Discussion

Acute rheumatic fever still continues to be an important health problem, especially in developing countries. Rheumatic heart diseases are the most important result of acute rheumatic fever and cause significant morbidity and mortality in advancing ages. The Global Burden of Disease study more recently estimated that there are 33 million prevalent cases of rheumatic heart disease, causing more than 9 million Disability-Adjusted Life Years lost and 275,000 deaths each year. ^{Reference Vos, Barber and Bell12}

Chronic secondary prophylaxis is recommended in patients with acute rheumatic fever who develop carditis, and this is the most important tool in the prevention of acute rheumatic fever recurrences. It is known that the appropriate and regular application of secondary prophylaxis reduces the recurrences of acute rheumatic fever. About 2/3 of patients with rheumatic carditis are aware of the situation and apply to the physician. The remainder constitutes the highest risk group for rheumatic heart disease. Because they will be deprived of prophylaxis. ^{Reference Gewitz, Baltimore and Tani2,Reference Dajani, Ayoub and Bierman3}

The last update regarding the Jones criteria used in the diagnosis of acute rheumatic fever was made by the AHA in 2015. ^{Reference Gewitz, Baltimore and Tani2} The WHF published a guideline in 2012 to be used in the diagnosis of rheumatic heart diseases. Recommendations regarding echocardiographic findings that provide criteria for distinguishing pathological rheumatic heart disease from physiological changes are presented in this guideline. In the presence of certain echocardiographic findings in patients who apply to cardiology clinics for any reason and are found to have mitral and/or aortic regurgitation, they recommend that these patients be considered to have had Acute rheumatic fever and that secondary prophylaxis should be given. ^{Reference Reméanyi, Wilson and Steer9} The Australian guideline published by Ralph et al ^{Reference Ralph, Noonan, Wade and Currie10} in 2020 is also presented further details on the use of echocardiograms.

Mitral and/or aortic regurgitation are the most common lesions caused by valvulitis leading to chronic rheumatic heart disease. ^{Reference Guilherme, Ramasawmy and Kalil13} Clinically, the rate of mitral valve involvement in rheumatic heart disease is between 90–95%, and about 20–25% of these are associated with aortic valve involvement. Isolated aortic valve involvement has been reported in less than 5–8% of cases. ^{Reference Markowitz, Markowitz and Gordis14,Reference Persellin15}

Valvulitis is among the life-threatening complications and it causes fibrosis of the heart valves, which results in damage of heart valve and cause heart failure or death of the patient. ^{Reference Liu, Lu, Sun, Zheng and Zhang16}

The pathogenesis of acute rheumatic fever and rheumatic heart disease is complex, and both environmental and genetic factors contribute to the aetiology. Occurrence of disease in only a small subset of children with untreated GABHS throat infection, furthermore, progress of only one-third of affected children to the development of rheumatic heart disease suggest that host genetic factors are also involved. ^{Reference Guilherme, Ramasawmy and Kalil13} Two phases have been described in the pathological process of acute rheumatic fever. The first stage of the disease, that is seen in the first 2-3 weeks, is called as the exudative-degenerative phase. It is characterized by interstitial edema, T-cell, B-cell, and macrophage infiltration, fragmentation of collagen tissue, and scattering fibrinoid deposition. The second phase, called the proliferative or granulomatous phase, lasts for months or even years. Typical Aschoff nodules are seen. ^{Reference Saphir17} Macroscopically, the heart is edematous, loose, and the cavities are enlarged. Mitral and aortic valves are initially edematous. In the acute period, elongation or even rupture of the mitral anterior leaflet chordae, annular dilatation, impaired coaptation, prolapse and regurgitation are seen. ^{Reference Câmara, Neubauer, Câmara and Lopes18,Reference Kamblock, N’Guyen and Pagis19} During the healing period, increase in vascularity and thickening of the valve with the emergence of granulation tissue occur, and eventually fibrosis develops.

It has been reported that anti-carbohydrate B, an antispotreptoccal antibody, remains elevated for longer than other antibodies in patients with a previous history of rheumatic carditis. Thus, it has been reported that these antibodies can be used to recognize rheumatic valve diseases. ^{Reference Shulman, Ayoub, Victorica, Gessner, Tamer and Hernandez20–Reference Dudding and Ayoub22} However, studies on the subject are few and do not provide a clear result. Today, there is a need for a test that can help in determination of whether an incidental aortic and/or mitral regurgitation is due to rheumatic heart disease or not.

Severe or permanent tissue damage cannot be repaired by parenchymal regeneration alone, as it causes damage to both parenchymal cells and the stroma framework. In this case, the repair is provided by the replacement of the parenchyma cells that cannot be regenerated by the connective tissue (fibrosis). Fibrosis in the early stage is formed in the granulation tissue consisting of loose extracellular matrix and new vessel roof at the repair site. The process has four components; 1) Angiogenesis, 2) Fibroblast migration and proliferation to the injury site, 3) Extracellular matrix deposition, 4) Fibrous tissue maturation and reorganisation. ^{Reference Oakes, Kumar, Abbas and Aster23} Angiogenesis is defined as the process by which new vessels are formed by branching from the existing vascular network. The formation of new capillaries is important not only for normal growth and development, but also for the progression of angiogenesis-related diseases. Angiogenesis involves a complex interaction between different cells, soluble factors, and extracellular matrix components. ^{Reference Carmeliet24,Reference Conway, Collen and Carmeliet25} Angiogenesis is the critical event in injury recovery. Various factors stimulate angiogenesis, but the most important are basic fibroblast growth factor and vascular endothelial growth factor. Both are secreted by various stromal cells and basic fibroblast growth factor bind proteoglycans to the basement membrane. A more comprehensive understanding of the molecules that regulate angiogenesis may be valuable for early diagnosis and targeting of therapy. ^{Reference Oakes, Kumar, Abbas and Aster23}

Stimulation and regulation of fibroblasts are regulated by growth factors. Many of the growth factors that regulate fibroblast proliferation also stimulate extracellular matrix synthesis. The extracellular matrix is a locally made dynamic, permanently outlined macromolecular complex that makes up a significant portion of every tissue. There are three basic extracellular matrix components: Fibrous structural proteins (collagen, elastin) forming resistance; lubricating aqueous gels and matrix elements (proteoglycans and hyaluronan); and adhesive glycoproteins (fibronectin, laminin, integrins, etc.) that bind cells together. The repair begins within 24 hours after the tissue injury and continues with the appearance of a special type of tissue called granulation tissue within 3–5 days. The granulation tissue then transforms into fibrous tissue composed largely of inactive spindle-shaped fibroblasts, dense collagen, elastic tissue fragments, and other extracellular matrix components by the progressive increase of the extracellular matrix. ^{Reference Mitchell, Kumar, Abbas and Aster26}

Endocan is a novel soluble dermatan sulfate proteoglycan secreted by cultured endothelial cells. ^{Reference Sarrazin, Adam and Lyon27} It plays a role in the regulation of cellular activities such as adhesion, migration, and proliferation. ^{Reference Lee, Choi and Bae28,Reference Gerszten, Garcia-Zepeda and Lim29} Endocan is upregulated by proangiogenic molecules as well as proinflammatory cytokines. Among many mediators, it is secreted by vascular endothelial cells in response to different stimuli such as tumor necrosis factor-α and vascular endothelial growth factor. ^{Reference Balta, Mikhailidis, Demirkol, Ozturk, Celik and Iyisoy30}

Endocan participates in molecular interactions underlying various biological processes such as cell adhesion, proliferation, as well as neovascularization and endothelial cell activation in response to proangiogenic signals. ^{Reference Sarrazin, Adam and Lyon27,Reference Lee, Choi and Bae28,Reference Balta, Mikhailidis, Demirkol, Ozturk, Celik and Iyisoy30–Reference Abu El-Asrar, Nawaz and De Hertogh33}

Serum levels of endocan are within normal limits in cases with functional endothelial tissue, while increased serum levels of endocan have been reported in patients with endothelial damage and neovascularization. ^{Reference Icli, Cure and Cure34} Due to the fibrotic changes that may develop after neovascularisation, new blood endothelial biomarkers may be important alternatives for diagnosing endothelial dysfunction, especially in the early stages of diseases. ^{Reference Wang, Yang, Luo, Wang and Jing35} Activation of endothelial cells and inflammation increases endocan secretion, which in turn feeds vascular inflammation. Therefore, it has been suggested that endocan can be used as a biomarker of endothelial dysfunction and pathological angiogenesis. ^{Reference Sarrazin, Adam and Lyon27,Reference Balta, Mikhailidis, Demirkol, Ozturk, Celik and Iyisoy30,Reference Oktar, Guney and Eren31,}

It has been reported that endocan may have diagnostic or prognostic value in many clinical problems. ^{Reference Sarrazin, Adam and Lyon27,Reference Kali and Rathan Shetty36} Because endocan can interact with bioactive proteins, it has been identified in tumours as a marker of proliferation, neovascularisation, ^{Reference Strasser, Kaminker and Tessier-Lavigne37,Reference Del Toro, Prahst and Mathivet38,} and endothelial cell activation ^{Reference Abid, Yi, Yano, Shih and Aird39,Reference Grigoriu, Depontieu and Scherpereel40} in response to proangiogenic signals. It is expressed at higher levels in endothelial cells during proliferation compared to non-proliferating cells. ^{Reference Abid, Yi, Yano, Shih and Aird39}

It has also been shown to elicit epithelial cell proliferation in vitro by interacting with growth factors such as hepatocyte growth factor/scattering factor via the dermatan sulfate chain. ^{Reference Béchard, Gentina and Delehedde41} In a study investigating serum endocan concentration in relation to different stages of liver diseases, it was shown that endocan levels were higher in advanced fibrosis than in the control group. ^{Reference Klisic, Kavaric and Abenavoli42}

It has been stated that endocan is a potential biomarker for microvascular manifestations and complications in patients with systemic sclerosis. ^{Reference Bălănescu, Lădaru, Bălănescu, Voiosu, Băicuş and Dan43} Proteoglycans have been shown to increase the activity of dermal fibroblasts to overexpress pro-fibrotic proteins. Thus, endocan, which acts as a circulating proteoglycan, also contributes to fibrosis in systemic sclerosis. ^{Reference Lo, Mandraffino and Rodríguez-Carrio44,Reference Liakouli, Cipriani and Di Benedetto45} In chronic kidney disease, risk factors include progressive glomerular scarring and interstitial fibrosis. In renal hypodysplasia, which is one of the causes of chronic kidney disease, serum endocan levels were found to be significantly higher than in the control group. ^{Reference Cayci, Aydin and Aygar46}

It is known that rheumatic heart disease causes typical chronic fibrotic changes in the heart valves. This study, which was conducted to answer the question of whether endocan, a marker of fibrosis, can distinguish these patients from patients with non-rheumatic aortic regurgitation, is the first study on the subject and points to promising results in this regard.

In our study, the median endocan level was found to be significantly higher in children with chronic rheumatic aortic regurgitation after a previous acute rheumatic fever (Group 1) and in children with aortic regurgitation evaluated as incidental rheumatic valve disease (Group 2) than in children with aortic regurgitation due to bicuspid aortic valve (Group 3) and normal healthy children (Group 4). It is also important that a long time has passed after the first attack in patients with rheumatic valve disease (Group 1). Our findings suggest that upregulation of endocan expression in rheumatic heart disease may be a reflection of angiogenesis-related endothelial cell activation and subsequent fibrosis.