Cutaneous iontophoresis of vasoactive medications in patients with scleroderma-associated pulmonary arterial hypertension.

BACKGROUND: It remains unknown whether the cutaneous microvascular responses are different between patients with scleroderma-associated pulmonary arterial hypertension (SSc-PAH) and SSc without pulmonary hypertension (PH). METHODS: We included 59 patients with SSc between March 2013 and September 2019. We divided patients into 4 groups: (a) no PH by right heart catheterization (RHC) (n = 8), (b) no PH by noninvasive screening tests (n = 16), (c) treatment naïve PAH (n = 16), and (d) PAH under treatment (n = 19). Microvascular studies using laser Doppler flowmetry (LDF) were done immediately after RHC or at the time of an outpatient clinic visit (group b). RESULTS: The median (IQR) age was 59 (54-68) years, and 90% were females. The responses to local thermal stimulation and postocclusive reactive hyperemia, acetylcholine, and sodium nitroprusside iontophoresis were similar among groups. The microvascular response to treprostinil was more pronounced in SSc patients without PH by screening tests (% change: 340 (214-781)) compared with SSc-PAH (naïve + treatment) (Perfusion Units (PU) % change: 153 (94-255) % [p = .01]). The response to A-350619 (a soluble guanylate cyclase (sGC) activator) was significantly higher in patients with SSc without PH by screening tests (PU % change: 168 (46-1,296)) than those with SSc-PAH (PU % change: 22 (15-57) % [p = .006]). The % change in PU with A350619 was directly associated with cardiac index and stroke volume index (R: 0.36, p = .03 and 0.39, p = .02, respectively). CONCLUSIONS: Patients with SSc-PAH have a lower cutaneous microvascular response to a prostacyclin analog treprostinil and the sGC activator A-350619 when compared with patients with SSc and no evidence of PH on screening tests, presumably due to a peripheral reduction in prostacyclin receptor expression and nitric oxide bioavailability.

A pilot study on the kinetics of metabolites and microvascular cutaneous effects of nitric oxide inhalation in healthy volunteers.

RATIONALE: Inhaled nitric oxide (NO) exerts a variety of effects through metabolites and these play an important role in regulation of hemodynamics in the body. A detailed investigation into the generation of these metabolites has been overlooked. OBJECTIVES: We investigated the kinetics of nitrite and S-nitrosothiol-hemoglobin (SNO-Hb) in plasma derived from inhaled NO subjects and how this modifies the cutaneous microvascular response. FINDINGS: We enrolled 15 healthy volunteers. Plasma nitrite levels at baseline and during NO inhalation (15 minutes at 40 ppm) were 102 (86-118) and 114 (87-129) nM, respectively. The nitrite peak occurred at 5 minutes of discontinuing NO (131 (104-170) nM). Plasma nitrate levels were not significantly different during the study. SNO-Hb molar ratio levels at baseline and during NO inhalation were 4.7E-3 (2.5E-3-5.8E-3) and 7.8E-3 (4.1E-3-13.0E-3), respectively. Levels of SNO-Hb continued to climb up to the last study time point (30 min: 10.6E-3 (5.3E-3-15.5E-3)). The response to acetylcholine iontophoresis both before and during NO inhalation was inversely associated with the SNO-Hb level (r: -0.57, p = 0.03, and r: -0.54, p = 0.04, respectively). CONCLUSIONS: Both nitrite and SNO-Hb increase during NO inhalation. Nitrite increases first, followed by a more sustained increase in Hb-SNO. Nitrite and Hb-SNO could be a mobile reservoir of NO with potential implications on the systemic microvasculature.

Gasometric gradients between blood obtained from the pulmonary artery wedge and pulmonary artery positions in pulmonary arterial hypertension.

INTRODUCTION: Little is known on the pulmonary gradients of oxyhemoglobin, carboxyhemoglobin and methemoglobin in pulmonary arterial hypertension (PAH). We sought to determine these gradients in group 1 PAH and assess their association with disease severity and survival. METHODS: During right heart catheterization (RHC) we obtained blood from pulmonary artery (PA) and pulmonary artery wedge (PAW) positions and used co-oximetry to test their gasometric differences. RESULTS: We included a total of 130 patients, 65 had group 1 PAH, 40 had pulmonary hypertension (PH) from groups 2-5 and 25 had no PH during RHC. In all groups, PAW blood had higher pH, carboxyhemoglobin and lactate as well as lower pCO2 than PA blood. In group 1 PAH (age 58 ± 15 years, 72% females), methemoglobin in the PAW was lower than in the PA blood (0.83% ± 0.43 vs 0.95% ± 0.50, p = 0.03) and was directly associated with the degree of change in pulmonary vascular resistance (R = 0.35, p = 0.02) during inhaled nitric oxide test. Oxyhemoglobin in PA (HR (95%CI): 0.90 (0.82-0.99), p = 0.04) and PAW (HR (95%CI): 0.91 (0.84-0.98), p = 0.003) blood was associated with adjusted survival in PAH. CONCLUSIONS: Marked differences were observed in the gasometric determinations between PAW and PA blood. The pulmonary gradient of methemoglobin was lower in PAH patients compared to controls and a higher PAW blood methemoglobin was associated with a more pronounced pulmonary vascular response to inhaled nitric oxide. Pulmonary artery and PAW oxyhemoglobin tracked with disease severity and survival in PAH.

Non-invasive screening for pulmonary hypertension in idiopathic pulmonary fibrosis.

BACKGROUND: Pulmonary hypertension (PH) is a common complication of idiopathic pulmonary fibrosis (IPF) that is associated with poor prognosis. Noninvasive screening for PH in IPF patients is challenging and a combination of several noninvasive determinations can improve discrimination. METHODS: We included 235 IPF patients who underwent right heart catheterization (RHC) as part of the lung transplant evaluation. We measured electrocardiographic (ECG) and echocardiographic variables as well as the pulmonary artery (PA) and ascending aorta (AA) diameters on chest CT. We recorded results of arterial blood gases (ABG), pulmonary function (PFT) and 6-min walk tests (6MWT). RESULTS: Several variables were predictors of PH in IPF patients in univariable models including a lower arterial oxygenation and 6MWT distance; worse right ventricular (RV) function, rightward deviation of the QRS axis and a higher FVC/DLCOc ratio, PA/AA diameter ratio, and estimated RV systolic pressure. In multivariable analysis, a worse RV function and higher PA/AA ratio remained predictors of PH (c-index 0.75 (0.65-0.84)). Similarly, a worse RV function, a higher PA/AA ratio and a rightward QRS axis deviation were independent predictors of precapillary PH (c-index 0.86 (0.76-0.92)). A combination of PA/AA diameter ratio <1.1, a QRS axis <90° and normal RV function showed a negative predictive value of 85% for precapillary PH. CONCLUSIONS: There are significant differences in ECG, echocardiographic, chest CT, PFT and ABG parameters between IPF patients with and without PH. However, these noninvasive tests alone or combination have limited discrimination ability for PH screening in IPF.