Research Article: Sex-dependent aortic valve pathology in patients with rheumatic heart disease

Date Published: June 29, 2017

Publisher: Public Library of Science

Author(s): Feng Xiao, Rui Zheng, Di Yang, Kejiang Cao, Shijiang Zhang, Bingruo Wu, Yongfeng Shao, Bin Zhou, Katherine Yutzey.


Rheumatic heart disease is an autoimmune disease caused by group A streptococci infection and frequently affects the aortic valve. Sex differences are common in the disease progression, treatment, and outcome. However, little is known about the sex differences in the pathology of aortic valves in rheumatic heart disease.

We studied the end-stage calcific aortic valves from male versus female patients to reveal the sex-dependent pathology differences and molecular changes associated with requiring valve replacement.

Aortic valves from 39 patients with rheumatic heart disease (19 males and 20 females) were collected at the time of aortic valve replacement for comparative pathology, immunohistochemistry, and gene expression analyses. Clinical characteristics were also analyzed and compared between the two groups.

Aortic valves from female patients exhibited increased expression of collagens, infiltration of monocytes/macrophages and neovascularization. Aortic valves from female patients also had increased expression of inflammatory genes involved in the NFKB pathway (phosphorylated NFKB p65 subunit, IL8, and NOS3) and Th1 cytokine genes (IFNA and IL12B). The severe valve pathology in female patients was correlated with a higher serum level of anti-streptolysin O antibodies.

Inflammation is more prominent in aortic valves of female patients with rheumatic heart disease. This sex difference may contribute to the severe valve pathology and worse outcome of female patients.

Partial Text

Rheumatic heart disease (RHD) causes 1.4 million deaths per year in developing countries[1, 2]. The disease starts with group A streptococci infection. Subsequent host autoimmune response to streptococcal antigens crossly reacts to human tissue proteins, affecting the heart, joints, skin, and brain. RHD patients have a high prevalence of severe cardiovascular complications, including rheumatic carditis, atrial fibrillation, pulmonary hypertension, and congestive heart failure. The most serious complication is rheumatic carditis, which often affects the mitral and aortic valve[3–5]. Chronic or recurrent valve inflammation results in valve stenosis and dysfunction, which underlies the disease’s morbidity and mortality. Thus, the essence of RHD is cardiac valve inflammation[1, 5, 6].

As an autoimmune disease triggered by group A streptococci, RHD presents many cardiovascular manifestations and complications, including cardiac valve deformation and deficiency, infective endocarditis, atrial fibrillation, pulmonary artery hypertension, and heart failure[1, 5]. Aortic valve stenosis and deficiency is a leading factor of morbidity and mortality. Despite its clinical importance, few studies have focused on aortic valve pathology and valve tissue inflammatory response in RHD patients. It is also worth to note that, like coronary artery disease and atrial fibrillation, RHD may have sex differences in etiology, presentation, co-morbidities, management and outcome[20–23]. Previous studies have reported the sex-dependent difference in disease prevalence, risk factor, progression and therapeutic outcome in RHD[7–9]. However, no study has been dedicated to investigate a potential sex difference in aortic valve pathology in RHD.




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