Hemodynamic theory of Calcific Aortic Valve Disease

The aortic valve

Located between the left ventricle and the aorta, the aortic valve ensures unidirectional blood flow by opening during systole and closing during diastole. The valve generally has a tricuspid structure as it consists of three leaflets identified as the left-, right- and non-coronary leaflets, and is also called tricuspid aortic valve (TAV). The leaflets are the moving components of the valve. They open during systole to allow the passage of blood from the left ventricle of the heart toward the aorta, and close during diastole as the ventricle relaxes to prevent backflow of blood into the left ventricle. In some rare instances (2-3% of the general population), the valve forms with only two leaflets due to the fusion between two adjacent leaflets. This abnormal valve anatomy is called the bicuspid aortic valve (BAV).

 

Calcific aortic valve disease (CAVD) and the need for mechanobiology

Calcific aortic valve disease consists of the formation of calcific lesions on the valve leaflets, and contributes to the obstruction of the left ventricular outflow and progressive heart failure. CAVD develops in both the normal aortic valve and the BAV but its progression in BAV patients is more severe and rapid. Consequently, BAV calcification affects patients who are typically younger than patients with an anatomically normal valve. Although tremendous progress has been made in the design of mechanical and bioprosthetic valves, the management of a calcifying valve is challenged by the limited lifespan of bioprostheses and the lifelong anticoagulation therapy associated with mechanical implants. Ideally, the next generation of therapies should focus on non-invasive disease management and early detection strategies, i.e., two objectives that rely on the identification of key mechanisms and molecular pathways involved in the development of CAVD. While CAVD has been historically linked to a genetic origin, hemodynamics has emerged as a potential alternate etiology. The demonstrated sensitivity of valvular tissue to the surrounding blood flow, and the ability of abnormal fluid stresses to trigger early events of CAVD have motivated studies aimed at characterizing the role played by hemodynamic stresses in the pathogenesis of CAVD.

 

Heart valve hemodynamics

 
Experimental studies

Our lab has designed a steady flow loop to assess valvular function and quantify energy loss in tricuspid and bicuspid aortic valves, under normal and disease (calcified) states. The flow setup is driven by a centrifugal pump capable of delivering flow rates between 5 and 20 L/min and features a valve chamber accomodating a tissue valve within a realistic aortic root geometry. Observation of the valve orifice at the maximum flow rate of 20 L/min indicates that the TAV generates a circular orifice while the BAV generates an elliptical orifice. Quantification of the energy loss index (ELI), which characterizes valvular function and valvular disease severity, also demonstrates the intrinsic degree of stenosis of the BAV relative to the TAV as well as a dramatic increase in resistance to blood flow under calcific conditions.

 
Computational studies

The MSCBL has also invested in the development of computational models to characterize the temporal and spatial mechanical stress characteristics on the surface of TAV and BAV leaflets. The models were designed to account for the complex transfer of momentum occurring between the moving valve leaflets and the surrounding pulsatile blood flow. The fluid-structure interaction models were developed in the commercial software package ANSYS. The valve geometries investigated thus far include a TAV, a type-0 BAV (i.e., BAV with two identical leaflets) and a type-I BAV (i.e., BAV with one large fused leaflet and one normal non-fused leaflet). The three models operated under a physiologic transvalvular pressure gradient and were used to quantify the wall shear stress environments on both surfaces of each leaflet.

Flow simulations in a TAV and in type-0 and type-I BAVs
Wall shear stress predictions on the fibrosa of TAV, type-0 and type-I BAV leaflets

Heart valve mechanobiology

The aortic valve functions in a mechanically complex environment, experiencing transvalvular pressures and pulsatile and oscillatory shear stresses, as well as bending and axial stress. Although valves were originally thought to be passive pieces of tissue, recent evidence has suggested an intimate interplay between the hemodynamic environment and biological response of the valve. In particular, while normal stress levels contribute to the maintenance of valvular physiology and function, abnormal stresses are suspected to play a role in valvular disease. The MSCBL is conducting research to elucidate the cause-and-effect relationships between wall shear stress abnormalities and valvular disease.

Shear stress bioreactor

One challenge in the study of valvular mechanobiology is the difficulty to replicate in the laboratory the native mechanical environment of cells and tissue. The wall shear stress environment of cardiovascular tissue and cells is often pulsatile, characterized by large temporal variations and abrupt changes in directionality. The MSCBL has invested in the design and development of a programmable device capable of replicating these characteristics. The device is based on the cone-and-plate principle and can subject cells or whole pieces of valvular tissue to double-sided wall shear stress.

 
 
Role of flow abnormalities in TAV calcification

The exact role played by flow abnormalities in the pathogenesis of CAVD is poorly understood. To fill this knowledge gap, the MSCBL has investigated the wall shear stress regulation of endothelial activation and tissue remodeling. Using the novel double-sided shear stress device, valve leaflets were subjected to different combinations of wall shear stress magnitude and frequency. Endothelial activation and paracrine signaling were investigated by measuring cell-adhesion molecule (ICAM-1, VCAM-1) and cytokine (BMP-4, TGF-beta1) expressions using standard biological assessment techniques (immunostaining, immunoblotting). This study confirmed the sensitivity of valve leaflets to both wall shear stress magnitude and frequency. Normal valve leaflets were able to sense wall shear stress abnormalities and to tranduce them into a pathological response within 48 hours. Among all the wall shear stress environments considered in the study, supra-physiologic levels and abnormal frequencies were found to be the most unfavorable to homeostasis and the most conducive to CAVD precursor events.

 
Role of BAV flow abnormalities in BAV calcification

Due to its abnormal anatomy, the BAV is a potential source of valvular flow abnormalities, which could be responsible for promoting and accelerating the calcification process. The MSCBL has investigated the role played by BAV flow on leaflet biology. The double-sided shear stress bioreactor was programmed to condition normal leaflet tissue to the native wall shear stress environments of TAV and BAV leaflets. Immunostaining, immunoblotting and zymography were performed to characterize endothelial activation, pro-inflammatory paracrine signaling, extracellular matrix remodeling and markers involved in valvular interstitial cell activation and osteogenesis. The results indicated that, while the wall shear stress experienced by the TAV and the non-coronary BAV leaflets essentially maintained valvular homeostasis, the wall shear stress normally present on the fused BAV leaflet promoted endothelial activation, paracrine signaling, catabolic enzyme secretion and activity, and bone matrix synthesis. These results demonstrate the key role played by BAV hemodynamic abnormalities in CAVD pathogenesis.

 

Did you know?

  • The cardiovascular system

    The cardiovascular system consists of the heart, the blood vessels, and the blood. Its function is to transport oxygen, nutrients, hormones, and cellular waste products throughout the body.

  • The heart

    The heart is the pump that drives blood flow throughout the cardiovascular system. It weighs about 300 grams and beats 70 times per minute. It pumps about 5 liters of blood every minute. The two ventricles of the heart pump blood to the lungs, and to the different organs and tissues in the body, respectively.

  • The aortic valve

    The aortic valve achieves unidirectional blood flow between the left ventricle and the aorta. It normally consists of three leaflets that open during systole and close during diastole, under the pressure difference established between the ventricle and the aorta.

  • What is a bicuspid aortic valve?

    The bicuspid aortic valve is the most common congenital valvular defect and affects 2% of the population. While a normal aortic valve consists of three leaflets, the bicuspid aortic valve forms with only two, as a result of fusion between two adjacent leaflets.

  • What is calcific aortic valve disease?

    Calcific aortic valve disease is the most common aortic valve disorder. It affects 4% of adults over 65 years of age and consists of the formation of calcific lesions on the valve leaflets.

  • What is discrete subaortic stenosis?

    Discrete subaortic stenosis is a type of constriction that is caused by the presence of a fibrous ring below the aortic valve, anywhere between the aortic valve and the mitral valve. It results in a restricted outflow from the left ventricle into the aorta.

  • Computational fluid dynamics (CFD)

    Computational fluid dynamics (CFD) is the science of predicting fluid flow, heat transfer, mass transfer, chemical reactions and related phenomena by solving the mathematical equations which govern these processes using a numerical approach.

  • Particle image velocimetry (PIV)

    Particle image velocimetry (PIV) is an optical method of flow visualization used to obtain instantaneous velocity measurements in a flow field. Tracer particles are used to seed the flow and are illuminated using a laser sheet. The motion of the seeding particles is used to calculate the local flow velocity field.

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