Desai, Ankit A.

Background&Hypothesis: Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme, essential for a variety of cellular processes. Pulmonary arterial hypertension (PAH) is associated with impaired metabolism and reduced NAD levels that contribute to its hyperproliferative state. CD38 is an ecto-enzyme that degrades NAD and produces several byproducts including cyclic ADPR. We hypothesized that CD38 mediates pathological reductions in NAD levels contributing to PAH vascular remodeling. Methods: To test this hypothesis, we evaluated expression levels of CD38 across PAH tissues, tested its functional role in human pulmonary artery endothelial cells (PAEC) and smooth muscle cells (PASMCs), and examined the response of a global CD38 knockout mouse ( CD38 -/- ) in an established chronic hypoxic (10% FiO2, 4 weeks) model of pulmonary hypertension. Results: CD38 expression was elevated in human PAECs derived from PAH cases and in rodent whole lung homogenates. Media from PAEC exposed to a CD38 inhibitor (78c) led to reduced PASMC proliferation. CD38 -/- mice exposed to chronic hypoxia exhibited attenuated PH compared to cage controls. Specifically, histological assessment of murine lungs revealed reduced PA medial thickness compared to control. CD38 -/- mice exhibited reduced right ventricular systolic pressure and a corresponding decrease in Fulton Index after hypoxic exposure. Consistent with these results, targeted metabolite measurements revealed that CD38 -/- mice exhibited elevated NAD levels in the lungs. Discussion: These results suggest that CD38 is a novel PAH target, and its deficiency restores NAD levels in the lungs and reduces pulmonary hypertension in mice.

AbstractThe prevalence of acute vasodilator response (AVR) to inhaled nitric oxide (iNO) during right heart catheterization (RHC) is 12% in idiopathic pulmonary arterial hypertension (IPAH). AVR, however, is reportedly lower in other disease‐associated pulmonary arterial hypertension (PAH), such as connective tissue disease (CTD). The prevalence of AVR in patients on PAH therapy (prevalent cases) is unknown. We sought to determine AVR prevalence in Group 1 PH in the PVDOMICS cohort of incident and prevalent patients undergoing RHC. AVR was measured in response to 100% O2 and O2 plus iNO, with positivity defined as (1) decrease in mean pulmonary artery pressure (mPAP) by ≥10 mmHg to a value ≤40 mmHg, with no change or an increase in cardiac output (definition 1); or (2) decrease in mPAP by ≥12% and pulmonary vascular resistance by ≥30% (definition 2). AVR rates and cumulative survival were compared between incident and prevalent patients. In 338 mainly prevalent (86%) patients, positive AVR to O2‐only was <2%, and 5.1% to 16.9%, based on definition 1 and 2 criteria, respectively; following O2 + iNO. IPAH AVR prevalence (4.1%–18.7%) was similar to prior reports. AVR positivity was 7.7% to 15.4% in mostly CTD‐PAH prevalent cases, and 2.6% to 11.8% in other PAH groups. Survival was 89% in AVR responders versus 77% in nonresponders from PAH diagnosis, and 91% versus 86% from PVDOMICS enrollment (log‐rank test p = 0.04 and p = 0.05, respectively). In conclusion, AVR in IPAH patients is similar to prior studies. AVR in non‐IPAH patients was higher than previously reported. The relationship between PAH therapy, AVR response, and survival warrants further investigation.