A Double Hit: Pulmonary Arterial Hypertension, Bmpr2 Mutation, and Exposure to Prescription Amphetamines

Abstract

HUZAIFA JALIAWALA KATHERINE SUMMERS AND ROBERTO BERNARDOINTRODUCTION: Pulmonary arterial hypertension (PAH) management during pregnancy is challenging. We present a case of PAH diagnosed during 3rd trimester of pregnancy, in a patient with familial history of PAH and exposure to prescriptionamphetamines.CASE PRESENTATION: 30-year-old primigravid female at 30 weeks of gestation was referred to our Pulmonary Hypertension program for evaluation of rapidly progressive dyspnea, lightheadedness and echocardiogram revealing increased pulmonary pressures. She had a history of Attention-deficit/hyperactivity disorder, treated with dextroamphetamine/amphetamine (AdderallÒ) and lisdexamfetamine (VyvanseÒ) for several years. Her mother had died of pulmonary hypertension at the age of 30. She had functional class III symptoms. An echo showed an estimated right ventricular systolic pressure of 69mm Hg, with right ventricular dilation and dysfunction, as well as interventricular septal flattening. A right heart catheterization (RHC) showed a mPAP of 34 mmHg, PAWP 10 mmHg, cardiac output 3.96 L/min, cardiac index of 2.08 L/min/m2 and PVR of 6.1 WU. She was admitted for expedited work-up and treatment of pulmonary hypertension. Investigational studies were negative for alternative etiologies of pulmonary hypertension, there was no evidence of chronic thromboembolic disease. She was started on a rapid titration with intravenous treprostinil. Once at a dose of 40 ng/kg/min, a repeated RHC showed mPAP of 28 mmHg, PAWP 6 mmHg, cardiac output 5.8 L/min, cardiac index of 3.1 L/min/m2 and PVR of 5.1 WU. A multidisciplinary discussion with highrisk OB, cardiac anesthesia, neonatology and our Pulmonary Hypertension program recommended for C-section under epidural anesthesia with VA-ECMO on stand-by, which was performed at 32 weeks of gestation. Her post-op course was uneventful and she was discharged home on triple therapy with sildenafil, ambrisentan and intravenous treprostinil. She was found to have the BMPR2 mutation. At follow-up, she is functional class II, six-minute walk distance is 530 meters and BNP values are 17 ?g/mL.DISCUSSION: Studies report 75% prevalence of BMPR2 mutations in cases of hereditary PAH, with an autosomal dominant mode of inheritance and incomplete penetrance. It is hypothesized that a "two-hit" phenomenon with environmental influencers like drugs, toxins or infection known to cause pulmonary hypertension may have a role in providing the "second hit" leading to development of the disease. We wonder if the exposure to prescription-amphetamines could have been a second hit, on top of her genetic background. PAH in pregnant females poses a very high risk of maternal and fetal mortality. Aggressive counseling focusing of avoiding pregnancy and early termination should be instituted in all patients. In cases where pregnancy is continued, care at centers with expertise in pulmonary hypertension and ECMO/transplant capability is recommended.

Genetic counselling and testing in pulmonary arterial hypertension: a consensus statement on behalf of the International Consortium for Genetic Studies in PAH

“…If a genetic test identified a familial variant, pre-implantation diagnostics may be discussed. While pregnancy itself is to be avoided in female PAH patients [2] it is being debated as a trigger for disease onset in asymptomatic variant carriers [84,85]. Because there is no proven way to prevent or cure PAH, genetic counselling is important to explore whether the individual is psychologically prepared to determine his/her genetic status and availability of emotional support.…”