypertension

A 44-year-old man with a history of obesity as well as long-standing methamphetamine and tobacco use presented with several months of progressive dyspnea on exertion, weight gain and lower extremity edema. He reported daily inhaled methamphetamine and tobacco use since the age of 26. Family history was notable for lung cancer in his father, likely secondary to tobacco use, but no other pulmonary, cardiac or autoimmune disease. Upon admission, he was found to be volume overloaded with decreased ambulatory oxygen saturations. Transthoracic echocardiogram showed evidence of right ventricular failure and right heart catheterization confirmed pre-capillary pulmonary hypertension. Since evaluation for other causes of pulmonary arterial hypertension (PAH) was unrevealing, it was thought that his pulmonary arterial hypertension was induced by methamphetamine use.

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The Pathways Consult Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on the three key questions:

1. What is the pathophysiology of methamphetamine-induced PAH?
2. What makes this patient more susceptible to methamphetamine-induced PAH?
3. What are the possible treatment options?

Background and Diagnosis

PAH is a rare disease with roughly 500-1,000 new cases diagnosed each year in the U.S. Familial PAH, commonly associated with mutations in bone morphogenic protein receptor 2 (BMPR2), exhibits incomplete penetrance; 43% of women and 14% of men with an inherited BMPR2 mutation will develop features of PAH. Other risk factors contributing to PAH include recreational drug use (e.g., methamphetamine), connective tissue disorders, infections and congenital heart abnormalities (Chest). In the U.S., methamphetamine is used by approximately 1.2 million individuals annually.

Mutations in BMPR2 are responsible for ~70% of inherited PAH cases and are found in 15% of idiopathic PAH in the absence of family history (Lancet Respir Med). Recent studies have implicated other components in the BMPR2 signaling pathway in the pathogenesis of PAH, including the ALK1 receptor and downstream SMAD proteins. Pathogenic mutations in this pathway result in aberrant gene expression in endothelial cells resulting in hyperproliferation and inhibition of apoptosis in adjacent tissue, with subsequent fibrosis and vascular remodeling (Pulm Circ). It is possible that our patient is a carrier for a BMPR2 mutation. Clinical studies on the development of PAH in methamphetamine users suggest approximately 10% of these users carry BMPR2 mutations, suggesting potential interactions between methamphetamine use and predisposing genetic factors (Curr Opin Pulm Med).

In addition to genetic contributions, methamphetamine-induced PAH has been linked to changes in pathways downstream of serotonin signaling. Serotonin signaling has been linked to methamphetamine-induced PAH. Methamphetamine increases the release of serotonin as well as the expression of the serotonin receptor 5HT1B found in pulmonary endothelial and smooth muscle cells. It is thought that serotonin induces pulmonary arterial smooth muscle cell contractions and proliferation via reactive oxygen species and the expression of nuclear growth factors (Pulm Circ). While it is possible that the development of PAH in the patient was triggered by a BMPR2 mutation, methamphetamine-mediated changes to serotonin signaling may have exacerbated disease manifestation and progression. Indeed, serotonin elevated susceptibility to PAH in BMPR2-deficient mice through increased right ventricular systolic pressure and pulmonary arteriole remodeling (Circ Res). The role of serotonin in PAH raises the question of the effect of commonly-used SSRIs on this pathway. However, studies of SSRI implication on PAH are conflicting—with some suggesting increased risk of PAH and others demonstrating a protective effect (Am J Physiol Lung Cell Mol Physiol).

This patient, who was unable to tolerate vasoreactivity testing, would likely benefit from continuous intravenous epoprostenol combined with an endothelin receptor antagonist and an agent targeting the nitric-oxide-cGMP pathway (e.g., phosphodiesterase-5 inhibitor) (Gen Thorac Cardiovasc Surg). These therapies target vasoconstriction and proliferation observed in PAH. Understanding the underlying pathology contributing to disease in the patient would provide insight into actionable targets for treatment. With or without a loss-of-function mutation in BMPR2, this patient may benefit from investigational therapies aimed at enhancing signaling via this pathway (e.g., tacrolimus or estrogen receptor antagonists which are being pursued in clinical trials). Perhaps more promising strategies include direct agonists of the BMPR2 pathway by BMP9 analogs. Antagonism of the TGF-β pathway using ligand traps (e.g., Sotatercept) can restore the relative balance between TFG-β and BMPR2 signaling (Nat Rev Cardiol). This can potentially prevent and reverse disease phenotypes when combined with standard of care therapies.

Summary and Future Steps

The underlying mechanisms contributing to the development of PAH in methamphetamine user is not well understood. We propose that our patient developed PAH by a two-hit mechanism—the development of PAH phenotype due to an underlying genetic susceptibility was exacerbated by chronic methamphetamine use. Genetic factors coupled with changes in hormone signaling pathways have been associated with methamphetamine-induced PAH. Whole-exome sequencing may provide a window into genetic susceptibility to PAH in this patient. Experimental models would be useful to determine the contribution of chronic methamphetamine use to the development of PAH in genetically susceptible individuals. This approach would enable a greater understanding of the development of PAG through examination of lung specimens, vasculature and measurements of potential "second hit" mediators such as serotonin. Further investigations of treatments strategies, including BMPR2 agonists and/or serotonin modulators, may be beneficial to this patient in the future.

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