Introduction:
Pulmonary hypertension due to left heart disease (PH-LHD) is the most common PH subtype and frequently complicates heart failure. By increasing right ventricular afterload, PH promotes right ventricular remodeling and failure, contributing to morbidity and mortality. Sustained pulmonary congestion may further trigger pulmonary vascular maladaption. Although leukocytes are known to drive vascular inflammation and remodeling, their role in pulmonary vascular maladaption in PH-LHD remains unclear. Here, we investigated monocyte counts, subsets and phenotypes in patients with PH-LHD, hypothesizing that PH-LHD is associated with distinct monocyte dynamics potentially involved in pulmonary vascular remodeling.
Methods:
LHD patients undergoing surgical treatment for aortic valve stenosis or mitral regurgitation (n = 24) were stratified according to the echocardiographic probability of pulmonary hypertension (PH) using peak tricuspid regurgitation velocity (TRV) in combination with echocardiographic signs of PH according to ESC guideline recommendations. Only LHD patients with measurable TRV were included. Low-to-intermediate PH probability in LHD patients (PHlo-LHD, n = 13) was defined as TRV <2.9 m/s irrespective of additional echocardiographic PH signs or TRV 2.9–3.4 m/s in the absence of additional PH signs. High PH probability (PHhi-LHD, n = 11) was defined as TRV 2.9–3.4 m/s with additional echocardiographic PH signs or TRV >3.4 m/s. Circulating blood monocyte subsets and phenotypes were assessed using multi-color flow cytometry. PH- and LHD-free healthy donors served as controls (ctrl, n = 13) to assess PH- and LHD-associated immune cell dynamics.
Results:
Mean patient age was 64.6 years in controls, 64.0 years in PHlo-LHD, and 71.7 years in PHhi-LHD. PHlo-LHD included six patients with aortic stenosis (AS) and seven with mitral valve regurgitation (MVR). PHhi-LHD included two patients with AS and nine with MVR. Mean LVEF was preserved in both LHD groups (58.7% vs. 53.3%, n.s.), whereas TRV was significantly higher in PHhi-LHD (3.55 vs. 2.38 m/s). Four PHhi-LHD patients were classified by additional echocardiographic PH signs despite TRV <3.4 m/s. Renal, metabolic, and CNS comorbidities did not differ significantly between all groups. Flow cytometry showed no differences in monocyte counts of classical, intermediate, and non-classical monocytes between all groups. PHhi-LHD patients showed reduced monocyte surface expression of c-c chemokine receptor type five (CCR5) involved in recruitment and immune cell migration, across all monocyte subsets compared to ctrls. Surface protein cluster of differentiation 36 (CD36), a scavenger receptor linked to lipid handling, phagocytosis, and inflammatory activation was markedly reduced in all monocyte subsets compared to ctrls. Interestingly, when comparing PHhi-LHD with PHlo-LHD patients CD36 protein expression only in non-classical monocytes was further reduced, suggesting that impaired CD36-related monocyte function may be linked to PH probability in LHD.
Conclusion:
In summary, our data reveal unique non-classical monocyte phenotypes in PHhi-LHD patients compared with ctrls and PHlo-LHD patients characterized by reduced CD36 protein expression. This observation provides a basis for future functional studies to determine how altered CD36 expression relates to monocyte functions involved in pulmonary vascular maladaptation.
