Katharine Clapham, MD - phaware® interview 416

May 23, 2023

Katharine Clapham, MD is an Assistant Professor in the Division of Cardiovascular Medicine at University of Utah Health. @UofUHealth

Dr. Clapham discusses methamphetamine-associated pulmonary arterial hypertension.

I am Katie Clapham. I'm an assistant professor of cardiology at the University of Utah. I'm a cardiologist that has done additional training in pulmonary hypertension, and I see patients together with pulmonologists in our group here at the University of Utah.

Today, I want to talk about methamphetamine-associated pulmonary arterial hypertension, which is a type of pulmonary hypertension that the medical community has grown increasingly aware of and for which there are some new emerging treatments.

As many of you know, pulmonary hypertension can have multiple different causes. We think about it in terms of the WHO groups as causes for pulmonary hypertension, but within Group I, pulmonary arterial hypertension, methamphetamine use is becoming an increasingly recognized cause of pulmonary arterial hypertension.

Some of the work that's demonstrated that has come out of Dr. Roham Zamanian's group at Stanford University. Our group at the University of Utah recently published a paper looking at the causes of pulmonary arterial hypertension that we see. It turns out that about one-third of our patients with associated pulmonary arterial hypertension have toxin-induced pulmonary arterial hypertension. In the majority of those patients, the toxin is methamphetamine use.

Patients will present to us a variety of ways. Some individuals have been hospitalized and found to have pulmonary hypertension when they're in the hospital. Some individuals are referred to us by providers in states like Utah, Wyoming, Nevada. Some individuals, they come to us for shortness of breath, and then we find that they have pulmonary hypertension. Then in our evaluation of the causes of pulmonary hypertension, we identify methamphetamine as the provoking cause.

I did most of my training on the East Coast in Boston, and methamphetamine use isn't as common there or at least not as commonly recognized a problem there. Methamphetamine use is more common in the Western United States and Midwest, although more recent research that we saw presented, for example, at the Drug-induced Pulmonary Hypertension Symposium at Stanford, showed that it is more prevalent in the East Coast than maybe people screen for or are aware of.

So moving out here to Utah, when I took this job at University of Utah, it was eye-opening for me to realize how common methamphetamine use is in this part of the United States and how common a cause of pulmonary hypertension in the patients that we see it is.

People are still late to be identified with pulmonary hypertension in the course of the disease, and we'd like to find people earlier. I think that is part of why it's important to raise awareness about the disease so both providers and patients know that this is a possibility.

The way that the majority of our patients get identified as potentially having pulmonary hypertension is after they have an echocardiogram performed, which is an ultrasound of the heart. The echocardiogram may indicate some signs of pulmonary hypertension, like right ventricular enlargement, right ventricular dysfunction, or we can estimate the pulmonary artery pressures from the echocardiogram. If those are very elevated, that raises suspicion for pulmonary hypertension. That often prompts a referral to our group.

The mechanism by which methamphetamine use causes pulmonary arterial hypertension is not that well understood. But we know that methamphetamine is pretty chemically similar to the anorexigens. I'm talking about Aminorex, the drug that was used for weight loss that was later found to cause pulmonary arterial hypertension. So methamphetamine looks chemically similar to that.

There have been some studies in the lab that show that methamphetamine can cause the formation of reactive oxygen species, which can damage the vasculature. It causes release of substances like dopamine, norepinephrine, and serotonin. Animal studies in mice, for example, show amphetamine exposure results in suppression of this factor called HIF-1-alpha, which in turn disrupts the response to mitochondrial oxidative stress. This leads to DNA damage and that leads to injury of the vasculature.

I don't think there's good data about whether people can reverse PAH with stopping methamphetamine use, but I would say anecdotally talking to physicians who take care of these patients and in our experience, we do see people with significant improvement in their pulmonary arterial hypertension and right ventricular function after stopping the drug. I think that's an area that needs more investigation. But we do know that these people also respond to pulmonary vasodilators just like other patients with different forms of PAH do. So I think it's really important that people who have methamphetamine PAH get into our care so that we can work with them, both to help them stop the use of methamphetamine as well as to treat the pulmonary arterial hypertension.

I think there is a lot of stigma around substance use disorders, but we've learned that substance use disorders affect people from all walks of life, both genders, many ages, different socioeconomic strata. That's why it's so important to include asking about methamphetamine use or screening for its use in a comprehensive evaluation of the patients that we see. I think because of that stigma that is associated with substance use, it's really important to communicate that we as the medical team are really on the side of the patient and want what's best for them and to help them. Not everyone is ready to stop using substances, but if they are, we really want to give our best effort to help them to achieve that goal. We've been working closely with our addiction medicine colleagues to figure out how to best support our patients. We have a lot of really wonderful resources available to us for people that are interested in them.

There is data, for example, from Dr. Roham Zamanian's paper published in 2018 that patients who have methamphetamine-associated pulmonary arterial hypertension are less frequently treated with parenteral therapies. That comes partly out of concern that having an indwelling line, for example, while engaging in drug use may present more of a risk for infection or harm. That does definitely impact the way our patients are treated. It's a tough problem because sometimes parenteral therapy might be the best therapy for our patients who have meth-associated pulmonary arterial hypertension, but because of the safety concerns, it isn't always possible to treat people with the therapies we would most like to.

We're working on trying to understand the disease better. There's a lot of variables at play here in terms of how much methamphetamine use can lead to pulmonary arterial hypertension. There's variation in the composition of methamphetamine that people use because it's a street drug and not regulated by any governmental agency. We don't always know what's in methamphetamine, and sometimes it contains dangerous substances like fentanyl, for example, and that also presents a challenge.

There are efforts to understand more about methamphetamine-associated PAH, including an NIH-sponsored registry called Expose PAH that we're participating in along with Stanford and other universities across the country, so hopefully that will be helpful in understanding more.

We also know, for example, through Dr. Vinicio de Jesus Perez’s work that some people may be more predisposed to develop methamphetamine-induced PAH. They may have mutations in their DNA that put them at higher risk of developing this problem so we're trying to understand that more. I think there's ongoing work too to understand the best way to support patients with methamphetamine substance use disorders. There's some literature about using VIVITROL for methamphetamine use disorder, or there's a behavioral intervention called contingency management that's had some success. Also, it might be that we may be able to use prescription stimulants to treat methamphetamine use disorders. That is also an area of ongoing investigation and learning. Then not only learning what interventions are most effective, but how to best integrate them into our PH practice is also an area that we're working on.

I think it's important both for patients and providers to know that this is an issue and it's probably more of an issue than we even realize. I want people to know that there's treatment out there for substance use disorders, and I want them to know there's treatment for methamphetamine-related PAH. While we're still learning, there are things we can do right now to help people.

My name is Katie Clapham, and I'm aware that my patients are rare.

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