Serum Biomarkers in Connective Tissue Disease-Associated Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening complication of connective tissue diseases (CTDs) characterised by increased pulmonary arterial pressure and pulmonary vascular resistance. CTD-PAH is the result of a complex interplay among endothelial dysfunction and vascular remodelling, autoimmunity and inflammatory changes, ultimately leading to right heart dysfunction and failure. Due to the non-specific nature of the early symptoms and the lack of consensus on screening strategies—except for systemic sclerosis, with a yearly transthoracic echocardiography as recommended—CTD-PAH is often diagnosed at an advanced stage, when the pulmonary vessels are irreversibly damaged. According to the current guidelines, right heart catheterisation is the gold standard for the diagnosis of PAH; however, this technique is invasive, and may not be available in non-referral centres. Hence, there is a need for non-invasive tools to improve the early diagnosis and disease monitoring of CTD-PAH. Novel serum biomarkers may be an effective solution to this issue, as their detection is non-invasive, has a low cost and is reproducible. Our review aims to describe some of the most promising circulating biomarkers of CTD-PAH, classified according to their role in the pathophysiology of the disease.

Eye signs as a novel risk predictor in pulmonary arterial hypertension associated with systemic lupus erythematosus

“…The REVEAL registry study in the United States revealed that CTD-related PAH accounts for 25.3% of all PAH patients. SLE and systemic sclerosis (SSc) are the most common CTDs associated with PAH [11]. An analysis of the causes of death in SLE patients in China over the past 30 years found that SLE-PAH is the third leading cause of death in SLE patients [12].…”

Biomarkers in Systemic Sclerosis: An Overview

“…Therefore, patients with SSc should be screened for PAH, even if asymptomatic, by cardiac echocolordoppler, respiratory testing, and NT-ProBNP assay. Diagnostic algorithms have been proposed to identify patients for RHC, which is still the gold standard tool for diagnosing PAH and PH [116][117][118][119][120][121][122][123][124][125][126]. Risk factors for PAH include severe Raynaud's phenomenon, severe digital ischemia, cutaneous telangiectasias, chronic disease, late onset of the disease, advanced age, postmenopausal status, reduced diffusing capacity (DLCO < 50%), DLCO/alveolar volume less than 70%, forced vital capacity/DLCO less than 1.6, and increased right ventricular systolic pressure greater than 2 mmHg/year [110][111][112][113][114][115][116][117][118][119].…”

“…Screening should include specific autoantibodies (anti-topoisomerase I (SCL-70), an-ticentromere and anti-RNA polymerase III and antiphospholipid antibodies), pulmonary function tests, echocardiography, pro-terminal brain natriuretic peptide (NT-proBNP), capillaroscopy of nail folds and initial high-resolution CT scan to rule out ILD, and, in case of PAH, right heart catheterization to determine PA pressure [118][119][120][121][122][123][124][125][126]151]. Many molecules have been associated with vascular complications of SSc, so there are many potential biomarkers for vascular disease and PAH in SSc.…”

“…Many molecules have been associated with vascular complications of SSc, so there are many potential biomarkers for vascular disease and PAH in SSc. Activation, endothelial cell apoptosis, specific autoantibodies, infectious agents, reactive oxygen species, and other causes that provide many potential biomarkers may contribute to vascular lesion formation [121][122][123][124][125][126]151]. Once activated, endothelial cells secrete endothelin-1 (ET-1), von Willebrand factor (vWF), nitric oxide, and endothelial nitric oxide synthase, resulting in unstable vascular tone, with decreased vasodilation and increased vasoconstriction causing ischemia and tissue hypoxia [119][120][121][122][123][124].…”

“…Activation, endothelial cell apoptosis, specific autoantibodies, infectious agents, reactive oxygen species, and other causes that provide many potential biomarkers may contribute to vascular lesion formation [121][122][123][124][125][126]151]. Once activated, endothelial cells secrete endothelin-1 (ET-1), von Willebrand factor (vWF), nitric oxide, and endothelial nitric oxide synthase, resulting in unstable vascular tone, with decreased vasodilation and increased vasoconstriction causing ischemia and tissue hypoxia [119][120][121][122][123][124]. Endothelin-1 stimulates fibroblasts to convert to activated myofibroblasts with increased ECM secretion, intimal hyperplasia, luminal narrowing, reduced capillary blood flow vessel obliteration and ischemia [120][121][122][123][124][125][126]151].…”