Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease characterized by immune dysregulation, vasculopathy, and progressive fibrosis affecting skin and internal organs. Pulmonary hypertension (PH) is a major contributor to morbidity and mortality in SSc, and SSc-related PH has a worse prognosis than idiopathic PH. Endothelial dysfunction plays a central role in SSc vasculopathy and in the development of PH through effects on vascular tone, inflammation, thrombosis, and vascular remodeling. This study evaluated endothelial function and platelet activity in SSc patients with differing PH probability and tested associations with echocardiographic parameters, including maximal tricuspid regurgitant velocity (TRVmax).
This prospective study obtained ethics approval from the Ramathibodi Hospital Ethics Committee (ID 2024/646). Recruitment occurred from February 16, 2023, to January 31, 2026. The protocol was registered in the Thai Clinical Trials Registry (TCTR20150518002). Clinically stable SSc patients and age-matched healthy controls were enrolled. SSc patients were classified into low, intermediate, or high (confirmed) PH probability according to the 2022 ESC/ERS echocardiographic criteria; confirmation of PH by right heart catheterization (RHC) required mean pulmonary arterial pressure (mPAP) > 20 mmHg.
Exclusion criteria included major comorbidities (heart failure, ischemic heart disease, COPD, chronic kidney disease, active infection, malignancy), and prior use of nitric oxide donors. Agents affecting platelet function were discontinued at least two weeks before study procedures.
All SSc participants underwent standard 2D transthoracic echocardiography. PH suggestive criteria included TRVmax > 3.4 m/s, or TRVmax 2.9–3.4 m/s with at least two additional echocardiographic signs of PH. Additional echocardiographic signs included right ventricular enlargement (RV/LV basal diameter ratio > 1.0), interventricular septal flattening, main pulmonary artery diameter > 25 mm, RV outflow tract acceleration time < 105 ms (when assessable), early diastolic pulmonary regurgitation velocity > 2.2 m/s (when assessable), right atrial area > 18 cm2, and inferior vena cava diameter > 21 mm with reduced inspiratory collapse. Intermediate probability was defined by TRVmax 2.9–3.4 m/s without extra signs, or TRVmax ≤ 2.8 m/s with at least two additional signs. Low probability was TRVmax ≤ 2.8 m/s and no other suggestive features. When echocardiographic criteria met, RHC was performed to confirm PH.
Endothelial function was assessed by brachial artery flow-mediated dilation (FMD) using a portable ultrasound system. Participants fasted overnight and rested supine before imaging. A distal forearm cuff was inflated to 50 mmHg above systolic pressure for 5 minutes, then deflated to induce reactive hyperemia. Peak brachial artery diameter was recorded up to 180 seconds after cuff release and FMD was calculated as percentage change from baseline. Intra-observer reproducibility was assessed by reanalysis of FMD in a subset of participants.
Blood nitrite, a bioactive product of nitric oxide (NO), was measured using a chemiluminescence method. Platelet function was evaluated by light transmission aggregometry in response to adenosine diphosphate (ADP) and thrombin receptor–activating peptide-6 (TRAP-6).
Clinical laboratory tests, spirometry, six-minute walk distance (6MWD), and high-resolution chest CT for interstitial lung disease assessment were performed according to guidelines.
The study reported group comparisons between healthy controls and SSc patients stratified by PH probability. Correlations between TRVmax and vascular/platelet parameters were assessed, and multivariable regression analysis evaluated independent associations with TRVmax. Details of specific statistical tests and adjustment variables were provided in the original article.
The paper compared clinically stable SSc patients across low, intermediate, and confirmed PH probability groups with age-matched healthy controls. Major comorbidities and medications that could affect vascular or platelet function were excluded or held per protocol. Full baseline demographic and laboratory details are reported in the study tables.
SSc patients showed marked impairment in endothelial function measured by FMD compared with controls. Reported FMD values were: controls 13.3 ± 3.9%, SSc with low PH probability 5.6 ± 1.7%, intermediate PH probability 4.6 ± 0.4%, and confirmed PH 3.8 ± 0.4%. Thus, FMD declined progressively from controls to SSc groups with increasing PH probability.
Blood nitrite levels were higher in SSc patients with confirmed PH than in controls or patients with low PH probability, according to the study measurements performed by chemiluminescence.
Platelet activity, measured by light transmission aggregometry in response to ADP and TRAP-6, was increased in SSc patients with higher PH probability. The study found that TRVmax correlated inversely with FMD and positively with platelet aggregation measures.
In multivariable regression analysis, TRAP-6–induced platelet aggregation and FMD were independently associated with TRVmax, suggesting that both endothelial dysfunction and platelet activation contribute independently to the echocardiographic marker of PH probability.
The authors also reported two patients in whom nebulized sodium nitrite transiently reduced TRVmax, illustrating a possible acute hemodynamic effect of inhaled nitrite in selected cases. Details on dosing, duration, and longer-term effects were not expanded beyond these case observations in the abstract.
The findings indicate that clinically stable SSc patients exhibit both endothelial dysfunction and increased platelet activity, and that these abnormalities correlate with an echocardiographic marker of PH probability (TRVmax). The progressive reduction in FMD across groups and the independent association of TRAP-6–induced aggregation with TRVmax support a role for both impaired vasodilatory endothelial function and platelet activation in the pathophysiology of SSc-associated PH.
Elevated blood nitrite in patients with confirmed PH may reflect altered NO metabolism or compensatory pathways in advanced disease, but the study reports only measured levels and associations rather than mechanistic causation. The transient TRVmax response to nebulized sodium nitrite in two patients suggests potential acute pulmonary vascular effects that warrant further investigation.
This study demonstrates that SSc patients have impaired brachial artery FMD and increased platelet aggregation, with both measures correlating with TRVmax by echocardiography. TRAP-6–induced platelet aggregation and FMD were independently associated with TRVmax in multivariable analysis. Two case observations suggest nebulized sodium nitrite can transiently lower TRVmax. The datasets are not publicly available due to patient privacy; anonymized data may be requested from the Ramathibodi Hospital Ethics Committee. Further studies are needed to clarify mechanisms and therapeutic implications.