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Pathophysiology of Aortic Stenosis and Mitral Regurgitation

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ABSTRACT

The global impact of the spectrum of valve diseases is a crucial, fast‐growing, and underrecognized health problem. The most prevalent valve diseases, requiring surgical intervention, are represented by calcific and degenerative processes occurring in heart valves, in particular, aortic and mitral valve. Due to the increasing elderly population, these pathologies will gain weight in the global health burden. The two most common valve diseases are aortic valve stenosis (AVS) and mitral valve regurgitation (MR). AVS is the most commonly encountered valve disease nowadays and affects almost 5% of elderly population. In particular, AVS poses a great challenge due to the multiple comorbidities and frailty of this patient subset. MR is also a common valve pathology and has an estimated prevalence of 3% in the general population, affecting more than 176 million people worldwide. This review will focus on pathophysiological changes in both these valve diseases, starting from the description of the anatomical aspects of normal valve, highlighting all the main cellular and molecular features involved in the pathological progression and cardiac consequences. This review also evaluates the main approaches in clinical management of these valve diseases, taking into account of the main published clinical guidelines. © 2017 American Physiological Society. Compr Physiol 7:799‐818, 2017.

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Figure 1. Figure 1. Aortic valve anatomy. Structure and nomenclature of aortic root components. The upper side of the figure represents thoracic aortic traits, with highlighted distinctions between ascending aorta and aortic arch. The lower part of the figure recapitulates the detailed aortic root components: the sinotubular junction of aortic root with ascending aorta; the aortic valve leaflets; the ventriculo‐aortic junction of aortic root and left heart ventricle.
Figure 2. Figure 2. Echocardiography of normal and stenotic aortic valve in systole. 2D‐echocardiography of a healthy (left) and a stenotic (right) aortic valve in short‐axis view. Red arrows (left) highlight the normal, thin leaflets with an optimal orifice area. Red stars (right) highlight thick calcific leaflet edges with a restricted aortic valve area.
Figure 3. Figure 3. Cellular features of stenotic aortic valve. The cartoon depicts the main cellular mechanisms involved in the pathogenesis of aortic valve stenosis. (A) The differentiation of monocytes into osteoclasts. (B) The endothelial damage leading to endothelial‐to‐mesenchymal transition (EndMT) into activated myofibroblasts. (C) The differentiation of valve interstitial cells (VIC) into activated myofibroblast and/or osteoblast‐like cells, leading to fibrosis and calcification, respectively. Adapted with permission from ().
Figure 4. Figure 4. Aortic valve stenosis pathophysiology. Phenotype of stenotic aortic valves and the involvement of valve stenosis in cardiac diseases. In the left side are depicted normal and stenotic aortic valves in diastole and systole. In the stenotic picture are present several leaflet regions of spotty calcification, which stiffen the valve structure and alter the dynamic of valve opening. In the right side of the figure are mentioned the main cardiac pathologies caused by aortic valve stenosis.
Figure 5. Figure 5. Mitral valve anatomy. Structure and nomenclature of mitral valve. The mitral valve represents the gate between left atrium and left ventricle. The perfect closure of the valve depends on cardiac papillary muscles, which orchestrate the leaflet traction during systole through chordae tendinae.
Figure 6. Figure 6. Echocardiography of healthy and prolapsed mitral valve in systole. 2D‐echocardiography of a healthy (left) and regurgitant (central and right) mitral valve in long axis view. The left echocardiography image shows the correct alignment (coaptation—red arrow) of healthy, thin mitral valve leaflets. The central echocardiography shows impaired closure (red star). The right color‐Doppler image shows the regurgitant volume toward the left atrium.
Figure 7. Figure 7. Cellular features of mitral valve regurgitation. The cartoon depicts the main cellular mechanisms involved in the pathogenesis of mitral valve regurgitation. (A) The endothelial damage leading to EndMT of VECs into myofibroblas (MyoFB). (B) The fragmentation of elastin in the atrialis layer. (C) The differentiation of VICs into MyoFB leading to fibrosis (collagen and glycosaminoglycans deposition depicted in blue in the spongiosa layer). (D) The collagen fragmentation in the fibrosa layer. Adapted with permission from ().
Figure 8. Figure 8. Mitral valve regurgitation pathophysiology. Phenotype of regurgitant mitral valve and its involvement in cardiac diseases. In the left side pictures of normal and regurgitant mitral valve in systole and diastole. In the closed regurgitant mitral valve picture is clear the improper coaptation of valve leaflets. In the right side of the figure are mentioned the main cardiac pathologies caused by mitral valve regurgitation.


Figure 1. Aortic valve anatomy. Structure and nomenclature of aortic root components. The upper side of the figure represents thoracic aortic traits, with highlighted distinctions between ascending aorta and aortic arch. The lower part of the figure recapitulates the detailed aortic root components: the sinotubular junction of aortic root with ascending aorta; the aortic valve leaflets; the ventriculo‐aortic junction of aortic root and left heart ventricle.


Figure 2. Echocardiography of normal and stenotic aortic valve in systole. 2D‐echocardiography of a healthy (left) and a stenotic (right) aortic valve in short‐axis view. Red arrows (left) highlight the normal, thin leaflets with an optimal orifice area. Red stars (right) highlight thick calcific leaflet edges with a restricted aortic valve area.


Figure 3. Cellular features of stenotic aortic valve. The cartoon depicts the main cellular mechanisms involved in the pathogenesis of aortic valve stenosis. (A) The differentiation of monocytes into osteoclasts. (B) The endothelial damage leading to endothelial‐to‐mesenchymal transition (EndMT) into activated myofibroblasts. (C) The differentiation of valve interstitial cells (VIC) into activated myofibroblast and/or osteoblast‐like cells, leading to fibrosis and calcification, respectively. Adapted with permission from ().


Figure 4. Aortic valve stenosis pathophysiology. Phenotype of stenotic aortic valves and the involvement of valve stenosis in cardiac diseases. In the left side are depicted normal and stenotic aortic valves in diastole and systole. In the stenotic picture are present several leaflet regions of spotty calcification, which stiffen the valve structure and alter the dynamic of valve opening. In the right side of the figure are mentioned the main cardiac pathologies caused by aortic valve stenosis.


Figure 5. Mitral valve anatomy. Structure and nomenclature of mitral valve. The mitral valve represents the gate between left atrium and left ventricle. The perfect closure of the valve depends on cardiac papillary muscles, which orchestrate the leaflet traction during systole through chordae tendinae.


Figure 6. Echocardiography of healthy and prolapsed mitral valve in systole. 2D‐echocardiography of a healthy (left) and regurgitant (central and right) mitral valve in long axis view. The left echocardiography image shows the correct alignment (coaptation—red arrow) of healthy, thin mitral valve leaflets. The central echocardiography shows impaired closure (red star). The right color‐Doppler image shows the regurgitant volume toward the left atrium.


Figure 7. Cellular features of mitral valve regurgitation. The cartoon depicts the main cellular mechanisms involved in the pathogenesis of mitral valve regurgitation. (A) The endothelial damage leading to EndMT of VECs into myofibroblas (MyoFB). (B) The fragmentation of elastin in the atrialis layer. (C) The differentiation of VICs into MyoFB leading to fibrosis (collagen and glycosaminoglycans deposition depicted in blue in the spongiosa layer). (D) The collagen fragmentation in the fibrosa layer. Adapted with permission from ().


Figure 8. Mitral valve regurgitation pathophysiology. Phenotype of regurgitant mitral valve and its involvement in cardiac diseases. In the left side pictures of normal and regurgitant mitral valve in systole and diastole. In the closed regurgitant mitral valve picture is clear the improper coaptation of valve leaflets. In the right side of the figure are mentioned the main cardiac pathologies caused by mitral valve regurgitation.
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Teaching Material

G. L. Perrucci, M. Zanobini, P. Gripari, P. Songia, B. Alshaikh, E. Tremoli, P. Poggio. Pathophysiology of Aortic Stenosis and Mitral Regurgitation. Compr Physiol 7 2017, 799-818.

Didactic Synopsis

 

Major Teaching Points:

     

  1. Understanding the anatomical structures of aortic and mitral valves is necessary to apprehend the pathophysiology of aortic valve stenosis and mitral valve regurgitation.
  2.  

     

  3. The major pathological processes involved in aortic valve stenosis are:

       

    1. valve interstitial cell phenotypic switching in osteoblast-like cells.
    2.  

       

    3. endothelial-to-mesenchymal transition of valve endothelial cells.
    4.  

       

    5. inflammatory cell infiltration.
    6.  

       

    7. fibrosis and osteogenesis.
    8.  

  4.  

     

  5. The main cardiac pathologies caused by aortic valve stenosis are:

       

    1. left ventricle pressure overload.
    2.  

       

    3. cardiac hypertrophy.
    4.  

       

    5. syncope.
    6.  

       

    7. pulmonary hypertension.
    8.  

       

    9. angina.
    10.  

       

    11. heart failure.
    12.  

  6.  

     

  7. To date, the aortic valve stenosis management is represented by surgical intervention, since no pharmacological treatments have been approved.
  8.  

     

  9. The major pathological stimuli involved in mitral valve regurgitation are:

       

    1. mechanical such as are tension, shear stress, compression, and flexure.
    2.  

       

    3. chemical such as serotonin and TGF-β signaling.
    4.  

  10.  

     

  11. The main cardiac pathologies caused by mitral valve regurgitation are:

       

    1. left atrium pressure overload.
    2.  

       

    3. pulmonary edema.
    4.  

       

    5. pulmonary hypertension.
    6.  

       

    7. left ventricle dysfunction.
    8.  

       

    9. heart failure.
    10.  

  12.  

To date, mortality rates are extremely high without surgical intervention. However, patient with acute MR will also benefit from hemodynamically stabilization by afterload reduction accomplished either by pharmacological (e.g., vasodilators) or by mechanical treatments (e.g., intra-aortic balloon pump).

 

 

Didactic Legends

The figures-in a freely downloadable PowerPoint format-can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

 

Figure 1. Teaching points: The aortic valve is an anatomical gate between the left ventricle and the ascending aorta. The aortic root components are: the leaflets, the junction of the aortic root with the ascending aorta, and the junction of the aortic root with the left ventricle.

Figure 2. Teaching points: Stenotic aortic valves show an impaired opening pattern, in systole, in comparison with healthy aortic valves. In physiological conditions, normal aortic valve leaflets are very thin, while in calcified aortic valves the leaflets show thickened edges.

Figure 3. Teaching points: The main cellular mechanisms involved in the pathogenesis of aortic valve stenosis are represented by the differentiation of monocytes into osteoclasts, by the endothelial damage leading to endothelial-to-mesenchymal transition of valve endothelial cells into activated myofibroblasts, by the differentiation of valve interstitial cells into activated myofibroblast and / or osteoblast-like cells, leading to fibrosis (such as collagen and proteoglycan deposition) and calcium nodules formation, respectively.

Figure 4. Teaching points: the stenotic valve shows several regions of spotty calcification. The stiffness of the valve impedes the correct opening of the leaflets during systole. The calcification of the aortic valve leads to left ventricle pressure overload, cardiac hypertrophy, syncope, pulmonary hypertension, heart failure, and angina.

Figure 5. Teaching points: The mitral valve is an anatomical gate between left atrium and left ventricle. The opening of mitral valve is controlled by cardiac papillary muscle contraction. The chordae tendinae linked to the papillary muscles guide the closing of the leaflets during systole.

Figure 6. Teaching points: Healthy mitral valves present a correct alignment of valve leaflets, while, the prolapsed one show an impaired closure. Clinically, the blood regurgitation caused by impaired closure of prolapsed mitral leaflets could be visualized by color-Doppler flow imaging.

Figure 7. Teaching points: The main cellular mechanisms involved in the pathogenesis of mitral valve regurgitation are represented by the endothelial damage leading to endothelial-to-mesenchymal transition of valve endothelial cells into activated myofibroblasts, by the fragmentation of elastin in the atrialis layer, by the differentiation of valve interstitial cells into activated myofibroblasts, leading to fibrosis (collagen and glycosaminoglycans deposition in the spongiosa layer), and by the collagen fragmentation in the fibrosa layer.

Figure 8. Teaching points: The regurgitant mitral valve improperly close at the end of systole. Pathologies caused by mitral valve regurgitation lead to left atrium pressure overload, pulmonary edema, pulmonary hypertension, left ventricle dysfunction, and heart failure.

 


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How to Cite

Gianluca L Perrucci, Marco Zanobini, Paola Gripari, Paola Songia, Bayan Alshaikh, Elena Tremoli, Paolo Poggio. Pathophysiology of Aortic Stenosis and Mitral Regurgitation. Compr Physiol 2017, 7: 799-818. doi: 10.1002/cphy.c160020