Pathophysiology of Aortic Valve Stenosis: Is It Both Fibrocalcific and Sex Specific?

Abstract

Our understanding of the fundamental biology and identification of efficacious therapeutic targets in aortic valve stenosis has lagged far behind the fields of atherosclerosis and heart failure. In this review, we highlight the most clinically relevant problems facing men and women with fibrocalcific aortic valve stenosis, discuss the fundamental biology underlying valve calcification and fibrosis, and identify key molecular points of intersection with sex hormone signaling.

Unanswered Questions Regarding Sex and BMP/TGF-β Signaling

“…We postulate that the balance of BMP/TGF-β signaling may differ in the valves from males and females. Many members of the TGF-β superfamily, particularly the founding members TGF-β1 and -β2, but also activin A, myostatin and BMP9, promote fibrosis in various tissues [ 4 , 53 ]. Others, for example TGF-β3, BMP2 and BMP7, oppose fibrosis in multiple organs [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ].…”

“…Recent reports described dissimilarities in the ratios of fibrotic to calcified tissue in equally stenotic valves from men versus women [ 4 , 5 , 6 , 7 ]. Because TGF-β signaling is generally pro-fibrotic and BMP signaling is generally anti-fibrotic, we wondered if sex-associated changes in this balance contributed to the skewed sex distribution of valvular heart disease [ 4 , 7 , 8 , 9 , 10 , 11 ]. Here, we review the current state of understanding regarding the impact of sex on BMP and TGF-β signaling and identify several unanswered questions.…”

Unanswered Questions Regarding Sex and BMP/TGF-β Signaling

“…We postulate that the balance of BMP/TGF-β signaling may differ in the valves from males and females. Many members of the TGF-β superfamily, particularly the founding members TGF-β1 and -β2, but also activin A, myostatin, and BMP9, promote fibrosis in various tissues [4,44]. Others, for example, TGF-β3, BMP2, and BMP7…”

“…Recent reports described dissimilarities in the ratios of fibrotic to calcified tissue in equally stenotic valves from men versus women [4][5][6][7]. Because TGF-β signaling is generally pro-fibrotic and BMP signaling is generally anti-fibrotic, we wondered if sex-associated changes in this balance contributed to the skewed sex distribution of valvular heart disease [4,[7][8][9][10][11]. Here we review the current state of understanding regarding the impact of sex on BMP and TGF-β signaling and identify several unanswered questions.…”

Physiology in Perspective: The Importance of Integrative Physiology

“…Although major advances have been made in our understanding and treatment of a number of cardiovascular diseases, our understanding of the pathophysiology of aortic valve stenosis-a condition in which severe calcification and fibrosis prevent normal valve opening and impede outflow of blood from the heart-remains largely in its infancy. In their review, Sritharen and colleagues (5) explore the emerging mechanisms contributing to excessive aortic valve calcification and fibrosis, and also highlight emerging clinical data suggesting there may be key differences between men and women in the pathophysiology of calcific aortic valve stenosis as well as in risks associated with surgical or interventional treatments for this disease. In an era where heart valve replacement has grown to be the second most common thoracic surgical procedure performed worldwide, integrative physiological research is imperative and will be instrumental in identifying novel therapeutic strategies to slow aortic valve calcification and fibrosis in aging men and women (thus delaying or preventing surgery) while leaving bone calcification and other important connective tissue processes intact.…”