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Pulmonary hypertension (PH) represents a group of disorders characterized by elevated mean pulmonary artery (PA) pressure, progressive right ventricular failure, and often death. Some of the hallmarks of pulmonary hypertension include endothelial dysfunction, intimal and medial proliferation, vasoconstriction, inflammatory infiltration, and in situ thrombosis. The vascular remodeling seen in pulmonary hypertension has been previously linked to the hyperproliferation of PA smooth muscle cells. This excess proliferation of PA smooth muscle cells has recently been associated with changes in metabolism and mitochondrial biology, including changes in glycolysis, redox homeostasis, and mitochondrial quality control. In this review, we summarize the molecular mechanisms that have been reported to contribute to mitochondrial dysfunction, metabolic changes, and redox biology in PH.

There are limited data nationwide on the burden of systemic sclerosis (SSc)-related mortality. We aimed to determine recent trends in SSc and SSc-related pulmonary arterial hypertension (PAH) mortality overall and across population subgroups.Using death certificate data from the National Center for Health Statistics, we computed the age-adjusted mortality rates of SSc and SSc-SSc−PAH, a lethal prevailing complication, across demographic groups, geographic regions and comorbid cardiorespiratory conditions, and used Joinpoint regression analysis to calculate the average annual percentage change (APC) in mortality.From 2003 to 2016, 25 175 death records contained a code for SSc. Decedents were predominantly female (81%) and white (73%), with an average age of 66±14 years. The age-adjusted mortality rate decreased by 3% per year from 6.6 in 2003 to 4.3 per 1 000 000 population in 2016. Also, a decreasing trend was found when SSc was stratified by age, sex, race and geographic region. The prevalence of PAH was 23%. The odds of PAH were highest in female and black decedents, and in decedents with concomitant pulmonary embolism, cardiomyopathy and interstitial lung disease (ILD). SSc−PAH mortality remained stable from 2003 to 2008 then decreased by 3% per year from 2008 to 2016. In decedents with SSc−PAH, among all concomitant comorbidities, the mortality rate associated with ILD had the highest increase (average APC 6%, 95% CI 2%−10%).The mortality rate from SSc decreased from 2003 to 2016. Decreases in mortality rates were similar across demographic groups and geographic regions. SSc−PAH-related mortality remained stable. The death rate for SSc−ILD and concomitant PAH increased during this period.

Introduction: Given the poor treatment options for pulmonary arterial hypertension–associated systemic sclerosis patients, we sought to determine clinical safety and efficacy of dimethyl fumarate, an Nrf2 agonist, and the effects on biomarkers of oxidative stress on pulmonary arterial hypertension–associated systemic sclerosis in an exploratory interventional clinical trial. Objectives: The primary objectives were to assess the safety and efficacy of treatment with dimethyl fumarate in patients with pulmonary arterial hypertension–associated systemic sclerosis. Methods: This was an investigator-initiated, double-blind, randomized, placebo-controlled trial conducted at two sites in the United States. The primary safety endpoint was the incidence of serious adverse events and all adverse events in dimethyl fumarate compared to placebo-treated patients. The primary efficacy endpoint was the change in 6-min walk distance from baseline to the end of treatment at Week 24 in dimethyl fumarate compared to placebo-treated patients. Results: Six participants were randomized to either placebo (n = 2) or dimethyl fumarate (n = 4). Baseline demographics were similar in both groups. A total of 25 adverse events occurred in 6 subjects, with 14 adverse events (56.0%) having occurred in dimethyl fumarate-treated subjects. Three occurrences were identified as nausea adverse events, and two participants withdrew due to nausea. One participant in the placebo group was withdrawn after a hospitalization serious adverse event due to worsening of heart failure and shortness of breath secondary to anemia. One participant in each group completed protocol. Subjects in the dimethyl fumarate-treated group showed a non-significant reduced decline in 6-min walk distance (relative mean change of −7.07%) from baseline to Week 24 as compared to placebo-treated subjects (relative mean change of −14.97%). Conclusion: Patients treated for pulmonary arterial hypertension–associated systemic sclerosis with 2- and 3-drug regimens, as is now typical for these patients, tolerate dimethyl fumarate poorly. Our small sample size did not provide power to suggest efficacy. We suggest that Nrf2 is still a valid therapeutic target for future trials, using better tolerated Nrf2 agonists.