Yonghoon Rim

The effect of patient-specific annular motion on dynamic simulation of mitral valve function

Most surgical procedures for patients with mitral regurgitation (MR) focus on optimization of annular dimension and shape utilizing ring annuloplasty to restore normal annular geometry, increase leaflet coaptation, and reduce regurgitation. Computational studies may provide insight on the effect of annular motion on mitral valve (MV) function through the incorporation of patient-specific MV apparatus geometry from clinical imaging modalities such as echocardiography. In the present study, we have developed a novel algorithm for modeling patient-specific annular motion across the cardiac cycle to further improve our virtual MV modeling and simulation strategy. The MV apparatus including the leaflets, annulus, and location of papillary muscle tips was identified using patient 3D echocardiography data at end diastole and peak systole and converted to virtual MV model. Dynamic annular motion was modeled by incorporating the ECG-gated time-varying scaled annular displacement across the cardiac cycle. We performed dynamic finite element (FE) simulation of two sets of patient data with respect to the presence of MR. Annular morphology, stress distribution across the leaflets and annulus, and contact stress distribution were determined to assess the effect of annular motion on MV function and leaflet coaptation. The effect of dynamic annular motion clearly demonstrated reduced regions with large stress values and provided an improved accuracy in determining the location of improper leaflet coaptation. This strategy has the potential to better quantitate the extent of pathologic MV and better evaluate functional restoration following MV repair.

Mitral Valve Repair Using ePTFE Sutures for Ruptured Mitral Chordae Tendineae: A Computational Simulation Study

Mitral valve (MV) repair using expanded polytetrafluoroethylene sutures is an established and preferred interventional method to resolve the complex pathophysiologic problems associated with chordal rupture. We developed a novel computational evaluation protocol to determine the effect of the artificial sutures on restoring MV function following valve repair. A virtual MV was created using three-dimensional echocardiographic data in a patient with ruptured mitral chordae tendineae (RMCT). Virtual repairs were designed by adding artificial sutures between the papillary muscles and the posterior leaflet where the native chordae were ruptured. Dynamic finite element simulations were performed to evaluate pre- and post-repair MV function. Abnormal posterior leaflet prolapse and mitral regurgitation was clearly demonstrated in the MV with ruptured chordae. Following virtual repair to reconstruct ruptured chordae, the severity of the posterior leaflet prolapse decreased and stress concentration was markedly reduced both in the leaflet tissue and the intact native chordae. Complete leaflet coaptation was restored when four or six sutures were utilized. Computational simulations provided quantitative information of functional improvement following MV repair. This novel simulation strategy may provide a powerful tool for evaluation and prediction of interventional treatment for RMCT.

Evaluation of Mitral Valve Dynamics

Mitral valve (mv) repair is the preferred treatment for patients with mv insufficiency. The unsolved problem in MV repair surgery is predicting the optimal repair for each patient. This is in part due to lack of physiological imaging modalities to provide this information prior to or at the time of valve repair. Moreover, the majority of cases have complex pathophysiological involvement including annular enlargement, chordal lengthening, chordal rupture, calcification, and ultimately lack of proper leaflet coaptation. Current clinical 3-dimensional (3D) transesophageal echocardiography (TEE) can demonstrate volumetric morphology of the MV apparatus. However, biomechanical information is not available from 3D echocardiography. If imaging techniques can be combined with appropriate computational MV evaluation methods, then improved diagnosis and therapeutic approaches to MV repair can be developed. In the present study, we describe a novel comprehensive evaluation protocol to improve diagnosis and treatment of MV pathology by combining 3D TEE and computational simulation techniques (Fig. 1). Virtual MV models were created by utilizing 3D TEE data of patients with normal and pathological MVs followed by computational simulations of MV function. Computational simulations clearly demonstrated deformation and stress distribution of the MV structure across the cardiac cycle at a microsecond scale and corresponded well to 3D TEE data (Figs. 2 and ​and3,3, Online Videos 1, 2, 3, and 4). Here we present 4 case studies (1 normal and 3 different types of pathological MVs). Figure 1 Flow Chart for Virtual MV Modeling and Computational Simulation of MV Function Figure 2 Images of a Normal MV Figure 3 Images of a Pathological MV With Posterior Chordal Rupture Case 1 (Fig. 4): a normal MV demonstrated complete coaptation with no regurgitation when closed. Figure 4 Case 1: A Normal MV With Complete Coaptation; A to D (Peak Systole), E to H (End Diastole) Case 2 (Fig. 5): this MV showed mild regurgitation with relatively small annular dilation. Computational simulation indicated increased leaflet stress values and reduced contact pressure between the leaflets. Figure 5 Case 2: A Degenerative MV With Mild Regurgitation and Small Annular Dilation; A to D (Peak Systole), E to H (End Diastole) Case 3 (Fig. 6): a degenerative MV with large annular dilation demonstrated severe regurgitation by 3D Doppler TEE and the lesion corresponded to regions with no leaflet contact in the computational simulation. Figure 6 Case 3: A Degenerative MV With Severe Regurgitation and Large Annular Dilation; A to D (Peak Systole), E to H (End Diastole) Case 4 (Fig. 7): chordal rupture of this MV caused posterior leaflet prolapse inducing the regurgitant jet. Computational simulation demonstrated an extremely asymmetric and large stress distribution over the leaflets and lack of leaflet coaptation in the regurgitant region. Figure 7 Case 4: A Degenerative MV With Severe Regurgitation due to Ruptured Chordae; A to D (Peak Systole), E to H (End Diastole) Comparative studies of the normal MV (Case 1) and the pathological MV with ruptured chordae (Case 4) clearly demonstrated differences in annular reaction forces and chordal stresses (Fig. 8), and in the degree of leaflet coaptation (Fig. 9, Online Videos 5 and 6). Figure 8 Assessment of Annular Reaction Force and Chordal Stress Distribution; Normal MV (Case 1) Versus MV With Ruptured Chordae (Case 4) Figure 9 Contact Pressure Distribution Between the Leaflets; Normal MV (Case 1) Versus MV With Ruptured Chordae (Case 4) Although MV morphology obtained with 3D TEE image data may demonstrate relatively normal function with no regurgitation, the leaflets may be under extremely high stresses which can result in annular dilation and MV deterioration. Biomechanical information from computational simulation further provides information to help better understand MV pathophysiology. This novel computational strategy has the potential to predict pathophysiological alterations in MV structure, help cardiologists to quantitatively evaluate the extent and severity of MV pathology, and help surgeons to better understand MV dynamics before and following repair to determine more suitable patient-specific repair techniques.

A novel finite element-based patient-specific mitral valve repair: virtual ring annuloplasty

Alterations of normal mitral valve (MV) function lead to mitral insufficiency, i.e., mitral regurgitation (MR). Mitral repair is the most popular and most efficient surgical intervention for MR treatment. An annuloplasty ring is implanted following complex reconstructive MV repairs to prevent potential reoccurrence of MR. We have developed a novel finite element (FE)-based simulation protocol to perform patient-specific virtual ring annuloplasty following the standard clinical guideline procedure. A virtual MV was created using 3D echocardiographic data in a patient with mitral annular dilation. Proper type and size of the ring were determined in consideration of the MV apparatus geometry. The ring was positioned over the patient MV model and annuloplasty was simulated. Dynamic simulation of MV function across the complete cardiac cycle was performed. Virtual patient-specific annuloplasty simulation well demonstrated morphologic information of the MV apparatus before and after ring implantation. Dynamic simulation of MV function following ring annuloplasty demonstrated markedly reduced stress distribution across the MV leaflets and annulus as well as restored leaflet coaptation compared to pre-annuloplasty. This novel FE-based patient-specific MV repair simulation technique provides quantitative information of functional improvement following ring annuloplasty. Virtual MV repair strategy may effectively evaluate and predict interventional treatment for MV pathology.

Personalized Computational Modeling of Mitral Valve Prolapse: Virtual Leaflet Resection

Posterior leaflet prolapse following chordal elongation or rupture is one of the primary valvular diseases in patients with degenerative mitral valves (MVs). Quadrangular resection followed by ring annuloplasty is a reliable and reproducible surgical repair technique for treatment of posterior leaflet prolapse. Virtual MV repair simulation of leaflet resection in association with patient-specific 3D echocardiographic data can provide quantitative biomechanical and physiologic characteristics of pre- and post-resection MV function. We have developed a solid personalized computational simulation protocol to perform virtual MV repair using standard clinical guidelines of posterior leaflet resection with annuloplasty ring implantation. A virtual MV model was created using 3D echocardiographic data of a patient with posterior chordal rupture and severe mitral regurgitation. A quadrangle-shaped leaflet portion in the prolapsed posterior leaflet was removed, and virtual plication and suturing were performed. An annuloplasty ring of proper size was reconstructed and virtual ring annuloplasty was performed by superimposing the ring and the mitral annulus. Following the quadrangular resection and ring annuloplasty simulations, patient-specific annular motion and physiologic transvalvular pressure gradient were implemented and dynamic finite element simulation of MV function was performed. The pre-resection MV demonstrated a substantial lack of leaflet coaptation which directly correlated with the severe mitral regurgitation. Excessive stress concentration was found along the free marginal edge of the posterior leaflet involving the chordal rupture. Following the virtual resection and ring annuloplasty, the severity of the posterior leaflet prolapse markedly decreased. Excessive stress concentration disappeared over both anterior and posterior leaflets, and complete leaflet coaptation was effectively restored. This novel personalized virtual MV repair strategy has great potential to help with preoperative selection of the patient-specific optimal MV repair techniques, allow innovative surgical planning to expect improved efficacy of MV repair with more predictable outcomes, and ultimately provide more effective medical care for the patient.

A novel liposomal nanomedicine for nitric oxide delivery and breast cancer treatment

Breast cancer is the most common type of cancer occurring among women in the United States. Nitric oxide (NO) is endogenous signaling molecules that regulate biological processes. NO has the potential to induce either cancer progression or cancer cell apoptosis depending on intra-tumoral NO concentration. High levels of NO have a cytotoxic effect on cancer cells. A novel cytotoxic gas delivery system has been developed using NO-loaded echogenic liposomes (ELIP) for breast cancer treatment. Empty ELIP and NO-ELIP were prepared using the previously developed freezing-under-pressure method with modified lipid composition. Echogenicity of NO-ELIP was measured to determine the stability of NO-ELIP. Two types of breast cancer cell (BCC) lines, MDA-MB-231 and MDA-MB-468, were utilized. MTT assay was performed after NO-ELIP treatment to determine BCC viability. Echogenicity data demonstrated improved stability of NO-ELIP with the use of BSA for resuspension of NO-ELIP. Cell death induced by NO-ELIP was not from lipid cytotoxicity but from NO. The cytotoxic effect of NO-ELIP on BCC was highly dependent on NO-ELIP concentration. NO-ELIP in concentration of 1.0-2.0 mg/ml induced dramatically decreased BCC viability. This novel cytotoxic gas delivery nanomedicine using liposomal carriers, NO-ELIP, has the potential to provide improved therapeutic effect for breast cancer treatment.

Nitric oxide improves molecular imaging of inflammatory atheroma using targeted echogenic immunoliposomes.

OBJECTIVE This study aimed to demonstrate whether pretreatment with nitric oxide (NO) loaded into echogenic immunoliposomes (ELIP) plus ultrasound, applied before injection of molecularly targeted ELIP can promote penetration of the targeted contrast agent and improve visualization of atheroma components. METHODS ELIP were prepared using the pressurization-freeze method. Atherosclerosis was induced in Yucatan miniswine by balloon denudation and a hyperlipidemic diet. The animals were randomized to receive anti-intercellular adhesion molecule-1 (ICAM-1) ELIP or immunoglobulin (IgG)-ELIP, and were subdivided to receive pretreatment with standard ELIP plus ultrasound, NO-loaded ELIP, or NO-loaded ELIP plus ultrasound. Intravascular ultrasound (IVUS) data were collected before and after treatment. RESULTS Pretreatment with standard ELIP plus ultrasound or NO-loaded ELIP without ultrasound resulted in 9.2 ± 0.7% and 9.2 ± 0.8% increase in mean gray scale values, respectively, compared to baseline (p < 0.001 vs. control). Pretreatment with NO-loaded ELIP plus ultrasound activation resulted in a further increase in highlighting with a change in mean gray scale value to 14.7 ± 1.0% compared to baseline (p < 0.001 vs. control). These differences were best appreciated when acoustic backscatter data values (RF signal) were used [22.7 ± 2.0% and 22.4 ± 2.2% increase in RF signals for pretreatment with standard ELIP plus ultrasound and NO-loaded ELIP without ultrasound respectively (p < 0.001 vs. control), and 40.0 ± 2.9% increase in RF signal for pretreatment with NO-loaded ELIP plus ultrasound (p < 0.001 vs. control)]. CONCLUSION NO-loaded ELIP plus ultrasound activation can facilitate anti-ICAM-1 conjugated ELIP delivery to inflammatory components in the arterial wall. This NO pretreatment strategy has potential to improve targeted molecular imaging of atheroma for eventual true tailored and personalized management of cardiovascular diseases.

Effect of leaflet-to-chordae contact interaction on computational mitral valve evaluation

BackgroundComputational simulation using numerical analysis methods can help to assess the complex biomechanical and functional characteristics of the mitral valve (MV) apparatus. It is important to correctly determine physical contact interaction between the MV apparatus components during computational MV evaluation. We hypothesize that leaflet-to-chordae contact interaction plays an important role in computational MV evaluation, specifically in quantitating the degree of leaflet coaptation directly related to the severity of mitral regurgitation (MR). In this study, we have performed dynamic finite element simulations of MV function with and without leaflet-to-chordae contact interaction, and determined the effect of leaflet-to-chordae contact interaction on the computational MV evaluation.MethodsComputational virtual MV models were created using the MV geometric data in a patient with normal MV without MR and another with pathologic MV with MR obtained from 3D echocardiography. Computational MV simulation with full contact interaction was specified to incorporate entire physically available contact interactions between the leaflets and chordae tendineae. Computational MV simulation without leaflet-to-chordae contact interaction was specified by defining the anterior and posterior leaflets as the only contact inclusion.ResultsWithout leaflet-to-chordae contact interaction, the computational MV simulations demonstrated physically unrealistic contact interactions between the leaflets and chordae. With leaflet-to-chordae contact interaction, the anterior marginal chordae retained the proper contact with the posterior leaflet during the entire systole. The size of the non-contact region in the simulation with leaflet-to-chordae contact interaction was much larger than for the simulation with only leaflet-to-leaflet contact.ConclusionsWe have successfully demonstrated the effect of leaflet-to-chordae contact interaction on determining leaflet coaptation in computational dynamic MV evaluation. We found that physically realistic contact interactions between the leaflets and chordae should be considered to accurately quantitate leaflet coaptation for MV simulation. Computational evaluation of MV function that allows precise quantitation of leaflet coaptation has great potential to better quantitate the severity of MR.

Mitral valve function following ischemic cardiomyopathy: a biomechanical perspective.

Ischemic mitral valve (MV) is a common complication of pathologic remodeling of the left ventricle due to acute and chronic coronary artery diseases. It frequently represents the pathologic consequences of increased tethering forces and reduced coaptation of the MV leaflets. Ischemic MV function has been investigated from a biomechanical perspective using finite element-based computational MV evaluation techniques. A virtual 3D MV model was created utilizing 3D echocardiographic data in a patient with normal MV. Two types of ischemic MVs containing asymmetric medial-dominant or symmetric leaflet tenting were modeled by altering the configuration of the normal papillary muscle (PM) locations. Computational simulations of MV function were performed using dynamic finite element methods, and biomechanical information across the MV apparatus was evaluated. The ischemic MV with medial-dominant leaflet tenting demonstrated distinct large stress distributions in the posteromedial commissural region due to the medial PM displacement toward the apical-medial direction resulting in a lack of leaflet coaptation. In the ischemic MV with balanced leaflet tenting, mitral incompetency with incomplete leaflet coaptation was clearly identified all around the paracommissural regions. This computational MV evaluation strategy has the potential for improving diagnosis of ischemic mitral regurgitation and treatment of ischemic MVs.

Effect of Congenital Anomalies of the Papillary Muscles on Mitral Valve Function.

Parachute mitral valves (PMVs) and parachute-like asymmetric mitral valves (PLAMVs) are associated with congenital anomalies of the papillary muscles. Current imaging modalities cannot provide detailed biomechanical information. This study describes computational evaluation techniques based on three-dimensional (3D) echocardiographic data to determine the biomechanical and physiologic characteristics of PMVs and PLAMVs. The closing and opening mechanics of a normal mitral valve (MV), two types of PLAMV with different degrees of asymmetry, and a true PMV were investigated. MV geometric data in a patient with a normal MV was acquired from 3D echocardiography. The pathologic MVs were modeled by altering the configuration of the papillary muscles in the normal MV model. Dynamic finite element simulations of the normal MV, PLAMVs, and true PMV were performed. There was a strong correlation between the reduction of mitral orifice size and the degree of asymmetry of the papillary muscle location. The PLAMVs demonstrated decreased leaflet coaptation and tenting height. The true PMV revealed severely wrinkled leaflet deformation and narrowed interchordal spaces, leading to uneven leaflet coaptation. There were considerable decreases in leaflet coaptation and abnormal leaflet deformation corresponding to the anomalous location of the papillary muscle tips. This computational MV evaluation strategy provides a powerful tool to better understand biomechanical and pathophysiologic MV abnormalities.