SSc patients have endothelial dysfunction and increased platelet activity, which exhibits correlation with TRVmax, and TRAP-6-induced platelet aggregation and FMD were independently associated with TRVmax in multivariable regression analysis.
Key Findings
Results
Flow-mediated dilation (FMD) was progressively lower in SSc patients compared to controls, decreasing with increasing pulmonary hypertension probability.
FMD was 13.3 ± 3.9% in age-matched controls
FMD decreased to 5.6 ± 1.7% in SSc patients with low PH probability
FMD further decreased to 4.6 ± 0.4% in SSc patients with intermediate PH probability
FMD was lowest at 3.8 ± 0.4% in SSc patients with confirmed PH
Endothelial function was assessed by flow-mediated dilation of the brachial artery
Results
SSc patients with confirmed pulmonary hypertension had higher blood nitrite levels than controls or patients with low PH probability.
Blood nitrite levels were measured by chemiluminescence method
Elevated nitrite in confirmed PH patients compared to both controls and low PH probability SSc patients
Blood nitrite serves as a marker of endothelial nitric oxide production and endothelial function
This elevation in confirmed PH patients was in contrast to the pattern of reduced FMD
Results
Maximal tricuspid regurgitant velocity (TRVmax) correlated inversely with FMD and positively with platelet aggregation.
TRVmax is an echocardiographic parameter used to assess PH probability
The inverse correlation with FMD indicates that worse endothelial function is associated with higher TRVmax
The positive correlation with platelet aggregation indicates that greater platelet activity is associated with higher TRVmax
Platelet activity was measured by light transmission aggregometry in response to ADP and TRAP-6 stimulation
Results
TRAP-6-induced platelet aggregation and FMD were independently associated with TRVmax in multivariable regression analysis.
Multivariable regression analysis was performed to assess independent associations with TRVmax
TRAP-6 (thrombin receptor-activating peptide-6) was used as a platelet stimulant in light transmission aggregometry
Both platelet aggregation (TRAP-6-induced) and FMD remained independently associated with TRVmax after adjustment for other variables
This suggests both endothelial dysfunction and increased platelet activity independently contribute to pulmonary vascular changes in SSc
Results
Nebulized sodium nitrite transiently reduced TRVmax in two SSc patients with pulmonary hypertension.
This was a proof-of-concept observation in two patients
Sodium nitrite was administered via nebulization
The reduction in TRVmax was transient
This finding suggests a potential therapeutic role for inhaled nitrite in SSc-associated pulmonary hypertension
Methods
PH diagnosis in SSc patients was confirmed by right heart catheterization, with probability assessed by echocardiography.
Patients were stratified into low PH probability, intermediate PH probability, and confirmed PH groups
Echocardiographic parameters including TRVmax were used to assess PH probability
Right heart catheterization was the gold standard for confirming PH diagnosis
Systemic sclerosis is described as an autoimmune connective tissue disease characterized by vasculopathy, inflammation, and fibrosis
What This Means
This research suggests that patients with systemic sclerosis (SSc), an autoimmune disease affecting connective tissue, experience progressive deterioration of blood vessel function and increased platelet activity (blood cell clotting tendency) as pulmonary hypertension (high blood pressure in the lungs) develops and worsens. The study measured how well the brachial artery in the arm could widen in response to increased blood flow (a test called flow-mediated dilation, or FMD) and found that SSc patients had significantly impaired vessel function compared to healthy controls, with the most severe impairment seen in those with confirmed pulmonary hypertension. Additionally, the speed at which blood leaks back through the tricuspid heart valve — an indicator of pulmonary pressure — was inversely related to vessel function and directly related to platelet stickiness.
Using statistical modeling, the researchers found that both poor endothelial (vessel lining) function and elevated platelet aggregation independently predicted higher pulmonary pressures, suggesting these two processes may each contribute separately to disease progression. In a small observation of two patients, inhaling a solution of sodium nitrite — a compound that can release nitric oxide, which relaxes blood vessels — temporarily lowered pulmonary pressures as measured by echocardiography.
This research suggests that monitoring endothelial function and platelet activity in SSc patients could help identify those at greatest risk of developing severe pulmonary hypertension. It also raises the possibility that therapies targeting these pathways, such as inhaled nitrite compounds, might offer benefit in SSc-associated pulmonary hypertension, though larger studies would be needed to confirm this.